Browsing Over 179 Presentations
5P - Comparison of PD-L1 expression before and after neoadjuvant chemoradiation or chemotherapy in stage III non-small cell lung cancer (NSCLC).
- David König (Basel, Switzerland)
- David König (Basel, Switzerland)
- Spasenija Savic Prince (Basel, Switzerland)
- Belinda Trachsel (Bern, Switzerland)
- Stefanie Hayoz (Bern, Switzerland)
- Miklos Pless (Winterthur, Switzerland)
Abstract
Background
The incorporation of immune-checkpoint inhibitors (ICIs) into the multimodal treatment of stage III NSCLC is likely to change future treatment standards. PD-L1 protein expression on tumor and/or immune cells has emerged as the first predictive biomarker for sensitivity to ICIs targeting the PD-1/PD-L1 axis. Little is known on the impact of treatment modalities such as chemotherapy (CT), radiotherapy (RT) and/or combinations on PD-L1.
Methods
We collected tissue samples from patients enrolled in three consecutive SAKK trials (16/96, 16/00, 16/01) and analyzed PD-L1 expression (SP263 assay) before and after neoadjuvant (neo-adj) treatment (NAT). The SAKK trials were designed for operable stage III NSCLC and conducted in a pre-immunotherapy era. All patients were treated with 3 cycles of induction chemotherapy (CT) (cisplatin/docetaxel), followed in some patients by radiotherapy (RT) (44Gy, 22 fractions) (16/00, 16/01). Thus, the cohort included a bimodal (CT/S) and a trimodal treatment approach (CT/RT/S).
Results
From 368 patients enrolled in the three trials, we obtained matched pre- and post-neo-adj samples from 100 patients, that were PD-L1 evaluable. Distribution of PD-L1 expression on tumor cells grouped into categories <1%, 1-49%, and ≥50% was 46%, 35% and 19%, respectively in the pre-neo-adj tissue samples. Overall, 58 patients were in the bimodal, 42 patients in the trimodal group. Median PD-L1 values were 1-4% for both the pre-neo-adj and post-neo-adj samples in the trimodal group. In the bimodal group, median pre-neo-adj PD-L1 value was <1% and post-neo-adj 1-4%. Statistically there was no significant difference in either of the groups (trimodal and bimodal group) for the median PD-L1 expression between the pre-neo-adj and the post-neo-adj samples. In the comparison of the treatment arms there was no statistically significant difference for the median PD-L1 value after NAT (p = 0.77).
Conclusions
In our analysis NAT did not impact on PD-L1. This was the case for both neo-adj CT as well as neo-adj CT/RT. If the observation that RT can sensitize to treatment with ICIs holds true (Shaverdian N, Lancet Oncol. 2017), it is unlikely to be mediated through an upregulation of PD-L1.
Legal entity responsible for the study
The authors.
Funding
Swiss Cancer League/Swiss Cancer Research (Grant Award Number: KFS-4381-02-2018).
Disclosure
All authors have declared no conflicts of interest.
6P - Pembrolizumab Plus Chemotherapy vs Chemotherapy in Asian Patients With PD-L1 Negative Advanced NSCLC: Pooled Analysis of KN021G, KN189 and KN407
- Ying Cheng (Changchun, China)
- Ying Cheng (Changchun, China)
- James Chih-Hsin Yang (Taipei, China)
- Isamu Okamoto (Fukuoka, Japan)
- Li Zhang (Beijing, China)
- Jie Hu (Shanghai, China)
- Donglin Wang (Chongqing, China)
- ChengPing Hu (Changsha, China)
- Jianying Zhou (Hangzhou, China)
- Lin Wu (Changsha, China)
- Lejie Cao (Hefei, China)
- Jiwei Liu (Dalian, China)
- Helong Zhang (Xi'an, China)
- Hong Sun (Xi'an, China)
- Ziping Wang (Beijing, China)
- Hongjun Gao (Beijing, China)
- Yan Yan (Shanghai, China)
- Suijun Xiao (Shanghai, China)
- Jianxin Lin (Kenilworth, United States of America)
- M. Catherine Pietanza (Kenilworth, United States of America)
- Takayasu Kurata (Osaka, Japan)
Abstract
Background
Pembrolizumab + chemotherapy (pembro–chemo) have shown improved OS, PFS and ORR vs chemo alone regardless of PD-L1 tumor proportion score (TPS) in patients (pts) with advanced NSCLC. This exploratory analysis presents pooled results of pembro–chemo vs chemo in East Asian pts with advanced/metastatic PD-L1–negative (ie, TPS <1%) NSCLC.
Methods
Pts enrolled in China, Japan, Korea, Thailand, and Taiwan in KEYNOTE-021 cohort G (NCT02039674), KEYNOTE-189 (NCT02578680), KEYNOTE-189 Japan extension (NCT03950674), KEYNOTE-407 (NCT02775435) and KEYNOTE-407 China extension (NCT03875092) were included. Pts were randomized to platinum-pemetrexed ± pembro (nonsquamous) or carboplatin-paclitaxel/nab-paclitaxel ± pembro (squamous). Efficacy was assessed in the pooled ITT population, safety in all treated pts. Tumor response was assessed by BICR per RECIST v1.1. Tumor PD-L1 expression was assessed centrally using the PD-L1 IHC 22C3 pharmDx assay. Analyses are descriptive.
