Background

The advent of personalized medicine and ever-increasing numbers of available cancer drugs necessitate better prognostic and predictive biomarkers. In turn, this requires a deeper profiling and understanding of tumors and the tumor microenvironment (TME). To address this challenge the Integrated iMMUnoprofiling of large adaptive CANcer patient cohorts (IMMUcan) consortium collects samples and longitudinal clinical data from up to 3000 patients. All samples undergo bulk RNA-seq and whole exome sequencing (WES) for molecular profiling, whole slide multiplexed immunofluorescence (mIF) for broad and imaging mass cytometry (IMC) for detailed cellular profiling.

Methods

We analyzed a retrospective sub-cohort of non-small cell lung cancer (NSCLC) consisting of stage I-IIIA resected tumor samples from 192 patients collected between 2012 and 2018 under the EORTC-SPECTA protocol (NCT 02214134). Median follow up was 2.8 years and 42 patients died of the disease. Bulk RNA-seq and WES data were processed using standard tools. An image analysis workflow for mIF and IMC data paired with a tiling approached from ecology and spatial data analysis were used for feature extraction and subsequent multivariate cox proportional hazard modeling.

Results

The TME did not differ across clinical stage, smoking status or driver mutations. The TME of squamous cell carcinoma (LUSC) subtypes was enriched for immune suppressed cell types compared to adenocarcinoma (LUAD) subtypes in mIF and IMC data. Most samples (78%) contained B cell aggregates or tertiary lymphoid structures but their amount, size and location were not prognostic for overall survival (OS). In this cohort, not the density of CD8⁺ T cells but the variability of CD8+ T cell density across tissue sections, next to factors such as CD8⁺ T cell exclusion and broad T cell activation/exhaustion were strong prognostic factors for OS. Finally, we highlight results obtained from multi-modal data integration for the identification of the strongest prognostic features.

Conclusions

Our analyses reveal the potential of multi-modal data analysis and integration, and form the basis for analyses of all molecular and cellular profiling data from IMMUcan patients for biomarker discovery.

Clinical trial identification

NCT 02214134.

Legal entity responsible for the study

EORTC.

Funding

IMI2 JU grant agreement 821558, supported by EU’s Horizon 2020 and EFPIA.

Disclosure

M. Morfouace: Other, Personal, Member, employee: Merck Healthcare. T. Trefzer: Other, Personal, Member, employee: Bayer AG. H.S. Hong: Other, Personal, Member, employee: Merck Healthcare. T. Cufer: Financial Interests, Personal, Invited Speaker: MSD, Pfizer, Roche; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Takeda; Financial Interests, Institutional, Local PI: MSD. A.C. Dingemans: Financial Interests, Institutional, Advisory Board: Roche, Sanofi, Amgen, Bayer, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker: Takeda, Lilly, Jansen, Pfizer, AstraZeneca; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Local PI: Lilly, Amgen, Daiichi, JNJ, Mirati; Financial Interests, Institutional, Coordinating PI: Roche; Financial Interests, Institutional, Steering Committee Member: Roche; Non-Financial Interests, Personal, Other, Chair EORTC lung cancer group: EORTC; Non-Financial Interests, Personal, Member: IASCL, ASCO, AACR. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Pfizer, Janssen, Onxeo, OSE Immunotherapeutics, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals; Financial Interests, Institutional, Research Grant: Genzyme Corporation, Chugai pharmaceutical, Eisai, Inivata, Ipsen, Turning Point Therapeutics. All other authors have declared no conflicts of interest.

Background

Metastatic NSCLC is a leading cause of cancer death globally. Although implementation of immunotherapies has improved overall survival (OS), certain subgroups such as never smokers appear to derive less benefit from immunotherapy monotherapy. This analysis of the IMpower110 trial explores the efficacy of atezolizumab compared to chemotherapy in the PD-L1 high (TC≥50%/IC≥10%) patients by smoking status, as well as the achievement of long-term benefit (LTB) in the ever-smoking population.

Methods

We analyzed baseline characteristics and efficacy outcomes (OS and progression-free survival (PFS)) in the aforementioned population and clinically relevant subgroups. Kaplan-Meier curves and forest plots are presented. We characterized the LTB population, defined as patients who lived ≥2 years since randomization. We performed Chi-square tests to assess factors associated with LTB.

Results

In the PD-L1 high population the OS HR was 1.80 (0.71-4.52) for never smokers and 0.71 (0.49-1.04) for ever-smokers. The following results refer to the ever-smoking, PD-L1 high population, which consists of 181 patients (88.3% of all patients with high PD-L1 expression by SP142): The median follow-up was 30.6 months (mo). A median OS of 23.13 mo in the atezolizumab arm was observed compared to 11.04 mo with chemotherapy (HR= 0.71; 95% CI: 0.49-1.04; p=0.079). Likewise, median PFS favored atezolizumab with 8.34 vs 4.88 mo (HR= 0.56; 95% CI: 0.40-0.78; p<0.001). LTB was achieved by 46% (n=45) of patients who received atezolizumab and 33% (n=27) of patients who received chemotherapy. In the atezolizumab arm, clinical factors such as ECOG, liver metastases and race were significantly associated with LTB.

Conclusions

This exploratory analysis of the IMpower110 study reiterates the difference in the efficacy of monotherapy immunotherapy compared to chemotherapy based on smoking status. Atezolizumab is associated with better efficacy outcomes and provided LTB in a higher number of patients compared to chemotherapy in the ever-smoking PD-L1 high population.

Legal entity responsible for the study

Roche Pharma.

Funding

Roche Pharma.

Disclosure

L. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, BeiGene, Daichii, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Personal, Member of Board of Directors, Board member: Stab Therapeutics; Financial Interests, Institutional, Coordinating PI: BMS, Janssen-Cilag international NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar, Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme corp; Financial Interests, Personal, Coordinating PI: Amgen; Financial Interests, Personal, Other, Foundation Board Member: AECC; Financial Interests, Personal, Other, Member: AACR, ASCO, ESMO; Financial Interests, Personal, Other, President: ASEICA (Spanish Association of Cancer Research); Financial Interests, Personal, Other, Foundation president: ONCOSUR; Financial Interests, Personal, Other, member: Small Lung Cancer Group. M.R. García-Campelo: Financial Interests, Personal, Speaker, Consultant, Advisor, travel/accomodation/expenses: Roche, Merck, BMS, AstraZeneca, Lilly, Pfizer; Financial Interests, Personal, Speaker, Consultant, Advisor: PharmaMar, Bayer, AbbVie, GSK, Boehringer. M.D. Isla Casado: Financial Interests, Personal, Speaker, Consultant, Advisor, travel/accomodation/expenses: Roche, Merck, BMS, AstraZeneca, Lilly, Pfizer, Amgen, Boehringer; Financial Interests, Personal, Research Grant: BMS, Roche, AstraZeneca, Lilly; Financial Interests, Personal, Speaker, Consultant, Advisor: Bayer; Financial Interests, Personal, Advisory Role: AbbVie, Takeda. E. Carcereny: Financial Interests, Personal, Advisory Role, travel/accomodation/expenses: Roche, Bristol Myers Squibb, MSD, Takeda; Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer, Novartis; Financial Interests, Personal, Other, travel/accomodation/expenses: Pfizer. D. Rodriguez Abreu: Financial Interests, Personal, Speaker, Consultant, Advisor, travel/accomodation/expenses: Roche, Merck, BMS, AstraZeneca; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Speaker, Consultant, Advisor: Boehringer, Takeda. J.J. Garcia Gonzalez: Financial Interests, Personal, Speaker, Consultant, Advisor, travel/accomodation/expenses: Roche; Financial Interests, Personal, Advisory Role, travel/accomodation/expenses: Merck, BMS, Boehringer; Financial Interests, Personal, Advisory Role: AstraZeneca, Lilly, Pfizer. D. Perez Parente: N. Gonzalez Mancha, E. Vilas,P. Ruiz Gracia, A. Greco: Financial Interests, Institutional, Member, employee: Roche Pharma Spain. D.R. Spigel: Consulting or Advisory Role: Genentech/Roche (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), GSK (Inst), Amgen (Inst), Ipsen (Inst), Jazz Pharmaceuticals (Inst), Sanofi/Aventis (Inst), Novocure (Inst), Regeneron (Inst), Lilly (Inst), AbbVie (Inst), BeiGene (Inst), Lyell (Inst), Monte Rosa Therapeutics (Inst). Research Funding: Genentech/Roche (Inst), Novartis (Inst), Celgene (Inst), Bristol Myers Squibb (Inst), Lilly (Inst), AstraZeneca (Inst), University of Texas Southwestern Medical Center-Simmons Cancer Center (Inst), Merck (Inst), G1 Therapeutics (Inst), Neon Therapeutics (Inst), Takeda (Inst), Nektar (Inst), Celldex (Inst), Clovis Oncology (Inst), Daiichi Sankyo (Inst), EMD Serono (Inst), Astellas Pharma (Inst), GRAIL (Inst), Transgene (Inst), Aeglea Biotherapeutics (Inst), Ipsen (Inst), BIND Therapeutics (Inst), Eisai (Inst), ImClone Systems (Inst), Immunogen (Inst), Janssen Oncology (Inst), MedImmune (Inst), Molecular Partners (Inst), Agios (Inst), GSK (Inst), Tesaro (Inst), Cyteir (Inst), Apollomics (Inst), Novocure (Inst), Elevation Oncology (Inst), Calithera Biosciences (Inst), Arcus Biosciences (Inst), Arrys Therapeutics (Inst), Bayer (Inst), BeiGene (Inst), BioNTech (Inst), Blueprint Medicines (Inst), Boehringer Ingelheim (Inst), Hutchison MediPharma (Inst), Incyte (Inst), Kronos Bio (Inst), Loxo Oncology (Inst), Macrogenics (Inst), Oncologie (Inst), Pfizer (Inst), PTC Therapeutics (Inst), PureTech (Inst), Razor Genomics (Inst), Repare Therapeutics (Inst), Rgenix (Inst), Tizona Therapeutics Inc (Inst), Verastem (Inst), AbbVie (Inst), Amgen (Inst), AnHeart Therapeutics (Inst), Ascendis Pharma (Inst), Asher Biotherapeutics (Inst), Ellipses Pharma (Inst), Endeavor (Inst), Erasca (Inst), Evelo Biosciences (Inst), Faeth Therapeutics (Inst), Foundation Bio (Inst), FujiFilm Pharmaceuticals (Inst), Gilead Sciences (Inst), Janux Therapeutics (Inst), Jazz Pharmaceuticals (Inst), Lyell Immunopharma (Inst), Millennium Pharmaceuticals (Inst), Moderna (Inst), Monte Rosa Therapeutics (Inst), Peloton Therapeutics (Inst), SeaGen (Inst), Shenzhen Chipscreen Biosciences (Inst), Strata Oncology (Inst), Stemline Therapeutics (Inst), Synthekine (Inst), Taiho (Inst), Tango Therapeutics (Inst), Tarveda (Inst), and Zai Laboratory (Inst). F. de Marinis: Consulting or Advisory Role: AstraZeneca, MSD Oncology, Bristol Myers Squibb, Roche/Genentech, Pfizer, Novartis, Takeda. J. Jassem: Consulting or Advisory Role: AstraZeneca, Amgen, Boehringer Ingelheim.

Background

This study intended to evaluate the immunological status of patients with stage IIIB/IV non-small cell lung cancer (NSCLC) comparing samples at diagnostics (DX), after chemotherapy (CT) and undergoing immune checkpoint blockade (ICB) immunotherapy.

Methods

Comprehensive immunophenotyping (>200 parameters defining T, B, NK, NKT-like cells, monocytes, dendritic cells, and myeloid-derived suppressor cells) was performed using peripheral blood from 44 stage IIIB/IV NSCLC patients. Immune related gene expression quantification for 103 targets, including 9 reference genes, was performed by RT-qPCR. Additionally, 103 immune-related plasmatic factors (cytokines, chemokines, growth factors and soluble immune checkpoints) were quantified using xMAP (Luminex®) technology.

Results

Most important finding consists in myeloid-derived suppressor cells (MDSCs) significant increase in all NSCLC patients compared to CTRL, particularly monocytic Myeloid-Derived Supressor Cells (M-MDSC). Similarly, type 2 myeloid dendritic cells (mDC2) demonstrated the same results for ICB patients. Particular T cells subsets (CD8, activated CD8, memory CD45RA+ and Tregs), transitional B cells, CD56bright NK cells and NKT-like cells were found significantly increased in ICB patients. Gene expression analysis revealed associations with genes involved in the T cell response, MHC class I expression, metabolism, adhesion molecules and vascular endothelial growth factors. Concerning the soluble factors associated with M-MDSC, a significant increase in VISTA/B7-H5 was observed in NSCLC patients under immunotherapy. A significant increase in IL-10 was observed, thus promoting the differentiation of Treg cells by cDC2. Using unsupervised machine-learning clustering analysis algorithms we were able to identify a global signature associated with checkpoint inhibitor blockade therapy and response to treatment (RECIST1.1).

Conclusions

In conclusion, this study suggests the importance of an extensive evaluation of cellular and soluble immune factors, which may prove useful in the selection and monitoring of patients undergoing immunotherapy in lung cancer.

Legal entity responsible for the study

The authors.

Funding

FCT - Portuguese Foundation for Science and Technology.

Disclosure

All authors have declared no conflicts of interest.

Background

We tested whether the longitudinal monitoring of peripheral blood (PB) immune-inflammatory benchmarks might intercept immune-related adverse events (irAEs) onset and their impact on clinical outcome in ICI-treated NSCLC.

Methods

On PB collected at baseline (T0) and first disease assessment (T1) from 105 advanced NSCLC undergoing ICIs, comprehensive immune cell phenotyping (flow-cytometry), LDH, derived Neutrophil-to-Lymphocyte ratio (dNLR), LIPI and serum multiplex cytokine array were prospectively evaluated, including their delta (Δ) variation [(T1-T0)/T0*100]. irAEs type and grading (G) were defined according to CTCAE (Common Terminology Criteria in Adverse Events) v5.0. Correlations of irAEs with clinicopathological/PB parameters and survival outcome were statistically analyzed.

Results

irAEs occurred in 51 (48.6%) patients with 14.3% G3-4 incidence and involving the skin (36%), diarrhea/colitis (24%), liver (12%), thyroid (4%) and multiple sites (33.3%); median time-to-onset: 48-278 days; and leading to temporary or permanent ICI discontinuation in 11.4% of cases. irAEs were more frequent in females (58.3%) and absent in performance status (PS) 2 patients. Baseline PB parameters didn’t substantially differ according to irAE occurrence, except for higher IFNγ (P=0.014) and lower IL1β and IL6 (P=0.02) levels in irAEs cases. At T1, lower NLR, dNLR and LIPI characterized irAE patients, together with increased CD8+ cytotoxic (Perforin+, P=0.09) and proliferating (Ki67+, P=0.05) activity, higher IFNγ and TNFα and lower TGFβ1 levels compared to no-irAEs cases. Intriguingly, PB immune cells dynamic more closely reflected irAE severity as G3-4 cases displayed a sharp rise (Δpos) in cytotoxic NKs and CD8+GnzB+ lymphocytes (P=0.04) and a drop (Δneg) in CD4+CD25+FOX3^high Tregs (P=0.07). Importantly, irAEs patients exhibited greater disease control rate (84% vs 65.1%, P=0.05) and significantly longer PFS (Median PFS=10.4 vs 5.4 mos, P=0.002, HR=0.47) and OS (Median OS=NR vs 11.3 mos, P<0.001, HR=0.34) vs no-irAEs NSCLC.

Conclusions

irAEs involve a distinctive cellular and humoral immune dynamic and might positively condition ICI efficacy.

Legal entity responsible for the study

University Hospital of Parma.

Funding

Associazione Italiana per la Ricerca sul Cancro-AIRC.

Disclosure

All authors have declared no conflicts of interest.

Background

PD-1-based immunotherapy is used for first- or second-line therapeutic regimens against NSCLC. Anti-PD-1 immunotherapy resistance occurs in diabetic patients with NSCLC. However, the characteristics of immune cell infiltration in such patients remain unexplored. Thus, we investigated the possible link between diabetes and immune cell infiltration in NSCLC.

Methods

We included patients (n = 437) with NSCLC treated with anti-PD-1 immunotherapy from the Zhejiang University School of Medicine. We analyzed the objective response rate, progression-free survival (PFS), overall survival (OS), T-cell infiltration, and peripheral blood immunological characteristics in diabetic and nondiabetic NSCLC patients. Differences in tumor microenvironment profiles were measured using CyTOF to elucidate the reasons for poor PFS and OS in diabetic NSCLC patients.

Results

Nondiabetic NSCLC patients had longer PFS than diabetic NSCLC patients (11.0 vs 7.0 months). The OS was 24.0 and 17.0 months in nondiabetic and diabetic NSCLC patients, respectively (P = 0.0065). Diabetic NSCLC patients had significantly lower CD8+T cell infiltration than nondiabetic NSCLC patients (P = 0.0227). Similarly, the anti-tumor effect of PD-1 blockade was decreased in diabetic mice with lung cancer. Additionally, compared with nondiabetic NSCLC patients before anti-PD1 treatment, CyTOF analysis showed that diabetic NSCLC patients had significantly more CD161⁺CD127⁺CD8⁺ T cells (P = 0.0071), and this trend continued after anti-PD1 treatment (P = 0.0393). Flow cytometry showed that diabetic NSCLC patients had a significantly higher CD161⁺CD127⁺CD8⁺T/CD8⁺ T cells ratio than nondiabetic NSCLC patients. Kaplan–Meier survival analysis showed that high levels of CD161⁺CD127⁺CD8⁺ T cells were positively related to the PFS in diabetic NSCLC patients.

Conclusions

We confirmed that diabetes is a risk factor for patients with NSCLC who undergo anti-PD-1 immunotherapy. CD161⁺CD127⁺CD8⁺ T cells in diabetic NSCLC patients serve as a key indicator of poor prognosis. Our findings provide a reference for understanding the characteristics of the tumor microenvironment in diabetic NSCLC patients.

Editorial acknowledgement

Prof. Nong Yang from the Lung Cancer and Gastroenterology Department, Hunan Cancer Hospital, and the Affiliated Tumor Hospital of Xiangya Medical School of Central South University for their technical support. Editage for English language editing.

Legal entity responsible for the study

Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, P. R. China.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81802278), Natural Science Foundation of Zhejiang Province (No.LY23H160020), Medicine Health Technology Plan of Zhejiang Province, China (No. 2022KY150), and General Project of Education Department of Zhejiang Province (Y202043420).

Disclosure

All authors have declared no conflicts of interest.

Background

PD-L1 expression is a current predictive biomarker of anti-PD-(L)1 immunotherapy in advanced non-small cell lung cancer (NSCLC) but has many limitations as a stand-alone biomarker. Tumor infiltrating T-lymphocyte might be the source of T-cell-derived circulating DNA. We explored T-cirDNA as a potential biomarker of anti-PD (L)1 inhibitor and its correlation tumor-infiltrating lymphocytes (TILs).

Methods

The prospective cohort of 78 advanced NSCLC who received anti-PD-(L)1 immunotherapy as monotherapy or combination fashion. Pre-treatment plasma T-cirDNA target rearranged TCR-β CDR3 region were quantified using multiplex real-time PCR assay. FFPE Tissue from 40 patients were stained using CD8 (C8-144B-Dako) and FOXP3 (236A/E7- Abcam). We defined patients into undetectable, low (<1% ratio) and high (>1% ratio) T-cirDNA/cirDNA. Baseline clinicopathological characteristic and prognostic factors were integrated by cox-regression analysis. The correlation of T-cirDNA/cirDNA and CD8/FOXP3 TILs were explored.

Results

77% of participants had detectable T-cirDNA/cirDNA with a median of 0.02 [range 52.3] ngml^-1. At median follow-up of 15.5 months, multivariate analysis revealed undetectable T-cirDNA/cirDNA and available subsequent treatment shown overall survival (OS) with the HR of 0.203 [95% CI 0.053-0.781, p-value 0.02] and 0.188 [95% CI 0.051-0.689 p-value 0.01] respectively. High level of T-cirDNA/cirDNA also correlated with better treatment outcome with the HR of 0.211 [95%Cl 0.055-0.815, p-value 0.02]. High level of T-cirDNA/cirDNA correlated with presence of intra-tumoral CD8 TIL 58.3% higher than low and undetectable T-cirDNA/cirDNA, 28.6% and 33.3% (p-value 0.17 and 0.19) respectively.

Conclusions

T-cell-derived circulating DNA shown paradoxical prognostic effect to anti-PD(L)1 treatment. The correlation with intra-tumoral CD8 TIL was demonstrated.

Legal entity responsible for the study

The authors.

Funding

National Research Council of Thailand (Grant number 347/2564).

Disclosure

All authors have declared no conflicts of interest.

Background

Although the establishment of checkpoint inhibitors (CPIs) has shown great success in the treatment of cancer patients, a significant number of patients do not respond to it. This demonstrates the highly individualized nature of patient response to therapy, highlighting the need of a more tailored therapeutic approach. To this end, we have developed a functional 3D in vitro model, generated directly from primary tumor to evaluate personalized therapy options in a clinically relevant manner to improve outcome prediction.

Methods

Freshly resected NSCLC tumor material from 20 patients with different TPS Scores was mechanically and enzymatically digested to obtain a single cell suspension. PMTs were then generated by seeding the suspension into ultra-low attachment plates, preserving the original cell composition, which was characterized prior to drug administration after six days of tissue maturation. In addition to treating PMTs with CPIs, combinations with chemotherapies were applied. The dynamic drug response was monitored over 14 days, using bright field imaging. Further analysis of the drug response was performed by cytokine release as well as bulk RNA sequencing.

Results

To test immune modulators in vitro, it is necessary to preserve the immune compartment of the original tumor. FACS data confirmed, that during the maturation process of the NSLCL microtumors and beyond, the original cell compartments, including the various immune cell populations were largely preserved. Overall, the clinical routine categorized objective response rates reflected the clinical outcome distribution. In addition, immunotherapy treatment resulted in characteristic cytokine release and gene-pathway up/down regulation as a proof of concept to build a HUMAN LUNG CANCER RESPONSOME database linking a wide range of patient-specific functional outcomes with in-depth changes in individual pathways.

Conclusions

The present PMT model in combination with a clinically relevant drug response analysis is one of the first to show the typical immunotherapy-dependent alteration of TME as well as immunotherapy-induced cancer cell death in a scalable long-term in vitro assay.

Legal entity responsible for the study

A. Amann.

Funding

PreComb Therapeutics AG.

Disclosure

All authors have declared no conflicts of interest.

Background

Immunotherapy plus chemotherapy are widely used in patients with advanced non-small cell lung cancer (NSCLC) without oncogenic driver alterations. The monocyte-to-lymphocyte ratio (MLR) might predict thetreatment outcomes of ICI therapy in advanced NSCLC patients but has not yet been investigated. In addition, the cutoff of MLR is controversial. Therefore, the present study aimed to explore the associations between changes in MLR at the initial stage of treatment and clinical outcomes in advanced NSCLC patients receiving first-line PD-1 inhibitor plus chemotherapy.

Methods

The present study included 139 stage IIIB-IV NSCLC patients treated with first-line PD-1 inhibitor plus chemotherapy. The blood results were assessed 10 days before initiation of combination therapy (baseline) and before the third cycle of combined therapy (time point 2). Compared to altered MLR, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in baseline and in time point 2, patients were divided into decreased MLR/NLR/PLR and increased MLR/NLR/PLR groups. The ORR, PFS, and the association with the changes in blood indicators were analyzed.

Results

Patients with decreased MLR had a significantly higher ORR in the univariate (P<0.001) and multivariate (P<0.001) analyses. Decreased MLR was significantly associated with prolonged PFS in the univariate (P=0.007) and multivariate (P=0.016) analyses. Decreased NLR exhibited high ORR (P=0.001) and prolonged PFS in univariate analysis (P=0.033). Decreased PLR was associated with high ORR in univariate (P<0.001) and multivariate (P=0.017) analyses. The subgroup analyses showed that decreased MLR was significantly associated with satisfactory outcomes in patients with all PD-L1 expressions.

Conclusions

Decreased MLR was associated with high ORR and long PFS and might have a potential predictive value in NSCLC treated with first-line PD-1 inhibitor plus chemotherapy. In addition, changes in MLR might have predictive value in all PD-L1-expressing populations. Decreased NLR and PLR also showed improved survival, suggesting that changes in NLR and PLR may be complementary to predicting prognosis.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Transcriptomic subtyping holds promise for personalized therapy in SCLC, but intratumoral transcriptomic heterogeneity and its clinical significance remain poorly defined. In this study, we aimed to assess transcription factor-defined subtypes within multiple regions of intact tissues and identify gene sets associated with long-term chemoimmunotherapy benefit.

Methods

We assessed baseline FFPE tumors from 26 ES-SCLC patients enrolled in the CANTABRICO clinical trial (EudraCT: 2020-002328-35). We used GeoMx^TM DSP to perform transcriptomic analysis from multiple intratumoral regions of interest (ROIs). We used an assay with +1800 genes (GeoMx^TM CTA) plus custom-designed and subsequently validated mRNA probes targeting subtype-defining transcription factors.

Results

We profiled 121 ROIs from 26 tumors. Cluster analysis based on ASCL1, NEUROD1, POU2F3 and YAP1 showed that all samples clustered within 3 groups: SCLC-A (58 ROIs, 47.93 %), SCLC-N (37 ROIs, 30.58 %) and SCLC-Y/I (26 ROIs, 21.49 %). SCLC-P subtype was not identified in this cohort. Gene set enrichment analysis (GSEA) using linear mixed models revealed that SCLC-A subtype was enriched in cell cycle and DNA damage repair genes and showed repression of multiple gene sets associated with anti-tumor immune response. SCLC-Y/I subtype showed the opposite pattern. Six patients (23%) had tumors with co-existence of more than one subtype, not evident through morphological inspection. Predominant subtype or the presence of subtype heterogeneity were not associated with outcomes. Tumors from patients with sustained benefit (time to progression >= 12 months) had mRNA profiles characterized by upregulation of interferon gamma (IFNg)-related genes and down-regulation of gen sets involved in glycolysis and aberrant metabolism.

Conclusions

This study reveals substantial intratumoral subtype heterogeneity in SCLC. In this limited cohort, we did not observe outcome significance for transcriptional subtypes. Our findings related to long-term treatment benefit require validation in independent cohorts.

Clinical trial identification

Data from patients enrolled in the CANTABRICO study (phase IIIb clinical trial, EudraCT 2020-002328-35).

Legal entity responsible for the study

Fundación OncoSur.

Funding

AstraZeneca.

Disclosure

C. Martí Cubells: Financial Interests, Personal, Invited Speaker: MSD, BMS, AstraZeneca; Financial Interests, Personal, Other, Reimbursement of conference attendance: MSD, BMS, Merck. B. Massuti Sureda: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: MSD, Roche; Financial Interests, Institutional, Funding, Research on Tumor Board: BMS; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca, MSD; Non-Financial Interests, Personal, Advisory Board: ASCO; Non-Financial Interests, Personal, Member: IASLC, SEOM; Non-Financial Interests, Personal, Leadership Role: SLCG. M. Majem: Financial Interests, Personal, Advisory Board: Amgen, Roche, AstraZeneca, Takeda, Janssen, Cassen Recordati, BMS; Financial Interests, Personal, Invited Speaker: Amgen, Roche, AstraZeneca, Pfizer, Takeda, Helsinn; Financial Interests, Institutional, Funding: BMS, AstraZeneca, Roche. M.R. García-Campelo: Financial Interests, Personal, Advisory Board: MSD, BMS, Roche, Boehringer Ingelheim, Medscape Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Janssen, Sanofi; Financial Interests, Personal, Invited Speaker: MSD, BMS, Roche, Boehringer Ingelheim, Medscape Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Janssen, Sanofi; Financial Interests, Personal, Principal Investigator: MSD, BMS, Roche, Boehringer Ingelheim, Medscape Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Janssen, Sanofi. P. Diz Tain: Financial Interests, Personal, Invited Speaker: BMS, AstraZeneca, Boehringer Ingelheim, Roche, MSD, Takeda, Pfizer, Amgen; Financial Interests, Personal, Advisory Role: BMS, AstraZeneca, Boehringer Ingelheim, Roche, MSD; Financial Interests, Personal, Training: BMS, AstraZeneca, Boehringer Ingelheim, Roche, MSD, Takeda, Pfizer; Financial Interests, Institutional, Principal Investigator: AstraZeneca, Roche, Mirati; Financial Interests, Personal, Advisory Board: Takeda. M.D. Isla Casado: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultation and speaker honoraria: Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, F. Hoffmann-La Roche, Janssen, MSD, Pfizer, Takeda; Financial Interests, Personal, Speaker, Consultant, Advisor, Consultation honoraria: Lilly, Merck, Sanofi; Financial Interests, Personal, Speaker, Consultant, Advisor, Speaker honoraria: Novartis; Financial Interests, Institutional, Other, Clinical trial: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, F. Hoffmann-La Roche, GSK, Janssen, Lilly, Merck, Mirati Therapeutics, MSD, Novartis, Pfizer, Sanofi; Financial Interests, Institutional, Research Grant: AstraZeneca, BMS, F. Hoffmann-La Roche, GSK; Other, Personal, Member of Board of Directors, Executive board member: Commission for the Approval of New Drugs, Regional Health Care Department (Spain). A. Moreno Paul: Financial Interests, Personal, Invited Speaker: Roche, MSD, Bristol; Financial Interests, Personal, Other, Reimbursement of conference attendance: Roche, MSD. E. Conde Gallego: Financial Interests, Personal, Research Funding: Roche, ThermoFisher; Financial Interests, Personal, Other, Honoraria: Roche, Lilly, Pfizer, AstraZeneca, Janssen. L. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, BeiGene, Daichii, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Personal, Member of Board of Directors, Board member: Stab Therapeutics; Financial Interests, Institutional, Coordinating PI: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme corp, BMS, Janssen-Cilag international NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar; Financial Interests, Personal, Coordinating PI: Amgen; Financial Interests, Personal, Other, Member: AACR, ASCO, ESMO; Financial Interests, Personal, Other, Foundation Board Member: AECC; Financial Interests, Personal, Other, President: ASEICA (Spanish Association of Cancer Research); Financial Interests, Personal, Other, Foundation president: ONCOSUR; Financial Interests, Personal, Other, member: Small Lung Cancer Group. J. Zugazagoitia: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultant: Sanofi, AstraZeneca, BMS, Roche, Pfizer, Novartis, Guardant Health; Financial Interests, Personal, Invited Speaker: Sanofi, Takeda, BMS, Pfizer, Roche, AstraZeneca, NanoString, Guardant Health; Financial Interests, Personal, Other, Travel honoraria: Sanofi, Takeda, BMS, Pfizer, Roche, AstraZeneca, NanoString; Financial Interests, Institutional, Research Funding: BMS, AstraZeneca, Roche. All other authors have declared no conflicts of interest.

