Background

Assessment of TMB for response stratification of cancer patients is emerging as a new biomarker for immunotherapy. TMB is defined as the total number of non-synonymous somatic mutations and it approximates the amount of neoantigens. Whole exome sequencing is recognized as the best approach to quantify TMB, nevertheless the cost and access represent relevant limitations. The aim of this investigation is to evaluate the capacity of out small panel to predict response to immunotherapy based on the calculation of a min-TMB score.

Methods

Patients with advanced tumors were screened for r targetable alterations. A customized hotspots NGS panel containing 87 genes, including 4 full CDS genes was used. Somatic mutations were selected as follow: 1) present in our somatic variant database; 2) mutation within cancer hotspot regions, in non-intronic regions with a population allele frequency < 0.1; 3) mutations with a known population frequency < 0.05%, with an unknown population frequency and not intronic; 4) Mutations in samples with a VAF over the selected thresholds (3%, 5% and 10%). A descriptive observational analysis was performed. Multivariable Cox regression analysis was carried out evaluating age, PS and TMB with R v3.6.2.

Results

Among 255 patients analyzed with our customized panel, only 46 received immunotherapy after the molecular screening as I or II line and were included. 25 received treatment with standard checkpoint inhibitors, while 21 received experimental immunotherapy. Median age was 61 (54-65). Tumor types represented were NSCLC, Melanoma HNSCC, GI and gynecological tumors. Median PFS was 5.4 (3.7-8.2) months. TMB was calculated and over patients treated with standard immunotherapy, the 3% non-synonymous mutations remained the only significant prognostic factor of PFS in the multivariable model (p=0.045).

Conclusions

The feasibility of the TMB score calculation depending on the panel size remains controversial. Our customized small panel shows that it could help in the identification of a predictive TMB score for those patients candidate to receive checkpoint inhibitors. Although these finding are promising, further investigation is needed.

Legal entity responsible for the study

The authors.

Funding

This study was supported by grants from the Instituto de Salud Carlos III (PI15/02180 and PI18/01909 to AC; PI18/01508 to TF). VG was supported by the ESMO 2014 fellowship program, and by Rio Hortega contract CM18/00241 from the Carlos III Health Institute; TF is supported by Joan Rodes contract 17/ 00026 from the Carlos III Health Institute. NT was supported by Rio Hortega contract CM15/00246 from the Instituto de Salud Carlos III and by the ESMO 2013 fellowship program; DR was supported by Joan Rodes contract 16/00040 from the Instituto de Salud Carlos III. SZ has a CA18/00042 contract for bio-informaticians from the Instituto de Salud Carlos III. R JMC is supported by a SEOM-Rio HOrtega contract 2019. MT has a predoctoral from the AECC (Spanish Cancer Association in Valencia). Part of the equipment used in this study has been funded by Generalitat Valenciana and co-financed with ERDF funds (OP ERDF of Comunitat Valenciana 2014-2020).

Disclosure

A. Cervantes: Honoraria (institution): Genentech; Honoraria (institution): F. Hoffmann-La Roche; Honoraria (institution): Astellas; Honoraria (institution): Merk-Serono; Honoraria (institution): BMS; Honoraria (institution): MSD; Honoraria (institution): Novartis; Honoraria (institution): Beigene; Honoraria (institution): Bayer; Honoraria (institution): Servier; Honoraria (institution): Lilly; Honoraria (institution): Takeda; Honoraria (institution): Fibrogen. All other authors have declared no conflicts of interest.

Background

Gastric cancer (GC) has poor prognosis and presents big heterogeneity and unknown mechanisms of drug resistance. Tumor organoids are a 3D in vitro culture platform from self-organizing tumor stem cells, which recapitulates the in vivo characteristics reflecting the heterogeneity of the original tumor. The establishment of gastric cancer organoids (GCO) represents a good strategy to evaluate tumor molecular features. GCO also permit testing drug resistance performing functional dynamical analyses, representing a relevant arm for precision medicine.

Methods

A prospective biobank of GCO derived from advanced GC patients, mostly from biopsies or palliative gastrectomy, was generated according to an in-house protocol from January 2019. Tissue samples were analyzed by a dedicated pathologist with immunohistochemistry for HER2, PD-L1, TILs and microsatellite status, tumor samples and GCO were also screened for EPCAM, CK7, CK20, CDX2 and MUC5A. The molecular profile was completed with next generation sequencing (NGS) analyses with an in-house panel (Illumina®) to match the original tumor and its GCO. To assess drug sensitivity, cell viability was analyzed through luminescent Cell Viability Assay.

Results

From February 2019, 25 GCO were established with a success rate of 68% (20 from gastroscopy, 3 from gastrectomy, 1 from ascites and 1 from pleural effusion). 64% of these tumors were intestinal, 24% diffuse and 12% mixed subtypes, according to Lauren classification. The organoids histopathological analysis matched with the original tumors. NGS analysis also showed a significant molecular concordance between the GCO and each original patient (R>0.90). The capability in reproducing GC heterogeneity was observed when GCO were generated from two different biopsies from the same patient. Copy number variation (CNV) analysis showed that only one of these lines was HER2+, being a mirror of the heterogenous expression of HER2 in the original tumor. Drug sensitivity assays were also performed to match the response observed in the GCO with each patient.

Conclusions

GCO could be a valuable tool for heterogeneity assessment as well as drug sensitivity for GC patients.

Legal entity responsible for the study

The authors.

Funding

This study was supported by grants from the Carlos III Health Institute (PI18/01508 to TF; PI15/02180 and PI18/01909 to AC). MC is supported by a pre-doctoral grant from the Spanish Cancer Association (AECC), Spain. FP is a recipient of an ESMO translational research grant. MFGB is a recipient of a Grisolia predoctoral grant (GRISOLIAP/2017/161) by the Conselleria de Educación, Investigación, Cultura y Deporte of Valencia. VG is supported by a Rio Hortega contract CM18/00241 from the Carlos III Health Institute. NT was supported by Rio Hortega contract CM15/00246 from the Carlos III Health Institute. DR was supported by Joan Rodes contract 16/00040 from the Carlos III Health Institute. TF is supported by Joan Rodes contract 17/00026 from the Carlos III Health Institute.

Disclosure

A. Cervantes: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Merck Serono; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Beigene; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Servier; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Takeda; Advisory/Consultancy, Research grant/Funding (institution): Astelas; Advisory/Consultancy: Pierre Fabre; Research grant/Funding (institution): Fibrogen; Research grant/Funding (institution): Amcure; Research grant/Funding (institution): Sierra Oncology; Research grant/Funding (institution): Astra Zeneca; Research grant/Funding (institution): Medimmune; Research grant/Funding (institution): BMS; Research grant/Funding (institution): MSD; Speaker Bureau/Expert testimony: Foundation Medicine; Research grant/Funding (institution): Genentech. All other authors have declared no conflicts of interest.