Results
107 Asian pts with PD-L1 TPS <1% were included (pembro–chemo, n = 56; chemo, n = 51). Median time from randomization to data cutoff was 33.4 (range, 25.3–49.2) mo. OS, PFS, PFS2, and ORR were improved for pembro–chemo vs chemo alone (Table). Grade ≥3 AEs occurred in 80% of pts receiving pembro–chemo and 82% receiving chemo. Among 18 pts who crossed over to pembro on study from the chemo group, median OS from pembro initiation was 11.7 (95% CI, 6.0–18.9) mo. 9 pts (16%) in the pembro–chemo group completed 35 cycles of pembro, all had PR (median DOR 31.1 [range, 9.1–34.5+] mo) and were alive at data cutoff.
Conclusions
Pembro–chemo provided clinically meaningful benefit vs chemo alone with manageable safety in East Asian pts with PD-L1–negative advanced/metastatic NSCLC. Results are consistent with global phase 3 studies and support continued use of pembro–chemo as standard-of-care therapy in pts with NSCLC, regardless of PD-L1 expression. '+’ indicates no progressive disease by the time of last disease assessment.aPFS2 defined as the time from randomization to second or subsequent disease progression on next line of treatment or death from any cause.
Pembro-Chemo n = 56 Chemo Alone n = 51 OS, median (95% CI) mo 21.3 (15.8–28.0) 12.6 (8.6–15.3) HR (95% CI) 0.55 (0.35–0.87) PFS, median (95% CI) mo 8.4 (6.1–10.4) 6.0 (4.2–6.5) HR (95% CI) 0.64 (0.43–0.96) PFS2, median (95% CI) moa 15.8 (13.2–20.1) 9.0 (6.7–10.5) HR (95% CI) 0.43 (0.28–0.66) ORR, % (95% CI) 71.4 (57.8–82.7) 43.1 (29.3–57.8) DOR, median (range), mo 6.7 (2.1 to 34.5+) 4.9 (1.4+ to 36.6+)
Clinical trial identification
NCT02039674, NCT02578680, NCT03950674, NCT02775435, NCT03875092.
Editorial acknowledgement
Medical writing assistance was provided by Kathleen Estes, PhD, of ICON plc (North Wales, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Legal entity responsible for the study
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Funding
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Disclosure
J.C. Yang: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Eli Lilly; Bayer; Roche/Genentech/Chugai; Astellas; Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Merck Serono; Pfizer; Novartis; Clovis Oncology; Celgene; Merrimack; Yuhan Pharmaceutical; Bristol Myers Squibb; On. I. Okamoto: Financial Interests, Personal, Other, Personal Fees: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Chugai Pharma, Eli Lilly, MSD Oncology, Ono Pharmaceutical, Taiho, Pfizer; Financial Interests, Personal, Research Grant: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Chugai Pharma, Eli Lilly, MSD Oncology, Ono Pharmaceutical, Taiho, AbbVie, Astellas Pharma, and Novartis. Y. Yan, S. Xiao: Financial Interests, Personal, Full or part-time Employment: MSD China. J. Lin: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. M.C. Pietanza: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Kenilworth, NJ, USA. T. Kurata: Financial Interests, Personal, Other, Personal Fees: AstraZeneca, MSD, Eli Lilly, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, Boehringer Ingelheim, and Pfizer; Financial Interests, Personal, Research Grant: AstraZeneca, MSD, Chugai Pharmaceutical, Takeda, and Bristol Myers Squibb. All other authors have declared no conflicts of interest.
7P - Distinct immune gene programs associated with host tumor immunity, neoadjuvant chemotherapy and chemoimmunotherapy in resectable NSCLC
- Pedro Simoes da Rocha (Houston, United States of America)
- Pedro Simoes da Rocha (Houston, United States of America)
- Jiexin Zhang (Houston, United States of America)
- Raquel Laza-Briviesca (Majadahonda, Spain)
- Alberto Cruz-Bermudez (Majadahonda, Spain)
- Katsuhiro Yoshimura (Houston, United States of America)
- Carmen Behrens (Houston, United States of America)
- Apar Pataer (Houston, United States of America)
- Edwin R Parra (Houston, United States of America)
- Cara Haymaker (Houston, United States of America)
- Junya Fujimoto (Houston, United States of America)
- Stephen G Swisher (Houston, United States of America)
- John V Heymach (Houston, United States of America)
- Don L Gibbons (Houston, United States of America)
- J. Jack Lee (Houston, United States of America)
- Boris Sepesi (Houston, United States of America)
- Tina Cascone (Houston, United States of America)
- Luisa M Solis (Houston, United States of America)
- Mariano Provencio (Majadahonda, Spain)
- Humam Kadara (Houston, United States of America)
- Ignacio I Wistuba (Houston, United States of America)
Abstract
Background
Our understanding of the immunopathology of early-stage NSCLC is still limited. While neoadjuvant immunotherapeutic strategies have recently shown anti-tumor effects in resectable NSCLC, their mechanisms remain inadequately understood. Here, we explore immune programs that inform of tumor immunity and response to neoadjuvant chemotherapy and chemoimmunotherapy in localized NSCLC.