Background

The phase II ALTER1202 trial demonstrated that patients who received anlotinib after failing at least two systemic chemotherapy regimens exhibited improved progression-free survival (PFS) and overall survival (OS) compared to the placebo group. In an effort to further enhance outcomes for small-cell lung cancer patients who have exhausted first-line platinum-based chemotherapy options, researchers are investigating the combination of anlotinib and penpulimab, a novel PD-1 inhibitor.

Methods

This open-label, single-arm, multi-center, phase II exploratory study enrolled patients with small-cell lung cancer who had previously undergone platinum-based chemotherapy. Patients received a combination therapy consisting of penpulimab (200mg every three weeks) and anlotinib (10mg daily), following a 2-week on and 1-week off schedule, until disease progression, unacceptable toxicity, or study discontinuation. The primary objective was to assess antitumor activity using the RECIST v1.1 criteria, focusing on the objective response rate (ORR). Secondary objectives included evaluating antitumor activity through the disease control rate (DCR), duration of response (DOR), PFS, OS, and assessing the safety and tolerability of this combination therapy.

Results

As of September 17, 2023, 38 patients were enrolled in the study and had received treatment. Of these 38 patients, 38 were evaluable using RECIST criteria, revealing an ORR of 26.30% (10 out of 38) and a DCR of 68.42% (26 out of 38). The median PFS was 4.36 months, with 6-month and 12-month PFS rates of 21.05% and 10.53%, respectively. The median DOR was 8.03 months, and the median OS was 15.71 months. Among the patients, 26 out of 38 (68.42%) experienced treatment-related adverse events, with 10 patients (26.32%) reporting grade 3 or higher adverse events. The most common adverse events related to anlotinib were hepatic injury, hematoxicity, and hypertension.

Conclusions

The combination of penpulimab and anlotinib showed promising clinical benefits and a favorable safety profile in small-cell lung cancer patients after platinum-based chemotherapy.

Clinical trial identification

NCT05001971.

Legal entity responsible for the study

Hunan Provincial Cancer Hospital.

Funding

Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.

Background

Immune checkpoint inhibitors (ICI) have shown efficacy in activating immune responses to tumours and in improving survival among cancer patients. However, highly heterogeneous patient responses highlight the need for predictive pipelines that leverage the immune cell dynamics associated with ICI as a biomarker.

Methods

The OS-T platform (Omniscope Inc.) was applied to deeply profile single T cell clonotypes from peripheral blood of colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) patients before and after receiving ICI (e.g., anti-PD1 therapy). For an integrated immune repertoire analysis, we developed a novel computational framework for tracking and modelling TCR clonotype dynamics, combining three complementary approaches: (i) statistical noise model detecting differentially expanded clonotypes after treatment, (ii) sequence similarity and density-based clustering of sequences with inferred similar specificity, (iii) recombination model that computes generation probabilities of immune receptor sequences [Murugan, A., at al., 2012, 109(40), 16161-16166].

Results

We identified T cell clonotype clusters with treatment-related immune receptor sequences specific to or conserved across patients and cohorts. Such clonotype sequences allowed us to quantify treatment efficacy and to track patient response over time. Conserved clonotypes across patients enabled the identification of sequence signatures associated with patient response to ICI, potentially applicable for systematic efficacy tracking or patient stratification.

Conclusions

Our results suggest the combination of deep single-cell T-cell receptor profiling and receptor sequence modelling to efficiently identify candidate clonotypes for ICI response monitoring in CRC, NSCLC, and beyond. Moreover, combining such orthogonal approaches optimises the nomination of cancer-related T cell receptor sequences for targeted cell therapies and similar immune receptor-based strategies.

Legal entity responsible for the study

Omniscope Inc.

Funding

Omniscope Inc.

Disclosure

J. L. Melero, A. Mendizabal-Sasieta, U. Perron, D. Pravdyvets, N. Borcherding, B. Colom-Sanmartí, M. Grzelak, M. Soto, E. Planas Rigol: Financial Interests, Personal, Full or part-time Employment: Omniscope. J.C. Nieto: Financial Interests, Personal, Advisor of Omniscope. H. Heyn: Financial Interests, Personal, Co-founder of Omniscope, SAB member of Nanostring and MiRXES and consultant to Moderna and Singularity.

Background

First-line therapy with PD-1 blockade and chemotherapy is recommended for human epidermal growth factor receptor 2 (HER2)–negative patients with advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC), but the clinical outcomes of this approach is very variable. Predictive biomarkers are thus urgently required, here we investigated the predictive ability of exosomal PD-L1 and lactate levels in advanced GC or GEJC patients.

Methods

This prospective study (RENMIN-221) enrolled 68 advanced GC or GEJC patients receiving first-line PD-1 blockade and standard chemotherapy from January 2022 to March 2023. Exosomes were isolated by ultracentrifugation method from plasma prior to therapy. PD-L1 and lactate levels of the recovered exosomes were determined by enzyme-linked immunosorbent assay (ELISA), and peripheral blood was obtained before each cycle of treatment. The composition of peripheral CD3⁺ T cells, CD4⁺T cells, CD8⁺T cells, regulatory T (CD4⁺CD25⁺CD127^low, Treg) cells, and the expression of their PD-1 were assessed by flow cytometry.

Results

Compared to the responders (CR+PR), exosomal PD-L1 (P=0.014) and lactate (P=0.012) was significantly higher than that of the non-responders (SD+PD) before the treatment. The receiver operating characteristic (ROC) curve showed that the combination of exosomal PD-L1 and lactate best distinguished responders from non-responders (area under the curve [AUC]: 0.787 vs. 0.748 vs. 0.706) among all the parameters tested. Combining predictor lower than -0.274 was associated with a better response to the therapy by ORR (82.1% vs. 30.0%, P<0.001), and mPFS (13.8 vs 5.5 months, P<0.001). Exosomal PD-L1 levels were signifcantly correlated with the frequency of CD8⁺T cells before treatment (P=0.025). And exosomal lactate was associated with less CD8⁺T cells and more Treg cells after treatment, while exosomal PD-L1was associated with more Treg cells and more PD-1⁺ Treg cells after treatment.

Conclusions

Exosomal PD-L1 and lactate levels could predict clinical outcomes, which provide accurate and convenient biomarkers in advanced GC or GEJC patients receiving first-line PD-1 blockade combined with chemotherapy.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Gastric cancer is a multifaceted condition exhibiting varied responses to treatment, emphasizing the need for tailored therapeutic strategies. This study endeavors to elucidate the cellular interactions and molecular mechanisms that underlie the response to Sintilimab plus SOX (fluorouracil plus oxaliplatin) therapy among gastric cancer patients.

Methods

Single-cell sequencing and multiplex immunohistochemistry (mIHC) were employed to elucidate the spatial characteristics linked to the response of gastric cancer to chemo- and immuno- treatment. By integration of mIHC, feature extraction, and machine learning algorithms, we elucidated the intricate interactions between cellular populations and developed a Support Vector Machine (SVM) model for the prediction of treatment response.

Results

We initially discovered a significant correlation between apical membrane cells and resistance to fluorouracil and oxaliplatin, both crucial components of the treatment regimen. This prompted us to delve into the involvement of apical membrane cells in treatment response. Through a thorough examination of cell interactions, we noted substantial connections between apical membrane cells and resident macrophages. Further analysis of ligand-receptor interactions unveiled specific molecular associations, with TGFB1-HSPB1 and LTF-S100A14 interactions standing out, indicating potential signaling pathways implicated in treatment response. To forecast treatment response, we developed an SVM model integrating six markers (DUOX2, HSPB1, S100A14, C1QA, TGFB1, and LTF), which demonstrated outstanding predictive capacity, achieving high area under the curve (AUC) values of 0.93 in the exploration cohort and 0.84 in the validation cohort.

Conclusions

Our research underscored the importance of integrating multi-omics data alongside spatial information in predictive model, holding the promise of steering personalized therapeutic decisions and enhancing treatment efficacy.

Legal entity responsible for the study

The First Affiliated Hospital, School of Medicine, Zhejiang University.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Immunotherapy (IO) has become an important component of systemic treatment in early-stage triple-negative breast cancer (eTNBC). Considering toxicity and financial burden, identifying reliable biomarkers of response is urgently warranted. Therefore, we investigated blood cell DNA methylation profiles as biomarker for achieving a pathologic complete response (pCR) at surgery after neoadjuvant chemoimmunotherapy.

Methods

eTNBC patients receiving systemic chemoimmunotherapy before surgery at the Medical University of Vienna were included in this analysis. DNA from peripheral blood mononuclear cells (PBMCs) was isolated from whole blood samples collected at start of neoadjuvant therapy and methylation profiling was performed with Infinium Methylation EPIC microarrays. Routine histologic work-up from surgery determined a pCR or non-pCR according to pathologic standard procedures.

Results

Seven eTNBC patients (all women), median age of 63 years (range 40-83 years), were available for this analysis. All patients received neoadjuvant chemoimmunotherapy with pembrolizumab plus weekly paclitaxel/carboplatin followed by pembrolizumab plus epirubicin/cyclophosphamide. Three out of 7 (42.9%) patients achieved a pCR, while 4/7 (57.1%) had residual disease at surgery. Notably, when focusing on their methylation patterns, patients with pCR and non-pCR could be clearly segregated into two distinct groups. This distinction was based on the methylation profiles of the top 500 differentially methylated CpG sites.

Conclusions

Our results revealed differentially methylated genes between patients w/o pCR that might play a role in response to chemoimmunotherapy. Blood cell methylation profiles might serve as predictive biomarker for pCR in eTNBC and larger patient cohorts are needed to validate our findings.

Legal entity responsible for the study

The authors.

Funding

Christian Doppler Laboratory for Personalized Immunotherapy, Department of Medicine I, Medical University of Vienna.

Disclosure

A.M. Starzer: Financial Interests, Personal, Invited Speaker, Lecture honoraria: AstraZeneca; Financial Interests, Institutional, Research Grant, Industry partner of institutional Christian Doppler Laboratory: Roche; Non-Financial Interests, Personal, Member, National Oncology Society: OeGHO; Non-Financial Interests, Personal, Member, Oncology society of USA: ASCO; Other, Personal, Other, Travel support for conference participation: MSD, Lilly. M. Preusser: Financial Interests, Personal, Advisory Board: Bayer, Bristol Myers Squibb, Novartis, Gerson Lehrman, CMC Contrast, GSK, Mundipharma, Roche, BMJ Journals, MedMedia, AstraZeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dohme, Tocagen, Adastra, Gan & Lee Pharmaceuticals; Financial Interests, Institutional, Research Grant, Clinical Trials and research: Boehringer Ingelheim, Bristol Meyers Squibb, Roche, Daiichi Sankyo, Merck Sharp & Dohme, Novocure, GSK, AbbVie; Financial Interests, Institutional, Coordinating PI: PharmaMar; Non-Financial Interests, Personal, Leadership Role, Brain Tumor Group Chair (current): EORTC; Non-Financial Interests, Personal, Leadership Role, EANO Past-President (current): EANO; Non-Financial Interests, Personal, Other, Member Multi-Site Guideline Advisory Group: ASCO. R. Bartsch: Financial Interests, Personal, Invited Speaker: AstraZeneca, Seagen, Roche, Novartis, Eli-Lilly, Pierre Fabre, Daiichi, Gilead, MSD, Pfizer, Eisai, Gruenenthal; Financial Interests, Personal, Advisory Board: Daiichi, AstraZeneca, Roche, Novartis, Eli Lilly, Pierre Fabre, MSD, Gilead, Seagen, Eisai, Gruenenthal; Financial Interests, Institutional, Funding, Investigator Initiated Trial: Daiichi; Financial Interests, Institutional, Coordinating PI, Drug support for investigator initiated trial: MSD. A.S. Berghoff: Financial Interests, Personal, Research Funding: Daiichi Sankyo, Roche; Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, Bristol Meyers Squibb, Merck, Daiichi Sankyo, AstraZeneca, CeCaVa; Financial Interests, Personal, Other, travel support: Roche; Financial Interests, Personal, Other, Travel support: Amgen, AbbVie. All other authors have declared no conflicts of interest.

Background

Overexpression of CD73 in breast cancer is associated with immunosuppressive, pro-angiogenic tumor microenvironment and with poor patient clinical outcomes. Anti-CD73 antibodies are being investigated in combination with immune checkpoint inhibitors in clinical trials. Here, we investigated the prognostic value of the soluble form of CD73 (sCD73) in patients with advanced triple negative breast cancer (TNBC) treated with first-line durvalumab and chemotherapy, with or without anti-CD73 antibody oleclumab in the randomized, phase II SYNERGY trial (NCT03616886).

Methods

sCD73 levels were measured by ELISA in baseline plasma of 124 patients included in SYNERGY and in 24 healthy donors (HD). We explored association between sCD73 levels and baseline clinical characteristics, treatment response, and survival. Tumor-infiltrating lymphocytes (TILs) were assessed on H&E staining; PD-L1 was analyzed using immunohistochemistry.

Results

TNBC patients had significantly higher baseline sCD73 levels than HD (Mann-Whitney, p<0.001). High baseline levels of sCD73 were associated with liver metastases, high neutrophil-to-lymphocyte ratio (>5), and elevated CA 15-3 at baseline. sCD73 levels showed no association with clinical benefit at 24 weeks or with progression-free survival (PFS). Median overall survival (OS) was significantly shorter in patients with high baseline sCD73 levels compared to those with low sCD73 (18.8 vs. 26.4 months; log-rank, p=0.03). Higher TILs levels correlated with better PFS (log-rank, p=0.04) and OS (log-rank, p=0.03). High PD-L1 expression correlated with better PFS (log-rank, p=0.004). No association was observed between sCD73 levels and TILs or PD-L1 expression. Multivariate analysis (including treatment arm, TILs, PD-L1, sCD73 and disease presentation) confirmed the independent prognostic value of sCD73 (OS; HR=0.5; p=0.02).

Conclusions

In our analysis high baseline sCD73 levels were associated with negative prognostic clinical factors at baseline and with worse OS. The role of sCD73 as independent prognostic factor requires external validation.

Clinical trial identification

NCT03616886; August 6, 2018.

Legal entity responsible for the study

Institut Jules Bordet.

Funding

Institutional grant from AstraZeneca for the clinical trial. Translational analyses were funded by the Association Jules Bordet and the Fondation contre le Cancer (Belgium).

Disclosure

E. Agostinetto: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy fee/honoraria: Eli Lilly , Sandoz, AstraZeneca; Financial Interests, Institutional, Research Grant: Gilead; Financial Interests, Personal, Other, Support to attend medical conferences (travel/accommodation/expenses): Novartis, Eli Lilly, Genetic, Istituto Gentili, Daiichi Sankyo. J. Stagg: Financial Interests, Personal, Advisory Board: Surface Oncology, Tarus Therapeutics, Domain Therapeutics, Iteos Therapeutics; Financial Interests, Personal, Stocks/Shares: Surface Oncology; Financial Interests, Institutional, Research Grant: Surface Oncology, Domain Therapeutics. C. Sotiriou: Financial Interests, Institutional, Advisory Board: Astellas, Vertex, Seattle Genetics, Amgen, INC, Merck & Co; Financial Interests, Personal, Advisory Board: Cepheid, Puma; Financial Interests, Personal, Invited Speaker: Eisai, Prime oncology, Teva; Financial Interests, Institutional, Other, Travel: Roche; Financial Interests, Institutional, Other, Internal speaker: Genentech; Financial Interests, Personal, Other, Regional speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Exact Sciences. L. Buisseret: Financial Interests, Institutional, Advisory Board: Domain Therapeutics; Financial Interests, Institutional, Other, Steering Committee: iTEOS Therapeutics; Financial Interests, Personal, Other, writing of clinical cases: Mirrors of Medicine; Financial Interests, Institutional, Other, Travel grant: Gilead; Financial Interests, Institutional, Research Grant, Research Grant for an investigator initiated trial: AstraZeneca; Non-Financial Interests, Personal, Principal Investigator: iTeos Therapeutics; Non-Financial Interests, Personal, Member: EORTC, BSMO. All other authors have declared no conflicts of interest.

Background

Biomarkers of response to IT are lacking in HGSC and PD-L1 expression failed to predict benefit in the randomized NeoPembrOv trial assessing peri-operative chemotherapy with or without pembrolizumab. We hypothesize that heterogeneity of samples site may impact the biomarker evaluation.

Methods

Biopsy of intra-abdominal metastases (M) or primary tubo-ovaries (TO) were obtained before any treatment. PD-L1 expression (Ventana SP263) (N = 85), multiplex immunofluorescence (mIF) (N = 64) and RNAseq data (N = 57) were assessed. Differentially expressed genes (DEG) and gene set enrichment analysis (GSEA) were obtained with DESeq2. Survival was analyzed with Cox models.

Results

No major difference of immune infiltration was seen between TO and M samples (mIF data). TO were enriched in tumor cells and TPS ≥ 1 samples (Table). In M, CPS ≥1 was predictive of better PFS in the pembrolizumab arm as compared to chemotherapy alone arm (HR interaction = 0.26 CI 95% 0.07-0.93 P = 0.034). No significant benefit was seen with TPS and IC, nor in TO. Intra-tumoral CD8 T cell (iCD8) density was higher in the IC, TPS and CPS ≥ 1 subgroups and was correlated with PD-L1 expression in M but not in TO (Table). Higher iCD8 T cells density (P = 0.03) and an enrichment of immune hallmarks (Interferon alpha and gamma, allograft rejection, inflammatory response, P < 0.05) was seen in CPS ≥ 1 M vs CPS ≥ 1 TO. On the other hand, CPS ≥ 1 TO samples were enriched in proliferative pathways (MYC and E2F target, G2M checkpoint, oxidative phosphorylation, P < 0.05) compared to CPS ≥ 1 M. Table: 20P

Conclusions

CPS ≥ 1 in M, but not in primitive tumor, is associated with pembrolizumab benefit, consistent with the increase of iCD8 T cells in PD-L1 positive M. This indicates that the site of tumor sampling influence prediction of potential efficacy of PDL1 inhibitors in HGSC.

Clinical trial identification

NCT03275506.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

M. Leheurteur: Financial Interests, Personal, Advisory Board: MSD. F. Selle: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, GSK/Tesaro, Eisai; Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, GSK/Tesaro. C. Sotiriou: Financial Interests, Institutional, Advisory Board: Astellas, Vertex, Seattle Genetics, Amgen, INC, Merck & Co; Financial Interests, Personal, Advisory Board: Cepheid, Puma; Financial Interests, Personal, Invited Speaker: Eisai, Prime oncology, Teva; Financial Interests, Institutional, Other, Travel: Roche; Financial Interests, Institutional, Other, Internal speaker: Genentech; Financial Interests, Personal, Other, Regional speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Exact Sciences. I.L. Ray-Coquard: Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca, Mersana, Deciphera, Amgen, Oxnea, Merck Sereno, Agenus, Novartis, Macrogenics, Clovis, EQRX, Adaptimmune, Eisai, SUTRO, BMS, Adaptimmune, Daiichi Sankyo; Financial Interests, Institutional, Other, COLIBRI translational research: BMS; Financial Interests, Institutional, Advisory Board, translational research NEOPREMBROV trial: MSD; Non-Financial Interests, Personal, Principal Investigator: PAOLA1; Non-Financial Interests, Personal, Other, President: GINECO. O. Le Saux: Financial Interests, Personal, Advisory Board: Novartis, MSD, GSK; Financial Interests, Personal, Invited Speaker: Lilly, AstraZeneca, Clovis; Financial Interests, Institutional, Trial Chair: Novartis, Hospira-Pfizer foundation, Astellas. All other authors have declared no conflicts of interest.

Background

Immune checkpoint inhibitors (ICI) were recently developed in advanced cervical cancer (CC). However, the efficacy of ICI monotherapy is limited and predictive biomarkers of ICI efficacy are scarce. To improve ICI efficacy in advanced CC, a promising strategy is to combined anti PD(L)-1, anti CTLA-4 and chemotherapy. Our objective is to discover immune circulating biomarkers in patients with metastatic CC in ≥2nd line, treated with anti PD-L1 and anti CTLA-4 in combination with metronomic oral vinorelbine (MOV).

Methods

Three immune panels of up to 40 markers were developed to explore the immune landscape (T cells, NK cells and myeloid cells) of advanced cervical cancer in liquid biopsy. We used high-dimensional mass cytometry (CyTOF) in baseline blood samples from patients with advanced CC treated with durvalumab/tremelimumab and MOV. CyTOF datas were analyzed by machine-learning algorithms for dimensionality reduction, automated clustering and candidate prediction. Immune candidates were confirmed by manual gating. Maxstat and log-rank test were used to determine optimal cut-off and compare groups, respectively.

Results

From the cervix cohort of the phase 1/2 MOVIE multicentric prospective clinical trial (NCT03518606, sponsor UNICANCER France), 29 patients were analyzed. Median age was 56 years old. Compared to healthy donors, CC patients presented a decrease of CD4⁺CD127⁺TCF1⁺ T cells and an increase in CD8⁺TIGIT⁺ T cells. In CC patients treated in MOVIE trial (durvalumab, tremelimumab and MOV), clustering analyses, machine-learning analyses and manual gating confirmation identified a population of exhausted and senescent CD8⁺ T cells (CD8⁺CD45RA⁺CCR7^-TIGIT⁺CD57⁺) associated with treatment efficacy. An optimal cut-off at 0.95% of CD45⁺ cells was determined. Patients with a high percentage of CD8⁺CD45RA⁺CCR7^-TIGIT⁺CD57⁺ T cells had an improved clinical benefit rate (p=0.005), an improved PFS (HR=0.35, CI95, 0.13-0.95, p=0.013) and an improved OS (HR=0.23, CI95, 0.08-0.69, p<0.001).

Conclusions

This study identified a population of exhausted and senescent CD8⁺ T cells associated with response and survival with dual ICI and MOV in advanced cervical cancer.

Legal entity responsible for the study

Unicancer France.

Funding

GIRCI PACA.

Disclosure

All authors have declared no conflicts of interest.

Background

In the phase 1 GARNET study, Dostarlimab (Dmab) a PD-1 inhibitor, demonstrated clinically meaningful and durable antitumor activity in patients (pts) with advanced/ metastatic mismatch repair deficient endometrial cancer (Adv MMRd EC) after chemotherapy (chemo). Recently, the RUBY trial showed a significant improvement in progression-free survival (PFS) with Dmab plus chemo vs chemo alone, changing the standard of care in the first-line setting of Adv MMRd EC. To date, there are no validated predictive biomarkers of response to Dmab. There is growing evidence that tertiary lymphoid structure (TLS) could be predictive of response and prognostic in early EC. In our pilot study, we aim to determine the predictive value of TLS in Adv MMRd EC.

Methods

Pts with Adv MMRd EC treated with Dmab as a second-line after chemo in GARNET and the French early access program at Institut Paoli-Calmettes were included. Tissue samples from hysterectomy, endometrial or metastasis biopsies were collected. Microscopic examination was performed using paraffin-embedded tissue blocks on HES-stained sections. The presence of TLS was defined by histomorphological and phenotypic (immunohistochemistry) criterias: a dense nodule of more than 200 closely grouped lymphoid cells, with an occasional germinal center; a mixture of CD20+ B cells forming a follicle and surrounded by CD3+ T cells. Mature TLS were defined by the presence of follicular dendritic cells CD23+, CD21+, L1CAM+.

Results

14 pts were included from 12/2017-10/2021. One patient was excluded (tissue sample not evaluable). 11/13 (84%) pts had endometrioid EC. TLS were identified in 6/13 (46%) pts (TLS+) on HES sections. Immunohistochemistry staining confirmed the diagnosis of TLS, but did not detect further TLS. Median PFS : 9 months in pts with TLS vs 3.5 months in pts with no TLS.

Conclusions

Presence of TLS on HES sections seemed associated with better PFS in Adv MMRd EC pts treated with second-line Dmab. HES seemed sufficient to identify TLS, and could in routine practice, help better select MMRd pts that could benefit from Dmab alone. Larger cohorts are required to confirm our observations and explore predictive factors of reponse to Dmab in first-line.

Legal entity responsible for the study

Institut Paoli-Calmettes.

Funding

Has not received any funding.

Disclosure

M. Kfoury: Financial Interests, Personal, Invited Speaker: AZ, GSK. F. Rousseau: Financial Interests, Personal, Financially compensated role: Eisai; Financial Interests, Personal, Other: Viatris. R. Sabatier: Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Invited Speaker: Eisai, Clovis Oncology; Financial Interests, Institutional, Research Grant: AstraZeneca; Non-Financial Interests, Personal, Other, Travel fees: MSD, Novartis; Non-Financial Interests, Personal, Other, Congress fees: GSK. All other authors have declared no conflicts of interest.

Background

Immune checkpoint inhibitors (IO) combinations are standard in metastatic renal cell carcinoma (mRCC) but validated biomarkers are lacking to guide strategies towards either dual IO or IO plus tyrosine kinase inhibitors (TKI). Circulating immune cells (CIC) may inform antitumor immune response but have been mostly studied with IO monotherapy. We aimed at exploring the association between CIC and outcomes in mRCC patients treated with IO including combinations.

Methods

Phenotyping of peripheral blood mononuclear cells was performed by flow cytometry before systemic treatment in PREMIS (NCT03984318) and NIVOREN trials (NCT03013335). CIC included T cells (total CD8+, senescent CD8+, total CD4+, senescent CD4+) and B cells (naive, naive transitional, switched and unswitched memory, double negative, plasmablasts) subpopulations. We assessed associations between CIC and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) across treatment subgroups. An exploratory analysis of CIC and tissue immune infiltrate was conducted.

Results

Among 112 patients, median age was 61 y.o; 75% had clear cell histology, 64% intermediate/poor risk disease. Regimens included IO-TKI in 28%, dual IO in 15%, IO monotherapy in 54%. A lower proportion of CD8+ T cells was associated with improved ORR in the overall population (p=0.008), and improved ORR (p=0.002) and PFS (HR 0.6, p=0.030) in patients treated with IO monotherapy or dual IO. No association between T cells and outcomes in patients treated with IO-TKI was observed. Senescent CD8+ T cells were highly associated with CD8+ T cell levels (r=0.51, p<0.001), and inversely associated with the presence of tertiary lymphoid structures or lymphoid aggregates within the tumor. Among B cells, plasmablasts were inversely associated with ORR (p=0.019) in the overall population with no impact on survival. Across treatment regimens, B cell subtypes were only predictive in IO monotherapy, with switched memory B cells associated with improved ORR (p=0.014) and PFS (HR 0.54, p=0.020).

Conclusions

Circulating CD8+ T cells and CD8+ senescence may inform resistance to dual IO but not IO-TKI. The role of B cells warrants further investigation. Longitudinal analyses are ongoing.

Clinical trial identification

NCT03013335, NCT03984318.

Legal entity responsible for the study

The authors.

Funding

French National Cancer Institute, ARC Foundation, Artur Foundation.

Disclosure

R. Flippot: Financial Interests, Institutional, Funding: Bayer; Financial Interests, Personal, Invited Speaker: Astellas, Janssen, MSD; Financial Interests, Personal, Non-financial benefits: BMS; Financial Interests, Personal, Speaker, Consultant, Advisor: Ipsen, Pfizer. B. Escudier: Financial Interests, Personal, Financially compensated role: Ipsen, Pfizer, Oncorena, Aveo, BMS, Ipsen; Financial Interests, Personal and Institutional, Research Funding: BMS. L. Albiges: Financial Interests, Institutional, Other, Consulting: Astellas, BMS, Eisai, Ipsen, Janssen, MSD, Novartis, Pfizer, Roche, Merck; Financial Interests, Personal, Other, Honoraria: Novartis; Non-Financial Interests, Personal, Principal Investigator, Clinical trial steering committee: Pfizer, BMS, AVEO, AstraZeneca, MSD; Non-Financial Interests, Personal, Principal Investigator: Ipsen; Non-Financial Interests, Personal, Other, Clinical trial steering committee: Roche, Exelixis; Non-Financial Interests, Personal, Member: ASCO; Non-Financial Interests, Personal, Other, Medical Steering Committee: Kidney Cancer Association; Non-Financial Interests, Personal, Other, Member of the Renal Cell Carcinoma Guidelines Panel: European Association of Urology (EAU). All other authors have declared no conflicts of interest.

Background

Identifying biomarkers for mRCC is an unmet need in actual immunotherapy (IO) era. Available data regarding chromosome 3p-related genes (i.e., VHL, PBRM1, SETD2) as potential predictors for therapy response is conflicting. We describe the correlation of these GA with clinical outcomes in mRCC pts treated with IO/IO or IO/tyrosine kinase inhibitor (TKI).

