786O - Tumor biomarker analysis from COLUMBUS part 1: Encorafenib + binimetinib for BRAF V600E/K-mutant advanced or metastatic melanoma

Background

In the randomized, 2-part, multicenter, open-label, phase 3 COLUMBUS study, encorafenib (enco) + binimetinib (bini)—approved in the US, EU, and other countries—and enco alone improved 5-year PFS and OS vs vemurafenib (vemu) in patients (pts) with BRAF V600E/K–mutant metastatic melanoma. We retrospectively investigated genetic and transcriptional correlates of response and intrinsic resistance to enco + bini in an exploratory biomarker (BM) analysis of COLUMBUS Part 1.

Methods

Baseline (BL) tumor samples were analyzed using the ACE ImmunoID NeXT whole exome and whole transcriptome sequencing assays (Personalis). PFS and OS were analyzed (data cutoff: 15 Sep 2020) based on treatment (tx) type and presence of specific genetic or transcriptomic alterations at BL. High tumor mutation burden (TMB) was defined as above median TMB [8.6 mutations (muts)/megabase].

Results

366 tissue samples were successfully analyzed. We present results from the comparison of enco + bini (116 pts) vs vemu arms (130 pts). Median (m) PFS in the enco + bini and vemu arms was 14.9 and 5.7 mo, respectively (HR [95% CI], 0.55 [0.40–0.76]), and mOS was 34.8 and 18.6 mo, respectively (HR, 0.67 [0.50–0.90], similar to that observed in the safety cohort. PFS and OS by tx arm and BM status are shown in the table. High TMB, PD-L1 expression (exp), and IFNg signature were associated with longer PFS and OS in the enco + bini arm vs vemu arm. High ErbB2 exp and PI3KCA pathway muts were associated with shorter survival outcomes in the enco + bini arm vs the vemu arm.

Conclusions

Pts with high immune-related signatures derived greater clinical benefit from enco + bini vs vemu. High ErbB2 exp and PI3KCA pathway muts are potential resistance mechanisms to enco + bini. Addition of checkpoint inhibitors or PI3KCA pathway–targeted therapies to enco + bini in selected pts may further improve clinical benefit for pts with BRAF V600E/K–mutant metastatic melanoma. Table: 786O

Clinical trial identification

NCT01909453.

Editorial acknowledgement

Medical writing support was provided by Qing Yun Chong, PhD, at MediTech Media, Nucleus Global, and Asu Erden, PhD, of Health Interactions, Nucleus Global, and was funded by Pfizer.

Legal entity responsible for the study

The COLUMBUS study was sponsored by Array BioPharma, which was acquired by Pfizer in July 2019.

Funding

Pfizer.