Background

Resistance to anti-HER2 drugs in HER2 amplified GC represents a limitation for precision medicine. In our HER2 amplified models, PI3K pathway activated NRF2, a master regulator of oxidative stress, inducing antiHER2-drug resistance. The aim of this study was to assess the role of chromosomal alterations and their relation with NRF2 antioxidant mechanism responsible for resistance in our resistant models.

Methods

The OE19 GC cell line and its lapatinib resistant subclones were used for this study. DNA and RNA extraction was carried out according to the manufacturers (ThermoFisher and Roche respectively). Gene expression profile was performed by Clariom™ S Assay (Applied Biosystems™). Chromosomal aberrations analysis was carried out with CytoScan HD Array (Applied Biosystems™) and analyzed with Chromosome Analysis Suite (ChAS) software. The results were analyzed with R. Cytoscape and the plug-in ClueGO, that integrates the terms Gene Ontology with KEGG and Reactome, were used to detect the activated pathways.

Results

Gene expression profile underlined a significantly higher expression of ARE-bearing genes, involved in the cellular response to oxidative stress, demonstrating a relevant role of NRF2 in antiHER2 resistance in our models. The chromosomal aberrations analysis showed an increase in genomic instability among resistant cells. In particular, the amplification of the ferritin light chain (FTL) gene (19q13.33) was detected with an increase of FTL/FTH (ferritin high chain) expression ratio that confers control of the oxidative stress promoting survival. The integrated analysis suggests that the activation of two antioxidative systems, NRF2, and ferritin, could effectively modulate oxidative stress causing antiHER2 resistance. The loss of CDKN1A (6p21.2) was also detected, confirming the worse proliferative phenotype.

Conclusions

Our results confirm the relevant role of control of oxidative stress in antiHER2 resistance. The integrated genomic and transcriptomic analysis would improve our understanding of the mechanisms of resistance leading to implement precision medicine.

Legal entity responsible for the study

The authors.

Funding

VG was supported by the ESMO 2014 fellowship program, and by Rio Hortega contract CM18/00241 from the Carlos III Health Institute; TF is supported by Joan Rodes contract 17/ 00026 from the Carlos III Health Institute. NT was supported by Rio Hortega contract CM15/00246 from the Instituto de Salud Carlos III and by the ESMO 2013 fellowship program; DR was supported by Joan Rodes contract 16/00040 from the Instituto de Salud Carlos III. JMC was supported by a Rio Hortega SEOM contract from the Instituto de Salud Carlos III 2019. SZ has a CA18/00042 contract for bio-informaticians from the Instituto de Salud Carlos III.

Disclosure

A. Cervantes: Honoraria (institution): Genentech; Honoraria (institution): Merck Serono; Honoraria (institution): BMS; Honoraria (institution): MSD; Honoraria (institution): Roche; Honoraria (institution): Beigene; Honoraria (institution): Bayer; Honoraria (institution): Servier; Honoraria (institution): Lilly; Honoraria (institution): Novartis; Honoraria (institution): Takeda; Honoraria (institution): Astellas; Honoraria (institution): Fibrogen. All other authors have declared no conflicts of interest.

Background

Colorectal cancer (CRC) patients derived organoids (PDOs) are an increasingly used model for precision medicine. Besides somatic mutations, CRC is characterized by certain levels of copy number alterations (CNAs), which can include oncogenes or tumor suppressors. Moreover, PDOs could be a platform for drug screening.

Methods

Metastatic CRC samples have been obtained from biopsies or surgical samples. After digestion, free cells have been seeded in basement membrane matrix with proper medium. Development of organoids has been observed. After reaching an appropriate volume, organoids have been fixed, stained for hematoxylin and eosin (H&E) and immunohistochemistry (IHC) with common CRC markers. Next generation sequencing (NGS) has been performed with a customized panel. For CNA analysis Cytoscan-HD (Thermo-Scientific) array and data analysis with Chromosome Analysis Suite (Applied Biosystems v4.0) has been performed. For drug assays, PDOs have been plated as single cells and after formation of organoids, chemotherapeutics and biological drugs according to mutational profile have been added. After 96 hours cell viability has been measured with CellTiter-Glo® 3D Reagent.

Results

The success rate in CRC-PDOs establishment is around 80%. PDOs morphology with H&E is comparable to the original tissue and IHC CDX2, CK20 and MUC2/5 positivity. Spectrum of PDOs mutations and polimorphisms is concordant with that of matched patients (R: 0.9). Cytoscan-HD reveals that PDOs maintain mosaicism indicating certain level of heterogeneity. Moreover, PDOs are enriched with CNAs segments. We were able to detect alterations in regions containing genes of interest, such as losses of SMAD2/4, MAP2K4, POLE2 and gains of MYC, CDX2, CARD11, AURKA and many others. Drug treatment showed a good concordance with patient response. Furthermore, we were able to confirm synergy of chemotherapeutics combination in our PDO’s models.

Conclusions

Metastatic CRC-PDOs recapitulate morphological and genomic features of the original patient. In addition to mutational profile, CNAs pattern allows to better capture genomic alterations. Drug assays are feasible and could be a valuable tool to predict patient’s response.

Legal entity responsible for the study

The authors.

Funding

This study was supported by grants from the Carlos III Health Institute (PI18/01508 to TF; PI15/02180 and PI18/01909 to AC). MC is supported by a pre-doctoral grant from the Spanish Cancer Association (AECC), Spain. FP is a recipient of an ESMO translational research grant. MFGB is a recipient of a Grisolia predoctoral grant (GRISOLIAP/2017/161) by the Conselleria de Educación, Investigación, Cultura y Deporte of Valencia. VG is supported by a Rio Hortega contract CM18/00241 from the Carlos III Health Institute. NT was supported by Rio Hortega contract CM15/00246 from the Carlos III Health Institute. DR was supported by Joan Rodes contract 16/00040 from the Carlos III Health Institute. TF is supported by Joan Rodes contract 17/00026 from the Carlos III Health Institute.

Disclosure

A. Cervantes: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Research grant/Funding (institution): Merck Serono; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Beigene; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Research grant/Funding (institution): Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Research grant/Funding (institution): Servier; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Lilly; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Novartis; Advisory/Consultancy: Takeda; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Astelas; Advisory/Consultancy: Pierre Fabre; Research grant/Funding (self), Research grant/Funding (institution): Genentech; Research grant/Funding (self), Research grant/Funding (institution): Fibrogen; Research grant/Funding (self), Research grant/Funding (institution): Amcure; Research grant/Funding (self), Research grant/Funding (institution): Sierra Oncology; Research grant/Funding (self), Research grant/Funding (institution): Astra Zeneca; Research grant/Funding (self), Research grant/Funding (institution): Medimmune; Research grant/Funding (self), Research grant/Funding (institution): BMS; Research grant/Funding (self), Research grant/Funding (institution): MSD; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: Foundation Medicine. All other authors have declared no conflicts of interest.