Methods

We performed a single-center retrospective analysis on mRCC pts treated with first line IO/IO or IO/TKI. A multi-gene panel was used, allowing the amplification of 841 amplicons (54.93kb, human reference sequence hg19/GRCh37) in the coding sequences of the following genes: ATM, BAP1, KDM5C, MET, MTOR, NF2, PBRM1, PIK3CA, PTEN, SETD2, SMARCB1, TP53, TSC1, TSC2, VHL.

Results

30 mRCC pts undergoing IO/IO and IO/TKI were included. Of these, 18 had tumor tissue adequate for molecular analysis: 77.8% male, 22.2% female. Histology was 100% clear cell. IMDC risk was 50% intermediate, 33.4% good, 16.6% poor. First line therapy was 89% IO/TKI, 11% IO/IO. 83.3% pts (n=15) carried GA, among which 61.1% had a known pathogenic mutation (PAT). Most common GA included VHL in 44% (n=8; 7 PAT and 1 variant of unknown significance - VUS), PBRM1 in 44% (n=8; 5 PAT and 3 VUS) and SETD2 in 33% (n=6; 4 PAT and 2 VUS). With the limit of a small sample that did not allow proper statistical analyses, SETD2 mutated pts had lower median progression free (mPFS) and overall survival (mOS) than non-SETD2 mutated pts. Higher mPFS and mOS were shown with VHL or PBRM1 GA, especially in PBRM1+VHL mutated pts (Table). Of note, all PBRM1+VHL mutated pts underwent IO/TKI. Table: 24P

Conclusions

Our data shows a possible negative predictive role of SETD2 GA for IO-based therapy in RCC. Concomitant VHL and PBRM1 GA could act as a predictor for IO/TKI efficacy. Our hypothesis-generating analysis highlights the need of an integrated evaluation of these genes as promising biomarkers in RCC. Further larger studies are required.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

In the treatment of advanced urothelial (aUC) and renal cell carcinoma (aRCC), biomarkers such as PD-1 and PD-L1 are not robust prognostic markers for immunotherapy (IO) response. Previously, a significant association between IO and a change in splenic volume (SV) was described for several tumour entities. To the best of our knowledge, this study presents the first correlation of SV to IO in aUC and aRCC.

Methods

All patients with aUC (05/2017–10/2021) and aRCC (01/2012–05/2022) treated with IO at our academic centre were included. SV was measured at baseline, 3 and 9 months after initiation of IO using an in-house developed convolutional neural network-based spleen segmentation method. Uni- and multivariate Cox regression models for overall survival (OS) and progression-free survival (PFS) were used.

Results

In total, 35 patients with aUC and 30 patients with aRCC were included in the analysis. Lower SV at the three-month follow-up was significantly associated with improved OS in the aRCC group.

Conclusions

We describe a new, innovative artificial intelligence-based approach of a radiological surrogate marker for IO response in aUC and aRCC which presents a promising new predictive imaging marker. The data presented implicate improved OS with lower follow-up SV in patients with aRCC.

Legal entity responsible for the study

University Medical Center, Johannes-Gutenberg University University Medical Center, Johannes-Gutenberg University University Medical Center, Johannes-Gutenberg University University Medical Center of the Johannes Gutenberg-University Mainz.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

As components of the liquid biopsy, Extracellular Vesicles (EVs) have gained major interest as biomarkers of diagnosis, prognosis and prediction of response/resistance therapies. Here we investigated if plasma EV immune profile, size and concentration with plasma proteomics might discriminate responding from non-responding pts affected by UC or VH undergoing CABO+DURVA.

Methods

We evaluated 40 pts for their plasma EV profile at baseline and at the first reassessment. Baseline samples of 50 pts were evaluated for predictive potential. EVs were profiled using modified MACSplex technology coupled with flow cytometry and nanoparticle tracking analysis. Whole plasma was also searched for further indicators of response/resistance by proteomics (92 analytes, Immune-oncology panel, Olink).

Results

Preliminary analysis of EV markers measured in baseline samples evidenced no major association with response, although VH histology (n=13) showed a significant enrichment of CD1c and CD14 expressing EVs. A significant increase of immune markers were detected on-therapy time point (CD14,CD1c,CD2,CD20,CD8 and CD69; EV markers CD9, CD63 and CD81; platelet markers CD29, CD31 and CD326). This was also reflected by the global distribution of EV markers, which evidenced unexpectedly high levels of EVs exposing CD81 EV marker and CD8 already at baseline, with a further increase after therapy initiation. Finally, the dichotomization by response (responders n=21 vs non-responders n=19) highlighted that a statistically significant increase of immune EVs was detectable almost exclusively in responding.

Conclusions

Our preliminary results suggest that the early dynamics in plasma EVs may inform on the clinical outcome to DURVA plus CABO. The significant increase of EVs expressing immune markers measured at first reassessment in responding may derive from the activation of the immune system induced by therapy. The comprehensive analysis of EV profiles, size and concentration together with plasma proteomics could give rise to predictive/prognostic biomarkers of response, especially in pts with non-UC VHs.

Clinical trial identification

NCT03824691.

Legal entity responsible for the study

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.

Funding

AIRC IG-25078, NET-2016-02361632 from Italian Health Ministry.

Disclosure

P. Giannatempo: Financial Interests, Personal, Advisory Board: Pfizer. All other authors have declared no conflicts of interest.

Background

Preliminary results of the interim analysis of the ARCADIA trial have shown that combining multitargeted receptor tyrosine kinase inhibitor CABO with the checkpoint inhibitor DURVA has promising activity in patients (pts) affected by UC after chemotherapy. To identify peripheral blood biomarkers potentially associated with clinical response, we carried out a quantitative profiling of innate and adaptive immune subsets from a subset of treated pts.

Methods

From 09/2019 and 08/2023 blood samples from 65 pts (45= pure UC, 20=VHs) were collected at baseline and before the third treatment cycle. Absolute cell counts for 29 innate and adaptive immune subsets were determined by multiparametric flow cytometry.

Results

In pre-therapy samples a significant higher counts for all CD45+ leukocytes were found in non-responders compared to responders (p=0.0053, Mann Whitney test, n= 27 patients). This was, explained by higher counts for CD16+CD15+ neutrophils (p=0.0005), classical CD14+CD16- (p=0.0119) and CD14++CD16+ intermediate (p=0.0186) monocytes, CD56dim CD16+ NK cells (p=0.0365) and Lin-HLA-DR-/LoCD33+CD14+CD15- M-MDSCs (p=0.0281). At baseline, higher neutrophils counts were associated with worse PFS (p=0.0117, log rank test), while higher eosinophils counts were associated with improved PFS (p=0.0158). Compared to responders, non-responders underwent a significant reduction in post-treatment counts for all CD45+ leukocytes (p=0,0024, Wilcoxon matched pair test), due to reduction of neutrophils (p=0.0068), CD15+CD16- eosinophils (p=0.0068), CD3+ T cells (p=0.0425) CD19+ B cells (p=0.0068), classical monocytes (p=0.0034), activated (HLA-DR+) CD56dim CD16- NK cells (p=0.0068), M-MDSCs (p=0.0161), Lin- HLA-DR-/Lo CD33+ CD14- CD15+ PMN-MDSCs (p=0.001), Lin- HLA-DR+ CD33- pDCs (p=0.0269) and Lin- HLA-DR+ CD33+ mDCs (p=0.0005).

Conclusions

These preliminary findings suggest that high baseline counts for granulocytes, monocytes and MDSCs may negatively impact on response in pts treated with CABO+DURVA. Moreover, baseline neutrophils and eosinophils counts show opposite impact on PFS.

Clinical trial identification

NCT03824691.

Legal entity responsible for the study

Fondazione IRCCS Istituto Nazionale Tumori.

Funding

NET-2016-02361632 from Italian Health Ministry to A. Anichini.

Disclosure

P. Giannatempo: Financial Interests, Personal, Advisory Board: Pfizer. All other authors have declared no conflicts of interest.

Background

CheckMate 274 met the primary endpoints of improved disease-free survival (DFS) with nivolumab (NIVO) v placebo (PBO) both in the intent-to-treat (ITT) population and in patients (pts) with programmed death-ligand 1 (PD-L1) expression ≥1% assessed by tumor cell score (TC). We report updated analysis of DFS by PD-L1 expression as assessed by both TC and combined positive score (CPS; measuring PD-L1 on both tumor and immune cells) with minimum follow-up in the ITT population of 31.6 months.

Methods

CheckMate 274 (NCT02632409) is a phase 3, randomized, double-blind, trial of adjuvant NIVO v PBO in pts with muscle-invasive urothelial carcinoma who are at high risk of recurrence after radical resection. Pts were randomized 1:1 to NIVO 240mg or PBO every 2 weeks intravenously for ≤1 year. Primary endpoints are DFS in the ITT population and in pts with TC PD-L1≥1%. CPS was determined retrospectively from the previously stained immunohistochemistry slides. This analysis only included pts with PD-L1 quantifiable by both CPS and TC.

Results

630 pts had quantifiable PD-L1 by TC and CPS; 250 (40%) had TC≥1% (NIVO, n=125; PBO, n=125), 380 (60%) had TC<1% (NIVO, n=191; PBO, n=189), 558 (89%) had CPS≥1 (NIVO, n=282; PBO, n=276), and 72 (11%) had CPS<1 (NIVO, n=34; PBO, n=38). In pts with TC<1%, 81% (n=309) had CPS≥1. Table shows the number of pts and DFS outcomes in pts with TC≥1% and CPS≥1. In pts with TC<1% who also had CPS≥1, median DFS (95% CI) was 19.2 (16.1-25.6) months with NIVO vs. 10.4 (8.2-19.4) months with PBO; HR for NIVO v PBO in these pts was 0.79 (95% CI, 0.60-1.05). Table: 28P

Conclusions

With extended follow-up, this exploratory analysis of PD-L1 expression by CPS showed that most pts with TC<1% had CPS ≥1. In pts with TC<1% and CPS≥1, median DFS with NIVO was nearly double that with PBO. These results support the interpretation that most pts with TC<1% also benefit from adjuvant NIVO.

Clinical trial identification

CheckMate 274 (NCT02632409).

Legal entity responsible for the study

BMS.

Funding

BMS.

Disclosure

F. Stenner-Liewen: Consulting or Advisoy role: BMS/Roche, Ipsen, MSD, Novartis, Pfizer. Research funding: BMS GmbH & Co. KG, Takeda. Travel, accommodations, expenses: BMS GmbH & Co. KG, Roche. M. Galsky: Consulting or Advisoy role: Biomotiv, Janssen, Dendreon, Merck, GSK, Lilly, Astellas Pharma, Genentech, BMS, Novartis, Pfizer, EMD Serono, AstaZeneca, Seagen, Incyte, Aileron Therapeutics, Dracen, Inovio Pharmaceuticals, NuMab, Dragongly Therapeutics, Basilea, UroGen Pharma, Infinity Pharmaceuticals, Gilead Sciences, Silverback Therapeutics, AbbVie; Patents, Royalties, Other Intellectual Property: Methods and compositions for treating cancer and related methods. Mount Sinai School of Medicine July 2012, Application number: 20120322792. Stock and Other Ownership Interests: Rappta Therapeutics. Research funding (my institution): AstraZeneca, Bristol Myers Squibb, Dendreon, Genentech/Roche, Janssen Oncology, Merck, Novartis. D. Bajorin: Consulting or Advisoy role: Merck, Dragonfly Therapeutics, Fidia Farmaceutici S.p.A., Bristol Myers Squibb Foundation; Travel, accommodations, expenses: Merck; Research funding (my institution): Novartis, Merck, BMS, AstraZeneca, Astellas Pharma, Seattle Genetics/Astellas. J. Witjes: Consulting or Advisoy role: Nucleix, BMS, MSD, Ipsen, Sanofi/Aventis, Janssen Oncology, Oncodiag, BeiGene, Ferring, AstraZeneca, Asieris Pharmaceuticals, Photocure; Honoraria: Astellas Pharma, BeiGene, Ferring, AstraZeneca, Janssen, MSD, BMS/Pfizer. J. Gschwend: Consulting or Advisoy role: Janssen-Cilag, Bayer Schering Pharma, BMS; Honoraria: Janssen-Cilag, Bayer Schering Pharma, BMS. Y. Tomita: Consulting or Advisoy role: Eisai, MSD Onco Pharmaceutical, Taiho Pharmaceutical; Honoraria: Astellas Pharma, BMS Japan, Chugai Pharma, Ono Pharmaceutical, Takeda, Merck, Pfizer, MSD; Research funding (my institution): Astellas Pharma, AstraZeneca, Chugai Pharma, Eisai, MSD, Ono Pharmaceutical, Pfizer, Takeda. F. Nasroulah, M. Askelson, J.M. David: Financial Interests, Institutional, Full or part-time Employment: BMS; Stock and Other Ownership Interests: BMS. B. Perez Valderrama: Consulting or Advisoy role: BMS/Medarex, MSD Oncology, Astellas Pharma, Novartis, Bayer, Advanced Accelerator Applications/Novartis; Travel, accommodations, expenses: Merck/Pfizer; Honoraria: BMS/Medarex, Roche, EUSA Pharma, Pfizer, Astellas Pharma, Bayer, Merck/Pfizer, Merck. M-O. Grimm: Consulting or Advisoy role: AstraZeneca, BMS, Ipsen, MSD, Pfizer, EUSA Pharma, Merck Serono, Takeda, Eisai, Bayer Vital, Janssen Cilag, Gilead Sciences, Novartis; Honoraria: AstraZeneca, BMS, MSD, Pfizer, Ipsen, Merck Serono, EUSA Pharma, Janssen Cilag; Travel, accommodations, expenses: BMS, Merck Serono, MSD, Janssen Cilag, Ipsen, AstraZeneca; Research funding (my institution): BMS, Intutive Surgical, Bayer Vital. L. Appleman: Consulting or Advisoy role: AADi; Travel, accommodations, expenses: BMS, Merck Serono, MSD, Janssen Cilag, Ipsen, AstraZeneca; Other relationship: Pfizer; Research funding (my institution): Pfizer, Exelixis, BMS, Astellas Pharma, Acerta Pharma, Novartis, Bayer, Agensys, Merck, Genentech/Roche, Tokai Pharmaceuticals, AVEO, Peloton Therapeutics, Calithera Bioscences, Seattle Genetics, Inovio Pharmaceuticals, Eisai, Lilly, Amgen, Surgace Oncology, BioNTech AG. G. Gravis: Research funding (my institution): BMS; Payment or honoraria for speakers’ bureaus (institutional): Janssen Oncology, Ipsen, BMS, Amgen, Sanofi/Aventis, MSD Oncology, Astellas Pharma; Support for attending meetings and/or travel: Janssen Oncology, BMS, Astellas Pharma, Pfizer, Ipsen, Sanofi, AstraZeneca; Participation on a Data Safety Monitoring Board or Advisory Board (institutional): BMS, Janssen, Ipsen, Sanofi/Aventis, MSD Oncology, Pfizer, Bayer, AstraZeneca. A. Necchi: Consulting or Advisoy role: Merck Sharp & Dohme, Roche, Bayer, AstraZeneca, Clovis Oncology, Janssen, Incyte, Seattle Genetics/Astellas, BMS, Rainier Therapeutics, GSK, Basilea Pharmaceutical, Catalym; Travel, accommodations, expenses: Roche, Merck Sharp & Donhme, AstraZeneca, Janssen, Rainier Therapeutics, Pfizer; Employment, other relationship and stock and other ownership interest: Bayer (An Immediate Family Member); Honoraria: Roche, Merck, AstraZeneca, Janssen, Foundation Medicine, BMS, Astellas Pharma; Research funding: Ipsen, Gilead Sciences Research funding (institution): Merck Sharp & Dohme, AstraZeneca. All other authors have declared no conflicts of interest.

Background

Studies on the correlation between high body mass index (BMI) and extended survival among patients receiving immune checkpoint inhibitors (ICIs) have been made, although findings have shown variability. Our research explored the phenomenon of the “obesity paradox” in patients with metastatic urothelial carcinoma (mUC) undergoing treatment with ICIs.

Methods

We conducted a retrospective analysis of patients diagnosed with mUC who received a minimum of one cycle of ICI treatment at two medical centers in Taiwan from September 2015 to January 2023. Features of patients’ clinicopathologic factors, including age, sex, primary or metastatic location, treatment line and BMI were examined. The primary outcome were overall survival (OS) and progression-free survival (PFS), which were assessed utilizing the Kaplan–Meier method. We employed the Cox regression model to adjust for multiple covariates.

Results

A total of 215 patients were included, with 128 (59.5%) being male, and the median age was 70 years. In the obese group (BMI ≥ 25), patients demonstrated significantly better median OS compared to the non-obese group (BMI < 25) (21.9 vs. 8.3 months; p = 0.021). However, there was no significant difference in median PFS between the high and low BMI groups (4.7 vs. 2.8 months; p = 0.16). Post-hoc subgroup revealed a survival benefit from ICI treatment in male patients within the BMI ≥ 25 group (HR 0.49, 95% CI 0.30-0.81, p = 0.005).

Conclusions

Based on real-world data from the Asia-Pacific region, there appears to be a correlation between obesity and prolonged OS in patients receiving ICI treatment for mUC.

Legal entity responsible for the study

The authors.

Funding

Chang Gung Memorial Hospital, Kaohsiung, Taiwan.

Disclosure

All authors have declared no conflicts of interest.

Background

The recurrence risk of patients diagnosed with oral squamous cell carcinoma (OSCC) is currently insufficiently predicted by conventional clinicopathological characteristics. This study investigates the added predictive value of the tumor microenvironment immune cell composition (TMICC) in addition to conventional clinicopathologic characteristics.

Methods

Primary tumor samples of 290 OSCC patients were immunohistochemically stained for TMICC, consisting of CD4, CD8, CD20, CD68, CD163, CD57, FoxP3 and Programmed cell Death Ligand 1 (PD-L1). Additionally, clinicopathologic characteristics were obtained from patients’ medical files. Predictive models were trained and validated by conducting Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses with cross-validation. To quantify the added predictive power of TMICC within models, receiver operating characteristic (ROC) analyses were used. Recurrence was defined to include locoregional recurrences and distant metastasis.

Results

Recurrence occurred in 74 (25.5%) of patients. Conventional clinicopathologic characteristics consisting of tumor localization, pathological T-stage, pathological N-stage, extracapsular spread, resection margin, differentiation grade, perineural invasion, lymph angioinvasion and treatment modality, were used to build a LASSO logistic regression-based predictive model. Addition of TMICC to the model resulted in a comparable AUC of respectively 0.79 (± 0.01) and 0.76 (± 0.1) in the training and test sets. The model showed that high numbers of CD4+ T cells and absence of lymph node metastasis, extracapsular spread and perineural invasion protected against recurrence. Positive surgical margins and reception of adjuvant treatment increased the risk for recurrence.

Conclusions

CD4+ T cells are the strongest predictor within the TMICC, however, addition to conventional clinicopathologic characteristics does not improve the performance of a predictive model for recurrence in OSCC treated with curative intent.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

E. Schuuring: Financial Interests, Institutional, Advisory Board, Unrelated to the publication of this article: AstraZeneca, Bayer, BMS, Roche, Pfizer, Novartis, Amgen, Lilly, BioCartis, Illumina, Astellas Pharma, Agena Biosciences, MSD/Merck, CC Diagnostics, Janssen Cilag (Johnson&Johnson), Diaceutics; Financial Interests, Institutional, Invited Speaker, Unrelated to the publication of this article: Bio-Rad, Abbott, Roche, Biocartis, Illumina, Pfizer, AstraZeneca, Agena Biosciences; Financial Interests, Institutional, Research Grant, Unrelated to the publication of this article: Pfizer, Biocartis, AstraZeneca, Bayer/Invitae, Biocartis, Cancer-ID, BMS, Bio-Rad, Roche, Agena Biosciences, Promega, Qiagen, CC Diagnostics, Boehringer Ingelheim. B. van der Vegt: Financial Interests, Institutional, Speaker, Consultant, Advisor, Unrelated to the publication of this article: Visiopharm; Financial Interests, Institutional, Advisory Board, Unrelated to the publication of this article: Phillips, AstraZeneca, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, Unrelated to the publication of this article: Diaceutics, MSD, MSD. All other authors have declared no conflicts of interest.

Background

HRAS mutations have been found in 6% of HNSCCs. T cell exhaustion, defined as dysfunctional T cells stimulated by continuous antigen exposure. To guide immunotherapeutic approaches, we sought to assess the immune landscape of HRAS-mutant tumors by investigating the subpopulations of pre-exhausted and exhausted T cells.

Methods

We found 10 cases of HRAS mutant tumors and 39 cases of HRAS wild-type (WT) tumors. We sought to characterize exhausted CD8+ T cell subpopulations by measuring the expression of T-cell Factor-1 (TCF-1) and Programmed Cell Death-1 (PD-1) in the tumor's center (C) and periphery (P). Multiplex immunohistochemistry (IHC) was performed in FFPE tissue sections using three primary antibodies (PD1-CD8-TCF1/7), followed by analysis of a manually trained algorithm in Qupath software.

Results

HRAS mutant tumors present numerically higher numbers of total immune cells both in the C and the P than HRAS-WT tumors, that reached statistical significance only in the P (5123.17/mm²vs. 3527.93/mm², p=0.002). In addition, the density of CD8+ T Cells was increased in both the C (694.10/mm² vs. 356.02/mm²) and the P (851.10/mm² vs. 333.30/mm2) in HRAS mutant tumors. Importantly, the percentage of pre-exhausted CD8 (+) T Cells was elevated in the P of HRAS mutant tumors (384.67/mm²vs. 51.18/mm², p=0.040), indicating a possible association of response to ICB, since pre-exhausted T cells mediate the proliferative response to immunotherapy. On the contrary, exhausted T cells, defined as PD-1(+)TCF-1 (-) were more abundant in the C of HRAS mutant tumors compared to WT (13.77% vs. 2.67% of total CD8+ cells, p=0.022). Moreover, increased area occupied by CD11c+ dendritic cells and numbers of CD8+ T cells were found in regional lymph nodes from HRAS mutant patients (79.25% vs 38.80%, p=0.036 and 10160.43 vs 4438.28/mm², p=0.036, respectively), consistent with data showing that maintenance of TCF1 by intratumoral T cells requires continuous migration from draining lymph nodes.

Conclusions

Pre-exhausted PD-1(+)TCF-1(+) T cells are significantly increased at the periphery of HRAS mutant tumors, suggesting a potential sensitivity of these tumors to ICB.

Legal entity responsible for the study

The authors.

Funding

Kura Oncology.

Disclosure

All authors have declared no conflicts of interest.

Background

Only 15-20% of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) patients derive long-term benefit from nivolumab or pembrolizumab. We developed a ctDNA tumor-agnostic assay aimed at the early prediction of single agent PD-1 inhibitor efficacy in R/M SCCHN.

Methods

Our tumor-agnostic assay included 37 genes frequently mutated in R/M SCCHN and two HPV16 genes. Primary endpoint was the concordance between ctDNA kinetics (ΔctDNA) and best overall response (BOR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1). ΔctDNA was defined as the difference in mean variant allele frequency (VAF) between the on-treatment sample harvested 6-10 weeks (FU1) after PD-1 inhibitor initiation and the pre-treatment plasma sample (ΔctDNA = mean FU1 VAF - mean pre-treatment VAF).

Results

ctDNA was detected in 35/44 (80%) of the pre-treatment plasma samples. The concordance between ΔctDNA and imaging response was observed in 74%. Median PFS was 8.6 months in the favorable ΔctDNA group and 2.5 months in the unfavorable ΔctDNA group (p=0.057). Median OS was 18.1 and 8.2 months in the favorable and unfavorable ΔctDNA groups, respectively (p=0.13). In patients with PD-L1 expressing SCCHN (Combined Positive Score ≥1), OS was significantly better in patients with favorable ΔctDNA compared with patients with unfavorable ΔctDNA: median OS was 8.4 and 41.5 months (p=0.033), respectively.

Conclusions

Tumor-agnostic ctDNA analysis for HPV-negative and HPV-positive R/M SCCHN is feasible. ctDNA kinetics show promising results in predicting the efficacy of PD-1 inhibitors in R/M SCCHN.

Clinical trial identification

NCT02139020.

Legal entity responsible for the study

The authors.

Funding

Foundation Saint-Luc.

Disclosure

C. Van Marcke de Lummen: Financial Interests, Institutional, Advisory Board: Eli Lilly, Novartis, AstraZeneca; Non-Financial Interests, Personal, Member of Board of Directors: BSMO. R. Galot: Other, Personal, Other, Travel expenses: Merck. J. Machiels: Financial Interests, Institutional, Advisory Board: Novartis, MSD, Pfizer, Roche, Debio, AstraZeneca, Innate, Nanobiotix, Bayer, Merck Serono, Boehringer Ingelheim, BMS, Pfizer, Cue Pharma, Incyte, Janssen, Johnson & Johnson, ALX Oncology, F-star, Nektar, F-star, Seagen, Astellas, Genmab; Financial Interests, Institutional, Other, Travel expense: Gilead, MSD, Sanofi; Financial Interests, Institutional, Steering Committee Member: AstraZeneca, MSD; Financial Interests, Institutional, Coordinating PI: MSD, iTeos, eTheRNA; Financial Interests, Institutional, Local PI: Pfizer, Ceylad, MSD, Novartis, KURA, Roche, Lilly, Boehringer, Sanofi-Aventis, Incyte, Bayer, Merck Serono, Janssen, Johnson & Johnson, Amgen, AbbVie, GSK; Non-Financial Interests, Personal, Leadership Role, Chair: EORTC head and neck group. All other authors have declared no conflicts of interest.

Background

In RELATIVITY-020, NIVO+RELA was well tolerated and demonstrated durable anti-tumor activity in pts with advanced melanoma refractory to prior immunotherapy (IO-rf), with enriched responses seen in pts whose tumors expressed programmed death ligand 1 (PD-L1) or lymphocyte activation gene-3 (LAG-3). To better understand subgroups of pts that may derive increased benefit from NIVO+RELA, we performed exploratory IO biomarker analyses in RELATIVITY-020.

Methods

LAG-3, PD-L1, and CD8 levels were evaluated by immunohistochemistry in tumor samples from pts at baseline who were IO-naïve (1L) or IO-rf, and within 4 weeks on NIVO+RELA. Immune-related gene expression signatures were evaluated by RNA-seq in pts with modified definitions of primary vs secondary anti–programmed death-1/PD-L1 resistance. Association between biomarkers and response was determined by RECIST v1.1.

Results

Baseline LAG-3, PD-L1, and CD8 levels were higher in IO-rf pts whose last therapy was IO (IO-prior) vs non-IO; objective response rate (ORR) with NIVO+RELA was 12.8 vs 8.3%, respectively. Baseline biomarkers were higher in NIVO+RELA responders vs non-responders (P<0.05) only in IO-prior pts. Lower immune and inflammatory gene expression signatures were observed in pts with primary vs secondary IO resistance. Baseline LAG-3, PD-L1, and CD8 levels were similar for 1L vs IO-rf pts despite a higher response to NIVO+RELA in 1L pts. After NIVO+RELA, a significant increase in LAG-3 in the TME was noted in both IO-rf and 1L pts (log₂ fold change: 0.73 and 1.46; both P<0.01), whereas PD-L1 and CD8 increased significantly in 1L pts only.

Conclusions

IO-rf pts whose last line of therapy prior to RELATIVITY-020 was IO vs non-IO had elevated inflammation-associated tumor biomarkers and may be more responsive to NIVO+RELA, although the ORR difference was modest. Variance in immune infiltration gene-expression signatures in primary vs secondary IO-resistant tumors suggest these subgroups have distinct TMEs and IO sensitivities. Modulation of LAG-3 in both IO-rf and 1L pts suggests NIVO+RELA can alter the TME in both settings, although modulation was greater in 1L pts.

Clinical trial identification

NCT01968109.

Editorial acknowledgement

Editorial support was provided by Allyson Koyen Malashevich, PhD, and Agata Shodeke, PhD, of Spark Medica Inc., funded by Bristol Myers Squibb.

