Checkpoint Blockade Combinations in Tumor Mutational Burden/Load-High Tumors: Insights from the Atezolizumab + Bevacizumab and Nivolumab + Ipilimumab Cohorts in the Drug Rediscovery Protocol

Abstract

PURPOSE: To evaluate the efficacy of atezolizumab plus bevacizumab (atezo + beva) in tumors with high tumor mutational burden (TMB; number of mutations per megabase) and nivolumab plus ipilimumab (nivo + ipi) in tumors with high TMB or tumor mutational load (TML; total number of nonsynonymous mutations across the genome). PATIENTS AND METHODS: Patients with treatment-refractory, solid tumors were treated in the Drug Rediscovery Protocol (2023-509152-33-00). Patients with microsatellite-stable tumors harboring a TML of 200 to 1,000 or TMB of 11 to 24 (Oncomine) or 15 to 39 (TSO500) were eligible for nivo + ipi. Similar patients with a panel-independent TMB ≥16 received atezo + beva. Clinical benefit (CB; confirmed objective response or stable disease ≥16 weeks) was the primary endpoint. Whole-genome sequencing and RNA sequencing were performed on pretreatment tumor biopsies. RESULTS: Among 25 evaluable patients with 14 different tumor types treated with atezo + beva, the CB rate was 60% [95% confidence interval (CI), 39-79], with an objective response rate of 24% (95% CI, 9-45) and a median duration of response of 25.0 months (95% CI, 13.8-not applicable). In the nivo + ipi cohort, the CB rate was 50% (95% CI, 29-71) and objective response rate was 37.5% (95% CI, 19-59) among 24 evaluable patients with 13 distinct tumor types. The median duration of response was not reached after a median follow-up of 36 months. In both cohorts, responses were observed only in patients with TMB >20, and TMB and (clonal) TML were significantly correlated with response. Various markers of adaptive immune infiltration were associated with longer progression-free survival. CONCLUSIONS: Atezo + beva and nivo + ipi showed durable responses in patients with TMB >20, underscoring their tumor-agnostic efficacy in this patient population.