Methods
Targeted immune gene sequencing using the HTG Precision Immuno-Oncology panel was performed in localized NSCLCs from three cohorts based on treatment: naïve (n=190), neoadjuvant chemotherapy (n=38) and neoadjuvant chemoimmunotherapy (n=21). Three tumor immune microenvironment (TIME) phenotypes (inflamed, cold, excluded) were derived based on CD8+ T cell infiltration. Signatures of immune cell abundance and immune genes were statistically compared based on tumoral PD-L1 expression, immune phenotypes, associated with pathological response, and were cross-compared across the three cohorts.
Results
PD-L1 positive tumors exhibited increased signature scores for various lymphoid and myeloid cell subsets (both, p<0.05). TIME phenotypes exhibited disparate frequencies by stage, PD-L1 expression, and mutational burden. Inflamed NSCLCs displayed overall significantly heightened levels of immune signatures with the excluded group representing an intermediate state. A signature of cytotoxic T cells was associated with favorable survival in neoadjuvant chemotherapy-treated NSCLCs (p<0.05). Major pathological response to chemoimmunotherapy was positively associated with CD8 T cells (p<0.05) and Th1 cells were significantly reduced post-chemoimmunotherapy (p<0.001). Among the three cohorts, chemoimmunotherapy-treated NSCLCs exhibited highest scores for various immune cell subsets including T effector and B cells (both, p<0.05).
Conclusions
Our findings highlight immune gene programs that may underlie host tumor immunity and response to neoadjuvant chemotherapy and chemoimmunotherapy in early-stage NSCLC.
Legal entity responsible for the study
The University of Texas MD Anderson Cancer Center.
Funding
MD Anderson Cancer Center.
Disclosure
All authors have declared no conflicts of interest.
8P - Pre-treatment blood gene expression changes associated with durable clinical benefit in metastatic non-small-cell lung cancer with high PD-L1 expression receiving first-line pembrolizumab
- Mariam Elshiaty (Heidelberg, Germany)
- Mariam Elshiaty (Heidelberg, Germany)
- Fabienne Lusky (Heidelberg, Germany)
- Farastuk Bozorgmehr (Heidelberg, Germany)
- Lena Gaissmaier (Heidelberg, Germany)
- Hannah Schindler (Heidelberg, Germany)
- Isabel Poschke (Heidelberg, Germany)
- Arlou Angeles (Heidelberg, Germany)
- Florian Janke (Heidelberg, Germany)
- Mark Kriegsmann (Heidelberg, Germany)
- Jonas B. Kuon (Heidelberg, Germany)
- Rajiv Shah (Heidelberg, Germany)
- Marc A. Schneider (Heidelberg, Germany)
- Lea Daniello (Heidelberg, Germany)
- Michael Meister (Heidelberg, Germany)
- Thomas Muley (Heidelberg, Germany)
- Florian Eichhorn (Heidelberg, Germany)
- Holger Sültmann (Heidelberg, Germany)
- Albrecht Stenzinger (Heidelberg, Germany)
- Michael Thomas (Heidelberg, Germany)
- Petros Christopoulos (Heidelberg, Germany)
Abstract
Background
Metastatic non-small-cell lung cancers (NSCLC) with PD-L1 tumor proportion score (TPS) ≥ 50% are immune reactive neoplasms with sensitivity to first-line pembrolizumab monotherapy. However, reliable biomarkers to identify patients who benefit from this line of treatment are still lacking.
Methods
We retrospectively analyzed baseline blood samples of newly diagnosed stage IV NSCLC patients with PD-L1 TPS ≥50% who received pembrolizumab monotherapy and experienced rapid progression (RP, progression-free survival [PFS] <3 months, n=17), or a durable benefit under treatment (DB, [PFS] >6 months, n=27). The expression for 13 genes (PD1, FOXP3, CD247, PRF1, GZMB, TBX21, MKI67, HLA-DRA, FAS, FASLG, GATA3, RORγt, IFNγ) of special immunologic interest was quantified in absolute terms using real-time PCR from reverse-transcribed whole blood RNA.
Results
Patients in the DB group had a significantly higher percentage of lymphocytes (Ly%, 15.7% vs 11.8%; p= 0.004), a lower neutrophil-to-lymphocyte ratio (NLR, 5.0 vs. 7.8, p=0.011), a higher absolute lymphocyte count (ALC, 1.49 vs 1.22 x103/μl; p =0.043) and a higher overall expression of PD1 (2,204 vs. 1,671 x103 copies/μg blood RNA, p=0.016) in peripheral blood compared to the RP group. Adjustment for the Ly% of each sample revealed that patients in the RP had a higher relative expression of FOXP3 and TBX21 compared to these in the DB group (6,150 vs. 3,531 x103 copies/μg RNA, p= 0.003; and 80,776 vs. 61,361 x103 copies/μg RNA, p= 0.023, respectively).
Conclusions
Durable clinical response to pembrolizumab monotherapy in NSCLC is associated with higher absolute counts and percentages of lymphocytes, a higher expression of PD-1, and a relative downregulation of FOXP3 and TBX21 in the peripheral blood prior to therapy start. Ongoing work aims to validate these findings in larger patient cohorts, evaluate longitudinal changes under treatment, and analyze the potential clinical utility in other NSCLC patient subsets.
Legal entity responsible for the study
Thoraxklinik Heidelberg.
Funding
German Center for Lung Research (DZL).