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

P.A. Ascierto: Financial Interests, Personal, Other, Consultant and Advisory Role: BMS, Roche Genentech, MSD, Novartis, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Nektar, Boehringer Ingelheim, Regeneron; Financial Interests, Personal, Other, Consultant and Advisory Role. Travel support: Pfizer/Array; Financial Interests, Personal, Other, Consultant Role: Italfarmaco; Financial Interests, Personal, Other, Advisory Role: Eisai, Seagen; Financial Interests, Personal, Other, Consultant Role: Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore; Financial Interests, Personal, Other, Consultant role and travel support: Bio-AI Health; Financial Interests, Personal, Other, Consultant role: Medicenna; Financial Interests, Personal, Advisory Board, Consultant and Advisory Role: iTeos; Financial Interests, Personal, Advisory Board, Consultant and Advisory role: ValoTx; Financial Interests, Personal, Advisory Board, Consultant and Advisor role. Travel support: Replimmune; Financial Interests, Personal, Advisory Board, Advisor role: Bayer; Financial Interests, Institutional, Funding, Clinical Trial: Pfizer/Array, Roche Genentech, Sanofi; Financial Interests, Personal, Advisory Board: Erasca; Financial Interests, Institutional, Funding, Clinical trial and translational research: BMS; Non-Financial Interests, Personal, Leadership Role, President since 2010: Fondazione Melanoma Onlus Italy; Non-Financial Interests, Personal, Leadership Role, President since 2014: Campania Society of ImmunoTherapy of Cancer (SCITO) Italy; Non-Financial Interests, Personal, Member: SITC, ASCO, EORTC Melanoma Cooperative Group, AIOM, SMR; Non-Financial Interests, Personal, Other, Member of Steering Committee since 2016: Society for Melanoma Research (SMR); Non-Financial Interests, Personal, Member of Board of Directors, November 2017 - December 2021: Society for Immunotherapy of Cancer (SITC). H. Tang, S. Dolfi: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. M.S. Nyakas: Financial Interests, Personal, Speaker, Consultant, Advisor, Lectures and/or expert meetings: Bristol Myers Squibb, Novartis, MSD, Roche, Pierre Fabre. I. Svane: Financial Interests, Personal, Advisory Board: BMS, Pierre Fabre, Novartis; Financial Interests, Personal, Invited Speaker: MSD, Pierre Fabre, Novartis, Roche, BMS; Financial Interests, Institutional, Research Grant: Enara Bio, Adaptimmune, Lytix Biopharma, TILT Biotherapeutics; Financial Interests, Personal, Writing Engagement: MSD; Financial Interests, Personal, Stocks/Shares, Cofounder and Founder warrents: IO Biotech; Financial Interests, Institutional, Funding: Evaxion; Non-Financial Interests, Personal, Principal Investigator: BMS, Novartis, Roche, TILT Biotherapeutics, Lytix Biopharma. E. Muñoz Couselo: Financial Interests, Personal, Advisory Board: BMS, Novartis, Sanofi, Pierre Fabre, Sun Pharma, MSD; Financial Interests, Personal, Invited Speaker: Novartis, Roche, BMS, Sanofi, MSD, Pierre Fabre. J.J. Grob: Financial Interests, Personal, Speaker, Consultant, Advisor, Personal fees: Novartis, Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Novartis, Bristol Myers Squibb, MSD, Philogen, Pierre Fabre, Sanofi, Roche, Amgen. C.A. Gomez-Roca: Financial Interests, Personal, Invited Speaker: BMS, Roche/Genentech, Pierre Fabre; Financial Interests, Personal, Other, IDMC member: PharmaMar; Financial Interests, Personal, Advisory Board: Macomics; Financial Interests, Institutional, Research Grant: Roche/Genentech; Financial Interests, Institutional, Coordinating PI: BMS, Amunix, Hookipa, Kazia Therapeutics, IDEAYA; Financial Interests, Personal, Steering Committee Member: BMS, Genentech; Non-Financial Interests, Personal, Member of Board of Directors: FITC (Société française d'Immuno-Thérapies du Cancer); Non-Financial Interests, Personal, Officer: ESMO Membership Committee, ESMO - MCBS Extended Working Group; Non-Financial Interests, Personal, Officer, Young Investigators Committee at imCORE: inFLAME; Non-Financial Interests, Personal, Member of Board of Directors, Network of Early Phase Units: OncoDistinct; Non-Financial Interests, Personal, Leadership Role: FITC (Société française d'Immuno-Thérapies du Cancer). V. Chiarion Sileni: Financial Interests, Personal, Other, Travel, registration, and accommodation to attend ASCO annual meetings: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Advisory Board: Merck Sharpe & Dohme; Non-Financial Interests, Personal, Other, Steering Committee: Roche. K. Peltola: Financial Interests, Personal, Advisory Board: MSD, Ipsen, Roche, BMS, Pfizer, Lilly, Novartis, Bayer; Financial Interests, Personal, Stocks/Shares: Faron Pharmaceuticals; Financial Interests, Institutional, Local PI, Conduct of sponsored clinical trial: Novartis; Financial Interests, Institutional, Local PI, Sponsored clinical trial: Exelixis; Financial Interests, Institutional, Local PI, Several clinical trials: BMS, MSD, Roche; Financial Interests, Institutional, Local PI, clinical trials: Incyte; Financial Interests, Institutional, Local PI, Conduct of clinical trials: Pfizer; Financial Interests, Institutional, Local PI, Conduct of clinical trial: Bayer. J. Larkin: Financial Interests, Personal, Invited Speaker: BMS, Pfizer, Roche, Pierre Fabre, AstraZeneca, Novartis, EUSA Pharma, MSD, Merck, GSK, Ipsen, Aptitude, Eisai, Calithera, Ultimovacs, Seagen, Goldman Sachs, eCancer, Inselgruppe, Agence Unik; Financial Interests, Personal, Other, Consultancy: Incyte, iOnctura, Apple Tree, Merck, BMS, Eisai, Debipharm; Financial Interests, Personal, Other, Honorarium: touchIME, touchEXPERTS, VJOncology, RGCP, Cambridge Healthcare Research, Royal College of Physicians; Financial Interests, Institutional, Funding: BMS, MSD, Novartis, Pfizer, Achilles, Roche, Nektar, Covance, Immunocore, Pharmacyclics, Aveo. I. Melero: Financial Interests, Personal, Advisory Board: Agneus, Alligator Bioscience, AstraZeneca, BMS, BioLineRx, Boehringer Ingelheim, Boston Pharma, CRISPR Therapeutics, CatalYm GmbH, Crescendo Biologics, Curon Biopharmaceutical, Highlight Therapeutics, EMD Serono, F-Star, Genentech, Genmab, Gossamer Bio, Hookipa Pharma, HotSpot Therapeutics, Inc., ImmuneSensor Therapeutics, Inc., Janssen, MSD, Merus N.V., Monopteros Therapeutics, Noxxon Pharma AG, Numab, Phenomic Bio, Pieris Pharmaceuticals GmbH, Pierre Fabre, Roche, Sanofi, Senti Biosciences, Servier, Shattuck Labs, Third Rock Ventures; Financial Interests, Personal, Other, Consultant: Pharma Mar; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Roche, BMS, Genmab, Alligator. M. Callahan: Financial Interests, Institutional, Research Funding, Support that goes to MSK: Bristol Myers Squibb. R. Dummer: Financial Interests, Personal, Other, Consulting and/or advisory role: Novartis, Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, MaviVAX SA, Simcere, touchIME, T3 Pharma, Pfizer. P. Djidel: Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb; Financial Interests, Personal, Full or part-time Employment: Bristo Myers Squibb. D. Warad: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Funding, Support for travel, meetings, equipment, as part of employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. E.J. Lipson: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Sanofi, Regeneron, Genentech, Eisai, Instil Bio, Natera, Nektar Therapeutics, Pfizer, Rain Therapeutics, CareDx, Immunocore, Novartis, Replimune, HUYA Bioscience International; Financial Interests, Personal, Other, Consultant: OncoSec; Financial Interests, Institutional, Coordinating PI: Bristol Myers Squibb; Financial Interests, Institutional, Local PI: Regeneron, Merck, Sanofi. C. Garnett-Benson: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Funding, Support for attending meetings and/or travel; Receipt of equipment, materials, drugs, medical writing, gifts or other services, as part of employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb.

Background

Existing therapy response assessments are based largely on summing changes in target lesion diameters assessed on CT or MRI (e.g., RECIST) and do not consider lesion response heterogeneity. Evaluating lesion-level response of all lesions enables identification of novel patterns, such as heterogeneous response (HeR). In our study, we use a lesion-level response model, based on ¹⁸F-FDG PET/CT analysis to correlate lesion response patterns and treatment outcomes in metastatic melanoma (MM) patients treated with immune checkpoint inhibitors (ICI).

Methods

We retrospectively assessed 27 MM patients treated with anti-PD-1 therapy in two academic centers. Lesions were manually segmented on baseline (PET1) and first follow-up (PET2, month 3-4) ¹⁸F-FDG PET/CT. Lesions were categorized based on relative change of SUV_total from PET1 to PET2: complete response (iCR, disappeared on PET2), partial response (iPR, ΔSUV_total<-30%), stable disease (iSD, |ΔSUV_total | ≤ 30%), progressive disease (iPD, ΔSUV_total>+30%), new disease (iND, new on PET2). HeR was defined as patients having at least one iCR or iPR and iPD or iND lesion. Survival analysis was done using Cox regression analysis. Patients were dichotomized into two groups based on their clinical status at the end of treatment (EOT): progressive disease (PD) and non-progressive disease patients (non-PD). Two-proportion z-test was used to compare proportion of patients with HeR in both groups.

Results

426 lesions were segmented and categorized as iCR (56%), iPR (10%), iSD (3%), iPD (8%), iND (23%). Patients with one or more iPD lesion (HR = 1.8, p= 0.003), two or more iND or iPD lesions (HR = 1.9, p=0.003), or identified with HeR (HR = 1.42, p=0.04) on PET2 had significantly shorter PFS. 37% (10/27) patients were identified to have HeR: 2/13 non-PD and 8/14 PD patients. Patients with HeR at PET2 have a significantly higher probability of progression at EOT (p=0.02).

Conclusions

Lesion-level analysis of ¹⁸F-FDG PET/CT response can recognize non-responding lesions. We found that patients with HeR had significantly shorter PFS. We anticipate a future interventional study where early identification of non-responding lesions may be amendable to local therapies.

Clinical trial identification

At University of Wisconsin Carbone Cancer Center, the study was approved by Institutional Review Board (UW14084). At Oncology Institute Ljubljana, the study was approved by the Ethics comitee of OIL and Comitee for assessment of Clinical protocols (ERDIKE-005/2020, ERID-KSOPKR-002/2020).

Legal entity responsible for the study

The authors.

Funding

University of Wisconsin Carbone Cancer Center (UWCCC), National Cancer Institute of the National Institutes of Health, The Slovenian Research Agency (ARRS).

Disclosure

R. Jeraj: Financial Interests, Personal and Institutional, Funding: AIQ Solutions. All other authors have declared no conflicts of interest.

Background

Current immune research on soft tissue sarcomas (STS) primarily focuses on analyzing the tumor microenvironment and adjacent lymph nodes. However, alternative methods are necessary to monitor immune responses in non-surgical patients due to limited opportunities to study tumor-infiltrating lymphocytes. This study aimed to assess the peripheral immune profile of STS patients and its impact on patient survival.

Methods

Blood samples were collected from 55 STS patients and age-matched healthy individuals. Flow cytometry and qRT-PCR were conducted on whole blood, to proceed with deep immunophenotyping and gene expression quantification, respectively. Proteomic analysis was also performed on plasma samples by xMAP technology. Unsupervised clustering analysis was used to classify patients based on their immunotype.

Results

Significant differences were found between STS patients and healthy individuals. STS patients showed lymphopenia, particularly affecting B and CD4 T cells, with an expansion of myeloid cells such as granulocytes and monocytic-derived suppressor cells (M-MDSC). Gene expression analysis revealed decreased levels of activatory and cytotoxic-related factors, along with increased expression of ARG1, which may inhibit anti-tumoral activity. A tendency for increased levels of IL-10 and soluble checkpoint inhibitors VISTA and TIMD-4 were also observed in plasma samples. Furthermore, patients were classified into three distinct immunotypes: \"immune-high,\" \"immune-intermediate,\" and \"immune-low.\" These immunotypes correlated significantly with time after collection (TAC), which refers to the time from sample collection to the end of the study or occurrence of a death event. \"Immune-high\" patients had elevated levels of immune-related factors associated with cytotoxic/effector activity and longer TAC, while \"immune-low\" patients had increased levels of immune-related factors associated with inflammation and inhibition, and shorter TAC.

Conclusions

The correlation between immunotypes and survival times emphasizes the importance of studying peripheral blood samples in STS. Evaluating the peripheral immune response can be a valuable tool for monitoring and predicting outcomes in STS patients.

Legal entity responsible for the study

The authors.

Funding

FCT - Portuguese Foundation for Science and Technology.

Disclosure

All authors have declared no conflicts of interest.

Background

Soft tissue sarcomas (STS) are a group of rare and heterogeneous tumors with different clinical and biological behaviors. Better prognosis has been associated to an inflamed tumor microenvironment (TME) characterized by the presence of tertiary lymphoid structures (TLSs) rich in B cells. However, studies are still needed to better characterize cellular and molecular components of the TME the that could favor or hamper B cell organization in STS-associated TLSs.

Methods

The transcriptomic immune profiling of STS TME was performed using the Human Immunology V2 Panel and the NanoString nCounter platform on 33 STS biopsies or surgical samples. Patients with primary or locally recurrent STS were enrolled and treated at the Careggi Hospital (Florence, Italy; RESEARCH study). Results were validated by retrieving RNA-sequencing and clinical data for 164 STS patients from The Cancer Genome Atlas (TCGA) SARC project.

Results

We investigated the impact of gene signatures discriminating for specific immune cells and we found a significant association with relapse-free survival (RFS) only for germinal center (GC) B cell- and T helper 17 (Th17) cell-related signatures (p < 0.05). We observed a correlation between GC-B and Th17 signatures (r = 0.77, p < 0.0001), and the combination of both GC B and Th17 signatures was associated with better RFS, while low expression of both GC B and Th17 signatures was associated with the worst survival outcome (p = 0.035). The prognostic value of the GC-B/Th17 signature was confirmed on data from TCGA SARC project for both RFS (p = 0.016) and overall survival (p = 0.014). Differential gene expression analysis showed a more inflamed landscape in GC-B/Th17-high tumors. Conversely, the upregulation of genes encoding immunosuppressive molecules and genes related to tumor-associated macrophages with an immunosuppressive phenotype, were observed in GC-B/Th17-low tumors.

Conclusions

Our data identified a novel prognostic signature composed of GC B cell- and Th17 cell-related genes for STS patients, and suggest a potential collaboration between GC B cells and Th17 cells in mediating antitumor immune responses and potentially TLS formation in STS.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Regulatory T cells (Treg) play a crucial role as prognostic factors and intervention targets for isocitrate dehydrogenase (IDH)-wild type (wt) glioblastoma (GBM). The study aimed to construct a model predicting the Treg infiltration in IDH-wt GBM patients using pathomics techniques and explore related biological processes.

Methods

Flow cytometry was used to detect the proportion of Treg in orthotopic mouse glioblastoma brain tissue. Clinical data of IDH-wt GBM patients from the TCGA database were analyzed retrospectively. Features were extracted from HE-stained biopsy sections using the Pyradiomics package. The pathomics model was constructed using the Gradient Boosting Machine algorithm after performing feature selection with mRMR and Relief algorithms. Cox proportional hazard regression analysis was employed to access the association between pathomics score (PS) and overall survival (OS). Transcriptomic data were analyzed through GSEA set enrichment, differential gene expression, and correlation analyses.

Results

The study established a pathomics model with 3 pathomics features that effectively predicted Treg infiltration (Training set: AUC=0.807; Validation set: AUC=0.735). PS positively correlated with high Treg expression. Survival analysis indicated that patients with high PS had significantly lower OS than the low PS group (median survival time: 12.0 vs 14.4 months; p=0.009). Multivariate COX analysis revealed that high PS expression independently served as a prognostic risk factor for IDH-wt GBM patients (HR, 2.16; 95% CI, 1.269-3.677; p=0.005). Subgroup analysis showed that high PS was a risk factor for OS in patients receiving chemotherapy (HR, 2.232; 95% CI, 1.309-3.905; p=0.003) or radiotherapy (HR, 1.882; 95% CI, 1.161-3.049; p=0.01).GSEA enrichment analysis revealed significant associations of PS with the NOTCH, IL-6/JAK/STAT3 signaling pathways. High PS significantly correlated with elevated RAD50 expression.

Conclusions

The developed pathomics model, based on machine learning algorithms, can noninvasively predict Treg infiltration and prognosis in IDH-wt GBM patients. The biological processes related to the model may involve RAD50 and pathways, including NOTCH, IL-6/JAK/STAT3.

Legal entity responsible for the study

The authors.

Funding

The Joint Funds for the Innovation of Science and Technology, Fujian Province (No.2021Y9301).

Disclosure

All authors have declared no conflicts of interest.

Background

FOXC1, MKI67 and PDL1 expression that tracks plasticity, proliferation and immune evasion accurately predicts efficacy of Immune Checkpoint Blockade (ICB) with PD1/PDL1 inhibitor drugs. We sought to validate whether patient selection based on predicted Hyperprogressive Disease (HPD) risk using such an approach can improve Progression-free Survival (PFS) and/or Overall Survival (OS) in clinical trial and real world cohorts.

Methods

Pre-treatment tumor RNA-Seq data obtained from patients diagnosed with advanced/metastatic (a/m) melanoma (n=154,121), non-small cell lung cancer (NSCLC, n=82,140) and renal cell carcinoma (RCC, n=250,120) were analyzed for FOXC1, MKI67 and PDL1 expression, and correlated with overall response rate (ORR), PFS, OS and HPD, the latter defined as time-to-treatment-failure (TTF) <=2 months post-treatment initiation. Optimized biomarker cutoff values based on model AUC were leave-one-out cross validated and cancer-type specific (CTS) prediction algorithms derived. The unmodified strategy was then validated in the independent, CTS validation datasets.

Results

Predicted Clinical Responders (CR) displayed marked improvement in PFS and OS compared to Predicted Non-Responders with standard Progressive Disease (PD) or Hyperprogressive Disease (HPD). [a/m Melanoma OS HR=0.35 (0.187-0.666)95%CI, p=0.0004; a/m NSCLC OS HR=0.24 (0.119-0.499)95%CI, p<0.0001; a/m RCC OS HR= 0.45 (0.255-0.810)95%CI, p=0.008]. Table: 39P

Patient stratification by HPD risk and median overall survival benefit

Conclusions

Compared to ICB administered in a non-patient stratified manner, restricting ICB treatment only to those patients who are predicted CRs results in nearly a two-fold or greater improvement in the median OS survival benefit in all cancer types examined. Patients predicted to have elevated HPD risk should be considered for treatment with non-ICB regimens or offered enrollment in clinical trials that combine ICB with other drugs.

Clinical trial identification

NCT01668784; Nov 5, 2015.

Legal entity responsible for the study

P.S. Ray.

Funding

Has not received any funding.

Disclosure

P.S. Ray: Non-Financial Interests, Institutional, Advisory Role: Onconostic Technologies: Practicing surgical oncologist and clinical investigator, identified as the presenting author on the submitted abstract. PSR is not an employee of the company (Onconostic Tehcnologies), but is founder and Chairman of the Scientific Advisory Board of the company which is an unpaid position. T. Ray, R. Hussa: Financial Interests, Personal, Full or part-time Employment: Onconostic Technologies, Inc.; Financial Interests, Personal, Stocks/Shares: Onconostic Technologies, Inc. C. Taylor: Financial Interests, Personal, Advisory Board: Onconostic Technologies, Inc.; Financial Interests, Personal, Stocks/Shares: Onconostic Technologies, Inc.

Background

T cell avidity plays a crucial role in antigen presentation and influences the quality of TCR signaling and T cell metabolic fitness. It is crucial in chronic inflammation e.g. cancer where persistent antigen exposure and chronic T cell stimulation may lead to exhaustion. Thus, mechanistic insights on the roles of CD8⁺ specificities and T cell avidity of naturally arising tumour-specific T cells where both high (Tet^hi) and low (Tet^lo) avidity T cells recognising the same pMHC co-exist in the same tumour, are crucial for understanding resistance to PD-1 immunotherapy.

Methods

CT26 models were treated with anti-PD-1 on days 3, 6 and 9 following tumour implantation generating variable responses during early tumour development. Tetramer staining and T cell avidity measurement using acoustic force spectroscopy were conducted to determine the frequency and avidity of CD8⁺ T cells targeting the tumour-specific epitope GSW11. Tet^hi and Tet^lo were functionally characterised using flow cytometry, RNA-seq, in vitro and in vivo cytotoxicity experiments.

Results

Treatment success with anti-PD-1 was associated with the preferential expansion of Tet^lo. Tet^lo were precursor exhausted with higher expression of Tcf-1 and T-bet, and lower expression of CD39, PD-1 and Eomes compared to Tet^hi. Pathways related to TCR signaling, cytotoxicity and oxidative phosphorylation were significantly upregulated in Tet^lo found in both responding and non-responding tumours compared to Tet^hi. Interestingly, a small percentage of Tet^lo found in the non-responding tumours were functional but metabolically challenged. In vitro studies showed that Tet^lo exhibited higher cytotoxicity than Tet^hi. Curative response was achieved when Te^tlo were adoptively transferred and in combination with anti-PD-1.

Conclusions

Targeting subdominant T cell responses with lower avidity against pMHC affinity neoepitopes showed potential for improving PD-1 immunotherapy. Future interventions may consider expanding low avidity populations via adoptive transfer or drugs targeting immunometabolism. These approaches may be combined with non-invasive tumour metabolism imaging and T cell tracking to understand the impact of immunometabolism on T cell dynamics at a system level.

Legal entity responsible for the study

The authors.

Funding

Worldwide Cancer Research Fund (20-0229), Cancer Research UK Programme Grant (A28279).

Disclosure

All authors have declared no conflicts of interest.

Background

Multiple genomic and transcriptomic biomarkers have been associated with response to immune checkpoint inhibitor (CPI) therapy. Our previously published meta-analysis of biomarkers included over 1000 patients across multiple cancer types, which demonstrated clonal TMB and CXCL9 expression as the strongest pan-cancer biomarkers of CPI response. However, over half of the variance in response to CPI treatment remains unexplained, for example 52% of patients who respond to CPI treatment were low-TMB and showed no evidence of an oncogenic viral infection.

Methods

To address the missing understanding in CPI response mechanisms, we have recently extended our dataset to 16 immunotherapy treated cohorts, across 10 solid tumour types, encompassing >2500 treated patients. Matched tumour/normal whole exome sequencing (WES) data and tumour transcriptomic data (RNAseq) was available. All data was accessed in raw sequencing read format and reprocessed through a standardized bioinformatics pipeline. Using pubmed key word search we completed a systematic literature review of ∼1,000 papers, which identified >200 unique biomarkers that could be quantified in exome or RNA-seq data. Data will be presented on these biomarkers to understand the full landscape of biomarkers responses to CPI therapy.

Results

Biomarkers with strongest effect size pan-cancer, and per cancer type will be presented, highlighting divergent mechanisms of CPI response across histology types. We will present data on emerging checkpoint targets in late-stage trials (e.g. LAG3, TIGIT, VISTA) across cancer types, to assess the potential of these new candidates to overcome resistance to current anti-PD-1 or anti-CTLA-4 treatment. We will additionally assess expression of tumor-associated antigen targets in solid tumour CAR T cell and vaccine trials (e.g. MAGE, NY-ESO-1, MUC1), to understand their role in CPI response. Lastly, we will discuss how these biomarkers can be combined into a multimodal test to accurately predict CPI response.

Conclusions

Results from this work have strongly highlighted the varying determinants of immunotherapy response across solid tumour types, offering unique insight into both tumour intrinsic and extrinsic drivers of immunogenicity.

Legal entity responsible for the study

The authors.

Funding

The Medical Research Council.

Disclosure

C. Swanton: Financial Interests, Personal, Invited Speaker, Activity took place in 2016: Pfizer, Celgene; Financial Interests, Personal, Invited Speaker, October 26th 2020: Novartis; Financial Interests, Personal, Invited Speaker: Roche/Ventana, BMS, AstraZeneca, MSD, Illumina, GSK; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board, Current - since 2018: Genentech; Financial Interests, Personal, Advisory Board: Sarah Canon Research Institute; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Other, Consultancy: Medicxi; Financial Interests, Personal, Advisory Board, Member of the Science Advisory Board. Also had stock options until June 2021: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; Financial Interests, Personal, Advisory Board, 29 November - 1 December 2022: Novartis; Financial Interests, Personal, Invited Speaker, Oncology Collective - 2nd Nov - 4 Nov 2022 - Atlanta, USA: Roche; Financial Interests, Personal, Advisory Board, ctDNA advisory Board - 24th March 2023: AstraZeneca; Financial Interests, Personal, Invited Speaker, Pfizer Oncology 'Leading the revolution for the future: Pfizer; Financial Interests, Personal, Full or part-time Employment, Chief Clinician since October 2017: Cancer Research UK; Financial Interests, Personal, Ownership Interest, Co-Founder of Achilles Therapeutics. Also, have stock options in this company: Achilles Therapeutics; Financial Interests, Personal, Stocks/Shares, Stocks owned until June 2021: GRAIL, Apogen Biotechnologies; Financial Interests, Personal, Stocks/Shares: Epic Biosciences, Bicycle Therapeutics; Financial Interests, Institutional, Research Grant, Funded RUBICON grant - October 2018 - April 2021: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, Collaboration in minimal residual disease sequencing technologies: Archer Dx Inc; Financial Interests, Institutional, Research Grant: Pfizer, Boehringer Ingelheim; Financial Interests, Institutional, Trial Chair, Chief Investigator for the MeRmaiD 1and 2 clinical trials and chair of the steering committee: AstraZeneca; Financial Interests, Institutional, Research Grant, Research grant from Oct 2019 - July 2023 - Genetics of CIN and SCNAs for Targeted Discovery (SCEPTRE): Ono Pharmaceutical; Financial Interests, Institutional, Research Grant, Research Grants from 2015: Roche; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Financial Interests, Institutional, Research Grant, from October 2022: Personalis; Non-Financial Interests, Personal, Principal Investigator, Chief Investigator for MeRmaiD 1 and 2 clinical trials: AstraZeneca; Non-Financial Interests, Personal, Member of Board of Directors, From 2019-2022: AACR; Non-Financial Interests, Personal, Other, Board of Directors: AACR; Non-Financial Interests, Personal, Advisory Role, EACR Advisory Council member: EACR. K.R. Litchfield: Financial Interests, Personal, Invited Speaker: Roche Tissue Diagnostics; Financial Interests, Personal, Other, Consulting work: Kynos Therapeutics, Monopteros Therapeutics, Tempus; Financial Interests, Personal, Invited Speaker, Invited speaker: Ellipses Pharma; Financial Interests, Institutional, Research Grant: Ono/LifeArc; Financial Interests, Institutional, Research Grant, Research funding: Genesis Therapeutics; Non-Financial Interests, Institutional, Proprietary Information, Collaboration on data analysis: BMS. All other authors have declared no conflicts of interest.

Background

Immunotherapies targeting immune checkpoints have gained increasing attention in cancer treatment, emphasizing the need for predictive biomarkers. Circular RNAs have emerged as critical regulators of tumor immunity, particularly in the PD-(L)1 pathway, and have shown potential in predicting the efficacy of immunotherapies. Therefore, the development of a comprehensive resource that integrates circRNA profiles, immunotherapy response data, and clinical benefits is crucial for advancing our understanding of circRNA-mediated tumor-immune interactions and developing effective immunotherapy biomarkers.

Methods

To address these gaps, we constructed the Cancer CircRNA Immunome Atlas (TCCIA), the first database that combines circRNA profiles, immunotherapy response data, and clinical outcomes across multi-cancer types. The construction of TCCIA involved applying standardized preprocessing to the raw sequencing FASTQ files, characterizing circRNA profiles using CIRCexplorer2, analyzing tumor immunophenotypes through IOBR, and compiling immunotherapy response data from diverse cohorts treated with ICBs.

Results

TCCIA encompasses over 3,700 clinical samples obtained from 18 cohorts treated with ICBs, including PD-1/PD-L1 and CTLA-4 inhibitors, along with other treatment modalities. The database provides researchers and clinicians with a cloud-based platform that enables interactive exploration of circRNA data in the context of ICB. The platform offers a range of analytical tools, including visualization of circRNA abundance and correlation, association analysis between circRNAs and clinical variables, assessment of the tumor immune microenvironment, exploration of tumor molecular signatures, evaluation of treatment response or prognosis, and identification of altered circRNAs in immunotherapy-sensitive and resistant tumors. To illustrate the utility, we performed a re-analysis on a melanoma cohort with TCCIA and found that an isoform of circTMTC3 played a significant role in predicting unfavorable survival outcomes and treatment nonresponse.

Conclusions

TCCIA represents a significant advancement over existing resources, providing a comprehensive platform to investigate the role of circRNAs in immune oncology.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

V-domain Ig suppressor of T-cell activation (VISTA) is a B7 family member that acts as an immune checkpoint regulator. VISTA is expressed in various cell subtypes such as tumor, myeloid, lymphoid, and endothelial cells. Within the tumor microenvironment (TME), its expression on myeloid cells favors immunosuppressive conditions and prevents T cell recruitment into tumors. In patients, high VISTA expression is associated with poor prognosis in multiple tumor indications, and act as a mediator of resistance to immune checkpoint therapies. Thus, VISTA appears as a potential therapeutic target in oncology requiring a more detailed characterization of its expression pattern across tumor indications to eventually inform future patient selection.

Methods

In tissue microarrays (TMAs) covering 23 solid tumor indications and representing more than 1000 patients, we investigated the expression of VISTA in combination with different immune and tumor cells markers. For this purpose, we developed and validated a 7-color multiplex immunofluorescence protocol to quantify VISTA expression on tumor cells (Cytokeratin/Melan A), cytotoxic CD8 T cells (CD8), myeloid cells (CD33), M2 macrophages (CD163), and PD-L1 positive cells (PD-L1).

Results

Consistent with the literature, we have observed that VISTA is not only predominantly expressed in the TME but also frequently and highly expressed in tumor cells in some indications such as sarcoma, mesothelioma, kidney, and gastric cancer for example. In the TME, VISTA is found to be highly expressed in CD33 and CD163 populations, particularly in kidney cancer and sarcoma. Moreover, we found that tumor infiltrating CD8 T-cells often expressed VISTA, notably in sarcoma, kidney cancer, and hepatocellular carcinoma.

Conclusions

Finally, we propose indications of interest that may support patient selection strategy for the development of anti-VISTA treatments.

Legal entity responsible for the study

Pierre Fabre Laboratories.

Funding

Pierre Fabre Laboratories.

Disclosure

P. Launay, A. Pillon, R. Bonnet, D. Vinet, A. Alloy, L. Lacastaigneratte, C. Welsch, C. Larzabal, G. Zorza, G. Gueguen Dorbes, O. Geneste, F. Hofmann, M-O. Roy: Financial Interests, Personal, Full or part-time Employment: Pierre Fabre.

