Biomarkers of treatment benefit with atezolizumab plus vemurafenib plus cobimetinib in BRAFV600 mutation-positive melanoma

Abstract

Background: The phase III IMspire150 study (NCT02908672) demonstrated significantly improved progression-free survival (PFS) with atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAFV600-mutated advanced melanoma. We report exploratory biomarker analyses to optimize targeting of patients who are more likely to benefit from triplet combination therapy.

Patients and methods: Five hundred fourteen patients were randomized to atezolizumab (n = 256) or control (n = 258). Outcomes were evaluated in subgroups defined by key biomarkers, including programmed death-ligand 1 (PD-L1) expression, lactate dehydrogenase (LDH) level, tumor mutational burden (TMB), and interferon-γ (IFN-γ) gene signature. Exploratory recursive partitioning analysis was then used to model associations between PFS and baseline covariates, including key biomarkers.

Results: PFS benefit for atezolizumab versus control was greater in patients with high TMB [≥10 mutations/Mb; hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.52-1.02; P = 0.067] versus low TMB (<10 mutations/Mb; HR 0.92; 95% CI 0.65-1.30; P = 0.64) and similar between patients with strong IFN-γ (≥median; HR 0.76; 95% CI 0.54-1.06) versus weak IFN-γ (<median; HR 0.79; 95% CI 0.58-1.08). In patients with elevated LDH, PFS benefit for atezolizumab versus control was greater in the PD-L1- subgroup (HR 0.53; 95% CI 0.29-0.95; P = 0.032) than in the PD-L1+ subgroup (HR 1.16; 95% CI 0.75-1.80; P = 0.51). Recursive partitioning analysis showed that IFN-γ discriminated PFS outcomes in patients with normal LDH, whereas TMB discriminated outcomes in patients with elevated LDH in the atezolizumab group. Neither IFN-γ nor TMB discriminated PFS outcomes in the control group.

Conclusions: Treatment benefits in the atezolizumab group seemed to be most evident in patients with elevated LDH and PD-L1- tumors. LDH remains the primary predictor of outcomes regardless of treatment. IFN-γ and TMB further differentiate outcomes for patients treated with atezolizumab, vemurafenib, and cobimetinib.

Keywords: atezolizumab; biomarkers; cobimetinib; melanoma; vemurafenib.

Conflict of interest statement

Disclosure CR reports personal fees and travel grants for participation in advisory boards from Amgen, Biothera, Bristol Myers Squibb, Roche, Pierre Fabre, Merck, Novartis, Amgen, Novartis, Merck Sharp & Dohme (MSD), Sanofi, and Ultimovacs. KDL reports grants from Roche/Genentech during the conduct of the study and personal fees from Roche/Genentech. RG reports other from Roche during the conduct of the study; personal fees and nonfinancial support from Bristol Myers Squibb, Roche Pharma, and Merck Serono; grants, personal fees, and nonfinancial support from Amgen, Novartis, Pierre Fabre, and Sanofi Regeneron; personal fees from 4SC, Almirall Hermal, MSD, and Sun Pharma; grants from Johnson & Johnson; and grants and personal fees from Pfizer. HG reports grants and personal fees from Bristol Myers Squibb, MSD, Novartis, and Roche; personal fees from Amgen; and personal fees from Pierre Fabre. RPP reports grants from Roche/Genentech during the conduct of the study; grants from AstraZeneca, BeiGene, Myovant, Pfizer, Regeneron, and Sanofi; and grants and personal fees from Roche/Genentech. TE reports other from Roche during the conduct of the study and personal fees from Bristol Myers Squibb, Leo Pharma, MSD, Novartis, Roche, Almirall Hermal, Pierre Fabre, and Sanofi. PR reports personal fees from Bristol Myers Squibb, Novartis, Roche, MSD, Pierre Fabre, and Blueprint Medicines. LD reports grants from Amgen, Bristol Myers Squibb, Roche, Novartis, and MSD. IC, HF, KS, and YY report employment with Roche/Genentech. GAM reports other from Array Biopharma and Roche/Genentech. PAA reports a consultant/advisory role for Bristol Myers Squibb, Roche/Genentech, MSD, Novartis, Array, Merck Serono, Pierre-Fabre, Incyte, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Takis, Lunaphore, and Seagen; research funding from Bristol Myers Squibb, Roche/Genentech, Array, and Sanofi; and travel support from MSD. All remaining authors have declared no conflicts of interest.

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