307 Atezolizumab plus vemurafenib and cobimetinib provides favorable survival outcomes in patients with high tumor mutation burden and proinflammatory gene signature in the phase 3 IMspire150 study

Background The phase 3 IMspire150 study (NCT02908672) showed that first-line atezolizumab (A) combined with vemurafenib (V) + cobimetinib (C) improved progression-free survival (PFS) vs placebo (P) + V + C in patients with BRAFV600 mutation–positive advanced melanoma (15.1 vs 10.6 months; hazard ratio [HR] 0.78; 95% CI 0.63–0.97; P=0.0249). Insights into the clinical benefit of the A+V+C triple combination in prognostic molecular subgroups of patients can inform treatment selection and future clinical research. Methods 514 patients were randomized 1:1 to A+V+C (n=256) or P+V+C (n=258). The efficacy endpoints analyzed included PFS and duration of response (DOR) estimated using the Kaplan-Meier method. Outcomes were based on investigator-assessed best overall response per Response Evaluation Criteria in Solid Tumors v1.1. Patients were primarily categorized into binary subgroups defined by tumor mutation burden (TMB; low or high: <10 or ≥10 mutations/Mb, respectively) or by the < or ≥ median values of interferon (IFN)-gamma or CD8+ tumor cells. In addition, these subgroups were further broken down based on the proportion of programmed death-ligand 1 (PD-L1)-expressing tumor-infiltrating cells as PD-L1+ (≥1%) or PD-L1– (<1%). Results Patients treated with P+V+C with high and low TMB had similar PFS outcomes. However, the magnitude of the PFS benefit with A+V+C vs P+V+C was markedly higher in patients with high TMB (≥10 mutations/Mb) compared with patients with low TMB (<10 mutations/Mb) in whom the benefit between treatment arms was comparable (figure 1A). The magnitude of the PFS benefit with A+V+C was further enhanced in patients with high TMB and PD-L1– compared with patients with high TMB and PD-L1+. Overall, patients with potential for increased antitumor immunity (IFN-gamma ≥ median or CD8+ ≥ median) who received A+V+C had more favorable outcomes compared with their counterparts with IFN-gamma < median or CD8+ < median. In general, the PFS benefit with A+V+C vs P+V+C was more readily apparent in PD-L1– subgroups. Similar trends were seen with DOR (figure 1B). Conclusions There was a trend of larger magnitude of PFS benefit with A+V+C vs P+V+C in PD-L1– patient subgroups, who benefit less with single-agent immunotherapy. The PFS and DOR benefits were more evident in patients with high IFN-gamma or TMB >10 mutations/Mb. Additional multivariate analyses are ongoing to delineate the PFS trends observed. Trial Registration ClinicalTrials. gov, identifier NCT02908672

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