Background

Sitra is a spectrum-selective tyrosine kinase inhibitor targeting multiple receptors, including VEGFR2. Here, we present an exploratory analysis of PD biomarkers in SAFFRON-103, a phase 1b study investigating Sitra with TIS, an anti-PD-1 antibody, in patients (pts) with solid tumors including advanced non-squamous-non-small cell lung cancer (NSCLC), squamous-NSCLC, melanoma, or ovarian cancer.

Methods

Peripheral blood samples were collected at Cycle (C) 1 Day (D) 1, C2D1, and C3D1 prior to Sitra dosing, to investigate changes in cytokines (Meso Scale Discovery [MSD] multiplexing), plasma proteins (ELISA), and immune cell populations (fluorescence-activated cell sorting [FACS]). Generalized linear mixed models were used to estimate fold change and analyze biomarker changes; Wald tests were used to generate P-values.

Results

Baseline characteristics were balanced across pts with evaluable biomarker results (n=186 cytokines/plasma proteins, n=113 immune cell populations) and in the overall population (N=216). For all pts, changes in individual biomarker levels were consistent from C1D1 to both C2D1 and C3D1, with significant increases in VEGFA (P<0.0001; both) and CXCL10 (P<0.0001; both) and significant decreases across soluble (s) VEGFR2 (P<0.0001; both), peripheral G-MDSCs (P=0.0005; P=0.0002), and monocytes (P<0.0001; both). Estimated fold changes of PD biomarkers across tumor types are shown (Table). Changes in VEGFA (increased) and monocytes (decreased) after treatment (C2D1/C1D1) were associated with improved objective response rates (odds ratio [OR] 4.67, P=0.0005; OR 5.82, P<0.0001). Table: 44P

Conclusions

VEGFA increased and sVEGFR2 decreased consistently and significantly after Sitra plus TIS therapy, demonstrating the on-target anti-angiogenesis effect of Sitra. Decrease of G-MDSCs and monocytes in peripheral blood indicates a potential immune-modulating role for Sitra with TIS.

Clinical trial identification

NCT03666143.

Editorial acknowledgement

This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Gemma Walker, BSc, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd.

Legal entity responsible for the study

BeiGene.

Funding

BeiGene.

Disclosure

Y. Wu: Non-Financial Interests, Personal, Advisory Role: AstraZeneca; Non-Financial Interests, Personal and Institutional, Coordinating PI: AstraZeneca, Roche, Merck; Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hengrui, MSD, Pfizer, Roche; Non-Financial Interests, Personal, Leadership Role: Chinese Thoracic Oncology Group (CTONG); Non-Financial Interests, Personal, Local PI: BeiGene, Innoven; Non-Financial Interests, Personal, Member: ASCO, ESMO, IASLC, CSCO; Financial Interests, Institutional, Research Grant: BMS, Pfizer. J.C. Goh: Non-Financial Interests, Institutional, Invited Speaker: Brisbane Cancer Conference; Financial Interests, Personal, Invited Speaker: GSK, MSD; Financial Interests, Personal, Speaker’s Bureau: MSD, GSK, Ipsen, Janssen, Eisai, AstraZeneca; Financial Interests, Personal, Advisory Board: Janssen, GSK, BMS, MSD, AstraZeneca; Financial Interests, Personal and Institutional, Full or part-time Employment, Part-time employment: Royal Brisbane & Women’s Hospital; Financial Interests, Personal and Institutional, Full or part-time Employment: ICON Chermside & Greenslopes; Financial Interests, Personal, Stocks/Shares: ICON Cancer Centres, Immutep; Non-Financial Interests, Personal and Institutional, Project Lead, Ceased; Collaborative Group: ITTACc trial; Non-Financial Interests, Institutional, Principal Investigator: MSD, BMS, Janssen, AstraZeneca, BeiGene, Sutro Biopharma, Exelixis, Pfizer, Alloplex, Alkermes, Mersana; Non-Financial Interests, Personal and Institutional, Member, Corporative trials group in ANZ, USA & Europe: ASCO, ANZGOG, ANZUP, ESMO; Non-Financial Interests, Institutional, Leadership Role: Member of ICON Cancer Centre MAC (Medical Advisory Committee). J. Zhao: Non-Financial Interests, Institutional, Coordinating PI: AstraZeneca; Non-Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Merck, BeiGene, Pfizer; Non-Financial Interests, Personal, Local PI: Merck, Roche; Non-Financial Interests, Personal, Steering Committee Member: Pfizer, Pierre Fabre, BeiGene. Q. Zhou: Financial Interests, Personal, Speaker, Consultant, Advisor: Lecture and presentations fees to myself from AstraZeneca; Non-Financial Interests, Personal, Speaker, Consultant, Advisor: Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, Sanofi outside the submitted work. M. Millward: Financial Interests, Personal, Advisory Board: BeiGene Australia Pty Ltd, Bristol Myers Squibb Australia Pty Ltd, AstraZeneca Australia Pty Ltd, The Limbic, Eli Lilly Australia Pty Ltd, IQVIA Australia Pty Ltd, Amgen Australia Pty Ltd, Merck Pte Ltd, Pfizer Australia Pty Ltd, Guardant Health, Roche Products Pty Ltd; Financial Interests, Personal, Full or part-time Employment, Employee: University of Western Australia; Financial Interests, Personal, Other, Consultant: Linear Clinical Research; Financial Interests, Institutional, Local PI, Trial payments to Institution: Bristol Myers Squibb, Genentech/Roche, BeiGene, Eli Lilly, Albion Laboratories, Akeso Biopharma, AbbVie, Five Prime Therapeutics, Dizal Pharma, Maxinovel, Amgen, Atridia, INXMED, Alpine Immune Sciences, Turning Point Therapeutics, IMPACT Therapeutics, Kinnate Biopharma, Rely Therapeutics, GenFleet Therapeutics, Vivace Therapeutics, Eucure Biopahrma, InventisBio, Cullinan Oncology, Tyra Biosciences, Axelia Oncology; Non-Financial Interests, Personal, Other, Scientific Advisory Committee member: Thoracic Oncology Group Australasia. T. Tian: Other, Institutional, Full or part-time Employment: GSDS, BeiGene USA, Inc. 1840 Gateway Drive, 3rd Floor, San Mateo, CA 94404; Financial Interests, Institutional, Stocks/Shares: GSDS, BeiGene USA, Inc. 1840 Gateway Drive, 3rd Floor, San Mateo, CA 94404. J. Guo: Financial Interests, Institutional, Speaker, Consultant, Advisor: Merck Sharp & Dohme, Roche, Bayer, Novartis, Simcere Pharmaceutical Group, Shanghai Junshi Biosciences, Oriengene. All other authors have declared no conflicts of interest.

Background

Immune related adverse events (IrAEs) are a growing challenge in oncology affecting an increasing number of patients and putting a large strain on patient health and hospital resources. The current availability of biomarkers is highly dependent on the affected organ and the management strategy based on consensus or experiences with non-CPI induced autoimmune disease. In this study, we apply proteome analysis of extracellular vesicles from plasma to assess and discover biomarkers with the potential to aid clinical staging and care of patients suffering from IrAEs.

Methods

Thirty-six patients with grade 3-4 IrAEs (colitis, hepatitis or nephritis) were included in the study. Blood samples were collected at hospital admittance before or early in management (At tox), after initiation of high dose immunosuppressive therapy (At management) and after management (After tox). The collected plasma samples were enriched for extracellular vesicles using a novel workflow and analyzed using liquid-chromatography tandem mass spectrometry (LC-MS/MS). The data analysis was performed in R using the Limma package.

Results

The sample workflow allowed median quantification of 2015 proteins in the plasma samples. In patients responding to prednisolone, we found significant decreases in CRP, SAA1 and SAA2 and a significant increase in MMP9 At management compared to At tox. CRP, SAA1 and SAA2 together with EPS8 and CFP was also significantly lowered After tox. By comparing the IrAE subtypes, definite proteins associated to specific toxicities could be identified including ALDOB, ASL and DXCR in hepatitis, SLC47A2 and PRPF40A in colitis and NCAPH in nephritis.

Conclusions

Biomarkers for monitoring IrAE management are needed to improve the clinical care of patients. Our study identifies several proteins that correlate to specific types of IrAEs and to response to toxicity management, thus, constituting relevant IrAE biomarker candidates.

Clinical trial identification

Regional Ethical Commitee reference number: H-21027448.

Legal entity responsible for the study

Capital Region of Denmark.

Funding

Novo Nordisk Foundation.

Disclosure

All authors have declared no conflicts of interest.

Background

Checkpoint inhibitors have revolutionized treatment outcomes of several types of cancer. However, their administration is associated with unpredictable immune-related adverse events (irAEs). The objective of this study is to assess the potential predictive value of immune cells in peripheral blood for anticipating irAEs.

Methods

We prospectively enrolled patients with metastatic cancer treated with PD-1 inhibitors (nivolumab or pembrolizumab). Patients were recruited between 2017 and 2021 at the Masaryk Memorial Cancer Institute (Czech Republic). Before starting immunotherapy we performed immunoprofiling of key regulators and effectors of the immune system from peripheral blood cells using flow cytometry. We compared differences between patients who did not develop any or only mild grade (G) 1 irAE and patients who experienced clinically relevant irAE, specifically G2 and higher.

Results

We consecutively enrolled 63 patients. The median age was 66 years, with 19 (30.2 %) being female. Histological tumor types included 31 patients with melanoma, 22 with non-small cell lung cancer, 8 with renal carcinoma, and 5 with other malignancies. The majority of patients initiated treatment as first-line therapy (35 patients, 53 %). Out of these patients, 39 (61.9%) did not experience any irAEs, while 14 patients had G1 toxicity (22.2%), 10 patients (15.9%) had G2 toxicity, and 1 patient (1.6%) had G3 toxicity. G4 or G5 toxicity was not observed. Using the Mann-Whitney test, we determined that patients who did not experience any or mild (G1) immunologically mediated toxicity during treatment had significantly lower level of T helper lymphocytes CD4+ in peripheral blood before the initiation of treatment (P=0.034) compared to patients who experienced G2 or G3 toxicity during treatment. Additionally, they had lower level of naive T lymphocytes CD4+RO-CD27+ (P=0.012), lower level myeloid dendritic cells CD4-HLADR+ (P=0.040), and higher level of memory lymphocytes CD4+RO+CD27+ (P=0.006).

Conclusions

Our results support the hypothesis that initial flow cytometry parameters detectable in peripheral blood could significantly predict irAE. These findings need to be validated in a larger patient population.

Legal entity responsible for the study

The authors.

Funding

Ministry of Health of the Czech Republic, grant nr. NV18-03-00339.

Disclosure

All authors have declared no conflicts of interest.

Background

Immune checkpoint inhibitors (ICIs) combined with chemotherapy has become the first-line treatment option for non-small cell lung cancer (NSCLC) patients without driver mutation genes. However, a large amount of clinical data has confirmed that only part of NSCLC patients can achieve durable clinical benefits, while the incidence of adverse reactions is high. So, there is still an urgent need for reliable biomarkers to construct models for accurate prediction and assessment of treatment outcomes. Recently, ctDNA and tumor mutation burden (TMB) have been proposed as biomarkers for predicting the outcome of immunotherapy, but no consensus has been reached on the cutoff value of TMB, ctDNA clearance threshold and optimal sampling time point. Therefore, this study aims to develop a prediction model for the efficacy of chemo-immunotherapy based on the clinical multiparameter data, and explore the ctDNA change threshold and the optimal time of collection with superior predictive value.

Trial design

This study was a single-center, real-world study to collect an estimated 56 patients from the Department of Respiratory and Critical Care Medicine, Southeast University Zhongda Hospital, who were diagnosed with inoperable stage IIIB to IV NSCLC and treated with standard chemo-immunotherapy from August 2022 to January 2024. Blood samples at baseline, within 2 days before medication in the 2nd and 3rd treatment cycles, and the time of progression were collected respectively for genetic testing. At the same time, clinical data such as blood counts, blood biochemical indexes, lymphocyte subpopulations, etc. were recorded, and patients were subsequently followed up to record anti-tumor efficacy such as objective responds rate (ORR), progression-free survival (PFS), overall survival (OS), and the occurrence of adverse events. Patients were categorized into durable clinical benefit group (DCB group) and non-durable benefit group (NDB group) according to whether the PFS was more than 8 months, and the predictive model was proposed to be constructed using the support vector mechanism.

Clinical trial identification

NCT05725915.

Legal entity responsible for the study

The authors.

Funding

Beijing Red Clove Public Welfare Development Center.

Disclosure

All authors have declared no conflicts of interest.

Background

M is a rare cancer with limited terapeutic options. Immunotherpy has shown hints of activity and, despite combination of immunotherapic agents is the new standard of care for non epithelioid tumors, further study are requested to improve therapeutic strategies. DCvax has shown activity in M with a good safety profile. Our data showed that DCvax induces the expression of PD-L1 on tumor cells. The addition of DC to P may sensitize patients to the effects of PD-1 blockade.

Methods

MESOVAX is a Ph1b study evaluating safety of P 200 mg Q3W and an autologous DCvax administered subcutaneously Q3W for a maximum of 6 cycles, in pretreated metastatic M patients (pts). Primary endpoint was safety; secondary were PD-L1 expression variations defined by immunohistochemistry (IHC) and efficacy (objective response rate [ORR], duration of response [DOR], progression-free survival [PFS], overall survival [OS]).

Results

As of 30 Aug 2023, 6 pts (median follow-up 20.1 mo) were treated and evaluable for safety pre-planned interim analysis. Median age was 64 yrs, all pts were male, 17%/83% were ECOG PS 0/1. All pts had epithelioid M. Any grade treatment-related adverse events (TRAEs) occurred in 5 pts (83%); most common were local reaction to injection site (4 pts, 67%), asthenia (2 pts, 33%) and fever (2 pts, 33%). None of the patients experienced grade 3–4 TRAEs. Concerning the treatment, 4 pts (67%) received 6 cycles of P+DC; 3 received maintenance P. In a preliminary analysis of tumor response, at the first planned evaluation (median treatment duration 2.1 mo),2 had SD, 1 had PR and 3 had PD. PD-L1 expression at baseline and at week 12 is summarized on Table. Table: 51P

PD-L1 expression defined by IHC at screening and at week 12

Conclusions

Preliminary results of MESOVAX trial of P combined with DC showed a manageable toxicity and demonstrated encouraging preliminary efficacy. The trial is actively recruiting.

Clinical trial identification

EudraCT 2018-000500-42.

Legal entity responsible for the study

The authors.

Funding

Merck MSD.

Disclosure

F. De Rosa: Financial Interests, Personal, Speaker, Consultant, Advisor: MSD, Pierre Fabre, Novartis, Sun Pharma. All other authors have declared no conflicts of interest.

Background

Lung cancer's multiple resistance to tyrosine kinase inhibitors is inexorable and often unexplained in many NSLCs with EGFR mutations or other oncogenes and epigenetic changes. This suggests the need for new treatment strategies.

Methods

We generated second-generation CD28-costimulated EGFR-specific CAR constructs using lentiviral vectors to modify NK92 cells. We evaluated the utility of NK92 cells expressing a CAR-EGFR against TKI-resistant lung cancer cells at a low effector-to-target ratio to allow possible escape or evolution of select lung cancer cells. EGFR expression was analyzed by flow cytometry.

Results

We evaluated the utility of NK92 cells expressing a CAR-EGFR against TKI-resistant lung cancer cells. Our approach used a low effector-to-target ratio to allow possible escape or evolution of select lung cancer cells. We found that Gefitinib-resistant lung cancer cells HCC827GR6 and TKI-sensitive HCC827 are equally attacked by NK92 cells. However, TKI-resistant HCC827GR6 were more sensitive to EGFR-CAR NK cell attacks than parental HCC827. Predictably, EGFR-CAR NK cell attacks led to reduced EGFR expression in HCC827 and growth without increasing resistance to naïve NK92 attacks. However, the EGFR-CAR NK cell attack caused an increase in EGFR expression in gefitinib-resistant HCC827GR6 cells with a slight reduction in growth. This paradoxical increased EGFR protein expression suggests a positive selection of mutant EGFR, reducing their chance of escaping new EGFR-CAR NK cell attacks. Indeed, in co-culture experiments of TKI-sensitive and TKI-resistant cells, the latter were more efficiently eliminated, suggesting the preferential killing of TKI-resistant lung cancer cells by EGFR-CAR NK.

Conclusions

Our data indicate that TKI-resistant lung cancer cells, which evolved to depend on the expression of a mutated EGFR, are targeted more efficiently by EGFR-CAR NK cells than TKI-sensitive cells.

Legal entity responsible for the study

Sumei Chen and Youssef Jounaidi.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Pancreatic cancer confers a dismal prognosis and better therapies are needed. Integrin αvβ6 is expressed in >90% of human pancreatic cancers with minimal expression in healthy tissues. αvβ6-targeted CAR T-cells are efficacious in heterotopic immunodeficient pancreatic models. However, these models do not recapitulate the profoundly immunosuppressive tumour microenvironment (TME) that is a hallmark of pancreatic cancer, and a barrier to effective therapy. This study aimed to create and evaluated αvβ6-targeted CAR T-cell therapies in an orthotopic, immunocompetent, metastatic model of PDAC.

Methods

We created a 2^nd generation murine CAR with the αvβ6-targeting A20FMDV2 peptide in a γ-retroviral backbone, and transduced splenocytes from C57BL/6 mice. Non-targeting (NT) CAR T-cells lacking the A20FMDV2 peptide were used as controls. In vitro cytotoxicity was evaluated with murine pancreatic cancer cells with minimal (TB32043) and ectopic expression of αvβ6 (TB32043mb6s2) using WST-1 viability assays, with T-cell activation measured by IFNγ assays. In vivo activity of the CAR T-cells were assessed in both immunocompetent C57BL/6 and immunodeficient NSG mice who had received orthotopic injections of TB32043mb6s2 cells, with cyclophosphamide preconditioning in C57BL/6 mice. The immune tumour microenvironment of TB32043mb6s2 tumours was evaluated using CyTOF.

Results

αvβ6-targeted murine CAR T-cells demonstrated dose-depending αvβ6-specific in vitro cytotoxicity and T-cell activation. αvβ6 CAR T-cells were tolerated in vivo in mice with metastatic pancreatic cancer, and led to improved survival in both immunocompetent mice (31 vs 21 days, p<0.05 vs NT CAR T-cells) and immunodeficient mice (39 vs 27 days, p<0.05). CyTOF evaluation of αvβ6-expressing TB32043mb6s2 tumours found the TME comprised ∼90% of the tumour, with immune cells comprising ∼ half of the TME.

Conclusions

Integrin-αvβ6 targeted CAR T-cell therapy was tolerated and improved survival in mice with an orthotopic immunocompetent model of pancreatic cancer. Further pre-clinical development is warranted.

Legal entity responsible for the study

Queen Mary University of London.

Funding

Pancreatic Cancer UK, Cancer Research UK, Medical Research Council.

Disclosure

All authors have declared no conflicts of interest.

Background

In recent years, immunotherapy has attracted much attention in the treatment of kidney cancer. Immune checkpoints, especially PD-L1, play an important role in the treatment of kidney cancer. Therefore, the treatment of immune-infiltration and immunosuppression through immune checkpoints has become an important direction in treating renal cancer.

Methods

Several high DPP9 expression and low DPP9 expression tumor tissues were selected for single-cell sequencing. Results told us that DPP9 regulates T-cell infiltrating and transcription of PD-L1. We used co-IP assay to discover the interaction between DPP9 and SHMT2-BRISC. Then we established the overexpression/knockout DPP9 renal cell lines to detect the upstream signal pathway of PD-L1, co-cultured with PBMC cells to observe the influence of immune escape. Meanwhile, we used organoids to confirm the above experiments. Finally, we used DPP9 inhibitor and PD-L1 monoclonal antibody in animal experiments.

Results

Single-cell sequencing showed that T-cell exhaustion signal was significantly up-regulated in the group with high DPP9 expression. IHC staining of DPP9, PD-L1, CD3, PD-1 in kidney cancer section was verified. Overexpression/knocked out of DPP9 in kidney cancer cells such as 786-O, 769P, caki-1 showed that DPP9 could regulate the transcription and translation of PD-L1. Then co-IP showed that DPP9 interacted with SHMT2, BRE, FAM175B proteins in the BRISC complex. The binding level of DPP9 and SHMT2-BRISC complex in the presence or absence of IFN-γ was detected, and dynamic binding was sought to determine whether more FAM175B and SHMT2 were involved in the formation of complex in the presence of DPP9, thus regulating the transcription of PD-L1 in the condition of IFN-γ. PD-L1 monoclonal antibody can inhibit the immune escape of renal cancer induced by DPP9, and the effect is better when combined with DPP9 inhibitors.

Conclusions

DPP9 can up-regulate the expression of PD-L1 in renal cancer cells through dynamically adjusting the stability of the BRISC complex via SHMT2. We provide the clinical principle and mechanism of DPP9 inhibitor combined with PD-L1 monoclonal antibody, and further determine the patient population suitable for immunotherapy.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

FOXM1D functions through interactions with proteins. We found that FOXM1D decreased in peripheral blood immune cells of renal cancer patients. It is speculated that FOXM1D is likely to regulate the expression level of immune checkpoint in immune cells through the way of interprotein interaction, and regulating the transcription of PD-1.

Methods

We detected the FD level in PBMC and CD3-positive T cells in clinical samples. PD-1 expression was detected. We performed mass spectrometry and found that HCFC1 function as a cotranscription factor. We examined the effect of FOXM1D on the HCFC1 protein. We detected the HCFC1 in cell lines with overexpression and knockdown of FOXM1D by karyoplasmic isolation. YY1 is predicted to be a transcription factor of PD-1, ChIP and Luciferase experiments to detect the binding sites to the PD-1 promoter. JKT co-culture tests with renal cancer cells in supernatant cytokine levels, observe the killer T cells. Finally, we proceed animal testing.

Results

The FD level in PBMC of renal cancer patients was significantly lower than that of normal people. The change of FOXM1D in CD3+T cells was the same as PBMC. The transcription level of PD-1 and the level of PD-1 on the surface of Jurkat-FOXM1D in cells overexpressing FOXM1D was significantly down-regulated. HCFC1 was found to function as a cotranscription factor. In immune cells, FOXM1D inhibits the entry of HCFC1 into the nucleus by interacting with the N-terminal of HCFC1, weakens the transcriptional activation of HCFC1 to YY1, and then inhibits the transcriptional regulation of PD-1 molecules. After co-culture with T cells, the cytokine in supernatant of 786O and 769P cells was changed. And the animal experiment was in progress.

Conclusions

HCFC1, as a co-transcription factor, can enhance its transcriptional function by interacting with YY1, and further regulate the transcription of immune checkpoint molecules PD-1. FOXM1D inhibits the nuclear entry of HCFC1 by interacting with the N-terminus of HCFC1, attenuates the transcriptional activation of YY1 by HCFC1, and then inhibits the transcription of various immune checkpoint molecules such as PD-1.

Legal entity responsible for the study

Fudan University Shanghai Cancer Center.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Adoptive cellular therapy (ACT) with TIL recently showed promising results in a multicenter phase 3 trial evaluating TIL in MM patients (NCT02278887). In this, 39 (49 %) of TIL-treated patients obtained a complete or partial response according to RECIST 1.1. The potential impact of the location of the resected metastasis for TIL production on the phenotype of the final TIL infusion product is essential knowledge for future development of TIL therapy.

Methods

Cryopreserved samples of TIL infusion product from all patients with unresectable stage IIIC-IV MM treated in the phase 3 trial were analyzed using multiparametric flow cytometry. Here, we investigated if the anatomical location of the metastasis used for TIL production impacted the composition of the final TIL infusion product. The Kruskal-Wallis test was used to test for statistical significance.

Results

In total, 80 patients were treated with TIL. Respectively, 37 (46.3 %), 29 (36.3 %), and 14 (17.5 %) underwent resection of a lymph node, (sub)cutaneous or a visceral metastasis for TIL production. Visceral metastases included lung (n=8), liver (n=2), spleen (n=1), small intestine (n=1), adrenal gland (n=1), and peritoneum (n=1). The location of the metastasis used for TIL production did not impact clinical response (p=0.84) or the composition of the final TIL infusion product, with no difference in the total number of TIL produced in major subsets including CD45+ CD3+ (p=0.42), CD8+ TCRab+ (p=0.37), CD4+ TCRab+ (p=0.09) or CD3+ TCRgd+ (p=0.36). For both CD4+ and CD8+ TIL, differentiation into naïve (CCR7+ CD45RO-), effector memory (CCR7- CD45RO+), central memory (CCR7+ CD45RO+), and terminally differentiated effector memory cells (CCR7- CD45RO-) was also not affected by the site of metastasectomy.

Conclusions

The anatomical location of the metastasis used for TIL production did not impact clinical response, the absolute number of TIL produced, or the overall phenotypic composition of the final TIL infusion product. Thus, easily accessible MM lesions can be preferred without the risk of impacting TIL phenotype or clinical outcome.

Clinical trial identification

NCT02278887, EudraCT 2013-005406-54.

Legal entity responsible for the study

National Center for Cancer Immune Therapy (CCIT-DK), Herlev Hospital (Denmark) and the Netherlands Cancer Institute (NKI), Amsterdam (the Netherlands).

Funding

This study was supported by the Dutch Cancer Society, the Netherlands Organization for Health Research and Development, the Dutch Ministry of Health, Stichting Avento, AVLFoundation, Copenhagen University Hospital, Herlev, the Danish Cancer Society and Capital Region of Denmark Research Foundation.

Disclosure

T.H. Borch: Other, Personal, Other, Speaker's honoraria: Bristol Myers Squibb. W. Van Houdt: Financial Interests, Institutional, Invited Speaker: Amgen; Financial Interests, Institutional, Advisory Board: Belpharma, Sanofi, MSD; Financial Interests, Personal, Other, travel grant: Novartis; Financial Interests, Institutional, Local PI: BMS. M. Donia: Financial Interests, Personal, Other, Advisor: Achilles Therapeutics; Non-Financial Interests, Personal, Other, Sub-investigator of clinical trial with connected translational research: Bristol Myers Squibb; Non-Financial Interests, Personal, Proprietary Information, Proprietary data access: Bristol Myers Squibb; Non-Financial Interests, Personal, Proprietary Information, Proprietary Data Access: Genentech; Other, Personal, Other, Chairman of the Melanoma and Non-melanoma Skin Cancer Scientific Committee: Danish Medicines Council (Medicinrådet). J.B.A.G. Haanen: Financial Interests, Institutional, Advisory Board: Bristol Myers Squipp, Achilles Therapeutics, Ipsen, Merck Sharpe & Dohme, Merck Serono, Pfizer, Molecular Partners, Novartis, Roche, Sanofi, Iovance Biotherapeutics, AstraZeneca; Financial Interests, Institutional, Advisory Board, SAB member: BioNTech, Immunocore, Gadeta, Instil Bio, PokeAcel, T-Knife; Financial Interests, Personal, Advisory Board, SAB member: Neogene Therapeutics, Scenic; Financial Interests, Personal, Advisory Board: Third Rock Venture, CureVac, Imcyse; Financial Interests, Personal, Stocks/Shares: Neogene Therapeutics; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, BioNTech US, Merck Sharpe & Dohme, Amgen, Novartis, Asher Bio, Sastra Cell Therapy; Non-Financial Interests, Personal, Member: ASCO, AACR, SITC; Other, Personal, Other, Editor-in-Chief IOTECH: ESMO; Other, Personal, Other, Editorial Board ESMO Open: ESMO; Other, Personal, Other, Editorial Board: Kidney Cancer. I. Svane: Financial Interests, Personal, Advisory Board: BMS, Pierre Fabre, Novartis; Financial Interests, Personal, Invited Speaker: MSD, Pierre Fabre, Novartis, Roche, BMS; Financial Interests, Institutional, Research Grant: Enara Bio, Adaptimmune, Lytix Biopharma, TILT Biotherapeutics; Financial Interests, Personal, Writing Engagement: MSD; Financial Interests, Personal, Stocks/Shares, Cofounder and Founder warrents: IO Biotech; Financial Interests, Institutional, Funding: Evaxion; Non-Financial Interests, Personal, Principal Investigator: BMS, Novartis, Roche, TILT Biotherapeutics, Lytix Biopharma. All other authors have declared no conflicts of interest.

Background

T-cell receptor-engineered T cells (TCR-Ts) have achieved encouraging success in anticancer clinical trials. The antigenic targets, however, were primarily focused on a few cancer/testis antigens (CTAs) which are not widely expressed in common solid cancers; the tested T-cell receptors (TCRs) were frequently from tumor-infiltrating lymphocytes of old patients and were not assured to have higher avidity. Here, we propose the isolation of high-avidity TCRs against CTAs that are frequently expressed in common solid cancers.

Methods

CT83 protein, which is frequently expressed in common solid cancers, was as a model antigen for screening of its specific TCR. The predicted CT83 epitopes with binding to HLA-I molecules, popular in the Chinese population, were integrated into three synthetic long peptides. CT83 reactive CD8+ T cells were stimulated with peptide-loaded dendritic cells (DCs) and sorted using the CD137 biomarker for single-cell sequencing to obtain the paired TCRαβ sequence.

Results

CT83 reactive T cells from young healthy donors (YHDs) were generated by repeated stimulation with DCs and peptides. The single-cell TCR sequencing results of reactive T cells indicated that a single TCR clonotype dominated the paired TCRs. T cells engineered with this dominant TCR led to HLA-A*11:01-restricted recognition of the CT83_14-22 epitope, with higher avidity. Functional assays showed powerful cytotoxicity in vitro against the targets of several CT83-positive solid cancer cell lines. Furthermore, TCR-Ts showed therapeutic efficacy in three xenograft solid tumor models. The meta-analysis of gene expression of 92 CTAs indicated that most CTAs did not or at low levels in the thymus, which suggested that those CTAs may experience incomplete thymic central tolerance.