Disclosure
M. Thomas: Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Bristol Myers Squibb; Financial Interests, Institutional, Funding: Roche; Financial Interests, Institutional, Funding: Takeda; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Chugai; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Beigene; Financial Interests, Personal, Advisory Board: GlaxoSmithKline. P. Christopoulos: Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Roche; Financial Interests, Institutional, Funding: Takeda; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Chugai; Financial Interests, Personal, Advisory Board: Kite; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Takeda. All other authors have declared no conflicts of interest.
9P - HLA-I homozygosity as a predictive biomarker for developing immune related adverse events (irAE) among non-small cell lung cancer (NSCLC) patients treated with single agent immunotherapy
- Afaf Abed (Perth, Australia)
- Afaf Abed (Perth, Australia)
- Ngie Law (Nedlands, Australia)
- Leslie Calapre (Joondalup, Australia)
- Samantha Bowyer (Nedlands, Australia)
- Michael Millward (Nedlands, Australia)
- Elin Gray (Joondalup, Australia)
Abstract
Background
Immune checkpoint inhibitors have revolutionised the management of NSCLC. However, the development of irAEs is associated with morbidity that can be lifelong and even fatal. While it has been suggested that human leukocyte antigen (HLA-I) homozygosity is associated with worse overall survival among NSCLC treated with single agent immunotherapy, its association with toxicity has not been examined.
Methods
We collected blood from 193 NSCLC patients treated with anti-PD1/L1 in the first- or second-line setting. Blood cells DNA was extracted and high-quality HLA typing performed. Toxicity data was collected and graded as per common terminology criteria for adverse event (CTCAE) V5.0. Univariate analysis using GraphPad Prism was used to correlate between HLA-I/II heterozygosity with toxicity. We investigated the relationship between toxicity, overall response rate (ORR), progression free survival (PFS) and overall survival (OS). In addition, we investigated the association between irAEs and different HLA-I/II supertypes and genotypes.
Results
We recorded 103 irAE among 179 patients suitable for analysis. Homozygosity at one or more HLA-I loci, but not HLA-II, was associated with reduced risk of irAE (RR=0.57, P=0.025). None of the patients with homozygosity at one or more HLA-I loci developed pneumonitis of any grade (RR=0.00, P=0.037) or grade 3 toxicity (RR=0.00, P=0.023). In addition, the HLA-A03 supertype or the HLA-DRB1*0401 allele were associated with increased risk of developing irAE, (RR=1.40, P=0.039) and (RR=1.51, P=0.023), respectively. None of the patients with HLA-DQB1*0301 experienced gastrointestinal toxicity (RR=0.00, P=0.048). The occurrence of any irAE was associated with improved ORR (RR=1.94, P<0.0001), PFS (HR=0.37, P<0.0001) and OS (HR=0.26, P<0.0001), respectively. The use of steroids to treat irAE did not diminish this association.
Conclusions
Maximal HLA-I loci heterozygosity may be a useful biomarker to predict irAEs, especially pneumonitis among NSCLC patients treated with anti-PD1/PD-L1 in the first- or second-line setting. However, the occurrence of any irAE is correlated with favourable clinical outcome.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
10P - Family history of cancer correlates with improved outcome from immunotherapy in NSCLC independent of somatic DNA damage response gene status.
- Alessio Cortellini (London, United Kingdom)
- Alessio Cortellini (London, United Kingdom)
- Marco Filetti (Rome, Italy)
- Fabrizio Citarella (Rome, Italy)
- Raffaele Giusti (Rome, Italy)
- Marco Russano (Rome, Italy)
- Francesco Grossi (Varese, Italy)
- Alain J. Gelibter (Rome, Italy)
- Federica Pecci (Ancona, Italy)
- Michele De Tursi (Chieti, Italy)
- Marianna Macerelli (Udine, Italy)
- Olga Nigro (Varese, Italy)
- Miriam G. Ferrara (Rome, Italy)
- Sebastiano Buti (Parma, Italy)
- Francesca Mazzoni (Firenze, Italy)
- Luca Cantini (Ancona, Italy)
- Maria Rita Migliorino (Rome, Italy)
- Alfredo Addeo (Geneva, Switzerland)
- Vincenzo Adamo (Messina, Italy)
- Alessandro Russo (Messina, Italy)
- David J. Pinato (London, United Kingdom)
Abstract
Background
Germline DDR genes mutations are the most frequently involved mechanism for inherited cancer susceptibility, and we reported that high burden of family history of cancer (FHC), namely FHC-high, was associated with prolonged OS/PFS to PD-1/PD-L1 inhibitors in a multiple-cancer cohort.
Methods
We present the outcome analysis according to FHC from two large multicentre cohorts of patients with metastatic NSCLC receiving either first-line pembrolizumab (PD-L1 expression ≥ 50%) or chemotherapy. Patients were categorized as FHC-high and FHC-low/negative, as previously reported. To explore the association between somatic DDR genes alteration and FHC, we gathered targeted DNA tumour sequencing (FoundationOne CDx assay), from a parallel cohort of patients with NSCLC identifying 24 genes of interest (MLH1-6, PMS2, ATM, ATR, CHEK1-2, BAP1, BARD1, BRCA1-2, BRIP1, PALB2, RAD51-52-51C, FANCA-C-G-L, POLD1, POLE, ERCC4, XRCC2).
