Tumor mutational burden and survival on immune checkpoint inhibition in >8000 patients across 24 cancer types.

Background: There is uncertainty around clinical applicability of tumor mutational burden (TMB) across cancer types, in part because of inconsistency between TMB measurements from different platforms. The KEYNOTE 158 trial supported United States Food and Drug Administration (FDA) approval of the Foundation Medicine test (FoundationOneCDx) at TMB≥10 mut/Mb as a companion diagnostic (CDx) for single-agent pembrolizumab in second+line. Using a large real-world dataset with validated survival endpoint data, we evaluated clinical validity of TMB measurement by the test in over 8000 patients across 24 cancer types who received single-agent immune checkpoint inhibitor (ICI).

Methods: Patients with advanced-stage cancers from 24 cancer types treated with single-agent anti-PD(L)1 therapy in standard-of-care settings were included. Deidentified data from electronic health records from approximately 280 cancer treatment facilities were captured into a clinico-genomic database. This study used the TMB algorithm from the FDA-approved test supporting solid tumor CDx and composite mortality variable validated against the national death index: real-world overall survival (rwOS). Following a prespecified analysis plan, rwOS by TMB level was assessed using Cox PH models adjusted for Eastern Cooperative Oncology Group performance status, prior treatment, microsatellite instability, sex, age, opioid rx pretherapy, and socioeconomic assessment.

Results: 8440 patients met inclusion criteria. Adjusting for aforementioned factors, increasing TMB was significantly associated with rwOS across tumor types; HRs (95% CIs) relative to TMB<5: TMB 5 to <10: 0.95 (0.89 to 1.02), TMB 10 to <20: 0.79 (0.73 to 0.85), TMB≥20: 0.52 (0.47 to 0.58). For individual cancer types with prespecified statistical power, adjusted rwOS comparing TMB≥10 vs TMB<10 significantly favored TMB≥10 in 9 of 10 cancer types. In microsatellite stable subcohorts (except colorectal cancer), TMB≥10 remained associated with enriched ICI benefit. Exploratory assessments of patients receiving ICI+chemotherapy (n=4369) observed more favorable rwOS only in TMB≥20.

Conclusions: Across >8000 patients treated with single-agent ICI, and within individual cancer types with sufficient power, elevated TMB based on the FDA-approved CDx was associated with more favorable rwOS compared with similar patients with lower TMB levels. This biomarker deserves further clinical investigation to potentially guide the use of immunotherapy in expanded clinical contexts.