Background

Pathologic response to neoadjuvant therapy is strong correlated with high HER2 expression, but the patients with HER2 equivocal overexpression and amplification with FISH are considered as HER2 positive and received the same therapy. We need to know the clinical course in this subset of patients and the benefit of the antiher2 standard therapy.

Methods

A serie of 71 early or locally advanced breast cancer patients with HER2 equivocal overexpression and FISH amplification who received neoadjuvant treatment with chemotherapy and antiHER2 drugs were analyzed their complete pathological response (pCR) and the clinical-pathological variables associated.

Results

Median age was 55 years (31-88), median tumour size was 30 mm (13-100) and 30 (42%) patients had nodal involvement. Median ki67 expression was 40% (4-95), 20 (28%) tumours were estrogen receptor (ER) negative and 41 (72%) positive. The ratio HER2/CEP17 was superior to 2 in 40/59 (67,8%). A total of 19/71 patients (27%) achieved a pCR. In the univariable analysis, only the estrogen receptor=0 (OR 0,193 IC 95% 0,061-0,611, p: 0,005), were correlated to pCR. We do not found any correlation with other variables and previous treatment with anthracyclines or pertuzumab plus trastuzumab. The pCR in ER negative was 52% and the subgroup with a ratio of HER2/CEP17 superior to 2.0 was the more responsive with a total of 80% pCR compared with 25% in the ratio inferior to 2.0. Conversely the pCR in ER positive was 17,6% % but the subgroup with a ratio of HER2 superior to 2.0 was only of 13,8% % of pCR compared with 26,7% in the ratio inferior to 2.0. We do not analyze the benefit on survival because the short median follow-up although the overall median survival of the global group was 148 months (IC 95% 125 to 171 months).

Conclusions

Patients with equivocal HER2 overexpression and FISH amplification have an overall pCR of only 28.8%. More than 70% have ER positive, and the proportion of pCR is only 17.6%. However, the subgroup with ER negative and high expression of HER2 / CEP17 ratio achieves a percentage of pCR that reaches up to 80%. Therefore, it is important to select these subgroups with a low proportion of pCR to offer other therapeutic alternatives.

Legal entity responsible for the study

Hospital Universitari Arnau de Vilanova de Lleida.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

ABTL0812 induces cytotoxic autophagy-mediated cell death. It inhibits Akt/mTOR axis by upregulating TRIB3, an endogenous Akt inhibitor, and induces reticular (ER)-stress. Preclinical data in endometrial cancer (EC) indicated efficacy as a single agent and synergy with chemotherapy. A phase I of ABTL0812 with P/C confirmed the safety of the triple combination.

Methods

A single-arm phase II study was designed where ABTL0812 was administered 1300 mg TID orally with P/C 175 mg/m²/ AUC5 D1 every 3 weeks, followed by ABTL0812 as a maintenance until disease progression or unacceptable toxicity. The study enrolled patients (pts) with advanced/recurrent EC except carcinosarcoma and leiomyosarcoma. Primary endpoint was overall response rate (ORR) by RECIST criteria v.1.1. Secondary endpoints were progression free survival (PFS), duration of response (DOR), safety and tolerability according to CTCAE v4.03 and pharmacokinetics (PK). Target modulation was assessed by two pharmacodynamic (PD) markers: TRIB3 and CHOP (an ER-stress biomarker) in blood.

Results

42 pts received at least 1 dose of ABTL0812 and 34 were evaluable (median age: 67.9 years old; 15 advanced / 19 recurrent; 23 endometrioid / 2 serous / 2 clear cell / 7 not determined -ND; 3 grade-1, 7 grade-2, 9 grade-3 / 15 ND). ORR was 66% (95% CI: 46-80%), DOR was 7.8 months (6.3-10.8) and PFS was 10.2 months (7.1-11.4). Most frequent hematological adverse events (AEs) were neutropenia (all grades 23.8%, grade≥3 14.3%), anemia (21.4%, 2.4%) and thrombocytopenia (9.5%, 2.4%). Most frequent non-hematological AEs were nausea (47.6%, 2.4%), asthenia (45.2%, 0), vomiting (42.9%, 0), diarrhea (26.2%, 0), arthralgia and neurotoxicity (both 23.8%, 0). PK and PD analysis performed at 4 weeks showed that Cmax were 8.0/5.5 mg/L and t_1/2 3.3/2.0 h for -/+-ABTL0812; TRIB3 and CHOP levels increased.

Conclusions

The combination of ABTL0812+P/C shows promising results with an acceptable safety and tolerability profile. These outcomes look promising compared with historical controls and warrant further investigation. PK and PD profiles indicate sustained target modulation.

Clinical trial identification

EudraCT: 2016-001352-21.

Legal entity responsible for the study

Ability Pharmaceuticals SL.

Funding

Ability Pharmaceuticals SL.

