Biomarkers of Treatment Benefit With Triplet Combination in BRAF-Positive Melanoma
An exploratory analysis of the IMspire150 study identified patients with BRAF V600E mutation-positive melanoma likely to benefit from combination treatment with atezolizumab, vemurafenib, and cobimetinib.
“The phase 3 IMspire150 study demonstrated significantly improved progression-free survival (PFS) with atezolizumab, vemurafenib, and cobimetinib versus placebo, vemurafenib, and cobimetinib in patients with BRAF V600E-mutated advanced melanoma,” wrote Prof Caroline Robert, Gustave Roussy and Université Paris-Saclay, Villejuif, France, and colleagues.
The double-blinded phase 3 trial enrolled 514 patients with stage IV or unresectable stage IIIc melanoma. Patients were randomized to receive atezolizumab (n = 256) or placebo (n = 258). Outcomes were evaluated in subgroups defined by biomarkers such as programmed death-ligand 1 (PD-L1) expression, lactate dehydrogenase (LDH) level, tumor mutational burden (TMB), and interferon-y (IFN-γ) gene signature. Of the cohort, 86% had BRAF V600Emutations.
Associations between PFS and baseline covariates, including key biomarkers, were analyzed using exploratory recursive partitioning.
The PFS benefit for atezolizumab vs control was greater in patients with high TMB (10 mutations/Mb; hazard ratio [HR], 0.73; P = .067) vs low TMB (<10 mutations/Mb; HR, 0.92; P = .64) and similar between patients with strong IFN-γ (HR, 0.76) vs weak IFN-γ gene signature (HR, 0.79).
In patients with elevated LDH levels, PFS benefit for atezolizumab vs control was greater in the PD-L1-negative subgroup (HR, 0.53; P = .032) than in the PD-L1-positive subgroup (HR, 0.51; P = .51).
Findings from the recursive partitioning analysis showed that IFN-γ prognosticated PFS outcomes in patients with normal LDH, whereas TMB prognosticated outcomes in patients with elevated LDH in the atezolizumab group. Neither IFN-γ nor TMB were prognostic of PFS outcomes in the control group.
Source:
Robert C, Lewis KD, Gutzmer R, et al. Biomarkers of treatment benefit with atezolizumab plus vemurafenib plus cobimetinib in BRAFV600 mutation-positive melanoma. Ann Oncol. 2022;33(5):544-555. doi:10.1016/j.annonc.2022.01.076