Conclusions

High-avidity TCR against CT83 could be isolated from YHDs and efficiently mediate regression of well-established xenograft common solid tumors. The high-avidity TCR repertoire in the peripheral blood of some donors for CT83 and other CTAs provides the basis for the efficient isolation of high-avidity TCRs to target numerous solid cancers.

Legal entity responsible for the study

The author.

Funding

National Key Research & Development Projects of China.

Disclosure

The author has declared no conflicts of interest.

Background

Cell therapy has emerged as a promising approach in cancer treatment, leveraging the potential of the patient's immune system to fight tumors. However, the assessment of the efficacy and safety of these therapies remains a significant challenge, since the current available approaches (i.e. 2D cell cultures and animals) have strong limitations in terms of predictability, reliability, and ability to fully mimic the human immune system. This study presents a groundbreaking technological approach in cell therapy testing by integrating 3D patient-derived cancer models with circulating immune cells co-cultured onto an Organ-on-Chip (OoC) platform.

Methods

Biologically relevant cancer samples have been optimized by using an alginate-based structure closely resembling the tumor extracellular matrix. Different cancer cell lines (i.e. MDA-MB-231, SKOV-3, HTLA-230) have been embedded in the matrix and cultured up to 2 months under fluid-dynamic conditions with a OOC chamber, simulating the bloodstream. Alternatively, patient derived tumor biopsies have been coated by a thin layer of alginate, to enhance their structural stability over time, and cultured ex vivo in the same OOC. At the same time, peripheral blood mononuclear cells have been injected in the circulatory OOC circuit and their extravasation and tumor infiltration analysed.

Results

While tumor cells are able to maintain a good viability, cytoskeleton reorganization and migration within the polymeric matrix up to 2 months of culture, patient derived biopsies displayed a challenging survival ex vivo, although the presence of the fluid flow was able to improve the tumor cells survival. The immune checkpoint ligands PD-L1 and PD-L2 were successfully upregulated by the presence of the IFN-gamma and 3% of PBMC derived natural killer cells were able to leave the circulatory flow, and infiltrate the tumor matrix where they induce apoptosis.

Conclusions

A novel fully humanized OOC based platform has been developed to co-culture clinically relevant human cancer model, while immune cells are in circulation, with the final aim to deepen insights into the crosstalk among immune /tumor cells and test cellular therapies in a reproducible and reliable way.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

S. Scaglione, M. Aiello: Financial Interests, Personal, Member of Board of Directors: React4life. All other authors have declared no conflicts of interest.

Background

Natural killer (NK) cells are promising tools for immunotherapy of different malignancies including childhood leukaemia and are shown to exhibit memory-like features. Epigenetic alterations including DNA methylation contribute to the generation of memory in these cells. Studying the DNA methylation profile of activated NK cells helps identify candidate genes of activation biomarkers and new approaches to enhance NK cytotoxicity by targeting intrinsic epigenetic regulators.

Methods

We investigated the DNA methylation profile in NK cells upon priming with activating cytokines. Basically, two types of peripheral blood NK cells were used in this study: Freshly antibody-bead isolated NK cells and expanded NK cells, generated by a 7-day coculture with irradiated K562 cells expressing membrane bound IL-21. Memory-like features were achieved by 16-h stimulation of NK cells with IL-12, IL-15, and IL-18, as previously published. The activation of NK cells was confirmed by higher production of Interferon-γ in preactivated cells. DNA was extracted from the FACS sorted NK cells, based on NK cells markers, in both experimental groups and were analysed by Illumina methylation bead array.

Results

Downstream bioinformatic analyses revealed differential methylation patterns with hypomethylated CpG sites predominantly in preactivated NK cells and in expanded NK cells, independent of cytokine pre-activation.

Conclusions

Our data suggest that the in vitro expansion of NK cells in coculture with K562 cells at least partially recapitulates the memory formation by cytokine-preactivation due to the encounter with K562 cell surface targets prior to being stimulated with cytokines resulting in DNA hypomethylation at a variety of loci in some genes encoding immune system ligands, receptors and regulators such as IL-5, C-C Motif Chemokine Receptor 5 (CCR5) and Programmed Cell Death Ligand 1 (PDL1). Targeted therapy of JAK-class Ph-like ALL with ruxolitinib might interfere with interleukin-signaling pathways in NK cells disrupting memory-formation and cytotoxic activities as shown by live cell imaging and multiparametric full spectrum flow cytometry.

Legal entity responsible for the study

The authors.

Funding

Research institute Children’s Cancer Center and Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Disclosure

All authors have declared no conflicts of interest.

Background

Natural killer (NK) cells may be particularly suited to cancer therapy. However, the heterogeneity of NK cell populations poses challenges in isolating highly functional subpopulations for therapeutic applications. This study presents a novel microfluidic platform that can select NK cells with enhanced avidity, aiming to improve the precision and efficacy of NK cell-based immunotherapies.

Methods

We used a microfluidics device that uses fluid shear stress to sort and isolate and sort NK cells based on their avidities to the target cells. Briefly, we sterilized our chip and coated it with fibronectin overnight and cultured lung cancer (A549) and ovarian cancer (SKOV3) cells for 24 hours until they achieved a monolayer. We then introduced NK cells on top of the monolayer and left these two types of cells to interact under static condition for 10 minutes. Using syringe pump, we applied fluid flow to induce shear ranging from 0.5Pa to 19.8 Pa in order to isolate the NK cells after each flow. To explore if avidity correlated with cytotoxicity, we cultured monolayer of A549 on our chip then introduced two types of NK cells: treated NK cells (adNK) and NK cells isolated from peripheral blood (cbNK). We followed the same protocol as described above to determine the NK cell type with high avidity.

Results

Our results show that at least 4.5 % and 4% cbNK cells remained attached to SKOV3 cells and A549 respectively after exposure to shear as high as 19.8 Pa. This avidity profile was different for adNK cells on A549. 30% of and NK cells remained attached to A549 cells after 19.8 Pa shear. This result also matched the cytotoxicity profile of adNK cells compared to that of cbNk cells for A549 cells.

Conclusions

In this study we used a novel method to sort and isolate NK cells based on their avidity to its target cancer cells. Although this device has been used to isolate and sort T cell population before, to our knowledge, for the first time we showed that NK cells can be isolated using their avidity to target cells. In addition, the higher avidity adNk cell aligned with its high cytotoxicity suggesting that selecting NK cells based on avidity may lead to selection of potent NK cells.

Legal entity responsible for the study

Imperial College London.

Funding

Imperial College London, Department of Bioengineering Imperial College London, Department of Life Sciences.

Disclosure

The author has declared no conflicts of interest.

Background

The clinical usefulness of tumor-infiltrating lymphocyte (TIL) has been limited due to an intensive lymphodepletion regimen and high-dose intravenous interleukin-2 (IL-2) administration. We explore the low dose regimens of lymphodepletion and infusion without IL-2 administration in TIL therapy, which showed encouraging outcome in a case report. Thus, a phase I study to evaluate the safety and efficacy of optimized TIL-therapy regimen for the treatment of advanced solid tumors was conducted.

Trial design

The phase 1a part used a conventional 3+3 dose-escalation design. The primary endpoint in the phase 1a part was the frequency of dose-limiting toxicities (DLTs). Patients received three consecutive daily infusions of cyclophosphamide (25 mg/kg/day) from day -5 to day -3, and oral administration of hydroxychloroquine (600 mg once) on day -5. On day 0, patients received a single intravenous adoptive transfer of TILs following the administration of anti-PD-1 antibody (100mg per patient, sintilimab). Adverse events (AEs) were assessed based on Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Clinical responses were assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Three patients were planned for DLT analysis at each dose level of TILs infusion: level 1 (5.0×10⁹± 20% cells), level 2 (1.5×10¹⁰± 20% cells), level 3 (3.0×10¹⁰± 20% cells), and level 4 (4.5×10¹⁰± 20% cells). As of September 15, 2023, ten participants (9/10 with PD-1 antibody resistance) have been enrolled and underwent TIL infusion. None DLT was observed and the clinical responses were observed across different dose levels, suggesting the modified regimen is safe and the recommended dose (RD) of TILs can be defined within a broad range. The phase 1b part would be started in soon future.

Clinical trial identification

NCT05417750.

Legal entity responsible for the study

Shanghai Juncell Therapeutics Co., Ltd.

Funding

Shanghai Juncell Therapeutics Co., Ltd.

Disclosure

H. Jin: Financial Interests, Institutional, Funding: Shanghai Juncell Therapeutics Co., LTD. All other authors have declared no conflicts of interest.

Background

PD-(L)1 inhibitors ± chemotherapy (CT) have demonstrated survival benefit vs CT in mNSCLC RCTs. However, STK11mut and KEAP1mut tumours have been characterised as immunologically ‘cold’ and are frequently associated with a concomitant KRASmut. One aim of CORRELATE was to describe rw outcomes of pts with mNSCLC and STK11, KEAP1 and/or KRAS mut receiving tx with anti-PD-(L)1 ± CT.

Methods

This analysis included pts from the US Flatiron Clinico-Genomic Database who started 1L anti-PD-(L)1 tx for mNSCLC between 1 Nov 2016 and 31 May 2021, and met eligibility criteria based on 4 RCTs for US-approved tx (KEYNOTE [KN]-024, n=94; KN-189, n=462; KN-407, n=122; IMpower150, n=4). OS and rwPFS were estimated in subgroups based on STK11, KEAP1 and KRAS mut status by Kaplan-Meier analysis. Unadjusted HRs were calculated by univariate Cox regression and adjusted HRs by multivariable Cox regression.

Results

Of 682 pts, 44% had ≥1 mut of interest. Among pts with ≥1 mut, there were more smokers, pts with ECOG PS 2 or ≥3, and pts with non-squamous tumours vs pts with no mut (each nominal p<0.05). There was a trend towards increased risk of death in pts with 1 mut vs no mut; pts with co-mut (≥2 mut) had almost 2x increased risk of death vs no mut, both with and without adjustment for pt characteristics (Table). Pts with STK11mut and pts with KRASmut (± co-mut) had a 46% and 28% increased risk of death vs STK11wt and KRASwt, respectively, after adjustment (Table). After adjusting for potential confounders, the 26% increased risk of death among pts with KEAP1mut vs KEAP1wt was not statistically significant. Trends were similar for rwPFS. Table: 68P

Conclusions

In US pts with mNSCLC receiving 1L anti-PD-(L)1 ± CT, those with mut in STK11, KEAP1, KRAS, and particularly co-mut, had worse OS and rwPFS. These results highlight the need for novel combination tx approaches in these pts that might further boost immune responses (e.g., incorporating anti-CTLA-4) and optimise outcomes.

Editorial acknowledgement

Medical writing support for the development of this abstract, under the direction of the authors, was provided by Samantha Holmes, DPhil, of Ashfield MedComms (Macclesfield, UK), an Inizio company.

Legal entity responsible for the study

AstraZeneca PLC.

Funding

AstraZeneca.

Disclosure

S. Peters: Financial Interests, Institutional, Invited Speaker: AiCME, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, ecancer, Eli Lilly, Foundation Medicine, GSK, Illumina, Imedex, Ipsen, Medscape, Merck Sharp and Dohme, Mirati, Novartis, PER, Peerview, Pfizer, Roche/Genentech, RTP, Sanofi, Takeda; Financial Interests, Institutional, Advisory Board, Consultation/Advisory role: AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, BerGenBio, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack; Financial Interests, Institutional, Member of Board of Directors: Galenica; Financial Interests, Institutional, Principal Investigator: Amgen, Arcus, AstraZeneca, BeiGene, Bristol Myers Squibb, GSK, iTeos, Merck Sharp and Dohme, Mirati, Pharma Mar, Promontory Therapeutics, Roche/Genentech, Seattle Genetics; Non-Financial Interests, Personal, Member: ESMO, ASCO, AACR, IASLC, SSOM, SAKK, ETOP; Non-Financial Interests, Personal, Advisory Role: Cf. advisory boards; Non-Financial Interests, Personal, Leadership Role: Vice President Swiss Cancer League, past President ESMO, Strategic Advisory board SPCC (Paris Saclay) Chair, ETOP Scientific Chair; Financial Interests, Institutional, Advisory Board: Foundation Medicine, Genzyme, Gilead, GSK, Hutchmed, Illumina, Imedex, IQVIA, Incyte, Ipsen, iTeos, Janssen, Medscape, Medtoday, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Novocure, OncologyEducation, Pharma Mar, Promontory Therapeutics, PER, Peerview, Pfizer, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, Vaccibody. R.J. Salomonsen: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Non-Financial Interests, Personal, Project Lead: AstraZeneca. F. Skoulidis: Financial Interests, Personal, Invited Speaker: ESMO, Japanese Lung Cancer Society, Medscape Llc, Intellisphere Llc, VSPO McGill Universite de Montreal, RV Mais Promocao Events LTDS, MJH Life Sciences, IDEOlogy Health, MI&T, PER Llc, CURIO Llc, DAVA Oncology, American Association for Cancer Research, IASLC; Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen Inc, Revolution Medicines, Novartis, BridgeBio, BeiGene, BergenBio, Guardant Health, Tango Therapeutics, Calithera Bioscieces, Hookipa Pharma, Novocure, Merck & Co; Financial Interests, Personal, Stocks/Shares: BioNTech SE, Moderna Inc; Financial Interests, Institutional, Research Grant: Revolution Medicines, Mirati Therapeutics, Amgen Inc, Novartis, Merck & Co; Financial Interests, Personal, Principal Investigator: Amgen Inc, AstraZeneca, Revolution Medicines, Novartis, Merck & Co, Tango Therapeutics, Genentech/Roche; Financial Interests, Personal, Advisory Role: AstraZeneca. I. Diaz Perez: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. A. Wang: Financial Interests, Personal, Full or part-time Employment, Contracted to AstraZeneca: AstraZeneca. M. Cooper: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. S.V. Liu: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Catalyst, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Merck, Merus, Mirati, Novartis, Regeneron, Sanofi, Takeda, Turning Point Therapeutics; Financial Interests, Institutional, Research Grant: AbbVie, Alkermes, Elevation Oncology, Ellipses, Genentech, Gilead, Merck, Merus, Nuvalent, RAPT, Turning Point Therapeutics.

Background

NSCLC treatment has evolved after approval of the 1st immunotherapy agent (IO) in 2015. The real-world LIST study of nivolumab for advanced NSCLC aims to describe patient/treatment characteristics, effectiveness, safety and rechallenge outcomes.

Methods

LIST is an ongoing longitudinal, prospective, observational study in patients (pts) with advanced NSCLC receiving nivolumab after one prior chemotherapy-based treatment alone or in combination with IO. Patient cohorts were: Cohort 1, IO-naïve patients; Cohort 2, IO-experienced patients who discontinued for non-IO-toxicity reasons; Cohort 3, IO-experienced patients who discontinued due to IO-toxicity. Descriptive interim analyses (follow-up ≥6 months) are presented.

Results

428 pts were enrolled between Sept 2020 and May 2022 at 99 centres – 278, 128 and 22 pts in cohorts 1, 2 and 3. Baseline patient characteristics were representative of advanced NSCLC: median age 65–70 years, male sex >65%, current/former smoker 22–27%/65–73%, non-squamous histology 60–75%. 41%/ 71%/ 76% of pts in cohorts 1/2/3 had PD-L1 expression (≥1%). At 6 months, respective overall survival (OS) rates were 70.0% [95% confidence interval 64.2–75.1%]/ 61.1% [51.6–69.3%]/ 61.2% [37.1–78.4%] and progression-free survival (PFS) were 33.4% [27.6–39.2%]/ 25.1% [17.2–33.8%]/ 51.0% [28.1–70.0%]. Current/former smokers and pts with tumour PD-L1 expression seem to have improved outcomes (table). All adverse events (AEs) occurred in 86%/ 78%/ 73% of pts and treatment-related grade 3/4 AEs in 11%/ 5%/ 18%, in cohorts 1/ 2/ 3. Table: 70P

Interim survival data by cohort and smoking and PD-L1 status

Conclusions

LIST interim results show nivolumab for IO-naïve pts in clinical practice has similar activity and safety as in the registrational CheckMate 017/057 trials. It shows encouraging results of rechallenge with nivolumab in pts with previous IO discontinuation, including for IO-toxicity.

Clinical trial identification

NCT04500535.

Editorial acknowledgement

We thank Sheridan Henness who provided medical writing assistance prior to submission on behalf of Springer Healthcare Communications.

Legal entity responsible for the study

The authors.

Funding

Bristol Myers Squibb.

Disclosure

B. Godbert: Financial Interests, Personal, Speaker, Consultant, Advisor: Bristol Myers Squibb, AstraZeneca, Sanofi, MSD; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, AstraZeneca, MSD, Sanofi; Financial Interests, Personal, Expert Testimony: Bristol Myers Squibb, AstraZeneca, Sanofi, MSD. M. Zysman: Financial Interests, Institutional, Other: AVAD; Financial Interests, Personal, Speaker, Consultant, Advisor: CSL Behring, GSK, Boehringer Ingelheim, AstraZeneca, Chiesi, Sanofi; Financial Interests, Personal, Other: Chiesi, AstraZeneca, GSK. E. Gobbini: Financial Interests, Institutional, Other: BMS; Financial Interests, Personal, Other: AstraZeneca, Roche, Pfizer, Merck Sharpe and Dohm, Bristol Myers Squibb, Takeda, Janssen, Sanofi. C. Decroisette: Financial Interests, Personal, Speaker, Consultant, Advisor: MSD, BMS, Takeda, Pfizer, Sanofi, Janssen, AstraZeneca, Amgen; Financial Interests, Personal, Other: Amgen, Janssen, Roche, MSD. H. Lena: Financial Interests, Personal, Speaker, Consultant, Advisor: Roche AstraZeneca, MSD, Novartis, Takeda, BMS, Roche, MSD, Pfizer, Lilly, Amgen; Financial Interests, Personal, Other: BMS, Takeda, Pfizer. D. Moro-Sibilot: Financial Interests, Personal, Speaker, Consultant, Advisor: BMS, MSD, Roche, AstraZeneca; Financial Interests, Personal, Other: Roche, MSD; Financial Interests, Personal, Advisory Board: BMS, Roche, MSD; Financial Interests, Institutional, Other: BMS, Roche, MSD. F. Guisier: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, BMS, MSD, Roche, Sanofi, Janssen, Pfizer, Takeda; Financial Interests, Institutional, Research Grant: Pfizer, Roche, Takeda. S. Couraud: Other, Personal, Advisory Board: Adene; Financial Interests, Personal and Institutional, Advisory Board, Institution Funding: Amgen, BMS, MSD, Novartis, Pfizer, Sanofi; Financial Interests, Personal and Institutional, Advisory Board, Institution Funding, Research Funding: AstraZeneca; Financial Interests, Institutional, Research Funding: BD, Transdiag, Volition; Financial Interests, Institutional, Funding: Celgene, Chugai, Janssen, Laidet, Lilly, Roche, Takeda; Financial Interests, Personal, Speaker, Consultant, Advisor: Health EvenT; Financial Interests, Personal, Advisory Board: MaaT Pharma. A. Caraux: Financial Interests, Personal, Affiliate: Bristol Myers Squibb. D. Reynaud: Financial Interests, Personal Boehringer Ingelheim, Affiliate: Bristol Myers Squibb. F. Breliier: Financial Interests, Personal, Affiliate: Bristol Myers Squibb; Financial Interests, Personal, Stocks or ownership: Bristol Myers Squibb. N. Girard: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, MSD, Roche, Pfizer, Mirati, Amgen, Novartis, Sanofi, Gilead; Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, MSD, Roche, Pfizer, Janssen, Boehringer Ingelheim, Novartis, Sanofi, AbbVie, Amgen, Lilly, Grunenthal, Takeda, Owkin, Leo Pharma, Daiichi Sankyo, Ipsen; Financial Interests, Institutional, Research Grant, Local: Roche, Sivan, Janssen; Financial Interests, Institutional, Funding: BMS, Leo Pharma; Financial Interests, Institutional, Research Grant: MSD; Non-Financial Interests, Personal, Officer, International Thymic malignancy interest group, president: ITMIG; Other, Personal, Other, Family member is an employee: AstraZeneca. All other authors have declared no conflicts of interest.

Background

The PACIFIC trial established consolidation therapy with durvalumab as the standard of care for patients (pts) with unresectable stage III non-small cell lung cancer (NSCLC) without progression after chemoradiotherapy (CRT), however, additional studies are still needed to further explore the optimal therapeutic strategies. Here, we reported the preliminary results of the phase 2 study of camrelizumab (an anti-PD-1 antibody) plus apatinib (an anti-angiogenic inhibitor targeting VEGFR2) as consolidation therapy after CRT in unresectable stage III NSCLC.

Methods

This was a multi-center, single-arm, phase 2 study done at seven sites in China. Adult pts with pathologically confirmed unresectable stage III NSCLC, an ECOG PS of 0 or 1, and no disease progression following platinum-based concurrent or sequential CRT received camrelizumab (200 mg, i.v., q3w) and apatinib (250 mg, orally, qd) until disease progression, unacceptable toxicity or for up to 12 months. The primary endpoint was progression-free survival (PFS).

Results

Between March 17, 2021 to July 17, 2023, 42 pts were enrolled. The median age was 61 years (range 26-78), with 39 pts (92.9%) being male and 31 (73.8%) having squamous NSCLC. According to RECIST 1.1, three (7.1%) of the 42 pts had a complete response and eight (19.0%) had a partial response, with the confirmed objective response rate of 26.2% (95% CI 13.9-42.0). Twenty-three pts (54.8%) had stable disease, with the disease control rate of 81.0 % (95% CI 65.9-91.4). As of August 28, 2023, the median follow-up was 11.4 months (95% CI 5.8-15.6). The median PFS was not reached (NR; 95% CI 11.4-NR), with the 6- and 12-month PFS rates of 88.8% (95% CI 72.8-95.7) and 68.6% (95% CI 47.4-82.7), respectively. The median overall survival was immature, with six deaths at data cutoff. Treatment-related adverse events (TRAEs) of grade 3-4 occurred in 18 pts (42.8%), with the most common being hypertension (21.4%), AST increased (7.1%) and hand-foot syndrome (4.8%). No grade 5 TRAEs occurred.

Conclusions

Camrelizumab plus apatinib as consolidation therapy showed preliminary activity in unresectable stage III NSCLC pts without disease progression after CRT, with no new safety signals.

Clinical trial identification

NCT04749394; February 11, 2021.

Legal entity responsible for the study

Cancer Hospital Chinese Academy of Medical Sciences.

Funding

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.

Background

Pulmonary sarcomatoid carcinoma (PSC) is a rare, poorly differentiated, highly invasive subtype of non-small cell lung cancer (NSCLC), with extremely poor prognosis. Immunotherapy and targeted therapy have become the mainstay of management of advanced NSCLC, however, have been scarcely reported in PSC. Herein, we conducted a multi-center, single-arm, phase II study to assess the efficacy and safety of camrelizumab plus famitinib as first-line treatment in pts with locally advanced or metastatic PSC.

Methods

In this study, treatment-naïve pts with histologically confirmed stage IIIB-IV PSC received camrelizumab (200 mg, i.v., q3w) plus famitinib (20 mg, orally, qd) until disease progression or intolerable toxicity. Simon's two-stage design was adopted, and 15 pts were planned to be enrolled in the first stage, with 3 or more responses observed to progress to the second stage. The primary endpoint was objective response rate (ORR) as per RECIST 1.1. Here, we reported the first-stage results.

Results

From August 4, 2021 to April 24, 2023, 15 pts were enrolled, with a median age of 64 years (range 45-72) and all being male (100%). Of the 15 pts, seven (46.7%) achieved a partial response and six (40.0%) had stable disease, with the confirmed ORR of 46.7% (95% CI 21.3-73.4) and disease control rate of 86.7% (95% CI 59.5-98.3). As of August 16, 2023, the median follow-up was 10.0 months (IQR 3.9-14.5). The median duration of response was 7.1 months (95% CI 5.0-NR), median progression-free survival was 7.8 months (95% CI 1.6-NR), and median overall survival was 18.2 months (95% CI 18.0-NR). The median number of camrelizumab cycles was 7.0 (range 1-19). Treatment-related adverse events (TRAEs) of any grade occurred in 15 pts (100.0%), with seven (46.7%) developing grade ≥3 TRAEs. The most common TRAEs were proteinuria (53.3%), hypertension, neutrophil count decreased, and platelet count decreased (46.7% each). Two pts had grade 5 AEs (unknown cause).

Conclusions

Camrelizumab plus famitinib as first-line therapy for PSC showed promising activity and acceptable safety during the first stage of this study. Enrollment for the second stage is ongoing.

Clinical trial identification

NCT04888429; May 17, 2021.

Legal entity responsible for the study

Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Surufatinib (S, a small-molecule inhibitor of VEGFR1-3, FGFR1 and CSF-1R) has exhibited encouraging efficacy in NSCLC patients (pts) as 3^rd line or futher therapy in a phase II trial (NCT04922658). The purpose of this study is to evaluate the efficacy and safety of S + Toripalimab (T, an anti-PD-1 antibody) + chemotherapy (AP) in nsq-NSCLC pts. Here, we report the preliminary results.

Methods

This single-arm, phase Ⅱ study (NCT05003037) has two cohorts. Naive advanced nsq-NSCLC pts without driver gene mutation were enrolled in cohort 1and pts with mutated driver genes failing with tyrosine kinase inhibitors (TKIs) entered cohort 2. Both cohorts received S (250mg, qd, po, adjusted by DLTs in 1^st cycle) plus T (240mg, iv, d1, q3w, fixed dose) and AP (q3w). After 4 cycles followed by maintenance therapy with S plus T and A, q3w. Primary endpoint is PFS. Secondary endpoints include ORR, DCR, OS, and safety.

Results

Until Sep 5, 2023, 40 pts were enrolled in cohort 1 (median age 60 years, male 89.7%, TNM stage IV 100%, brain metastases (BMs) 48.7%). 25 pts were assigned to cohort 2 (median age 58 years, male 48%, TNM stage IV 96%). The most common mutated genes were EGFR (64%), HER2 (16%), and MET (8%). Most commonly used TKIs included osimertinib (36%), gefitinib (24%), and almonertinib (24%). RP2D of S was 250mg, po, qd, q3w in both cohorts (1/0 DLT occurred in 6 pts in cohort 1/2). Among pts with at least one post-baseline tumor assessment (n=38 in cohort 1, 24 in cohort 2), ORRs were 57.9% and 54.2%, DCRs were 94.7% and 95.8%. Median PFS was 10.2 months (95%CI 6.8, 13.4; BMs: 7.2m; non-BMs: not reached) in cohort 1, was not reached in cohort 2. The most common treatment-emergent adverse events (Total; Grade ≥3) in cohort 1 were diarrhea (67.5%; 2.5%), proteinuria (57.5%; 5.0%), and anemia (50.0%; 2.5%); in cohort 2 were decreased platelet count (56.0%; 32.0%), fatigue (48.0%; 0) and diarrhea (40.0%; 0).

Conclusions

Surufatinib plus toripalimab and AP showed promising anti-tumor activity and acceptable toxicity for the treatment of advanced nsq-NSCLC, whether the driver gene is mutated or not. The combination of the 4 agents might be a novel therapeutic option for advanced nsq-NSCLC.

Clinical trial identification

NCT05003037; Release date: December 8, 2021.

Legal entity responsible for the study

Sun Yat-sen University Cancer Center.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

As part of key subgroup analyses of EMPOWER-lung 3 (NCT03409614), a double-blinded, randomized (2:1) phase 3 trial, an improvement in overall survival (OS) was observed with cemiplimab + chemotherapy (CEMI+CHEMO, n=47) vs placebo + chemotherapy (CHEMO, n=23) in patients with baseline liver metastases from advanced NSCLC (median OS: 14.4 vs 8.9 months; hazard ratio (HR): 0.61 (95% confidence interval (CI): [0.31, 1.20]). The safety results of patients with baseline liver metastases were generally similar to those of the overall study population. We conducted exploratory analyses to evaluate PROs within this subgroup of patients.

Methods

PROs were assessed at day 1 (baseline), the start of each treatment cycle (every 3 weeks) for the first 6 doses, and then at start of every third cycle, using the EORTC-QLQ-C30 and -QLQ-LC13 questionnaires. A mixed-effect model for repeated measures analysis was performed to compare CEMI+CHEMO vs CHEMO for all scales. Time to definitive clinically meaningful deterioration (TTD) was evaluated using Kaplan-Meier analysis and between-arm TTD comparisons were made using a log-rank test and proportional hazards model.

Results

Statistically significant delay in TTD was observed favouring CEMI+CHEMO over CHEMO for role functioning (HR: 0.28, 95% CI [0.10, 0.79]; p=0.011), cognitive functioning (0.18, [0.06, 0.55]; p=0.001), haemoptysis (<0.01, [<0.01, not calculable]); p=0.021), and alopecia (0.25, [0.09, 0.72]; p=0.007). When comparing between arms, no statistically significant differences between CEMI+CHEMO vs CHEMO in overall change from baseline across all C30 or LC13 scales were observed. No analyses yielded statistically significant PRO results favouring CHEMO vs CEMI+CHEMO for any C30 or LC13 scales.

Conclusions

Among patients with baseline liver metastases from advanced NSCLC, CEMI+CHEMO resulted in significant delay in TTD in role functioning, cognitive functioning, haemoptysis, and alopecia when compared with CHEMO. Overall change from baseline across all PROs were maintained. These PRO results further support the favourable benefit–risk profile of CEMI+CHEMO vs CHEMO in advanced NSCLC with baseline liver metastases.

Clinical trial identification

NCT03409614.