Disclosure

A. Leary: Honoraria (self): Medscape; Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: GSK; Advisory/Consultancy: Biocad; Advisory/Consultancy: AbilityPharma; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: MSD; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Gamamabs; Research grant/Funding (self): Inivata; Research grant/Funding (self): Sanofi; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Clovis; Travel/Accommodation/Expenses: Tesaro. R. Sabatier: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: GSK; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Research grant/Funding (institution): Eisai. L. Fariñas-Madrid: Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Ability Pharma; Advisory/Consultancy, Speaker Bureau/Expert testimony: Tesaro; Advisory/Consultancy, Speaker Bureau/Expert testimony: GSK; Speaker Bureau/Expert testimony: MSD. J.A. Pérez-Fidalgo: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Ability Pharma; Advisory/Consultancy: Clovis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: GSK. M. Romeo: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Tesaro; Travel/Accommodation/Expenses: Pfizer. M.P. Barretina Ginesta: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: GSK; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony: Clovis Oncology; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: PharmaMar. M. Gil-Martin: Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: PharmaMar; Travel/Accommodation/Expenses: MSD. E. Garralda: Research grant/Funding (self): Novartis; Speaker Bureau/Expert testimony, Research grant/Funding (self): Roche; Advisory/Consultancy, Research grant/Funding (self): Thermo Fisher; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: F. Hoffmann/La Roche; Advisory/Consultancy: Ellipses Pharma; Advisory/Consultancy: Neomed Therapeutics Inc; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Janssen Global Services; Advisory/Consultancy: SeaGejn; Advisory/Consultancy: TFS; Advisory/Consultancy: Alkermes; Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: MSD; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Menarini; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Glycotope. J. Rodon: Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self): Eli Lilly; Honoraria (self): Orion Pharmaceuticals; Honoraria (self): Peptomyc; Honoraria (self), Advisory/Consultancy: Kelum Pharmaceuticals/Klus Pharma; Honoraria (self), Advisory/Consultancy: Spectrum Pharmaceuticals Inc; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self): Roche Pharmaceuticals; Honoraria (self): Ellipses Pharma; Honoraria (self): Certera; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Bayer; Honoraria (self): Ionctura; Research grant/Funding (institution): GlaxoSmithKline; Travel/Accommodation/Expenses: ESMO; Travel/Accommodation/Expenses: Department of Defense; Travel/Accommodation/Expenses: MSD; Travel/Accommodation/Expenses: Louisiana State University; Travel/Accommodation/Expenses: Hutsman Cancer Institute; Travel/Accommodation/Expenses: Cancer Core Europe; Travel/Accommodation/Expenses: Karolinska Cancer Institute; Travel/Accommodation/Expenses: King Abdullah International Medical Research Center; Travel/Accommodation/Expenses: WIN Consortium; Travel/Accommodation/Expenses: Janssen; Research grant/Funding (institution): Tocagen; Research grant/Funding (institution): Symphogen; Research grant/Funding (institution): BioAlta; Research grant/Funding (institution): GenMab; Research grant/Funding (institution): CytomX; Research grant/Funding (self): Kelun-Biotech; Research grant/Funding (institution): Takeda-Millennium; Research grant/Funding (institution): Ipsen. J.M. Lizcano: Advisory/Consultancy, Research grant/Funding (institution): Ability Pharmaceuticals. P. Muñoz Guardiola, H. Pérez-Montoyo, M. Yeste-Velasco, M. Cortal, J. Alfon: Full/Part-time employment: Ability Pharmaceuticals. C. Domènech: Shareholder/Stockholder/Stock options, Full/Part-time employment: Ability Pharmaceuticals. I.L. Ray-Coquard: Honoraria (self), Advisory/Consultancy: AbbVie; Honoraria (self), Advisory/Consultancy: Agenus; Honoraria (self): Advaxis; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): BMS; Honoraria (self), Advisory/Consultancy: PharmaMar; Honoraria (self), Advisory/Consultancy: Genmab; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: GSK; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): MSD; Honoraria (self), Advisory/Consultancy: Deciphera; Honoraria (self), Advisory/Consultancy: Mersena; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck Serono; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: Tesaro; Honoraria (self), Advisory/Consultancy: Clovis; Advisory/Consultancy: Advaxis. A. Oaknin: Honoraria (self): AbbVie Inc; Honoraria (self), Honoraria (institution): Amgen SA; Honoraria (self): AstraZeneca; Honoraria (self), Honoraria (institution): Clovis Oncology; Honoraria (self), Honoraria (institution): F Hoffman - La Roche Ltd; Honoraria (self): Genmab; Honoraria (self): GlaxoSmithKline SA; Honoraria (self), Honoraria (institution): Inmunogen; Honoraria (self): MSD; Honoraria (self), Honoraria (institution): PharmaMar SA; Honoraria (self): Prime; Honoraria (self), Honoraria (institution): Tesaro; Honoraria (institution): AbbVie Deutchland; Honoraria (institution): Ability Pharmaceuticals; Honoraria (institution): Advaxis Inc; Honoraria (institution): Aeterna Zentaris; Honoraria (institution): Aprea Therapeutics; Honoraria (institution): Eisai Limited; Honoraria (institution): Regeneron Pharmaceuticals; Honoraria (institution): MSD Spain; Honoraria (institution): Millennium Pharmaceuticals; Honoraria (institution): BMS. All other authors have declared no conflicts of interest.

Background

Complete pathologic response (pCR) in HER2 positive breast cancer patients after neoadjuvant treatment (NAC) is well correlated with high HER2 expression and is a surrogate for survival, but oestrogen receptor positive (ER +) patients have a lower pCR. Therefore, it should be specified which subgroup of these patients could have a higher pCR and would benefit more from NAC.

Methods

We analysed the clinical pathological variables associated with a pCR in a series of 108 patients with early or locally advanced breast cancer with ER + positive tumours and HER2 overexpression who received NAC.

Results

Median age was 54 years (31-89), median tumour size was 39 mm (14-100) and 52 (48%) patients had nodal involvement. Median Ki67 expression was 40% (3-80), 50 patients (57%) showed HER2 overexpression with FISH amplification (HER+ +2). 32 patients (29%) received anti-HER2 therapy with trastuzumab plus pertuzumab and 74 (68%) received anthracycline treatment. A total of 32/108 patients (29,6%) achieved a pCR. In the univariable analysis, oestrogen receptor expression (P: 0,006) and Ki67 level (P:0,015) and HER2 +3 (P:0,004), were correlated to pCR. We found no correlation with other variables or with previous treatment with anthracyclines or pertuzumab plus trastuzumab. In the multivariable analysis, the variables with significance were HER2 +3 expression (OR: 4,49 IC 95% 1,66-12.12) and Ki67 levels higher than 38 (OR: 3,54 IC 95% 1,34.9,35). We summarized the rate of pCR according to these variables with significance, the group with ER+<250 plus Ki67> 38 and HER2 +3 was the most sensitive, with 65% of patients achieving pCR, while the group with RE >250 plus Ki67>38 and HER2 +2 was the least sensitive, with only 6% achieving pCR.

Conclusions

In breast cancer patients with HER2 positive and ER positive tumours, only 29% achieve pCR . Of this group, 60% had a high proportion of equivocal HER2 overexpression and only 14% of the patients in this subgroup achieved pCR . Similarly, 60% of the patients in this group had a KI67 index of less than 38 and only 16% of this subgroup achieved pCR. Oestrogen receptor EXPRESSION, Ki67 index and HER2 expression could help us select the patients with the best chance of obtaining a complete response, especially when they have low expression of ER, High Ki67 index and HER2 +3 expression.

Legal entity responsible for the study

Hospital Arnau De Vilanova De Lleida.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Limited data are available on RW outcomes of current mNSCLC treatments in the United Kingdom. By analysing ≈10% of adult UK patients with mNSCLC, this study aimed to fill the data gap by investigating treatment patterns, RW tumor response, overall survival (OS), and time to discontinuation (TTD) in patients who started first-line (1L) treatment. To our knowledge, this is the first large-scale, RW study in mNSCLC in the United Kingdom.

Methods

This retrospective, observational study collected data from electronic prescribing records (EPRs) of patients with mNSCLC who started 1L treatment between June 1, 2016, and March 31, 2018 (minimum follow-up to December 31, 2018). EPR data gaps were supplemented by chart reviews. RW tumor response was based on physician-defined best 1L response of a partial or complete response. Kaplan-Meier method estimated OS and TTD (time to earliest of death or end of treatment).

