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

Robert, C; Lewis, KD; Gutzmer, R; Stroyakovskiy, D; Gogas, H; Protsenko, S; Pereira, RP; Eigentler, T; Rutkowski, P; Demidov, L; Caro, I; Forbes, H; Shah, K; Yan, Y; Li, H; McArthur, GA; Ascierto, PA

Author(s): Robert, C; Lewis, KD; Gutzmer, R; Stroyakovskiy, D; Gogas, H; Protsenko, S; Pereira, RP; Eigentler, T; Rutkowski, P; Demidov, L; Caro, I; Forbes, H; Shah, K; Yan, Y; Li, H; McArthur, GA; Ascierto, PA;
Details: Publication Year 2022-05,Volume 33,Issue #5,Page 544-555
Journal Title: Annals of Oncology
Publication Type: Research article
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 BRAF(V600)-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-gamma (IFN-gamma) 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-gamma (>/=median; HR 0.76; 95% CI 0.54-1.06) versus weak IFN-gamma (<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-gamma discriminated PFS outcomes in patients with normal LDH, whereas TMB discriminated outcomes in patients with elevated LDH in the atezolizumab group. Neither IFN-gamma 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-gamma and TMB further differentiate outcomes for patients treated with atezolizumab, vemurafenib, and cobimetinib.
Keywords: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; B7-H1 Antigen/genetics/therapeutic use; Biomarkers, Tumor/genetics; Humans; *Melanoma/drug therapy/genetics/pathology; Mutation; Piperidines; *Proto-Oncogene Proteins B-raf/genetics; Vemurafenib; atezolizumab; biomarkers; cobimetinib; melanoma
Department(s): Medical Oncology; Laboratory Research
PubMed ID: 35131452
Publisher's Version: https://doi.org/10.1016/j.annonc.2022.01.076
Open Access at Publisher's Site: https://doi.org/10.1016/j.annonc.2022.01.076
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-03-07 05:57:22

Last Modified: 2025-03-07 06:00:21