Impact of initial treatment and prognostic factors on postprogression survival in BRAF-mutated metastatic melanoma treated with dacarbazine or vemurafenib ± cobimetinib: a pooled analysis of four clinical trials

Abstract

Background: We sought to identify patient subgroups with distinct postprogression overall survival (ppOS) outcomes and investigate the impact of original treatment assignment and initial postprogression treatment (ppRx) on ppOS.

Methods: Recursive partitioning analysis (RPA) was performed to model relationships between prespecified covariates and ppOS in patients with BRAFV600-mutated metastatic melanoma who had experienced progressive disease (PD) following treatment with cobimetinib plus vemurafenib, vemurafenib monotherapy, or dacarbazine in the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies. Prognostic subgroups identified by RPA were then applied to pooled treatment cohorts. The primary endpoint was ppOS, defined as time from first PD to death from any cause.

Results: RPA identified baseline lactate dehydrogenase (LDH), baseline disease stage, Eastern Cooperative Oncology Group performance status at PD, and ppRx as significant prognostic factors for ppOS. Median ppOS was longest in patients with normal baseline LDH, stage M1c disease at baseline, and ppRx with immunotherapy or targeted therapy (12.2 months; 95% CI 10.3-16.1) and shortest in those with elevated baseline LDH > 2 × upper limit of normal (2.3 months; 95% CI 1.8-2.7). Original treatment assignment did not impact ppOS. Across treatment cohorts, patients treated with immunotherapy or targeted therapy after PD had better ppOS than those given other treatments.

Conclusion: A combination of factors at baseline (LDH, disease stage) and PD (performance status, ppRx) impact ppOS outcomes. ppRx with immunotherapy or targeted therapy is an independent prognostic factor for improved overall survival following progression regardless of original treatment. Trial registration The trials included in this analysis are registered with ClinicalTrials.gov: NCT00949702 (BRIM-2), NCT01006980 (BRIM-3), NCT01271803 (BRIM-7), and NCT01689519 (coBRIM).

Keywords: Cobimetinib; Dacarbazine; Melanoma; Survival analysis; Vemurafenib.

