TY - JOUR
TI - Biomarkers of treatment benefit with atezolizumab plus vemurafenib plus cobimetinib in BRAFV600 mutation–positive melanoma
AU - Robert, C.
AU - Lewis, K.D.
AU - Gutzmer, R.
AU - Stroyakovskiy, D.
AU - Gogas, H.
AU - Protsenko, S.
AU - Pereira, R.P.
AU - Eigentler, T.
AU - Rutkowski, P.
AU - Demidov, L.
AU - Caro, I.
AU - Forbes, H.
AU - Shah, K.
AU - Yan, Y.
AU - Li, H.
AU - McArthur, G.A.
AU - Ascierto, P.A.
JO - Annals of Oncology
PY - 2022
VL - null
TODO - null
SP - null
PB - Elsevier Ireland Ltd
SN - 0923-7534, 1569-8041
TODO - 10.1016/j.annonc.2022.01.076
TODO - null
TODO - 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. © 2022 The Authors
ER -