Editorial acknowledgement

Editorial support was provided by John G Facciponte, PhD, of Prime, Knutsford, UK.

Legal entity responsible for the study

Regeneron Pharmaceuticals, Inc.

Funding

Regeneron Pharmaceuticals, Inc., and Sanofi.

Disclosure

A. Baramidze: Other, Personal, Other, Travel support: Regeneron Pharmaceuticals, Inc. C. Gessner: Financial Interests, Personal, Advisory Board: AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, GSK, Novartis, Merck Sharp & Dohme, Pfizer, Roche, Sanofi. A. Sezer: Financial Interests, Institutional, Funding: Roche, Merck Sharp & Dohme, Merck Serono, AstraZeneca, Lilly, Novartis, Johnson & Johnson, Regeneron Pharmaceuticals, Inc., Sanofi. M. Gumus: Financial Interests, Personal, Other, Honoraria: Roche, Merck Sharp & Dohme, Gen İlaç, Novartis. X. He, G. Gullo, P. Rietschel, R. Quek: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.

Background

While ICIs demonstrate improved clinical trial outcomes in patients with NSCLC, little is known about real-world ICI retreatment patterns and outcomes after 2L+ nivo therapy. This analysis aimed to understand these endpoints in a real-world patient group in France.

Methods

Patients with locally advanced/metastatic NSCLC who initiated 2L+ nivo from 2015–2020 were included from ESME-AMLC, a retrospective observational cohort involving 39 centres in France (NCT03848052). Patient demographics, clinical and retreatment characteristics and outcomes were determined. Patients were followed from 2L+ nivo start date to last medical information date. Retreatment patterns were defined as: rechallenge (any ICI following an intervening non-ICI anticancer treatment after 2L+ nivo discontinuation); resumption (any ICI post-treatment break >6 weeks), ICI switch (any non-nivo ICI post-treatment break <6 weeks).

Results

After a median follow-up of 24 weeks, 2985/4001 (74.6%) patients discontinued 2L+ nivo treatment, 1604 received chemotherapy (CT) or targeted therapy (40.1%), 800 (20%) had no further treatment, and 226 (7.6%) were retreated with ICI. Of these: 110 (48.7%) were rechallenged (median treatment duration 2.1 months), 102 (45.1%) resumed (median treatment duration 3.3 months), and 14 (6.2%) switched ICI. Most patients retreated with ICI had non-squamous histology (80 [72.7%] patients with rechallenge, 76 [74.5%] with resumption, and 12 [85.7%] with ICI switch). Median duration of initial nivo treatment was 5.5 months for rechallenge, 7 months for resumption and 7 months for ICI switch. Median overall survival (OS) from retreatment date was 16.6 months vs 8.3 months for patients who resumed or were rechallenged. Patients who received initial 2L+ nivo for >26 weeks had higher ICI retreatment rates (15.8% overall) than patients who received 2L+ nivo for <13 weeks (3.6% overall).

Conclusions

Following 2L+ nivo discontinuation, most patients received CT. Few received ICI retreatment, although this increased with 2L+ nivo duration. Patients resuming ICI had longer OS than those with rechallenge.

Clinical trial identification

NCT03848052.

Editorial acknowledgement

Medical writing support was provided by Latitude (Powered by AXON).

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

G. Justeau: Non-Financial Interests, Personal, Advisory Role: BMS. M. Pérol: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, MSD, BMS, Lilly, Novartis, Takeda, Gritstone, Sanofi, Pfizer, Amgen, Janssen, GSK, Eisai, Ipsen; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, MSD, BMS, Boehringer Ingelheim, Takeda, Illumina, Pfizer, Medscape; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Takeda, Boehringer Ingelheim; Financial Interests, Personal, Steering Committee Member: Roche; Financial Interests, Personal, Other, DMSB: Roche. C. Audigier Valette: Financial Interests, Personal, Advisory Board: Roche, BMS, MSD, AstraZeneca, Sanofi, Janssen; Financial Interests, Personal, Invited Speaker: Pfizer. D. Debieuvre: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, MSD, Janssen, Pfizer, OSE Immunotherapeutics, Novartis, SanofiAventis, Amgen, Roche, Ipsen; Financial Interests, Personal, Invited Speaker: Gilead, Takeda; Financial Interests, Personal, Coordinating PI: Pfizer; Financial Interests, Institutional, Funding: Roche, AstraZeneca, Janssen, MSD, Pfizer, BMS, Lilly, Boehringer Ingelheim, GSK, Chugaï, Chiesi, Novartis, Takeda, Bayer, SanofiAventis. X. Quantin: Financial Interests, Institutional, Invited Speaker: Sanofi; Financial Interests, Institutional, Advisory Board: BMS; Financial Interests, Institutional, Other, Educational support: AstraZeneca. H. Lena: Non-Financial Interests, Personal, Research Funding: Bristol Myers Squibb; Non-Financial Interests, Personal, Coordinating PI: Regeneron Pharmaceuticals, Sanofi Aventis, GSK, Pfizer; Financial Interests, Personal, Advisory Board: Sanofi Aventis, Pfizer, Takeda, Roche, Amgen. P. Macouillard: Financial Interests, Institutional, Full or part-time Employment: Unicancer. L. Bosquet: Financial Interests, Institutional, Full or part-time Employment, In charge of scientific projects at Unicancer, Health Data and Partnership Department: Unicancer. M.J. Schoemaker, M. Mella, B. Correia: Financial Interests, Personal, Full or part-time Employment: IQVIA. C. Rault: Financial Interests, Personal, Speaker, Consultant, Advisor: Bristol Myers Squibb; Financial Interests, Personal, Full or part-time Employment: Data Gnosis. M.J. Daumont: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks or ownership: Bristol Myers Squibb. J. Penrod: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks or ownership: Bristol Myers Squibb. C. Chouaid: Financial Interests, Personal, Advisory Board: AZ, BI, GSK, Roche, Sanofi Aventis, BMS, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer, Janssen and Amgen; Financial Interests, Institutional, Funding: AZ, BI, GSK, Roche, Sanofi Aventis, BMS, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer, Janssen and Amgen.

Background

EVIDENS was a prospective, non-interventional, multicenter study evaluating nivolumab in metastatic NSCLC, initiated before immunotherapy was available in first-line. This final analysis presents results at 36-months’ follow-up.

Methods

Adults with pathologically confirmed lung cancer initiating nivolumab between October 2016–November 2017 were included and followed up until December 2020. Patient characteristics were recorded at diagnosis & nivolumab initiation. Survival was evaluated with the Kaplan-Meier method & quality of life (QoL) with the EuroQol-5D-3 Level (EQ-5D-3L) questionnaire and visual analog scale (VAS).

Results

A total of 1423 patients with NSCLC (69% male, median age 66 years) were included in this analysis. At nivolumab initiation, most patients had an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0–1 (83.0%), non-squamous histology (69.1%), stage IV disease (91.5%) & were current/former smokers (89.8%); 19.9% had brain metastases. Most patients (99.7%) had previously received chemotherapy; nivolumab was second line therapy in 73.5% of patients with a median treatment duration of 73.0 days. Median overall survival (OS) was 11.0 months (95%CI: 9.8–12.2) & progression-free survival (PFS) 3.0 months (95% CI: 2.6–3.2). In multivariate analyses, patients with squamous NSCLC, liver metastasis, ECOG-PS ≥2 or who never smoked had significantly higher risk of shorter OS & PFS. Age, brain metastasis, or corticosteroid therapy at nivolumab initiation had no effect on OS & PFS. The overall response rate was 12.1%; median duration of response was 13 months. Treatment-related adverse events occurred in 35.7% (any grade), 8.0% (grade 3) and 0.8% (grade 4) of patients. Patients continuously treated with nivolumab had better EQ-5D-3L VAS scores than those who discontinued.

Conclusions

EVIDENS final analysis confirm the effectiveness, safety & effect on QoL of nivolumab reported in clinical trials. They help inform clinical practice by virtue of a long-term follow-up & subgroup analyses suggesting greater benefit in certain patients. This conclusion might be explored further in the LIST study.

Clinical trial identification

NCT03382496.

Editorial acknowledgement

Tracy Harrison of Springer Healthcare Communications provided editing of the abstract prior to submission. Yaacoub Khalife of Bristol Myers Squibb France Medical Oncology Department provided editing of the abstract prior to submission.

Legal entity responsible for the study

The authors.

Funding

Bristol Myers Squibb.

Disclosure

F. Barlesi: Financial Interests, Institutional, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd, Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Sanofi Aventis, Seattle Genetics, Takeda, AbbVie, ACEA, Amgen, Eisai, Ignyta; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd., Innate Pharma, Mirati. D. Debieuvre: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, MSD, Janssen, Pfizer, OSE Immunotherapeutics, Novartis, Sanofi Aventis, Amgen, Roche, Ipsen; Financial Interests, Personal, Invited Speaker: Gilead, Takeda; Financial Interests, Personal, Coordinating PI: Pfizer; Financial Interests, Institutional, Funding: Roche, AstraZeneca, Janssen, MSD, Pfizer, BMS, Lilly, Boehringer Ingelheim, GSK, Chugaï, Chiesi, Novartis, Takeda, Bayer, Sanofi Aventis. J.B. Auliac: Financial Interests, Personal, Speaker, Consultant, Advisor: Sanofi, Janssen, AstraZeneca, Takeda, BMS, MSD. D. Moro-Sibilot: Financial Interests, Personal, Advisory Board: Lilly, Roche, BMS, MSD, AbbVie, Becton Dickinson, Pfizer, Takeda, AstraZeneca, Boehringer Ingelheim, Novartis, GSK, Sanofi; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Institutional, Funding, IFCT clinical trials: Pfizer; Financial Interests, Institutional, Funding: Roche, AbbVie, AstraZeneca. B. Asselain: Financial Interests, Personal, Other: BMS, AstraZeneca, Pierre Fabre, Servier, Daiichi Sankyo, Gilead. C. Audigier-Valette: Financial Interests, Personal, Advisory Board: Roche, BMS, MSD, AstraZeneca, Sanofi, Janssen; Financial Interests, Personal, Speaker, Consultant, Advisor: Pfizer. F. Breliier, E. Gauthier, D. Reynaud: Financial Interests, Personal, Full or part-time Employment: BMS. F. Cotté: Financial Interests, Personal, Full or part-time Employment: BMS; Financial Interests, Personal, Stocks/Shares: BMS. M. Pérol: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, MSD, BMS, Lilly, Novartis, Takeda, Gritstone, Sanofi, Pfizer, Amgen, Janssen, GSK, Eisai, Ipsen; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, MSD, BMS, Boehringer Ingelheim, Takeda, Illumina, Pfizer, Medscape; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Takeda, Boehringer Ingelheim; Financial Interests, Personal, Steering Committee Member: Roche; Financial Interests, Personal, Other, DMSB: Roche. All other authors have declared no conflicts of interest.

Background

Perioperative immunotherapy has been shown to be promising option for resectable non-small cell lung cancer(NSCLC). This study aimed to investigate the efficacy and safety of perioperative treatment with tislelizumab (PD-1 inhibitor) plus chemotherapy in resectable stage II-III NSCLC.

Methods

This open-label, single-arm, phase 2 trial planned to enroll 20 patients(pts) with resectable II-IIIB(N2) (AJCC 8th) NSCLC. Pts received neoadjuvant treatment with intravenous tislelizumab combined with chemotherapy Q3W for 2-3 cycles before surgery and 1-2 cycles after surgery (up to 4 cycles perioperative chemotherapy), followed by tislelizumab Q3W for 1 year. Primary endpoints were major pathological response (MPR) rate, the secondary endpoints included pathologic complete response (pCR) rate, objective response rate (ORR), event-free survival (EFS) and overall survival (OS). This study is registered with chictr.org.cn, ChiCTR2300068140.

Results

Between February 2023 and August 2023, 15 pts (median age: 67; male:80%) were enrolled, of whom 66.7% pts had stage III disease, 93.3% pts had squamous cell lung cancer. Among 15 enrolled pts, 5 pts are on neoadjuvant period; 10 pts completed neoadjuvant treatment, and 9 of them underwent surgery with 100% R0 resection. Of 9 pts who underwent resection, 5 pts (55.6%) achieved MPR and pCR. ORR was 63.6%, DFS and OS data was immature. The most common TRAEs were anemia (n=8; 53.3%), and thrombocytopenia (n =5; 33.3%). Most of the TRAEs were grade 1or 2. 3 pts experienced Grade 3 TRAE of WBC count decreased, increased creatine kinase and pneumonia, respectively. No grade 4-5 adverse events were reported.

Conclusions

Tislelizumab combined platinum-based chemotherapy demonstrated high MPR and pCR rate, feasible surgical resection and manageable toxicity in stage II-IIIB NSCLC. Pts will be followed for long-term survival.

Clinical trial identification

ChiCTR2300068140.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Although IMpower150 demonstrated atezolizumab combined with bevacizumab plus chemotherapy was a standard of care for advanced NSCLC, the efficacy and safety remained to be improved. This study was aimed to evaluate the efficacy and safety of tislelizumab (tis)plus anlotinib (anlo) combined with 2-cycles chemotherapy as first-line treatment for advanced NSCLC.

Methods

This study was a single-arm, one set and phase II study. Eligible patients were histologically confirmed locally advanced or metastatic (Stage IIIB-IV) NSCLC and untreated, excluding driver mutations. Twenty patients received 2 cycles of tis (200mg, iv, Q3W) plus anlo (12mg, QD for 2W, Q3W) and platinum-based dual agent chemotherapy, followed by tis plus anlo maintenance therapy. The primary endpoint was progression free survival. The second endpoints included over survival, object response rate, during of response, disease control rate and safety. The number of planned enrollment patients was 30.

Results

As of the data cutoff of August 31, 2023, the median follow-up time was 8 months (95%CI 4-12).There were 20 pts eligible for inclusion,18/20 pts were stage IV and 14/20 pts were non-squamous NSCLC. The median PFS was 8.5months(95%CI:4.5-NA), the 6m-PFS% and 12m-PFS% were 75.9% (95%CI 0.477-0.902) and 36.1% (95%CI 0.103-0.634) respectively. The median OS has not arrived, the 12m-OS% was 77.9% (95%CI 0.440-0.927). The ORR was 75% and DCR was 100%, the median DOR was 5.2months (95%CI 1.68-NA). The safety was manageable and none ≥3TRAE and ≥3irAE occurred. Table: 80P

Conclusions

The preliminary result of this study indicated that tislelizumab, anlotinib combined with 2-cycles chemotherapy as first-line treatment for advanced NSCLC showed promising efficacy and good safety.

Clinical trial identification

TISAL-FE-01.

Legal entity responsible for the study

The authors.

Funding

BeiGene and Nanjing Zhengda Tianqing Pharmaceutical Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.

Background

Significant unmet needs exist for patients with mNSq NSCLC who experience disease progression after treatment with PCT and an ICI. Docetaxel (DOC)-based regimens are commonly used to treat such patients; however, data on the characteristics of and outcomes for those receiving these therapies in the real world are lacking. The objective of this study was to provide a benchmark for survival with present standard-of-care therapies by conducting a retrospective cohort study of real-world patients treated with DOC or DOC plus ramucirumab (DOC+RAM) in the US.

Methods

The study utilized data from US patients included in the ConcertAI Patient 360 NSCLC database who initiated first-line treatment between 01-Jul-2016 and 31-Dec-2020. Patients who had mNSq NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and received DOC or DOC+RAM following disease progression after PCT and an ICI (in combination or separately) were eligible. Patients’ demographics and clinical characteristics as well as outcomes (real-world overall survival [OS], progression-free survival [PFS], time to treatment discontinuation [TTD], and time to next treatment [TTNT]) were analyzed.

Results

For patients receiving DOC (N=41; mean age: 65 years) or DOC+RAM (N=87; mean age: 64 years), median OS was 6.0 months (95% confidence interval [CI]: 4.8, 11.6) and 5.9 months (95% CI: 4.2, 11.6), respectively. Median PFS was 2.9 months (95% CI: 1.9, 4.6) for DOC and 2.7 months (95% CI: 2.3, 4.6) for DOC+RAM. Median TTD and TTNT were 2.1 months (95% CI: 1.4, 3.4) and 7.4 months (95% CI: 5.7, not estimable [NE]) for DOC and 1.5 months (95% CI: 1.4, 2.1) and 15.2 months (95% CI: 12.3, NE) for DOC+RAM, respectively. Estimates for TTNT should be considered with caution, given that a large number of patients were censored because of death or end of follow-up.

Conclusions

This study highlights the poor prognosis for real-world mNSq NSCLC patients who experience disease progression after PCT and ICI. The results can be used to help evaluate novel therapies in this population.

Editorial acknowledgement

Hriticka Choudhurry and Pranshu Roy from Sanofi provided medical writing support.

Legal entity responsible for the study

Sanofi.

Funding

Sanofi.

Disclosure

M.A. Bittoni: Financial Interests, Institutional, Speaker, Consultant, Advisor, consultancy services: Sanofi. S. Keeping, J.E. Park, A.T.H. Nguyen, K. Toor: Financial Interests, Institutional, Full or part-time Employment: PRECISIONheor; Professional service fees for conducting this research: Sanofi. D.P. Carbone: Financial Interests, Institutional, Speaker, Consultant, Advisor, consultancy services Sanofi. N. Petruski-Ivleva, A.K. Vadanahalli Shankar, G. Konidaris: Financial Interests, Institutional, Full or part-time Employment: Sanofi; Financial Interests, Institutional, Stocks/Shares: Sanofi.

Background

Circadian rhythms are known to influence adaptive immune responses. A seminal study showed that immune checkpoint inhibitors (ICI) infusions administered in the evening (later than 16:30h) to stage IV melanoma patients led to significantly shorter progression-free survival (PFS) and overall survival (OS). Subsequent retrospective studies suggested worse outcomes for metastatic non-small cell lung cancer (NSCLC) patients who received over 20% of their ICI doses in the evening. We hypothesized that the timing of the initial dose could be responsible for this observed effect.

Methods

We conducted a retrospective review of patients diagnosed with advanced or metastatic NSCLC who initiated palliative first line pembrolizumab treatment between June 2017 and April 2023 at The Christie. Sociodemographic and clinical data were collected. Patients were stratified into two groups based on the timing of their first dose infusion: those before 16:30h (early group) and those after 16:30h (evening group).

Results

276 patients met the inclusion criteria: 237 in the early group and 39 in the evening group. Both cohorts were similar, with no significant differences in sex, ECOG, histology, brain metastases at diagnosis, or PD-L1 expression (≥ or <90%). Inflammatory blood biomarkers (NLR, PLR, PNI) were consistent between groups. The evening group had a significantly shorter median OS (16m vs. 19m; HR 1.5; p=0.047), corroborated by the multivariate analysis (Table). Although median PFS was comparable between groups, the 3-year PFS rates stood at 10% for the evening group and 22% for the early group. Table: 82P

Multivariate Cox regression model

Conclusions

Our findings add to the emerging body of evidence suggesting a link between circadian rhythms and immunotherapy efficacy. While this study indicates a difference in OS based on the timing of the first dose, further prospective research is imperative. Modifying infusion timings could provide a straightforward approach to potentially optimizing patient outcomes.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

F. Blackhall: Financial Interests, Personal, Invited Speaker, Educational Symposium lecture: AstraZeneca; Financial Interests, Personal, Advisory Board, NTRK Advisory Board and guidelines for diagnosis: Bayer; Financial Interests, Personal, Other, IDMC Chair: AstraZeneca; Financial Interests, Personal, Advisory Board, Small cell Advisory Board Oct 2020: Amgen; Financial Interests, Personal, Invited Speaker, ESMO Satellite Symposium November 2020: Takeda; Financial Interests, Personal, Other, Consultancy for RETinhibitor development: Blueprint; Financial Interests, Personal, Other, Real world evidence research study design and analysis (EGFR): Janssen; Financial Interests, Institutional, Coordinating PI, Institutional payment for clinical trial activities: Amgen, Pfizer; Financial Interests, Institutional, Coordinating PI, Payment for clinical trial activities: Mirati; Financial Interests, Institutional, Coordinating PI, Clinical trial activities: BMS; Financial Interests, Institutional, Funding, Real world evidence research programme: Roche; Non-Financial Interests, Personal, Advisory Role, Application of genotyping platforms in lung cancer: Guardant Health; Non-Financial Interests, Personal, Advisory Role, Clinical trials of IMPs in lung cancer and translational lung cancer biomarkers: AstraZeneca. R. Califano: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Lilly Oncology, Roche, Pfizer, MSD, Takeda, Amgen, Bayer, Janssen and Novartis, Sanofi, GSK and PharmaMar; Financial Interests, Personal, Invited Speaker: AstraZeneca, Lilly Oncology, Roche, Pfizer, MSD, Takeda, Amgen, GSK and Janssen; Financial Interests, Personal, Other, speaker in educational activities: Medscape, Touch IME and PeerVoice; Financial Interests, Personal, Ownership Interest, partnership: The Christie Private Care - LOC; Financial Interests, Personal, Stocks/Shares: Supportive care UK; Financial Interests, Institutional, Local PI, principal investigator for clinical trial: Roche, AstraZeneca, Pfizer, Clovis, Lilly Oncology, MSD, BMS, AbbVie, Takeda, Janssen, and Novartis; Financial Interests, Institutional, Local PI: PharmaMar and GSK; Non-Financial Interests, Personal, Member, member of Lung Cancer Group: EORTC. All other authors have declared no conflicts of interest.

Background

The association between immune-related adverse events (irAEs) and survival outcomes in non-small cell lung cancer (NSCLC) patients treated with programmed-death-(ligand)1 [PD-(L)1] inhibitors remains controversial, partly due to variations in dealing with immortal-time bias (ITB).

Methods

We retrospectively enrolled 425 patients with advanced NSCLC who received anti-PD-(L)1 monotherapy between January 2016 and June 2021, stratifying them into irAEs (n=127) and non-irAEs (n=298) groups. The primary endpoint was to assess the impact of irAEs on progression-free survival (PFS) and overall survival (OS). Landmark and time-dependent Cox analyses were performed in addition to conventional analysis to eliminate ITB.

Results

127 patients (29.9%) experienced 186 irAEs, with 89 single-organ and 38 multi-organ. 42 skin irAEs, 39 thyroid irAEs, 27 pneumonitis, 25 hepatic irAEs, and some less frequent irAEs et.al. With a median follow-up of 38.8 months, the occurrence of overall irAEs was significantly associated with superior PFS (11.2 vs 3.4 months, P<0.0001) and OS (31.4 vs 14.0 months, P<0.0001), and this positive association persisted in landmark (3-, 6-, and 9-month; all P<0.05) and time-dependent Cox analyses (adjusted HR for PFS=0.55, 95% CI 0.43-0.71; for OS=0.53, 95% CI 0.41-0.70). For the main organ-specific irAEs, skin, thyroid, and hepatic irAEs, respectively, showed significantly improved survival compared to the non-irAE group, whereas pneumonitis did not. Single-organ irAEs had the best outcomes compared with multi-organ or no irAE, which also held across subgroups of skin, thyroid and hepatic irAEs. Moreover, severe grade irAEs and immunotherapy discontinuation had a detrimental effect on survival, systemic steroid therapy showed little effect, while immunotherapy resumption had tolerable safety and a trend of improved survival.

Conclusions

After adequately adjusting ITB, the occurrence of overall irAEs predicts for favourable efficacy of anti-PD-(L)1 monotherapy in NSCLC, with better outcomes observed in patients with skin, thyroid, or hepatic irAEs, particularly those with single-organ involvement.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

In the phase 3 CAPSTONE-1 study, adebrelimab, a humanized IgG4 anti-PD-L1 monoclonal antibody, plus chemo as first-line treatment for ES-SCLC significantly improved overall survival (OS) vs placebo plus chemo. Here we reported updated outcomes ∼3 years after the enrollment of the last patient.

Methods

462 patients with systemically untreated ES-SCLC were randomized 1:1 to receive 4-6 cycles of adebrelimab (20 mg/kg, iv, d1, q3w) or placebo, with carboplatin (AUC 5, d1, q3w) plus etoposide (100 mg/m², d1, d2, d3, q3w), followed by maintenance therapy with adebrelimab or placebo. The primary endpoint was OS.

Results

As of data cutoff of Aug. 11, 2023, median follow-up was 15.1 mo for all patients in the adebrelimab group and 12.8 mo in the placebo group; median follow-up for censored patients was 45.8 mo and 42.5 mo, respectively. OS events were recorded in 188 (81.7%) patients in the adebrelimab group and 212 (91.4%) in the placebo group. Median OS was 15.3 mo (95% CI 13.2-17.3) with adebrelimab plus chemo vs 12.8 mo (95% CI 11.3-13.9) with placebo plus chemo (HR 0.73, 95% CI 0.60-0.89; one-sided p=0.0008). Over 10% improvement in OS rate was seen at 12, 24 and 36 mo in the adebrelimab group vs placebo group (Table 1). The OS benefits with adebrelimab were generally consistent across clinically relevant subgroups. No new safety signals were observed. Table: 84P

OS outcomes

Conclusions

After prolonged follow-up, the addition of adebrelimab to chemo continued to demonstrate OS benefits with manageable toxicities, further supporting this regimen as a new first-line treatment option for ES-SCLC.

Clinical trial identification

NCT03711305.

Legal entity responsible for the study

Jiangsu Hengrui Pharmaceuticals.

Funding

Jiangsu Hengrui Pharmaceuticals.

Disclosure

C. Zhou: Financial Interests, Personal, Speaker’s Bureau: Lily China, Sanofi, BI, Roche, MSD, Qilu, Hengrui, Innovent Biologics, C-Stone, Luye Pharma, TopAlliance Biosciences Inc., Amoy Diagnositics, Anheart Therapeutics; Financial Interests, Personal, Advisory Role: Innovent Biologics; Financial Interests, Personal, Advisory Board: Hengrui, Qilu, TopAlliance Biosciences Inc. X. Li, K. Ma: Financial Interests, Personal, Full or part-time Employment: Hengrui. All other authors have declared no conflicts of interest.

Background

First-line chemo-immunotherapy has shown significant survival improvement in ES-SCLC, however, rapid drug resistance frequently occurs. Sitravatinib (Sitra), a selective tyrosine kinase inhibitor targeting TAM, VEGFR2 and KIT, can alter immune landscape to favor immunotherapy and overcome resistance. This single-arm, phase Ⅱ trial evaluated the efficacy and safety of tislelizumab (TIS, a PD-1 inhibitor) plus Sitra as maintenance therapy in ES-SCLC patients (pts) after induction therapy with TIS plus chemotherapy (chemo), aiming to postpones disease progression.

Methods

Eligible pts with untreated ES-SCLC received TIS (200 mg) plus platinum–based chemo Q3W for 4 cycles (induction), followed by maintenance TIS 200 mg Q3W and Sitra 70 mg daily. Maintenance analysis set (MAS) included pts who received ≥1 dose maintenance therapy. Efficacy outcomes in MAS were calculated from the start of maintenance TIS+Sitra. The primary endpoint was 1-year PFS rate per RECIST v1.1 in MAS.

Results

Between March 2022 and August 2022, 21 pts were enrolled and received induction therapy. Of these, 18 pts entered maintenance phase, with 27.8% having liver metastases, 27.8% bone metastases, 16.7% brain metastasis, and 94.4% ECOG PS 1. As of 21 Jul 2023, among the 18 pts in MAS, median PFS was 6.4 months and 1-year PFS rate was 27.8% from the start of maintenance therapy. Median OS was not reached. In MAS, 4 pts achieved further PR during maintenance therapy, yielding a confirmed ORR of 22.2%, and the DCR was 88.9%. In MAS, TRAEs and irAEs of grade 3-4 occurred in 10 (55.6%) and 2 (11.1%) pts, respectively. Serious TRAEs occurred in 4 (22.2%) pts. No TRAEs led to treatment discontinuation or death. Table: 85P

Conclusions

TIS plus Sitra showed promising efficacy with manageable toxicities as maintenance therapy in ES-SCLC pts after induction TIS+chemo. It provides a new treatment strategy to delay drug recurrence and prolong the survival for ES-SCLC pts.

Clinical trial identification

NCT05228496.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

First line durvalumab in extensive-stage small-cell lung cancer (ES-SCLC) demonstrated significant improvement of OS in CASPIAN trial. PARP inhibitors have the potential to confer antitumor activity, modify tumor immunogenicity, and sensitize tumors to anti-PD-1/PD-L1 therapy. Here, we investigated the efficacy and safety of durvalumab plus Olaparib as maintenance therapy in ES-SCLC pts after Durvalumab plus chemotherapy as first line treatment.

Methods

TRIDENT is a single arm, multicenter, phase 2 study. Treatment-naïve ES-SCLC aged ≥18 with ECOG PS 0-2 were eligible. Durvalumab (1500 mg) was concurrently administered with platinum–etoposide every 3 weeks for 4 cycles, followed by durvalumab 1500 mg every 4 weeks plus Olaparib 300 mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was the rate of progression free survival at 12 months (APF12). Secondary endpoints included PFS, Overall Survival, Objective Response Rate (according to RECIST1.1.) and safety profile.

Results

60 patients were enrolled from 4 sites in China between August 2021 and August 2022. At the data cutoff on August 9, 2023, the median duration of follow-up was 13.0 months. 10 (16.7%) patients were still receiving study treatment. The primary endpoint of PFS at 12 months was 24.5% (95% CI, 14.3%-36.2%). Median PFS from first line treatment was 6.7 months (95% CI, 5.1-8.4), median overall survival was 14.6 months (95% CI 10.9–21.8); 2 (3.3%) patients received complete response (CR), 42 (70%) patients received partial response (PR) and the ORR was 73.3% (95%CI, 60.3-83.9%). Treatment-emergent adverse events (TEAE) occurred in 58 (96.7%) patients, with 22 (36.7%) of grade ≥3; 15 (25%) patients reported serious adverse events; TEAEs leading to death of any cause occurred in 2 (3.3%) patients.

