Tumor mutational burden predicts the efficacy of pembrolizumab monotherapy: a pan-tumor retrospective analysis of participants with advanced solid tumors

Abstract

Background: Several studies have evaluated the relationship between tumor mutational burden (TMB) and outcomes of immune checkpoint inhibitors. In the phase II KEYNOTE-158 study of pembrolizumab monotherapy for previously treated recurrent or metastatic cancer, high TMB as assessed by the FoundationOne CDx was associated with an improved objective response rate (ORR).

Methods: We retrospectively assessed the relationship between TMB and efficacy in participants with previously treated advanced solid tumors enrolled in 12 trials that evaluated pembrolizumab monotherapy, including 3 randomized trials that compared pembrolizumab with chemotherapy. TMB was assessed in formalin-fixed, paraffin-embedded pretreatment tumor samples by whole-exome sequencing. High TMB was defined as ≥175 mutations/exome. Microsatellite instability (MSI) phenotype was based on whole-exome sequencing results. Programmed death ligand 1 (PD-L1) expression was assessed by immunohistochemistry. The primary end point was ORR assessed per RECIST V.1.1 by independent central review. Other end points included progression-free survival (PFS) assessed per RECIST V.1.1 by independent central review and overall survival (OS).

Results: Of the 2234 participants in the analysis, 1772 received pembrolizumab monotherapy and 462 received chemotherapy. Among the pembrolizumab-treated participants, ORR was 31.4% (95% CI 27.1 to 36.0) in the 433 participants with TMB ≥175 mutations/exome and 9.5% (95% CI 8.0 to 11.2) in the 1339 participants with TMB <175 mutations/exome. The association of TMB with ORR was observed regardless of PD-L1 expression and not driven by specific tumor types or participants with very high TMB or high MSI. In the 3 randomized controlled trials, TMB was associated with ORR (p≤0.016), PFS (p≤0.005), and OS (p≤0.029) of pembrolizumab but not of chemotherapy (p≥0.340, p≥0.643, and p≥0.174, respectively), and pembrolizumab improved efficacy versus chemotherapy in participants with TMB ≥175 mutations/exome.

Conclusions: TMB ≥175 mutations/exome is associated with clinically meaningful improvement in the efficacy of pembrolizumab monotherapy and improved outcomes for pembrolizumab versus chemotherapy across a wide range of previously treated advanced solid tumor types. These data suggest TMB has broad clinical utility irrespective of tumor type, PD-L1 expression, or MSI status and support its use as a predictive biomarker for pembrolizumab monotherapy in participants with previously treated advanced solid tumors.

Trial registration: ClinicalTrials.gov NCT01295827 NCT01704287 NCT01905657 NCT01848834 NCT02054806 NCT02256436 NCT02255097 NCT02335411 NCT02370498 NCT02447003 NCT02674061 NCT02787005.

Keywords: immunotherapy; programmed cell death 1 receptor; tumor biomarkers.

Figure 1

Validation of the optimal cutpoint for TMB assessed by WES. (A) Comparison of inflammation in the tumor microenvironment assessed using an 18-gene T-cell inflamed GEP in participants with TMB above versus below potential WES cutpoints for mutational burden. P values are two-sided and assessed using the Wilcoxon rank-sum test. The vertical dotted line represents TMB 175 mut/exome. (B) The optimal TMB cut-off assessed by WES that corresponds with the FoundationOne CDx TMB cutpoint of 10 mut/megabase. The Youden index of 175 mut/exome assessed per WES is the point of maximal average positive and negative agreement rates with 10 mut/megabase by the FoundationOne CDx. The area under the receiver-operating characteristic curve is 0.92. GEP, gene expression profile; mut, mutations; TMB, tumor mutational burden; WES, whole-exome sequencing.

Figure 2

Proportion of participants in the pooled pembrolizumab population with whole-exome sequencing TMB ≥175 mut/exome and TMB <175 mut/exome by tumor type. The tumor types are presented in order of descending median tumor mutational burden. For a listing of tumor types included in the ‘other’ category, see online supplemental table S2. HNSCC, head and neck squamous cell carcinoma; mut, mutations; NSCLC, non-small-cell lung cancer; TMB, tumor mutational burden; TNBC, triple-negative breast cancer.

Figure 3

Objective response rate in participants in the pooled pembrolizumab population by TMB ≥175 mut/exome and <175 mut/exome. (A) ORR in the overall population and by tumor type. Tumor types are presented in order of descending median TMB; for a listing of tumor types included in the ‘other’ category, see online supplemental table S2. (B) Participant-level TMB scores in responders and non-responders overall and by tumor type. Tumor types are presented in order of descending median TMB; for a listing of tumor types included in the ‘other’ category, see online supplemental table S2. The center line represents the median, the box limits represent the upper and lower quartiles, and the whiskers represent the maximum within 1.5×IQR from the 75th percentile and the minimum within 1.5×IQR from the 25th percentile. (C) ORR in the overall population by PD-L1 expression status. (D) ORR in the overall population by MSI genotype. HNSCC, head and neck squamous cell carcinoma; MSI-H, microsatellite instability high; mut, mutations; NSCLC, non-small-cell lung cancer; ORR, objective response rate; PD-L1, programmed death ligand 1; TMB, tumor mutational burden; TNBC, triple-negative breast cancer.

Figure 4

Longitudinal outcomes in participants in the pooled pembrolizumab population by TMB ≥175 mut/exome and <175 mut/exome. (A) Kaplan-Meier estimates of duration of response assessed per RECIST V.1.1 by independent central review among participants in the pooled pembrolizumab population with a complete or partial response. (B) Kaplan-Meier estimates of progression-free survival assessed per RECIST V.1.1 by independent central review in the overall pooled pembrolizumab population. (C) Kaplan-Meier estimates of overall survival in the overall pooled pembrolizumab population. mut, mutations; TMB, tumor mutational burden.

Figure 5

Objective response rate by treatment arm in participants in the 3randomized clinical trials included in the analysis by TMB ≥175 mut/exome and <175 mut/exome. Response was assessed per RECIST V.1.1 by independent central review. mut, mutations; NSCLC, non-small-cell lung cancer; TMB, tumor mutational burden.