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

Abstract

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.

Keywords: Biomarker; Immune Checkpoint Inhibitor; Immunotherapy; Tumor mutation burden - TMB.

Figure 1. ICI monotherapy cohort overview. Cohort selection diagram. CGDB, clinico-genomic database; ICI, immune checkpoint inhibitor; TMB, tumor mutational burden.

Figure 2. Pan-tumor assessment of the clinical validity of TMB to prognosticate rwOS on single-agent ICI. Stratified CoxPH models were used to assess the pan-tumor associations of observed features with rwOS. Plot shows HRs with 95% CI. Associations with time to next treatment are included in online supplemental figure 1). ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; MSI, microsatellite instability; MSS, microsatellite stable; rwOS, real-world overall survival; SES, socioeconomic status; TMB, tumor mutational burden.

Figure 3. Per tumor type assessment of the clinical validity of TMB to prognosticate real-world overall survival on single-agent ICI. Cox models adjusted for ECOG PS, line of therapy, sex, age, and opioid prescription pretreatment are shown per disease type for rwOS for (A) all records meeting selection criteria and (B) the subgroup of these also testing MSS. The statistical analysis plan prespecified reporting any individual cancer type of at least 15 events. Any cancer type with at least five death events are shown, with forest plots colored by amount of power for assessment. Associations with real-world time to next treatment are included in online supplemental figure 3. crc, colorectal cancer; cup, cancer of unknown primary; ECOG PS, Eastern Cooperative Oncology Group performance status; gbm, glioblastoma multiforme; hcc, hepatocellular carcinoma; hnc, head and neck cancer; ICI, immune checkpoint inhibitor; lnec, large neuroendocrine carcinoma; MSS, microsatellite stable; nsclc, non-small cell lung cancer; rcc, renal cell carcinoma; rwOS, real-world overall survival.

Figure 4. Exploratory cut-offs. Forest plots indicate the relative hazards of death when comparing patients grouped as “high“ versus “low“ TMB by the indicated threshold. Associations with patients testing MSS only are included in online supplemental figure 9. crc, colorectal cancer; cup, cancer of unknown primary; hnc, head and neck cancer; MSS, microsatellite stable; nsclc, non-small cell lung cancer; rwOS, real-world overall survival; sclc, small cell lung cancer; TMB, tumor mutational burden.

Figure 5. Summary of comparative analyses by TMB. A summary of published analyses comparing ICI versus chemotherapy by TMB levels. CGDB, clinico-genomic database; FMI, Foundation Medicine Incorporated; ICI, immune checkpoint inhibitor; KN, KEYNOTE; NSCLC, non-small cell lung cancer; RCT, randomized controlled trial; rwOS, real-world overall survival; TMB, tumor mutational burden; WES, whole exome sequencing.