Conflict of interest statement

PAA reports consulting/advisory role for Bristol-Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, Genmab, NewLink Genetics, MedImmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, and Immunocore; research funding from Bristol-Myers Squibb, Roche/Genentech, and Array; and travel, accommodations, or expenses from Merck Sharp & Dohme. AR reports honoraria from Amgen, Chugai, Genentech, Merck, and Novartis; consulting/advisory role for Amgen, Chugai, Genentech, Merck, and Novartis; and stock or other ownership in Advaxis, Arcus, Bioncotech, Compugen, CytomX, Five Prime, FLX-Bio, ImaginAb, IsoPlexis, Kite-Gilead, Merus, Rgenix, Lutris, PACT Pharma, and Tango Therapeutics. JL reports honoraria from Achilles Therapeutics, AstraZeneca, Boston Biomedical, Bristol-Myers Squibb, Eisai, EUSA Pharma, GlaxoSmithKline, Ipsen, Imugene, Incyte, Onctura, Kymab, Merck Serono, Merck Sharp & Dohme, Nektar, Novartis, Pierre Fabre, Pfizer, Roche/Genentech, Secarna, and Vitaccess; consulting/advisory role for Achilles Therapeutics, AstraZeneca, Boston Biomedical, Bristol-Myers Squibb, Eisai, EUSA Pharma, GlaxoSmithKline, Ipsen, Imugene, Incyte, Onctura, Kymab, Merck Serono, Merck Sharp & Dohme, Nektar, Novartis, Pierre Fabre, Pfizer, Roche/Genentech, Secarna, and Vitaccess; research funding from Achilles Therapeutics, Aveo, Bristol-Myers Squibb, Merck Sharp & Dohme, Nektar, Novartis, Pfizer, Roche/Genentech, Covance, and Immunocore. GAM reports steering committee membership and principal investigator roles for Roche/Genentech. KDL reports a consulting/advisory role for Roche, Merck, Regeneron, and Array; and research funding from Roche, Merck, Array, Regeneron, Iovance, Incyte, Neon, Nektar, and Bristol-Myers Squibb. AH reports honoraria from Amgen, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Philogen, Pierre Fabre, Provectus, Regeneron, Roche, OncoSec, Sanofi-Genzyme, and Novartis Pharma; consulting/advisory role for Amgen, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Philogen, Pierre Fabre, Provectus, Regeneron, Roche, OncoSec, Sanofi-Genzyme, and Novartis Pharma; research funding from Amgen, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Philogen, Pierre Fabre, Provectus, Regeneron, Roche, Sanofi-Genzyme, and Novartis Pharma. KTF reports consulting/advisory role for Roche, X4 Pharmaceutical, Apricity, PIC Therapeutics, Sanofi, Amgen, Asana, Adaptimmune, Fount Therapeutics, Aeglea, Array BioPharma, Shattuck Labs, Arch Oncology, Tolero Pharmaceuticals, Oncoceutics, Fog Pharma, Neon Therapeutics, Tvardi, Novartis, Genentech, Bristol-Myers Squibb, Merck, Takeda, Verastem, Checkmate, Boston Biomedical, Pierre Fabre, Cell Medica, and Debiopharm; research funding from Roche; stock ownership for Loxo Oncology, Clovis Oncology, Strata Oncology, Vivid Biosciences, X4 Pharmaceuticals, Apricity, PIC Therapeutics, Fount Therapeutics, Shattuck Labs, Oncoceutics, Fog Pharma, and Tvardi; and served on the board of directors for Loxo Oncology, Clovis Oncology, Strata Oncology, and Vivid Biosciences. EM and YM report employment with Genentech and stock or other ownership in Genentech. QZ reports employment with Edwards Lifesciences; stock or other ownership in Edwards Lifesciences; and a consulting/advisory role with Genentech. BD reports honoraria from Bristol-Myers Squibb, Roche, Novartis, and Pierre Fabre; consulting/advisory roles for Bristol-Myers Squibb, Roche, Novartis, and Pierre Fabre; research funding from Bristol-Myers Squibb and Roche; and travel, accommodations, or expenses from Roche and Bristol-Myers Squibb.

Figures

Fig. 1

Recursive partitioning analysis for prognostic subgroups in all pooled patients. Recursive partitioning decision tree and ppOS outcomes by identified prognostic subgroups for all pooled patients. Data are presented as percentage (95% CI). ECOG PS Eastern Cooperative Oncology Group performance status, IT immunotherapy, LDH lactate dehydrogenase, PD progressive disease, ppOS postprogression overall survival, ppRx postprogression treatment, TT targeted therapy, ULN upper limit of normal

Fig. 2

Postprogression overall survival by treatment cohort. Kaplan–Meier curves of ppOS in a cobimetinib plus vemurafenib cohort, b vemurafenib monotherapy cohort, and c dacarbazine cohort. CI confidence interval, ECOG PS Eastern Cooperative Oncology Group performance status, IT immunotherapy, LDH lactate dehydrogenase, NE not estimable, PD progressive disease, ppOS postprogression overall survival, ppRx initial postprogression treatment, TT targeted therapy, ULN upper limit of normal

Fig. 3

Postprogression overall survival by initial postprogression treatment. Kaplan–Meier curves of ppOS in all pooled patients receiving initial postprogression treatment with immunotherapy or targeted therapy (n = 300). ppOS postprogression overall survival

Fig. 4

Postprogression treatment patterns by initial postprogression treatment. Postprogression treatment patterns in patients who received initial postprogression treatment with a immunotherapy (n = 218), b targeted therapy (n = 82), and c other (n = 727). CTLA-4 cytotoxic T lymphocyte–associated antigen 4, PD-1 programmed death receptor 1