Results

In total, 1,003 patients were included from 9 UK hospitals. Of these, 698 (70%) received nontargeted chemotherapy (NTC), 179 (18%) received immuno-oncological monotherapy (IO), and 126 (12%) received targeted therapy (TT; EGFR/ALK inhibitors) (Table). Median age was 67 years (range, 28-93 years), and 54% were male. Table: 1379P

Key clinical characteristics and outcomes by drug class in 1L

Conclusions

The majority of patients received an NTC regimen as 1L treatment. Results suggested poorer OS in NTC patients. IO resulted in a longer median OS vs NTC; however, this was shorter than that observed in clinical trials. Patients receiving TT had the longest median OS. As innovative IO-based regimens enter practice, future RW studies should investigate whether the proportion of patients receiving NTC alone decreases and outcomes in mNSCLC improve.

Legal entity responsible for the study

Merck KGaA, Darmstadt, Germany and Pfizer Inc.

Funding

This analysis was supported by Merck KGaA, Darmstadt, Germany as part of an alliance between Merck KGaA, Darmstadt, Germany and Pfizer.

Disclosure

J. Lester: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp Dohme; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Lilly. C. Escriu: Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp Dohme; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Boehringer Ingelheim; Honoraria (self): Pfizer; Honoraria (self), Travel/Accommodation/Expenses: Roche. E. Hudson: Advisory/Consultancy: Roche; Advisory/Consultancy: Tesaro; Advisory/Consultancy: GlaxoSmithKline. T. Mansy: Honoraria (self), Travel/Accommodation/Expenses: Merck Sharpe Dohme; Honoraria (self), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Roche; Honoraria (self), Travel/Accommodation/Expenses: Boehringer Ingelheim; Honoraria (self), Travel/Accommodation/Expenses: PharmaMar; Honoraria (self), Travel/Accommodation/Expenses: Tesaro. A. Conn: Research grant/Funding (self): Servier. S. Chan: Honoraria (self): Bristol-Myers Squibb. C. Powell: Honoraria (self), Travel/Accommodation/Expenses: Boehringer Ingelheim; Travel/Accommodation/Expenses: Roche; Honoraria (self): Bristol-Myers Squibb. X. Zhuo: Full/Part-time employment, I was a Merck KgaA employee when the analysis was conducted.: EMD Serono Research & Development Institute, Inc., Billerica, USA; a business of Merck KGaA, Darmstadt, Germany. A. Durand: Full/Part-time employment, I was a Merck KgaA employee when the analysis was conducted.: Merck KGaA. A. Amin: Full/Part-time employment, Merck employee: Merck Serono Ltd., Feltham, United Kingdom; an affiliate of Merck KGaA, Darmstadt, Germany. P. Martin: Full/Part-time employment: Merck Serono Ltd. X. Zhang, V. Pawar: Full/Part-time employment, EMD Serono employee: EMD Serono Research & Development Institute, Inc., Billerica, USA; a business of Merck KGaA, Darmstadt, Germany. All other authors have declared no conflicts of interest.

Background

Advanced differentiated thyroid carcinoma (aDTC), herein defined as locally unresectable or metastatic disease, frequently develops into RR-DTC, one of the most common late-stage endocrine tumours. However, available data about its evolution is limited. ERUDIT is a multicentre, observational, retrospective study of patients diagnosed with aDTC in Spain and Portugal. The study describes its natural history from the initial diagnosis until the advanced stages of disease. This communication is focused on the RR-DTC subpopulation, its diagnosis, treatment patterns, and specialties involved in its management.

Methods

Clinical records from patients ≥18 y-o diagnosed with aDTC (including poorly differentiated DTC) with first evidence of advanced disease documented between January 2007 and August 2017 were retrospectively reviewed until death or lost to follow-up.

Results

213 patients were identified in 23 centres. Median age at initial diagnosis was 63 y-o, 59% were females. aDTC presented de novo in 54% of the cases. In all, 77.5% were initially diagnosed or developed into RR-DTC along study follow-up. Median (Q1-Q3) time to RR-DTC from first radioiodine dose was 27.6 (9.5-50.6) months. Computed (CT) and fluorodeoxygucose positron emission tomography (FDG PET-CT) were the most used methods to follow refractory disease (41% and 27%, respectively). Management was multimodal, with surgery (15%), watchful waiting (48%), locoregional (35%), and systemic therapies (ST) (37%) being used. Median (Q1-Q3) time from RR-DTC diagnosis to start of ST was 8.9 (1.4-34.7) months, while median overall survival (95%CI) reached 4.7 (3.4-8.0) years in this subpopulation. Endocrinology (59%) and Oncology (33%) were the leading medical specialties responsible for patient monitoring, while two thirds of the patients were evaluated by multidisciplinary committees.

Conclusions

Most of aDTC tumours either present or become RR-DTC in around 2.3 years and are treated multidisciplinarily. Survival expectancy of this group nears 5 years, confirming an unfavourable evolution of most aDTC at their late treatment stages.

Legal entity responsible for the study

Eisai Farmacéutica SA.

Funding

Eisai Farmacéutica SA.

Disclosure

C. López, R.J. Santos, M. Llanos Muñoz, J.A. Vallejo, E. Navarro González, J. Aller Pardo, V. Pubul Núñez, M. Sambo Salas, S. Guadalix Iglesias, G. Crespo, C. Zafon, C. González Blanco, Á.A. Segura Huerta, M. Navarro Martín, J. Santamaría Sandi, P. Gajate Borau, J. Valdivia, M. Gómez Balaguer: Honoraria (institution), ERUDIT Study Investigator: Eisai Farmacéutica SA. L. Orcajo Rincon: Full/Part-time employment, ERUDIT Study Director: Eisai Farmacéutica SA. J. Rodríguez-Villanueva: Full/Part-time employment, ERUDIT Study Medical Monitor: Eisai Farmacéutica SA.

Background

T-cell–inflammation gene-expression profiling (GEP), programmed death-ligand 1 (PD-L1) expression, and tumour mutational burden (TMB) have been proposed as predictive biomarkers to anti-PD-1/PD-L1 immune checkpoint inhibitors (ICI). While TMB and PD-L1 have a widespread implementation in early clinical trial reference centers, the more novel GEP is lagging behind. We have developed the VIGex gene panel, a gene set selected for immune profiling and subtyping of patients. The panel includes 51 different genes, allowing detection of an immune activation signature consistent with interferon-γ signaling (CXCL9-11, GZMB, IFNG), along with indicators of immunosuppressive processes: T-cell exhaustion markers (CTLA4 or CD274), presence of Tregs (FOXP3), tumour associated macrophages (TAM) (MRC1, CD163) as well as antiinflammatory cytokines (IL10, IL11, TGFB1-3).

Methods

RNA analysis using the VIGex panel was performed on 638 FFPE tumour samples. The most frequent tumour types in our series were CRC (n=155), pancreas (n=130), NSCLC (n=74), gastric (n=45) and CNS (n=41). Gene expression analysis was performed using Nanostring nCounter and analyzed with nSolver software and R in-house scripts. After intra- and inter-run normalization, an unsupervised hierarchical clustering with Ward’s minimum variance method and correlation-based distance was performed. Tumour infiltrating lymphocytes (TILs) were evaluated by a pathologist in a subset of the samples (n=40).