Results
728 and 652 patients were included in the pembrolizumab/chemotherapy cohorts. We performed a perfect random case-control matching between the two cohorts and 607 patients from each cohort were randomly paired on the basis of the FHC, age, ECOG-PS, and burden of disease. As compared to FHC-low/negative patients, FHC high achieved longer OS (HR=0.67, 95%CI: 0.46-0.95; p = 0.028), longer PFS (HR=0.65, 95%CI: 0.48-0.89; p = 0.007) and higher DCR (86.4 vs 67.5, p = 0.009), within the pembrolizumab cohort. On the contrary, no significant associations were found between FHC and OS (p = 0.075), PFS (p = 0.001), and DCR (p = 0.120), within the chemotherapy cohort. 118 patients were included in the DDR cohort, of which 20 FHC-high (16.9%) and 98 FHC-low/negative (83.1%). The prevalence of at least one DDR genes somatic mutations was 20% and 24.5% for FHC-low/negative and FHC-high patients, respectively (p = 0.668). The median TMBs were 6 and 7.6 Mut/Mb for FHC-high and low/negative (p = 0.6018), no association with PD-L1 was reported.
Conclusions
FHC-high identifies NSCLC with improved outcomes to pembrolizumab but not chemotherapy, suggesting its role as a surrogate marker. Somatic DDR genes are not associated with FHC and further investigations with broader germline testing are warranted.
Legal entity responsible for the study
Imperial College London and University of L'Aquila.
Funding
Has not received any funding.
Disclosure
A. Cortellini: Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: AstraZeneca. D.J. Pinato: Financial Interests, Personal, Invited Speaker: ViiV Healthcare; Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Advisory Board: Mina Therapeutics; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Funding: MSD; Financial Interests, Institutional, Funding: Bristol Myers Squibb. All other authors have declared no conflicts of interest.
11P - Senescent Immune Phenotype (SIP) status that predicts resistance to Immune Checkpoint Blockers (ICB) among CMV+ advanced Non-Small Cell Lung Cancer (aNSCLC) patients is not associated with chronic type I IFN signature
- Marie Naigeon (Villejuif, Cedex, France)
- Marie Naigeon (Villejuif, Cedex, France)
- Caroline De Oliveira (Villejuif, Cedex, France)
- François-Xavier Danlos (Villejuif, France)
- Boris Duchemann (Bobigny, France)
- Patrick Saulnier (Villejuif, Cedex, France)
- Lisa Boselli (Villejuif, Cedex, France)
- Jean-Mehdi Jouniaux (Villejuif, Cedex, France)
- Frank Griscelli (Villejuif, Cedex, France)
- Aurelien Marabelle (Villejuif, France)
- Ludovic Lacroix (Villejuif, Cedex, France)
- Lydie Cassard (Villejuif, Cedex, France)
- Benjamin Besse (Villejuif, France)
- Nathalie Chaput-Gras (Villejuif, France)
Abstract
Background
Immunosenescence is a progressive remodeling of immune functions with a multifactorial etiology (aging, chronic inflammation, persistent infections, cancer). CMV has been shown to act as chronic antigenic stressor and to accelerate immune ageing by affecting peripheral blood T cell phenotypes, including loss of CD28 or overexpression of CD57. Latent viral infections were shown to be associated with chronic type I IFN signature that might promote lymphocyte senescence. We defined SIP as the proportion of CD28–CD57+KLRG1+CD8+ circulating T cells. We showed that a high pretreatment SIP (>39.5%, SIP+) was associated with resistance to ICB in patients with aNSCLC. We aimed to assess the role of SIP combined to CMV status on outcomes in aNSCLC patients and the association between SIP and chronic type I IFN signature.
Methods
Baseline SIP status was assessed by flow cytometry on fresh blood samples from ICB-treated and polychemotherapy-treated (PCT) aNSCLC patients. Type I IFN score was calculated by the sum of relative expression of 5 IFN-stimulated genes (IFI44, IFIT1, IFITM1, LY6E, MX1), determined by RT-qPCR. Soluble factors associated to interferons (IFNα, IFNβ, IFNλ, IP-10, PD-L1) were quantified using the MSD assay.
Results
203 aNSCLC patients (142 ICB-treated, 61 PCT-treated) were evaluable for SIP (19.7% SIP+) and 180 patients (89%) for CMV status. CMV+ patient’s rate was significantly higher in SIP+ compared to SIP- patients (91.4% vs 50%, p<0.0001). Among CMV+ patients, SIP+ represents only 30%. In ICB-treated patients, CMV status was not sufficient to predict outcomes (median PFS 6.21 in CMV- vs 3 months in CMV+ patients, p=0.087). Among CMV+ patients, SIP+ patients had lower PFS (1.9 vs 3.3 months, p=0.006) and OS (6.2 vs 22.8 months, p=0.008) than SIP-. Otherwise, at baseline, no association between SIP and type I IFN signature nor plasmatic levels of IFN-related factors was found.
Conclusions
SIP+ patients are CMV+, SIP+ identifies patients with poorer outcomes in CMV+ ICB-treated aNSCLC. No association between type I IFN signature or IFN-related plasmatic factors and SIP was found.
Clinical trial identification
NCT02666612, NCT02105168, NCT03984318.
Legal entity responsible for the study
Gustave Roussy.
Funding
Malakoff Médéric.
