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

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 non-synonymous 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 200-1000, or TMB of 11-24 (Oncomine) or 15-39 (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 and RNA-sequencing were performed on pre-treatment tumor biopsies. Results: Among 25 evaluable patients with 14 different tumor types treated with atezo+beva, the CB-rate (CBR) was 60% (95% confidence interval [CI], 39-79), with an objective response rate (ORR) of 24% (95% CI, 9-45) and median duration of response (mDoR) of 25.0 months (95% CI, 13.8-NA). In the nivo+ipi cohort the CBR was 50% (95% CI, 29-71) and ORR 37.5% (95% CI, 19-59) among 24 evaluable patients with 13 distinct tumor types. The mDoR was not reached after a median follow-up of 36 months. In both cohorts, responses were only observed 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.