Results

Unsupervised hierarchical clustering analysis revealed the presence of two main ‘hot’ (HT) and ‘cold’ (CT) tumour immune entities (32.5% and 67.5% of the samples, respectively). In the HT or T-cell inflamed group, the most frequent tumour type was NSCLC (n=47, 29.2%). CT tumours had low expression in T-cell inflammation-related genes. As expected, TILs were significantly higher in the HT group (median 35) than in the CT one (median 5, P value = 0.0018). Interestingly, a subgroup of CT, enriched in CNS tumours (n=40, 23%), showed increased TGFb signaling and presence of TAMs.

Conclusions

Our results indicate that gene expression-based tests, such as VIGex, will aid in tumour microenvironment assessment in FFPE solid tumours.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

A. Oaknin: Honoraria (self), Honoraria (institution): AbbVie, Inc. ; Honoraria (self), Honoraria (institution): Amgen, S.A. ; Honoraria (self): AstraZeneca ; Honoraria (self), Honoraria (institution): Clovis Oncology ; Honoraria (self): F. Hoffmann - La Roche Ltd ; Honoraria (self): Genmab ; Honoraria (self): GlaxoSmithKline SA ; Honoraria (self), Honoraria (institution): Inmunogen ; Honoraria (self): Merck Sharp & Dohme; Honoraria (self), Honoraria (institution): Pharma Mar, SA ; Honoraria (self): prIME ; Honoraria (self), Honoraria (institution): Tesaro; Honoraria (institution): Abililty Pharmaceuticals; Honoraria (institution): Advaxis Inc.; Honoraria (institution): Aeterna Zentaris; Honoraria (institution): Aprea Therapeutics AB; Honoraria (institution): Eisai limited LTD; Honoraria (institution): F. Hoffmann – La Roche LTD; Honoraria (institution): Regeneron Pharmaceuticals; Honoraria (institution): Merck, Sharp & Dohme de España SA; Honoraria (institution): BMS, Bristrol-Myers Squibb. M. Alsina: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Servier; Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Travel/Accommodation/Expenses: Lilly; Honoraria (self), Travel/Accommodation/Expenses: Roche; Honoraria (self), Travel/Accommodation/Expenses: Amgen; Research grant/Funding (self), Travel/Accommodation/Expenses: Merck. E. Elez: Honoraria (self), Honoraria (institution): Hoffman -La Roche; Honoraria (self), Honoraria (institution): Sanofi Aventis; Honoraria (self), Honoraria (institution): Amgen; Honoraria (self), Honoraria (institution): Merck Serono; Honoraria (self), Honoraria (institution): Servier; Honoraria (self), Honoraria (institution): MSD; Honoraria (self), Honoraria (institution): Array Pharmaceuticals; Honoraria (self), Honoraria (institution): Bristol-Myers Squibb; Honoraria (institution): Boehringer Ingelheim; Honoraria (institution): AbbVie; Honoraria (institution): Pierre Fabre; Honoraria (institution): Novartis; Honoraria (institution): GlaxoSmithKline; Honoraria (institution): Medimmune. T. Macarulla Mercade: Advisory/Consultancy: Shire Pharmaceuticals; Advisory/Consultancy: Roche; Advisory/Consultancy: Batxer; Advisory/Consultancy, Travel/Accommodation/Expenses: Sanofi; Advisory/Consultancy, Travel/Accommodation/Expenses: Celgene; Advisory/Consultancy: QED Therapeutics; Advisory/Consultancy: Baxalta; Advisory/Consultancy: Incyte; Advisory/Consultancy, Travel/Accommodation/Expenses: Servier; Advisory/Consultancy: Lilly; Advisory/Consultancy: Ipsen ; Travel/Accommodation/Expenses: Merck; Travel/Accommodation/Expenses: H3 Biomedicine. C. Saura: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: BMS; Advisory/Consultancy: Celgene; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Eisai; Advisory/Consultancy: Roche; Advisory/Consultancy: Genomic health; Advisory/Consultancy: MSD; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Philips Healthwork; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Puma; Advisory/Consultancy: Synthon ; Advisory/Consultancy: Sanofi. J. Capdevila: Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (self): Bayer; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (self): Eisai; Research grant/Funding (self): AstraZenca; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (self): AAA; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (self): Ipsen; Honoraria (self), Speaker Bureau/Expert testimony: Novartis; Honoraria (self), Speaker Bureau/Expert testimony: Pfizer; Honoraria (self), Speaker Bureau/Expert testimony: Merk; Honoraria (self), Speaker Bureau/Expert testimony: Sanofi; Honoraria (self), Speaker Bureau/Expert testimony: Amgen. M. Vieito: Advisory/Consultancy: Debio; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: TFS; Travel/Accommodation/Expenses: Merck-Serono. E. Felip: Advisory/Consultancy: AbbVie; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZenca; Advisory/Consultancy: Blue Print Medicines; Advisory/Consultancy, Speaker Bureau/Expert testimony: Boehringer Ingelheim; Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony: Eli Lilly; Advisory/Consultancy: Guardant Health; Advisory/Consultancy: Janssen; Speaker Bureau/Expert testimony: Medscape; Advisory/Consultancy: Merck KGaA; Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Speaker Bureau/Expert testimony: prIME Oncology; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: SAMSUNG; Advisory/Consultancy, Speaker Bureau/Expert testimony: Takeda; Speaker Bureau/Expert testimony: Touchime; Advisory/Consultancy: GSK; Advisory/Consultancy: Bayer; Research grant/Funding (self): Grant for Oncology Innovation (GOI); Research grant/Funding (self): Fundación Merck Salud; Officer/Board of Directors: Grifols. R. Dienstmann: Honoraria (self), Speaker Bureau/Expert testimony: Roche; Honoraria (self), Speaker Bureau/Expert testimony: Ipsen; Honoraria (self), Speaker Bureau/Expert testimony: Amgen; Honoraria (self), Speaker Bureau/Expert testimony: Sanofi; Honoraria (self), Speaker Bureau/Expert testimony: Servier Laboratories; Honoraria (self), Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Research grant/Funding (self): Merck; Research grant/Funding (self): Pierre Fabre. A. Gros: Honoraria (self): Neon Therapeutics; Honoraria (institution): Achilles Therapeutics; Honoraria (self): PACT Pharma; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche Pharma; Licensing/Royalties: Cellular Biomedicine Group, Inc.; Leadership role: Novartis; Leadership role: EMD Serono; Leadership role: Roche Genentech. J. Seoane: Honoraria (self), Research grant/Funding (self), Shareholder/Stockholder/Stock options: Mosaic Biomedicals; Officer/Board of Directors: Northern Biologics; Research grant/Funding (self): Roche Glycart AG; Research grant/Funding (self): Ridgeline; Research grant/Funding (self): Isarna Therapeutics; Research grant/Funding (self): Hoffmann - La Roche, Ltd. P.G. Nuciforo: Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Bayer; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Merck Sharp & Dohme; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Targos Molecular Pathology GmbH. J. Tabernero: Advisory/Consultancy: Array Biopharma; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: BeiGene; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Chugai; Advisory/Consultancy: Genentech, Inc.; Advisory/Consultancy: Genmab A/S; Advisory/Consultancy: Halozyme; Advisory/Consultancy: Imugene Limited; Advisory/Consultancy: Inflection Biosciences Limited; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Kura Oncology; Advisory/Consultancy: Lilly; Advisory/Consultancy: MSD; Advisory/Consultancy: Menarini; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Merrimack; Advisory/Consultancy: Merus; Advisory/Consultancy: Molecular Partners; Advisory/Consultancy: Novartis; Advisory/Consultancy: Peptomyc; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Pharmacyclics; Advisory/Consultancy: ProteoDesign SL; Advisory/Consultancy: Rafael Pharmaceuticals; Advisory/Consultancy: F. Hoffmann-La Roche Ltd; Advisory/Consultancy: Sanofi; Advisory/Consultancy: SeaGen; Advisory/Consultancy: Roche Diagnostics. E. Garralda: Research grant/Funding (self): Novartis; Speaker Bureau/Expert testimony, Research grant/Funding (self): Roche; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (self): Thermo Fisher; Honoraria (self), Leadership role: Roche/Genentech ; Honoraria (self): F.Hoffmann/La Roche ; Honoraria (self): Ellipses Pharma; Honoraria (self): Neomed Therapeutics1 Inc; Honoraria (self): Boehringer Ingelheim ; Honoraria (self): Janssen Global Services ; Honoraria (self): SeaGen; Honoraria (self): TFS; Honoraria (self): Alkermes; Honoraria (self), Travel/Accommodation/Expenses: Bristol-Mayers Squibb; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Merck Sharp & Dohme; Travel/Accommodation/Expenses: Menarini; Leadership role, Travel/Accommodation/Expenses: Glycotope; Leadership role: Agios Pharmaceuticals; Leadership role: Amgen; Leadership role: Bayer; Leadership role: Beigene USA ; Leadership role: Blueprint Medicines ; Leadership role: BMS; Leadership role: Cellestia Biotech; Leadership role: Debiopharm; Leadership role: F.Hoffmann La Roche Ltd ; Leadership role: Forma Therapeutics; Leadership role: Genmab B.V.; Leadership role: GSK; Leadership role: Incyte Biosciences; Leadership role: Incyte Corporation. A. Vivancos: Honoraria (self), Honoraria (institution), Advisory/Consultancy: Sysmex; Honoraria (self), Honoraria (institution), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Honoraria (institution), Advisory/Consultancy: Roche; Honoraria (self), Honoraria (institution), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Guardant Health; Honoraria (self), Advisory/Consultancy: Bayer; Licensing/Royalties: Ferrer; Honoraria (institution): Debio; Honoraria (institution): Cellestia Biotech; Honoraria (institution): Chittern. All other authors have declared no conflicts of interest.