Disclosure
B. Duchemann: Non-Financial Interests, Institutional, Other: Roche; Non-Financial Interests, Institutional, Other: Oxyvie; Non-Financial Interests, Institutional, Other: Pfizer; Non-Financial Interests, Institutional, Other: AstraZeneca; Financial Interests, Institutional, Other: MSD; Financial Interests, Institutional, Other: Bristol Myers Squibb; Financial Interests, Institutional, Other: Chiesi. N. Chaput: Financial Interests, Institutional, Sponsor/Funding: AstraZeneca; Financial Interests, Institutional, Sponsor/Funding: Bristol Myers Squibb; Financial Interests, Institutional, Sponsor/Funding: GlaxoSmithKline; Financial Interests, Institutional, Sponsor/Funding: Roche; Financial Interests, Institutional, Sponsor/Funding: Sanofi; Financial Interests, Institutional, Sponsor/Funding: Cytune Pharma. All other authors have declared no conflicts of interest.
12P - Blood-based Biomarker Analysis for Predicting Efficacy of Definitive Concurrent Chemoradiotherapy and Durvalumab Consolidation in Patients with Unresectable Locally Advanced Non-Small Cell Lung Cancer
- Cheol-Kyu Park (Hwasun, United States of America)
- Cheol-Kyu Park (Hwasun, United States of America)
- Hyun-Ju Cho (Hwasun, Korea, Republic of)
- In-Jae Oh (Hwasun, Korea, Republic of)
- Young-Chul Kim (Hwasun, Korea, Republic of)
Abstract
Background
This study aimed to investigate the feasibility of using circulating tumor cells (CTCs) and peripheral blood cells (PBCs) as biomarkers for predicting the efficacy of concurrent chemoradiotherapy (CCRT) and durvalumab consolidation (DC) in patients with locally advanced non-small cell lung cancer (NSCLC).
Methods
We recruited patients diagnosed with unresectable stage III NSCLC who received definitive CCRT between March 2020 and March 2021. DC was permitted in patients who did not progress after CCRT and tumor PD-L1 ≥1%. Blood samples were collected before (C0) and after CCRT (C1) to calculate PBC counts and analyze CTCs. CTCs, isolated using CD-PRIMETM system, exhibited EpCAM/CK+/CD45− phenotype in BioViewCCBSTM.
Results
A total of 50 patients were enrolled and 23 patients received DC. The median progression-free survival (PFS) was not significantly different between patients with and without DC (12.7 vs. 11.7 months; p=0.532). In overall, patients with higher platelets (PLThi, >252ⅹ103/uL) at C1 had worse median PFS than those with lower platelets (PLTlo, ≤252ⅹ103/uL) (5.9 vs. 13.5 months; p<0.001). In DC group, patients with residual CTC clusters after CCRT (C1) had worse median PFS than those without detectable CTC cluster (9.5 vs. 13.1 months; p=0.099). In multivariate analysis, PLThi at C1 was an independent factor for PFS (hazard ratio [HR] 10.86, 95% confidence interval [CI] 2.83-41.77; p=0.001), and patients with DC who had PLThi and residual CTC clusters at C1 showed the worst PFS (2.6 months, HR 33.30; p=0.001), even worse than those without DC who had PLThi (5.9 months, HR 13.37; p=0.004).
Conclusions
Comprehensive analysis of CTC and PBC counts before and after CCRT, especially CTC clusters and platelets at C1, demonstrated they might be biomarkers for predicting survival. This finding could aid in risk stratification of patients with unresectable stage III NSCLC who are eligible for DC after definitive CCRT.
Legal entity responsible for the study
The authors.
Funding
Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT).
Disclosure
All authors have declared no conflicts of interest.
13P - High Neutrophils-to-Lymphocyte Ratio (NLR) Predicts Poor Survival of High-PD-L1-expressing metastatic Non Small Cell Lung Carcinoma Patients Undergoing First Line Immunotherapy with Pembrolizumab
- Francesco Jacopo Romano (Napoli, Italy)
- Francesco Jacopo Romano (Napoli, Italy)
- Carmela Barbato (Napoli, Italy)
- Dario Arundine (Napoli, Italy)
- Francesca Ambrosio (Napoli, Italy)
- Riccardo Ronga (Napoli, Italy)
- Giuseppe Failla (Naples, Italy)
- Livio Moccia (Naples, Italy)
- Nadia Corcione (Naples, Italy)
- Gianluca Guggino (Naples, Italy)
- Antonio Raucci (Naples, Italy)
- Luigia Romano (Naples, Italy)
- Severo Campione (Naples, Italy)
- Gianfranco De Dominicis (Naples, Italy)
- Carlo Santoriello (Naples, Italy)
- Aniello Tinto (Naples, Italy)
- Christian Russo (Naples, Italy)
- Fausto De Michele (Naples, Italy)
- Antonio Russo (Naples, Italy)
- Antonio Starace (Naples, Italy)
- Ferdinando Riccardi (Napoli, Italy)
Abstract
Background
Systemic inflammatory response has independent prognostic value, across tumour types and geographical locations, in patients with advanced cancer: an elevated ratio of peripheral neutrophils-to-lymphocytes (NLR) has been recognized as a poor prognostic indicator in various cancers. This study aimed to determine whether NLR and platelets-to-lymphocytes ratio (PLR) reflect poor treatment benefits in patients suffering from metastatic Non Small Cell Lung Cancer (mNSCLC) who underwent first-line pembrolizumab monotherapy.