Disclosure

R. Dummer: Financial Interests, Personal, Other, Consulting and/or advisory role: Novartis, Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, MaviVAX SA, touchIME, T3 Pharma, Pfizer. N. Pathan: Financial Interests, Personal, Full or part-time Employment: Pfizer. S. Deng: Financial Interests, Personal, Full or part-time Employment: Pfizer. C. Robert: Financial Interests, Personal, Advisory Board: BMS, Roche, Pierre Fabre, Novartis, Sanofi, MSD, AstraZeneca, Pfizer. A.M. Arance Fernandez: Financial Interests, Personal, Advisory Board, Consultant /Advisory/ Speaker / Travel, Accomodations, Expenses/: Pierre Fabre, Novartis, Roche, BMS, MSD, Merck, Sanofi; Financial Interests, Institutional, Other, Research Funding: Pierre Fabre, Novartis, MSD, BMS, Merck, Roche, Sanofi, Amgem. J.W.B. de Groot: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, MSD, Pierre Fabre, Servier. C. Garbe: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, CeCaVa, MSD, NeraCare, Novartis, Philogen, Sanofi. H.J. Gogas: Financial Interests, Personal, Advisory Board: MSD, BMS, Pierre Fabre; Financial Interests, Personal, Invited Speaker: MSD, BMS, Novartis, Pierre Fabre, Sanofi; Financial Interests, Invited Speaker: Amgen, Replimune; Financial Interests, Institutional, Invited Speaker: Amgen, MSD, BMS, Replimune, Iovance; Financial Interests, Institutional, Research Grant: BMS, Pfizer. R. Gutzmer: Financial Interests, Personal, Other, Receiving honoraria for a speaker, consultancy, or advisory role: 4SC, Almirall, Amgen, Bristol Myers Squibb, Immunocore, Merck Serono, MSD, Novartis, Pierre Fabre, Roche, Sanofi, Sun Pharma. G. Liszkay: Financial Interests, Personal, Other, Invited speaker, serving as a Principal Investigator: Bristol Myers Squibb, MSD, Novartis, Pfizer, Roche; Financial Interests, Personal, Principal Investigator: Incyte. C. Loquai: Financial Interests, Personal, Advisory Board: Almirall, BioNTech, Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Roche, Sanofi, Sun Pharma; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Roche, Sanofi, Sun Pharma; Financial Interests, Personal, Other, Receiving travel reimbursement: Almirall, BioNTech, Bristol Myers Squibb, Kyowa Kirin, Merck, MSD, Novartis, Pierre Fabre, Roche, Sanofi, Sun Pharma. M. Mandala: Financial Interests, Personal, Advisory Board: MSD, Novartis, Sanofi, BMS, Pierre Fabre; Financial Interests, Personal, Invited Speaker: Sun Pharma. D. Schadendorf: Financial Interests, Personal, Invited Speaker: BMS, Novartis, MSD, Roche, Merck Serono, Sanofi, Merck, Novartis, BMS, MSD, 4SC, Nektar; Financial Interests, Personal, Advisory Board: BMS, Novartis, MSD, Roche, Merck Serono, Immunocore, 4SC, Pierre Fabre, Sanofi/Regeneron, Array Biopharma, Pfizer, Philogen, NEKTAR, Sandoz, Neracare; Financial Interests, Institutional, Research Grant: Novartis, BMS, MSD, Array/Pfizer; Financial Interests, Institutional, Invited Speaker: Novartis, BMS, MSD, Pierre Fabre, Sanofi, Roche, Philogen, 4SC, Nektar; Non-Financial Interests, Invited Speaker: EORTC-MG. N. Yamazaki: Financial Interests, Personal, Invited Speaker, +Advisory Board: Ono Pharmaceutical, MSD; Financial Interests, Personal, Advisory Board: Chugai pharna; Financial Interests, Personal, Invited Speaker: Novartis, Bristol Myers Squibb Japan; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical, Bristol Myers Squibb Japan, Novartis, Astellas Amgen Biopharma, Merck Serono, Takara Bio. A. di Pietro: Financial Interests, Personal, Full or part-time Employment: Pfizer. T. Xie: Financial Interests, Personal, Full or part-time Employment: Pfizer. P.A. Ascierto: Financial Interests, Personal, Other, Consultant and Advisory Role: BMS, Roche Genentech, MSD, Novartis, Pfizer/Array, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Nektar, Boehringer Ingelheim, Regeneron; Financial Interests, Personal, Other, Consultant Role: Italfarmaco; Financial Interests, Personal, Other, Advisory Role: Eisai, Seagen; Financial Interests, Personal, Other, Consultant Role: Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore; Financial Interests, Personal, Other, Consultant role: Medicenna, Bio-AI Health; Financial Interests, Personal, Advisory Board, Consultant and Advisory Role: Dohme, iTeos; Financial Interests, Institutional, Funding, Clinical trial and translational research: BMS; Financial Interests, Institutional, Funding, Clinical Trial: Roche Genentech, Pfizer/Array, Sanofi; Non-Financial Interests, Leadership Role, President since 2010: Fondazione Melanoma Onlus Italy; Non-Financial Interests, Leadership Role, President since 2014: Campania Society of ImmunoTherapy of Cancer (SCITO) Italy; Non-Financial Interests, Other, Member of Steering Committee since 2016: Society for Melanoma Research (SMR); Non-Financial Interests, Invited Speaker, November 2017 - December 2021: Society for Immunotherapy of Cancer (SITC); Non-Financial Interests, Member: ASCO, SITC, EORTC Melanoma Cooperative Group, AIOM, SMR; Other, Travel Support: MSD. K. Flaherty: Financial Interests, Personal, Member of the Board of Directors: Checkmate Pharmaceuticals, Clovis Oncology, Strata Oncology, Vivid Biosciences; Financial Interests, Personal, Advisory Board: Adaptimmune, Aeglea, Amgen, Apricity, Asana, Fog Pharma, Fount, Monopteros, Neon, Oncoceutics, PIC Therapeutics, Sanofi, Shattuck Labs, Tolero, Tvardi, Vibliome, X4 Pharmaceuticals, xCures, Boston Biomedical; Financial Interests, Personal, Other, Consultant: Bristol Myers Squibb, Debiopharm, Genentech, Lilly, Merck, Novartis, Takeda, Verastem; Financial Interests, Personal, Other, ConsultantConsultant: Pierre Fabre; Financial Interests, Personal, Other, Research funding: Novartis, Sanofi. All other authors have declared no conflicts of interest.