Background

Most patients (pts) with advanced cancer do not benefit from immunotherapy (IT) and no predictive and reliable biomarker exists across cancer-types. Here, we studied lymphocyte subpopulations on peripheral blood as easily quantifiable biomarkers of response to IT.

Methods

From 11/2016 to 06/2019, pts with advanced solid cancer treated with IT at Hospital Clinic Clinical Trials Unit were recruited. Blood samples were collected at baseline (C1D1), at day 1 of cycle 2 (C2D1) and at each radiologic evaluation. Flow cytometry analyses were performed using the lineage and differentiation markers CD25, CD3, FOXP3, CD40L, HLA-DR, CD4, CD62L, CD69, CD8, CTLA4, CD19, CD16/56, CD28, PDL1, PD1, CD45RO/RA and CCR7. Forty-four lymphocyte subpopulations (LSP) were identified and quantified. The primary objective was to associate the levels of LSP with response according to iRECIST criteria. Secondary objectives were progression-free survival (PFS) and overall survival (OS). Cox models, logistic regressions, and areas under the ROC (AUC) were performed. Adjustment for multiple comparisons was considered.

Results

71 evaluable pts with non-small cell lung cancer (25%), colorectal (15%), breast (12%), head and neck (10%), bladder (8%), melanoma (7%), renal (5%), prostate (5%) and others (10%) were recruited. Median age was 62 (22-80), 63% of pts were male and 90% were immune naïve. 50 pts received anti-PD1 (71%) and 69% of ITs were given as monotherapy. The overall response rate (ORR) was 13.5% (95% CI 8-22%). At C1D1, no LSP was found associated with ORR. At C2D1 (n=61) higher levels of effector memory T cells (TEM: CD3+CD45RO+CCR7-) were found associated with response (AUC=0.81, 100% sensitivity, 59.6% specificity, PPV 27.6% and NPV 100%), PFS and OS. The ORR in high-TEM (above median) was 26.7% vs 0% in low-TEM. Compared to low-TEM, high-TEM (above median) was associated with improved PFS (hazard ratio [HR]=0.23; p<0.001) and OS (HR=0.33; p=0.003). All associations were independently of cancer-type, sex, type of immunotherapy and immune-naïve state.

Conclusions

Levels of peripheral blood effector memory T-cells during IT might help predict response across cancer-types. Further characterization and validation of this LSP is ongoing.

Legal entity responsible for the study

Medical Oncology and Immunology departments at Hospital Clinic Barcelona.

Funding

Has not received any funding.

