Prevalence of High Tumor Mutational Burden and Association With Survival in Patients With Less Common Solid Tumors

Abstract

Importance: Tumor mutational burden (TMB) is a potential biomarker associated with response to immune checkpoint inhibitor therapies. The prognostic value associated with TMB in the absence of immunotherapy is uncertain.

Objective: To assess the prevalence of high TMB (TMB-H) and its association with overall survival (OS) among patients not treated with immunotherapy with the same 10 tumor types from the KEYNOTE-158 study.

Design, setting, and participants: This retrospective cohort study evaluated the prognostic value of TMB-H, assessed by Foundation Medicine (FMI) and defined as at least 10 mutations/megabase (mut/Mb) in the absence of immunotherapy. Data were sourced from the deidentified Flatiron Health-FMI clinicogenomic database collected up to July 31, 2018. Eligible patients were aged 18 years or older with any of the following solid cancer types: anal, biliary, endometrial, cervical, vulvar, small cell lung, thyroid, salivary gland, mesothelioma, or neuroendocrine tumor. Patients with microsatellite instability-high tumors were excluded from primary analysis. For OS analysis, patients were excluded if immunotherapy started on the FMI report date or earlier or if patients died before January 1, 2012, and patients were censored if immunotherapy was started later than the FMI report date. Data were analyzed from November 2018 to February 2019.

Main outcomes and measures: Overall survival was analyzed using the Kaplan-Meier method and Cox proportional hazards model, adjusting for age, sex, cancer types, practice type, and albumin level.

Results: Of 2589 eligible patients, 1671 (64.5%) were women, and the mean (SD) age was 63.7 (11.7) years. Median (interquartile range) TMB was 2.6 (1.7-6.1) mut/Mb, and 332 patients (12.8%) had TMB-H (≥10 mut/Mb). Prevalence of TMB-H was highest among patients with small cell lung cancer (40.0%; 95% CI, 34.7%-45.6%) and neuroendocrine tumor (29.3%; 95% CI, 22.8%-36.6%) and lowest was among patients with mesothelioma (1.2%; 95% CI, 0.3%-4.4%) and thyroid cancer (2.7%; 95% CI, 1.2%-5.7%). Adjusted hazard ratio for OS of patients not treated with immunotherapy with TMB-H vs those without TMB-H was 0.94 (95% CI, 0.77-1.13). Comparable results were observed when including patients with high microsatellite instability tumors and calculating OS from first observed antineoplastic treatment date.

Conclusions and relevance: These findings suggest that prevalence of TMB-H varies widely depending on tumor type and TMB-H does not appear to be a factor associated with OS among patients across these cancer types treated in the absence of immunotherapy.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Shao reported owning stock in Merck and Co outside the submitted work. Dr Li reported receiving personal fees from Foundation Medicine and having equity ownership in F. Hoffmann-La Roche outside the submitted work. Dr Huang reported owning stock in Merck and Co outside the submitted work. Dr Castellanos reported owning equity in Flatiron Health and stock from Roche outside the submitted work. Dr Carson reported receiving personal fees from Tempus Labs and Flatiron Health outside the submitted work. Dr Snow reported receiving personal fees from and owning stock in Roche and owning equity in Flatiron Health outside the submitted work. Dr Fabrizio reported having a patent for Methods and Systems for Evaluating Tumor Mutational Burden pending. Dr Alexander reported receiving personal fees from Roche during the conduct of the study and grants from Eli Lilly and Co, Puma, and Celgene outside the submitted work. Dr Zhou reported receiving stock and stock options in Merck and Co outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Distribution of Tumor Types and High Tumor Mutational Burden (TMB-H) Across the Entire Cohort

Analysis included all tumor types. Evaluation of TMB-H was performed using the FoundationOne assay or FoundationOne Companion Diagnostic platforms. TMB-H was defined as 10 or more mutations per megabase. All patients had at least 1 documented clinical visit observed in the clinicogenetic database after January 1, 2011. Meso indicates mesothelioma; NET, neuroendocrine tumor; SCLC, small cell lung cancer.

Figure 2.. Kaplan-Meier Estimate of Overall Survival Among Patients With High Tumor Mutational Burden (TMB) and Without High TMB

All patients were included for primary analysis. Survival was defined as the time from Foundation Medicine report date to the date of death due to any cause or censor date. High TMB was defined as 10 or more mutations per megabase.

Figure 3.. Sensitivity Analyses Evaluating Association Between Tumor Mutational Burden (TMB) and OS Among Patients With All 10 Tumor Types

The study population was derived from patients tested by FoundationOne (F1) assay or F1 Companion Diagnostic (CDx) assay vs any FMI assay. OS was calculated from Foundation Medicine (FMI) report date vs date of first antineoplastic treatment. CGDB indicates clinicogenomic database; HR, hazard ratio; MSI-H, high microsatellite instability; TMB, tumor mutational burden; TMB-H, high TMB (≥10 or ≥13 mutations per megabase).