Methods
We retrospectively analyzed 87 mNSCLC patients with programmed cell-death ligand 1 (PD-L1) TPS ≥50%, who received pembrolizumab monotherapy in our institution between 2017 and 2020. NLR and PLR were calculated from pre-treatment complete blood counts. We evaluated univariate Kaplan Meier estimated overall survival and multivariate Cox Regression Hazard Ratio: cut point of NLR and PLR were obtained with a Survival Analysis for Continuous Explanatory Variable.
Results
Patients with NLR lower than 8.59 had a median OS of 19 months vs 2,8 months of NLR high counterpart (p-value 0,0005); patients with PLR higher and lower than 207 have a median OS of 18,8 vs 12,1 months, respectively (p-value 0,173). Multivariate analysis revealed that high NLR, bone and liver metastases significantly and independently correlated to poor overall survival.
Conclusions
High NLR is associated to significantly shorter overall survival in previously untreated patients with NSCLC with high expression of PD-L1 treated with pembrolizumab monotherapy.
Legal entity responsible for the study
Francesco Jacopo Romano.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
14P - Circulating tumor DNA (ctDNA) residual and dynamics of ctDNA clonality indicated therapeutic efficacy of Sintilimab plus Docetaxel in previously treated advanced non-small cell lung cancer
- Zhehai Wang (Jinan, China)
- Zhehai Wang (Jinan, China)
- Xiao Han (Jinan, China)
- Jun Guo (Jinan, China)
- Xiaoyong Tang (Jinan, China)
- Changbin Zhu (Xiamen, China)
- Hui Zhu (Jinan, China)
- Dongyuan Zhu (Jinan, China)
- Xiqin Zhang (Jinan, China)
- Xiangjiao Meng (Jinan, China)
Abstract
Background
Sintilimab + docetaxel showed encouraging efficacy and tolerable safety profile in advanced Chinese NSCLC pts who had failed first-line therapy. This study aims to explore potential circulating biomarker(s), especially dynamics of ctDNA, predicting therapeutic response and long-term outcome.
Methods
Advanced NSCLC pts who had failed standard platinum doublet or EGFR-TKI without receiving any ICIs before would be enrolled in this single-arm phase II study. Docetaxel (75mg/m2, day 1) + Sintilimab (200mg, day 3) every 3 weeks for 4-6 cycles followed by Sintilimab maintenance were prescribed until disease progression, unacceptable toxicity, or up to 2 years. 10 mL blood would be drawn from each patient immediately after enrollment (baseline, C0D0) and after two cycles of treatment. ctDNA was detected via a 448-gene panel. bTMB was calculated as the number of mutations divided by sequence length (1.16Mb). Positivity was defined as ≥ 2 somatic variants, ≤ 1 somatic variant within a sample was considered negative. Clonality was defined as AF/AFmax ≥ 50%.
Results
Pts with positive ctDNA after 2 courses of treatment (at 6th week) displayed inferior prognosis (mPFS, 91d vs NR, ctDNA (+) vs ctDNA (-) after 2 treatment courses respectively, P < 0.0001; mOS, 147d vs 467d, P = 0.0039). Irrespective of driver mutations (EGFR, ERBB2 in this study), ctDNA residual at 6th week was an independent risk factor for progression or death (HR = 100 [4.10-2503.00], P = 0.005, Cox Regression). Furtherly, clearance of clonal mutations and no clonal formation at 6th week were associated with longer PFS (mPFS 89d vs 266d, HR = 4.40 [0.84-23.16], P = 0.003); Clearance of clonal mutations was associated with longer OS (mOS 147d vs 467d, HR = 7.01 [1.30-37.69], P = 0.0048). Baseline bTMB was not associated with the efficacy of Sintilimab+ Docetaxel treatment.
Conclusions
ctDNA residual, as well as dynamics of clonality in ctDNA could predict long-term clinical benefit of sintilimab + docetaxel in pts with previously treated advanced NSCLC, irrespective of driver mutations as well as bTMB. Further validation of ctDNA residual and dynamics of clonality as robust predictive biomarkers is warranted.
Clinical trial identification
ChiCTR1900027634.
Legal entity responsible for the study
Zhehai Wang.
Funding
Has not received any funding.
Disclosure
C. Zhu: Other, Institutional, Full or part-time Employment: Amoy Diagnostics. All other authors have declared no conflicts of interest.
15P - Serum immune checkpoint biomarkers as predictors of response to anti-PD-1/PD-L1 treatment in Non-Small Cell Lung Cancer (NSCLC) patients
- Afsheen Raza (Ad-Dawhah, Qatar)
- Afsheen Raza (Ad-Dawhah, Qatar)
- Reyad Mohsin (Ad-Dawhah, Qatar)
- Aladdin Kanbour (Ad-Dawhah, Qatar)
- Suma Vijayakar (Ad-Dawhah, Qatar)
- Anite Philip (Ad-Dawhah, Qatar)
- Melissa A. Tauro (Ad-Dawhah, Qatar)
- Shereena Sherif (Ad-Dawhah, Qatar)
- Maysaloun Merhi (Ad-Dawhah, Qatar)
- Varghese Inchakalody (Ad-Dawhah, Qatar)
- Abdul Rehman Zar Gul (Ad-Dawhah, Qatar)
- Mohammed Ussama Al Homsi (Ad-Dawhah, Qatar)
- Said Dermime (Ad-Dawhah, Qatar)
Abstract
Background
There is limited data on the predictive biomarkers of response to immune checkpoint blockade (ICB) treatment of non-small cell lung cancer (NSCLC) patients. The main aim of this prospective study is to understand the utility of pre-treatment soluble immune checkpoint and tumor markers as early predictors of response in locally advanced/metastatic NSCLC patients treated with ICBs.