Disclosure

J. Garcia-Corbacho: Speaker Bureau/Expert testimony: Bayer; Travel/Accommodation/Expenses: BMS; Advisory/Consultancy: Solti; Honoraria (institution), Clinical Trials: MSD; Honoraria (institution), Clinical Trials: Amgen; Honoraria (institution), Clinical Trials: BMS; Honoraria (institution), Clinical Trials: Novartis; Honoraria (institution), Clinical Trials: Bayer; Honoraria (institution), Clinical Trials: Astellas; Honoraria (institution), Clinical Trials: Boeringher Ingelheim; Honoraria (institution), Clinical Trials: Cytomx; Honoraria (institution), Clinical Trials: Pfizer; Honoraria (institution), Clinical Trials: Tesaro. N. Vinolas Segarra: Honoraria (self): Roche; Honoraria (self): Boeringher Ingelheim; Honoraria (self): Pierre-Fabre; Travel/Accommodation/Expenses: BMS; Honoraria (self): Lilly; Honoraria (self): AstraZeneca. B. Mellado: Research grant/Funding (self): Astellas; Research grant/Funding (institution): Jansen; Non-remunerated activity/ies: Sanofi; Research grant/Funding (institution): Roche; Non-remunerated activity/ies: BMS; Honoraria (self): Merck; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Bayer. J. Maurel: Honoraria (self): Sirtex; Honoraria (self): Servier; Honoraria (self): Pierre Fabre; Honoraria (self): Advance Medical; Honoraria (self): Shire; Honoraria (self): AstraZeneca; Honoraria (self): Bayer; Honoraria (self): Sanofi; Honoraria (self): Roche; Honoraria (institution): Merck; Honoraria (self): Amgen; Honoraria (institution): Biocartis; Honoraria (institution): Nanostring; Honoraria (institution): Incyte. L. Gaba: Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: MSD; Speaker Bureau/Expert testimony: Tesaro; Honoraria (self): GSK. N. Baste: Advisory/Consultancy: Merck; Advisory/Consultancy: BioNtech; Advisory/Consultancy: Nanobiotix; Advisory/Consultancy: BMS; Speaker Bureau/Expert testimony: MSD; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Eisai. N. Reguart: Speaker Bureau/Expert testimony: MSD; Speaker Bureau/Expert testimony: BMS; Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: Boeringher Ingelheim; Speaker Bureau/Expert testimony: Guardant Health; Speaker Bureau/Expert testimony: Pfizer; Speaker Bureau/Expert testimony: Abbie; Speaker Bureau/Expert testimony: Ipsen; Speaker Bureau/Expert testimony: Novartis; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Lilly; Speaker Bureau/Expert testimony: Takeda; Speaker Bureau/Expert testimony: Amgen; Honoraria (institution), Clinical Trials: MSD; Honoraria (institution), Clinical Trials: BMS; Honoraria (institution), Clinical Trials: Roche; Honoraria (institution), Clinical Trials: Boeringher Ingelheim; Honoraria (institution), Clinical Trials: Pfizer; Honoraria (institution), Clinical Trials: Abbvie; Honoraria (institution), Clinical Trials: Novartis; Honoraria (institution), Clinical Trials: AstraZeneca; Honoraria (institution), Clinical Trials: Takeda; Honoraria (institution), Clinical Trials: Amgen; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer. A. Prat: Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: BMS; Speaker Bureau/Expert testimony: Daiichi Sankyo; Advisory/Consultancy: Puma; Advisory/Consultancy: Oncolytics Biotech; Advisory/Consultancy: MSD; Advisory/Consultancy: Lilly; Speaker Bureau/Expert testimony: Nanostring technologies; Leadership role, Member Executive Board Breast International Group (BIG): BIG; Leadership role, Member of the Board Solti's Foundation: Solti Foundation; Leadership role, Patronage committee: Actitud Frente al Cancer Foundation; Leadership role, Member Executive Board: SOLTI; Honoraria (institution), Contracted Research, Clinical Trials: Boeringher Ingelheim; Honoraria (institution), Clinical Trials: Lilly; Honoraria (institution), Contracted Research, Clinical Trials: Roche; Honoraria (institution), Contracted Research: Pfizer; Honoraria (institution), Contracted Research, Clinical Trials: Nanostring technologies; Honoraria (institution), Clinical Trials: Novartis; Honoraria (institution), Clinical Trials: Amgen; Honoraria (institution), Clinical Trials: Daiichi Sankyo; Honoraria (institution), Contracted Research: Roche Farma SA; Honoraria (institution), Contracted Research: Sysmex Europa GmbH; Honoraria (institution), Contracted Research: Medica Scientia inno, research, SL; Honoraria (institution), Contracted Research: Celgene, SLU; Honoraria (institution), Contracted Research: Astellas Pharma, SA. All other authors have declared no conflicts of interest.

Background

21-gene Recurrence Score Assay (OncotypeDx®, RSA) testing is strongly recommended to guide adjuvant chemotherapy in HR+/HER2- early breast cancer (eBC). However, it is not available for all patients. At our site, RSA has been offered since 2012, initially according to a set of regionally defined criteria and with a limited number of tests. Following TAILORx reports, criteria broadened and the number of tests expanded. Here, we investigated whether a high agreement between oncologists might overcome the added value of RSA testing in a real-world scenario.

Methods

Six staff oncologists of the Breast Cancer Section independently completed a survey on a retrospective series of consecutive patients with HR+/HER2- eBC. Patients had been surgically treated at Hospital del Mar between 2016 and 2019. We addressed three questions: 1) The degree of agreement between oncologists (based on patient age, pTNM, histology, grade, ER/PR levels, and Ki67) on whether chemotherapy (CHT) should have been discussed with the patient besides hormone therapy (HT). High agreement (HiA) was considered if ≥ 5 oncologists agreed either for CHT or for HT, and the rest was considered low agreement (LoA); 2) The proportion of RSA testing in HiA compared to LoA cases; and 3) In patients with HiA that had undergone RSA testing, the rate of change in adjuvant therapy recommendation.

Results

We included 291 patients, of which 44% had undergone RSA testing. Mean age was 61 (range 35-91), 75% had stage I and 18% N1 disease. HiA was reached in 80% of cases (234/291): 72% for HT and 28% for CHT. RSA was ordered for 35% (82/234) of HiA cases (49% for HT and 51% for CHT) compared with 82% (47/57) of LoA cases (p<0.001). In the HiA subgroup that had undergone RSA testing, 79% (33/42) of cases with HiA for CHT received HT alone, while 13% (5/40) with HiA for HT received CHT, leading to an overall rate of change of 46% in therapy recommendation after RSA.

Conclusions

Oncologists highly agreed on adjuvant therapy recommendations in 80% of cases. RSA testing was more frequent in LoA cases. High agreement between oncologists was not sufficient to overcome the need for RSA testing in driving adjuvant treatment in eBC.

Legal entity responsible for the study

Cancer Research Program, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain.

Funding

Has not received any funding.

Disclosure

M. Castro-Henriques: Advisory/Consultancy, Non-remunerated activity/ies: Roche; Speaker Bureau/Expert testimony: MSD; Travel/Accommodation/Expenses: Sanofi. D. Casadevall Aguilar: Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Pfizer. M. Martinez-Garcia: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Travel/Accommodation/Expenses: Celgene; Speaker Bureau/Expert testimony: Pierre Fabre. I. Tusquets Trias Bes: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche Diagnostics; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Celgene; Speaker Bureau/Expert testimony: AstraZeneca. J. Albanell: Advisory/Consultancy: Roche; Advisory/Consultancy: Amgen; Advisory/Consultancy: Pfizer; Advisory/Consultancy: MSD; Advisory/Consultancy: Genomic Health; Advisory/Consultancy: Palex. S. Servitja: Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: MSD; Advisory/Consultancy: Genomic Health. All other authors have declared no conflicts of interest.