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.

Conflict of interest statement

Competing interests: RC, DA-G, AA, LX, AL, LL, FJ, EHR, and JL are full-time employees of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, New Jersey, USA and hold stock in Merck & Co, Inc, Kenilworth, New Jersey, USA. XQL is a full-time employee of MSD China. AS was a full-time employee of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, New Jersey, USA at the time the study was conducted.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

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

Figure 3

Objective response rate in participants in the pooled pembrolizumab population by TMB ≥175 mut/exome and

Figure 4

Longitudinal outcomes in participants in the pooled pembrolizumab population by TMB ≥175 mut/exome and

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