Methods
The study was conducted at the National Center for Cancer Care and Research (NCCCR), HMC, Qatar. A total of 26 patients on anti-PD-1/PDL-1 treatment were enrolled, and pre-treatment blood samples were collected. Multiplex Magnetic Bead Panel kits were utilized to measure concentrations of soluble immune checkpoint and tumor markers including BTLA, GITR, HVEM, IDO, LAG-3, PD-1, PDL-1, PDL-2, TIM-3, CD28, CD80, 4-1BB, CD27, CTLA-4, ICOS Ligand, CD276, VISTA, B7-H6; CD47 (IAP), BLAST-1, Galectin-9, TIMD-4; OX40, S100A8/A9, E-cadherin, MICB, Nectin 2, NTSE, PVR, Singlec 7, Singlec 9,CEA, CA-19-9, CA-125 CYFRA21-1 and CA-15-3. Mann-Whitney test was used to evaluate difference in medians in responders and non-responders. Response to treatment was assessed 4 months after initiation of treatment via PET CT imaging data.
Results
Clinical response to ICB treatment was determined based on RECIST criteria and PET CT imaging data. 12/26 (46%) patients showed clinical response to the treatment while 14/26 (54%) were identified as non-responders. Interestingly, in clinically responding patients, significant upregulation of the immune inhibitory soluble programmed death-ligand 1 (sPD-L1) molecule (<0.002**) and the immune stimulatory biomarkers glucocorticoid-induced TNFR-related protein (GITR) (<0.0005***), and Herpes virus entry mediator (HVEM) (<0.006**) were recorded. However, non-responding patients showed significant upregulation of 3 important immune suppressive biomarkers; T-cell immunoglobulin and mucin domain containing 4 (TIMD-4) (p<0.0361*), Nectin 2 (p<0.0310*) and the carcinoembryonic antigen (CEA) tumor marker (p<0.0484*).
Conclusions
The study shows that soluble immune suppressive/stimulatory biomarkers can serve as plausible early biomarkers of response to ICB treatment.
Legal entity responsible for the study
Medical Research Center, Hamad Medical Corporation.
Funding
Medical Research Center, Hamad Medical Corporation.
Disclosure
All authors have declared no conflicts of interest.
16P - Stromal compartment specific gene signatures dissect immunotherapy response groups in non-small cell lung cancer
- Arutha Kulasinghe (Brisbane, Australia)
- Arutha Kulasinghe (Brisbane, Australia)
- Kenneth J. O'Byrne (Woolloongabba, Australia)
Abstract
Background
Immunotherapies, such as immune checkpoint inhibitors (ICI) have shown durable benefit in a subset of non-small cell lung cancer (NSCLC) patients. The composition and activation status of the cellular milieu contained within the tumour microenvironment (TME) is becomingly increasingly recognised as a driving factor in treatment-refractory disease.
Methods
Here, we employed multiplex IHC (mIHC), and digital spatial profiling (DSP) to capture the targeted immune proteome and transcriptome of tumour and TME compartments of pre-treatment samples from a 2nd line NSCLC ICI-treated cohort (n=41 patients; n=25 responders, n=16 non-responders).
Results
Patients sensitive to ICI therapy expressed higher levels of IL2 receptor alpha (CD25, p=0.028) within the tumour compartments, which corresponded with the increased expression of IL2 mRNA(p=0.001) within their stroma. IL2 mRNA levels within the stroma positively correlated with the expression of pro-apoptotic markers cleaved caspase 9(p=2e-5) and BAD(p=5.5e-4) and negatively with levels of memory T cells (CD45RO) (p=7e-4). Immuno-inhibitory markers CTLA-4(p=0.021) and IDO-1(p=0.023) were supressed in ICI-responsive patients. Tumour CD44(p=0.02) was depleted in the response group and corresponded inversely with significantly higher stromal expression of its ligand SPP1 (osteopontin,p=0.008). Analysis of differentially expressed transcripts indicated the potential inhibition of stromal interferon-gamma (IFNγ) activity and estrogen-receptor and Wnt-1 signalling activity within the tumour cells of ICI responsive patients. Cox survival analysis indicated tumour CD44 expression was associated with poorer prognosis (HR=1.61, p=0.01), consistent with its depletion in ICI sensitive patients. Interestingly, stromal mRNA for E-selectin (HR=652, p=0.001), CCL17 (HR=70, p=0.006) and MTOR (HR=1065, p=0.008) were highly associated with poorer outcome, indicating pro-tumourigenic features in the tumour microenvironment that may facilitate ICI resistance.
Conclusions
Through multi-modal approaches, we have dissected the characteristics of NSCLC and provide evidence for the role of IL2 and stromal activation by osteopontin in the efficacy of ICI therapy.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.