Conclusions

Durvalumab plus Olaparib as maintenance therapy in ES-SCLC patients showed encouraging anti-tumor activity without new safety signal observed. Further exploration of ES-SCLC subpopulation who may benefit from durvalumab combined with Olaparib modality is needed.

Clinical trial identification

NCT05245994.

Legal entity responsible for the study

Sun Yat-sen University Cancer Center.

Funding

Sun Yat-sen University Cancer Center and AstraZeneca.

Disclosure

All authors have declared no conflicts of interest.

Background

This retrospective multicenter real-world study aims to investigate the potential prognostic value of AEs in HCC patients treated with AB in first-line setting.

Methods

The study’s population consisted of 823 HCC patients from five countries (Italy, Germany, Portugal, Japan, and the Republic of Korea) treated with AB between October 2018 and April 2022.

Results

Median overall survival (OS) was 15.9 months and median progression-free survival (PFS) was 7.6 months. 73.3% of patients presented at least one AE during the study period. The most common AEs were proteinuria (29.6%), arterial hypertension (27.2%), and fatigue (26.0%). 17.3% of the AEs were grade (G) 3. One death due to bleeding was reported. The multivariate analysis confirmed the appearance of decreased appetite G < 2 versus G ≥ 2 [hazard ratio (HR): 0.60; p < 0.01] and immunotoxicity G < 2 versus G ≥ 2 (HR: 0.70; p = 0.04) as independent prognostic factors for OS, and the appearance of decreased appetite G < 2 versus G ≥ 2 (HR: 0.73; p = 0.01), diarrhea of any G versus no diarrhea (HR: 0.57; p = 0.01), fatigue of any G versus no fatigue (HR: 0.82; p < 0.01), arterial hypertension G < 2 versus G ≥ 2 (HR: 0.68; p < 0.01), and proteinuria of any G versus no proteinuria (HR: 0.79; p = 0.03) as independent prognostic factors for PFS. The objective response rate (ORR) was 27.3%: complete responses (CR) were 35 (4.2%), partial response 190 (23.1%), stable disease 428 (52.0%), and progressive disease 170 (20.7%). The appearance of hypothyroidism of any G (odds ratio: 0.52; p = 0.04) and immunotoxicity of any G (odds ratio: 0.54; p < 0.01) were correlated with higher ORR, while the absence of fatigue of any G (odds ratio: 3.90; p = 0.02) and decreased appetite of any G (odds ratio: 9.71; p = 0.02) were correlated with more CR.

Conclusions

As also demonstrated for other therapies, also for the combination of AB there is a correlation between the occurrence of AEs and HCC patient outcomes.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Hepatic arterial infusion chemotherapy (HAIC), transarterial embolization (TAE), and lenvatinib are main treatments in unresectable hepatocellular carcinoma (HCC). This study aims to evaluate the safety and efficacy of HAIC sequential TAE combined with lenvatinib and tislelizumab (an anti-PD-1) as a first-line treatment in patients with high-risk unresectable HCC.

Methods

This is a single-arm, open-label, phase 2 trial (NCT05532319), which is ongoing. Eligible patients with high-risk unresectable HCC (CNLC stage Ib, II and III), ECOG performance status of 0 or 1 and adequate liver function received at least one cycle of HAIC sequential TAE (every 4 weeks) combined with lenvatinib and tislelizumab (200 mg intravenously every 3 weeks). The primary endpoint was the progression-free survival (PFS) rate at six months. Secondary endpoints included objective response rate (ORR), the proportion of patients who underwent curative treatments, significant tumour necrosis, PFS, OS and safety.

Results

Between Nov 1, 2022 and Aug 12, 2023, 35 patients with high-risk unresectable HCC were enrolled. The tumour load of 14 (40%) patients exceeds 50% of the liver volume. The PFS rate at six months was 83.6%. The ORR after one cycle of HAIC sequential TAE was 31.9% (15/47, RECIST 1.1) and 63.8% (30/47, mRECIST). The ORR after two cycle of HAIC sequential TAE was 35.1% (26/40, RECIST 1.1) and 80.0% (32/40, mRECIST). 19 patients (54.3%) received curative treatment after reaching partial response, including 10 (28.6%) curative hepatic resection, 6 (17.1%) radiotherapy, 2 (5.7%) radiofrequency ablation and 1 (2.9%) liver transplantation. Significant tumour necrosis was observed in 100% tumours based on postoperative histopathology in patients who received completed hepatectomy. Median PFS and OS were not reached. Most adverse events were grade 1 or 2. The most common were thrombocytopenia (22.9%), alanine aminotransferase elevating (20%) and serum albumin decreasing (17.1%).

Conclusions

HAIC sequential TAE combined with lenvatinib and tislelizumab is a safe and effective treatment modality in patient with high-risk unresectable HCC.

Legal entity responsible for the study

The authors.

Funding

BGNE.

Disclosure

All authors have declared no conflicts of interest.

Background

The combination treatment using sintilimab (a PD-1 antibody) and bevacizumab (bev) biosimilar demonstrated excellent efficacy and safety in ORIENT-32 study and HAIC performed impressive tumor response in researches. We assessed the efficacy and safety of the combination therapy as first-line treatment for initial unresectable HCC.

Methods

The study was an ongoing open-label, single-arm, phase II trial. Treatment-naïve HCC patients (pts) with initial unresectable and BCLC stage B or C were enrolled in this phase II trial. Eligible pts received sintilimab (200 mg, IV, D1) and bev (15 mg/kg, IV, D1) per 3 weeks, as well as FOLFOX-HAIC per 3-6 weeks. Pts eligible for resection were referred for hepatectomy after bev weaned over at least a 4-week period. Sintilimab and bev were given until disease progression or unacceptable toxicity or up to 24 months, and FOLFOX-HAIC were given 3-6 times. Primary endpoints were progression-free survival (PFS) per RECIST v1.1 and key secondary endpoints included objective response rate (ORR), disease control rate (DCR), surgical conversion rate, pathologic response, overall survival (OS) and safety.

Results

At data cutoff on July 25, 2023, 43 pts were enrolled, 41 of them underwent at least one course of treatment and 38 enrollees received at least one tumor assessment. The median follow-up time was 6.34 months (range 0.2–14.62). mPFS and mOS were not reached. According to RECIST v1.1, ORR and DCR were 68.42% and 100% (26 PR and 12 SD). Moreover, ORR and DCR were 86.84% and 100% (8 CR, 25 PR and 5 SD) based on mRECIST, respectively. 10 pts met the criteria for hepatectomy and 6 pts received liver resection. Among this 6 pts, 5 pts was in stage IIIA and 1 in IIIB before enrollment. No postoperative mortality was observed. Most treatment-related AEs (TRAE) were grade 1-2, and the incidence of grade 3 TRAEs was 14.63%. Grade 3 TRAEs includes decreased platelet count, hypertension, increased ALT, decreased white blood cell count, rash, hematencephalon and upper gastrointestinal hemorrhage.

Conclusions

Systemic therapy using HAIC plus Sintilimab and bev as first-line therapy for initial unresectable HCC was well tolerated and effective. Longer follow up is ongoing.

Clinical trial identification

ChiCTR2000034758.

Legal entity responsible for the study

Shanghai Eastern Hepatobiliary Surgery Hospital.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Data on elucidating the efficacy and safety of tislelizumab combined with tyrosine kinase inhibitors (TKIs) in hepatocellular carcinoma (HCC) are lacking. Herein, we explored the regimen of tislelizumab plus TKIs for intermediate or advanced HCC patients (pts) in a real-world setting.

Methods

In this study, 73 pts were included between Jul. 2021 and Jul. 2023. Pts were assigned either with tislelizumab plus TKIs (n=33), or tislelizumab plus TKIs plus TACE (n=40), where TKIs included lenvatinib (49.3%), regorafenib (23.3%), donafenib (21.9%), apatinib (2.7%) and anlotinib (2.7%). The primary endpoints were objective response rate (ORR, mRECIST criteria) and progression-free survival (PFS). The secondary endpoints included 6-month and 12-month PFS rates, disease control rate (DCR) and safety.

Results

Among the 73 pts, 80.8% were male, 53.4% had BCLC stage B, 75.3% were Child-Pugh A, 69.9% were first-line recipients and the average age was 62.8 years. The mean follow-up period was 13.3 (95% CI: 11.9-14.8) months and the mean number of TACE sessions were 0.8 (range 0-3) for all patients. The ORR and DCR were 42.5% and 79.5% with a median PFS of 12.6 months (95% CI: 8.71-16.49) and the 6-month, 12-month PFS rates were 69.6% and 50.4%. Compared to the tislelizumab plus TKIs group, the tislelizumab plus TKIs plus TACE group achieved longer median PFS (12.7 months (95% CI 9.17-16.23) vs. 8.4 months (95% CI 4.83-11.97), P=0.132), higher ORR (55.0% vs 27.3%, P = 0.017) and DCR (87.5% vs 69.7%, P = 0.061). Any-grade TRAEs were reported in 59 (80.8%) pts, and grade 3 TRAEs were reported in 16 (21.9%) pts. Most frequent TEAEs (≥10%) included hand-foot syndrome (24.7%), increased transaminase (15.1%), hyperbilirubinemia (13.7%), diarrhea (13.7%) and fever (11.0%). G3 TRAEs occurred in more 5% pts included hand-foot syndrome (8.2%), increased transaminase (6.8%). No grade 4/5 TRAE and new safety signal were identified.

Conclusions

Tislelizumab plus TKIs with TACE appeared to deliver encouraging efficacy and acceptable safety for pts with intermediate or advanced HCC. Further patient recruitment and longer follow up are warranted.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Systemic therapy combined with transarterial-based therapy has demonstrated promising results for unresectable HCC. Atezolizumab plus bevacizumab (“T+A”) is the standard first-line therapeutic regimen for advanced HCC, while lenvatinb combined programmed death-1 (PD-1) inhibitors shows synergistic anti-tumor effect as well. This study aims to compare the efficacy and safety of TAE-HAIC plus lenvatinib and PD-1 inhibitors versus TAE-HAIC plus “T+A” for unresectable HCC.

Methods

In this retrospective study, treatment-naïve unresectable HCC patients who were treated with TAE-HAIC plus lenvatinib and PD-1 inhibitors (THLP group) or TAE-HAIC plus “T+A” (THTA group) were included. The primary endpoint was overall survival (OS). The secondary outcomes included progression-free survival (PFS) and tumor response according to modified RECIST, and adverse events (AEs). We performed propensity score matching (PSM) approaches to reduce bias between two groups.

Results

From June 2020 to June 2023, 339 patients were enrolled in this study: 233 in the THLP group and 106 in the THTA group. After PSM with a ratio of 3:1, 153 and 51 patients were assigned to the THLP and THAT group, respectively. The THLP group showed a longer median OS (21.3 versus 18.2 months; P = 0.486), while median PFS was longer in the THTA group (6.8 versus 6.3 months; P = 0.552), both without statistical differences. There were no statistical differences in objective response rate (ORR) (73.3% versus 68.3%; P =0.635) and disease control rate (DCR) (91.7% versus 89.3%; P =0.716) neither. No significant difference in the rate of the grade 3/4 AEs was observed between the two groups, and all AEs were controllable. No treatment-related grade 5 AE took place in the two groups.

Conclusions

TAE-HAIC plus lenvatinib and PD-1 inhibitors or TAE-HAIC plus “T+A” demonstrated similar outcomes for unresectable HCC with acceptable toxic effects, which needs to be validated with larger-scale randomized clinical trials.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed death cell ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). The present study investigated for the first time the survival impact resulted from the addition of durvalumab to cisplatin/gemcitabine in a real-world setting.

Methods

The analyzed population included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab in combination with cisplatin/gemcitabine or cisplatin/gemcitabine alone. The impact of the addition of durvalumab to chemotherapy in terms of both overall survival (OS) and progression free survival (PFS) was investigated with uni- and multivariate analysis.

Results

Overall, 358 patients were included in the analysis: 213 received cisplatin/gemcitabine alone, 145 received cisplatin/gemcitabine plus durvalumab. At the univariate analysis, the addition of durvalumab resulted to have a survival impact, since the median OS was 11.2 Vs 12.9 months (HR 1.8, 95% CI 1.3-2.5, p=0.0005) in patients who received cisplatin/gemcitabine alone compared to those who received cisplatin/gemcitabine plus durvalumab. Moreover, patients who received cisplatin/gemcitabine alone showed worse PFS compared to those who received cisplatin/gemcitabine plus durvalumab (mPFS 6.0 Vs 8.9 months, HR 1.8, 95% CI 1.4-2.3, p<0.0001). The multivariate analysis confirmed that the addition of durvalumab to cisplatin/gemcitabine is a independent prognostic factor for both OS and PFS. Finally, an exploratory analysis of the prognostic factors in the cohort of patients who received durvalumab was performed: NLR>3 and ECOG PS>0 resulted to be independent prognostic factors in terms of both OS and PFS in this cohort of patients. The interaction test highlighted NLR>3 and ECOG>1 as predictive factors of response to cisplatin/gemcitabine plus durvalumab.

Conclusions

Accordingly to the results of the TOPAZ-1, the addition of durvalumab to cisplatin/gemcitabine has been confirmed to confer a survival benefit in terms of both OS and PFS in a real-world setting of advanced BTC patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Gallbladder carcinoma (GBC) is a highly malignant tumor of the biliary tract. The prognosis for advanced GBC is generally very poor with scarce evidence on effective treatment options. In light of the limited therapeutic strategies, this study aims to shed light on the outcomes of using chemotherapy alone or in combination with PD-1 inhibitor as the first-line therapy.

Methods

All the patients who received systematic treatment for unresectable or recurrent GBC were included in this study from January 2018 to December 2022. The systematic treatment involved either chemotherapy alone or combination therapy. Clinical data were collected, including baseline characteristics, therapeutic response to the treatment, overall survival, and progression-free survival. Additionally, adverse events (AEs) during the treatment period were carefully documented to access the safety of the treatment.

Results

The eligible patients were divided into two groups: one group received combination therapy consisting of chemotherapy and PD-1 inhibitor (n=31), while the other group received mono-chemotherapy (n=19). The results of the study showed that the overall survival (OS) and progression-free survival (PFS) were longer in the combination therapy group compared to the mono-chemotherapy group. The patients who received combination therapy had a median OS of 18.2 months, whereas those who received mono-chemotherapy had a median OS of 6.1 months (P=0.016). The median PFS for combination therapy was 11.3 months, compared to 5.5 months for mono-chemotherapy, with a p-value of 0.008. The overall response rate (ORR) was 35.5% in the combination therapy group and 5.3% in the mono-chemotherapy group (P=0.037). Despite these favorable outcomes, the combination therapy did not demonstrate a significant advantage over mono-chemotherapy in terms of disease control rate (DCR). The DCR was 74.2% in the combination therapy group and 57.9% in the mono-chemotherapy group (P=0.230).

Conclusions

The present findings imply that combining chemotherapy and PD-1 inhibitor may be an effective and safe first-line treatment option for patients with unresectable or recurrent GBC, offering improved OS, PFS and ORR compared to chemotherapy alone.

Clinical trial identification

SYSKY-2022-282-01.

Legal entity responsible for the study

Sun Yat-sen Memorial Hospital.

Funding

This work was supported by the Special Research Foundation of the National Nature ScienceFoundation of China (82273476, 81972262, 81972255, 82173195); Grant [2013]163 from Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology; Grant KLB09001 from the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes; Grant from Guangdong Science and Technology Department (2015B050501004, 2017B030314026); Sun Yat-sen University Clinical Research 5010 Program (2018008).

Disclosure

All authors have declared no conflicts of interest.

Background

Anlotinib is a multi-target TKI that has been proved to have good efficacy and tolerable toxicity whether as first-line treatment when combined with TP in advanced ESCC. TQB2450 is a novel humanized anti-PD-L1 monoclonal antibody. We conducted a phase II trial to evaluate the efficacy and safety of alotinib combined with TQB2450, cisplatin, and paclitaxel as first-line treatment for advanced ESCC. Here is the update results.

Methods

Eligible patients (pts) with previously untreated unresectable locally advanced or metastatic ESCC received TQB2450 (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1∼14, q3w) combined with paclitaxel (135mg/m2 , iv, d1, q3w) and cisplatin (60∼75mg/m2 , iv, d1∼3, q3w) for 4 - 6 cycles as initial therapy. Patients without progressive disease (PD) continued to receive same dose of anlotinib plus TQB2450 as maintenance therapy until PD or unacceptable toxicity. The primary endpoint was PFS (RECIST version 1.1). Secondary endpoints included iPFS (iRECIST), ORR (RECIST version 1.1), DCR, DOR and safety.

Results

At the data cutoff date of April 15, 2023, 50 pts were enrolled with a median age of 64 years (range 41-74), male (38/50, 76%) and ECOG PS 1 (39/50, 78%). Among 45 tumor response evaluable pts, the ORR was 82.2% (95% CI: 68.3%, 91.7%) and the DCR was 100.0% (95% CI: 92.1%, 100.0%). The preliminary median PFS was not reached. The incidence of grade 3-4 treatment emergent adverse events was 66% (33/50), there was no grade 5 TRAE. 20 pts (40%, 20/50) occurred treatment related serious AEs. 25 patients received maintenance treatment for more than 10 cycles, the median DOT was 12.19m(9.53m-18.53m). Only 5 patients experienced grade 3-4 AE, mainly include leukopenia, hypertension, hyponatremia and hypokalemia.

Conclusions

TQB2450 plus anlotinib with paclitaxel and cisplatin showed promising activity with well-tolerated toxicities in pts with advanced ESCC as first-line treatment and the maintenance treatment also showed manageable safety.

Clinical trial identification

NCT05013697.

Legal entity responsible for the study

The authors.

Funding

Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.

Background

Chemotherapy combined with anti-PD-1 monoclonal antibody has already become the first-line treatment in advanced ESCC, while the benefits in objective responses and survival were limited. Cadonilimab (AK104), a bispecific antibody simultaneously targeting PD-1 and CTLA-4, was designed to boost anti-tumour activity with an improved safety profile. Here, we first evaluated the safety and efficacy of AK104 combination therapy as the first-line treatment in advanced ESCC.

Methods

Eligible pts with previously untreated unresectable locally advanced or metastatic ESCC received AK104 (10mg/kg, iv, d1, q3w) combined with paclitaxel or nab-paclitaxel (175 mg/m², iv, d1, q3w) and cisplatin (65 to 75 mg/m², iv, d1, q3w) for up to 6 cycles, then continued AK104 (10mg/kg, iv, d1, q3w) treatment as maintenance until progressive disease or unacceptable toxicity, with a maximum of 24 months. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety.

Results

As of data cut-off (September 21, 2023), 22 pts were enrolled with a median age of 61 years (range 44-75), 50.0% had PD-L1 CPS<10. In the efficacy-evaluable population (n=15), 13 pts reached partial response and 2 pts had stable disease. The ORR was 86.7% (95%CI: 58.4%-97.7%) and the DCR was 100.0% (95%CI: 74.7%-100%). Both median PFS and OS were not reached. Among evaluable pts with PD-L1 CPS≥10 and PD-L1 CPS<10, the ORR were 83.3% (5/6) and 88.9% (8/9), respectively. Seven (31.8%) pts experienced grade 3-4 TRAEs, which mainly included neutropenia (22.7%), leukopenia (9.1%) and hyponatremia (9.1%). Immune-related AEs were observed in 3pts (13.6%). 3 pts (13.6%) suffered from serious AEs, and no grade 5 TRAE was observed. AEs led to discontinuation of AK104 in 2 (9.1%) of enrolled pts.

Conclusions

Bispecific antibody AK104 combined with taxane and cisplatin showed better ORR and manageable safety as first-line treatment in advanced ESCC, regardless of PD-L1 expression. Survival outcomes will be reported in the future and single AK104 cohort in pts with PD-L1 CPS≥5 ESCC is being explored.

Clinical trial identification

NCT05522894.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Colorectal cancer (CRC) is the third most often-diagnosed cancer in both men and women, with more than 1.9 million new cases worldwide in 2020. Immune-checkpoint inhibitors (ICI) show modest activity and efficacy in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients harbouring a proficient mismatch repair system (pMMR). However, even the fact that MSS tumours are infiltrated by T cells was proved, they will not respond to therapy with anti-PD-1 mAbs as they do not express ICI but escape from immunosurveillance, for example, by downregulating HLA expression. Importantly, there is a hypothesis that a particular fraction of non-hypermutated MSS tumours might in theory respond to PD-1/PD-L1 blockade therapy. Some trials demonstrated benefits for surveillance for MSS tumours treated by intensive combination of chemotherapy with ICI, but fragile and older patients cannot receive these regimens. Treatment with less toxicity could be the option for some specific group of patients with MSS tumours.

Methods

We performed a retrospective analysis of the efficacy and safety of pembrolizumab and lenvatinib for late-stage colorectal cancer as a salvage line. The Kaplan-Meier method was used to estimate survival distribution and response rate (RR).

Results

There were 20 cases (male:13, female:7), and the median average age was 63 (32-75) years old. The median progression-free survival (PFS) and overall survival (OS) were 4.5 (95%CI;1.4-14) months and 10 (95%CI;2.5-26.4) months, respectively. Response rate (RR) was 16% and disease control rate (DCR) was 25.6%. Also in analysis, Grade 2 or more severe diarrhea was an independent prognostic factor for PFS (p = 0.004) and OS (p < 0.0001). The common treatment-related adverse events were gastrointestinal toxicity and hepatic dysfunction, but they were not severe and no treatment related death was observed.

Conclusions

Even though LEAP-017 was not effective, we suggest that some populations of patients could have benefits from this regimen as a salvage therapy for MSS colorectal cancer. Also, our findings assume that the possibility that Grade 2 or more severe diarrhea may be a predictive factor. In conclusion, we think that further investigations in this field are needed.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Combining immune checkpoint blockade (ICB) with chemotherapy may significantly improve efficacy in patients with breast cancer. Whether metronomic chemotherapy is more suitable for ICB than conventional chemotherapy is still unclear.

Methods

This study is a multicenter randomized phase 2 trial using a multi-arm design with Bayesian adaptive randomization and efficacy monitoring. Eligible patients have advanced HER2-negative breast cancer, with no more than one prior line of standard chemotherapy. Patients were randomized to 5 groups: 1) metronomic vinorelbine (NVB, 40 mg/day, TIW) monotherapy (the control cohort); 2) NVB + toripalimab (anti-PD1 antibody, 240 mg Q3W); 3) bevacizumab (5 mg/kg Q3W) + NVB+ toripalimab (the BEV cohort); 4) cisplatin (50mg/m Q3W) + NVB + toripalimab (the DDP cohort); 5) cyclophosphamide (50mg/day, QD) + capecitabine (500 mg, TID) + NVB+ toripalimab (the VEX cohort). The primary endpoint was disease control rate (DCR). Mass cytometry time-of-flight analyses of paired blood samples were performed to demonstrate dynamic changes in systemic immune profile.

Results

A total of 103 patients were randomized. The rate of nausea was significantly higher in the cisplatin cohort than in the others (P< 0.001). Among the five treatment cohorts, the VEX cohort and the cisplatin cohort had the highest DCR, 69.7% (95% CI 51.7–85.9%) and 73.7% (95% CI 56.1–88.7%), respectively. It is worth noting that the PFS of patients in the VEX cohort was the longest, reaching 6.6 months (95% CI 4.0-5.9). The PFS of patients in the DDP cohort was relatively short, only 3.5 months (95% CI 2.2-5.3). In the TNBC subgroup, again, patients in the VEX cohort had the highest DCR (74.1%, 95%CI 47.9%-95.4%) and longest PFS (9.8 months, 95%CI 3.8-21.9). We clustered CD45+ immune cells into 32 clusters. Only the change of cluster 30 differed between responders and non-responders. This is a group of intermediate monocytes with a high expression of CD38. Meanwhile, the overall expression of CD38 in monocytes was significantly increased by DDP and BEV treatment compared with baseline, but not in the VEX groups.

Conclusions

These data suggest promising clinical efficacy and evidence of cooperativity between metronomic VEX chemotherapy and PD-1 blockade.

Clinical trial identification

NCT04389073.

Legal entity responsible for the study

The authors.

Funding

CAMS Innovation Fund for Medical Sciences (CIFMS 2022-I2M-C&T-B-067).

Disclosure

All authors have declared no conflicts of interest.

Background

Patients (pts) with persistent, recurrent, or metastatic cervical cancer are at high risk of progression after first-line standard treatment with platinum-doublet chemotherapy ± bevacizumab. Adding a PD-1 inhibitor to this standard treatment improves the survival of PD-L1⁺ pts. The preliminary results showed that tislelizumab plus bevacizumab and platinum-based chemotherapy had a promising efficacy with unconfirmed ORR of 78.4% (29/37, 95% CI, 61.8%-90.2%), irrespective of PD-L1 expression status (J Zhu, et al., JCO 2023 41:16_suppl). Here, we presented the updated results based on the full efficacy analysis set.

Methods

Eligible pts with persistent, recurrent, or metastatic cervical cancer received tislelizumab (200 mg, Q3W) plus bevacizumab (7.5 mg/kg, Q3W) and platinum-based chemotherapy. PD-L1 expression was accessed using VENTANA PD-L1(SP263) assay. The primary endpoint was PFS. Secondary endpoints were ORR, DCR, DOR and safety.

Results

A total of 50 pts were enrolled, with 46 (92.0%) having squamous cell carcinoma. 41 pts were detected for PD-L1 expression; 35 (85.4%) pts were PD-L1⁺, 6 (14.6%) were PD-L1^–. As of 10 Aug 2023, the median follow-up was 7.8 months (range 0.8-14.6). Among 47 pts in the efficacy analysis set, the confirmed ORR was 72.3% (34/47, 95% CI 57.4%-84.4%), with CR rate of 14.9% (6/47). Subgroup analysis showed that ORR for pts with squamous cell carcinoma and adenocarcinoma were 72.7% (32/44) and 66.7% (2/3), respectively; ORR for pts with PD-L1⁺ and PD-L1^– tumors were 70.6% (24/34) and 100% (5/5), respectively. DCR was 100% (95% CI 92.4%-100.0%). Median DOR and PFS were not reached. After a median treatment duration of 6.8 months, grade ≥3 treatment-related adverse events occurred in 48.0% of pts. Immune-related adverse events (irAE) were reported in 32.0% of pts, with no grade ≥3 irAE reported. Serious adverse events occurred in 20.0% of pts.

Conclusions

The updated results further demonstrated the efficacy and tolerability of tislelizumab plus bevacizumab and chemotherapy, with increased CR rate observed during extended treatment duration.

Clinical trial identification

NCT05247619.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Immunotherapy has become a standard of care for recurrent and metastatic cervical carcinoma resulting in the need to carefully assess for surrogacy focusing on new therapeutic scenarios. This study delves into a systematic review and meta-analysis to unravel the potential of progression-free survival (PFS) as a surrogate endpoint in cervical cancer.

Methods

We performed a comprehensive search of randomized phase 2 and 3 clinical trials in advanced and recurrent cervical cancer. PRISMA guidelines were followed, and the study was registered in PROSPERO (CRD42023405604). Inclusion criteria required RCTs with mature PFS and OS data. Trials with adjuvant treatment or disease-free survival as primary endpoint were excluded. Subgroup analysis was performed by type of treatment (i.e. chemotherapy-based, chemo-immunotherapy combinations).

Results

11,348 articles were screened, and 31 included in the final analysis. In the overall population, a robust correlation between PFS and OS was observed (Spearman's rho = 0.66, p-value < 0.001). We calculated the Surrogate Threshold Effect (STE) at the PFS intersection with null OS outcome (p = 0.05), resulting in a threshold for PFS z-score (z-PFS) of 2.23. When examining the results by treatment modality, chemotherapy trials exhibited a notably weak and non-significant correlation (Spearman 0.34, p = 0.31) with a significantly higher STE (z-PFS = 2.92). Conversely, in chemo-immunotherapy combinations, the correlation was notably robust and statistically significant (Spearman 0.94, p = 0.017), associated with a considerably lower STE (z-PFS = 2.1).

Conclusions

PFS may serve as a surrogate endpoint in cervical cancer. Notably, PFS was a more promising surrogate marker in the context of chemo-immunotherapy when compared to chemotherapy alone. This aligns with the hypothesis that chemo-immunotherapy induces a response, which is further sustained through maintenance immunotherapy, thereby enabling PFS to better capture the impact on OS. Conversely, in chemotherapy-based treatments, the expected survival benefit may be more limited, and PFS may not as strongly capture the effect of chemotherapy alone.

Legal entity responsible for the study

European Organisation for Research and Treatment of Cancer (EORTC), Young Gynaecological Cancer Group.

Funding

Has not received any funding.

Disclosure

F. Herrera: Financial Interests, Institutional, Research Grant, Grant/Research Support: Accuracy Inc, Bioprotext, BMS, Roche-ImFlame/ImCore, Nanobiotix, AstraZeneca, Eisai, MSD, Seagen; Financial Interests, Institutional, Research Grant, Grant/Research Support Foundations: Prostate Cancer Foundation, San Salvatore Foundation; Financial Interests, Personal, Advisory Board, Consultation, fees, travel expenses: Johnson & Johnson, Seagen, MSD, BMS, AstraZeneca, Eisai; Non-Financial Interests, Institutional, Non-financial benefits, Academic Collaborations: EORTC chairman GCG, ESMO Scientific Committee member for drug development, ASTRO Scientific Committee Annual Meeting. A. Madariaga Urrutia: Financial Interests, Personal, Invited Speaker: GSK, AstraZeneca, Clovis, MSD; Financial Interests, Personal, Advisory Board: GSK, AstraZeneca, PharmaMar. All other authors have declared no conflicts of interest.