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

J Immunother Cancer. 2022 Jan;10(1):e003091. doi: 10.1136/jitc-2021-003091.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • B7-H1 Antigen / metabolism
  • Biomarkers, Tumor / genetics*
  • Exome Sequencing
  • Female
  • Humans
  • Immune Checkpoint Inhibitors / therapeutic use*
  • Male
  • Microsatellite Instability
  • Mutation*
  • Neoplasms / drug therapy*
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Retrospective Studies
  • Treatment Outcome


  • Antibodies, Monoclonal, Humanized
  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • Immune Checkpoint Inhibitors
  • pembrolizumab

Associated data

  • ClinicalTrials.gov/NCT01295827
  • ClinicalTrials.gov/NCT01704287
  • ClinicalTrials.gov/NCT01905657
  • ClinicalTrials.gov/NCT01848834
  • ClinicalTrials.gov/NCT02054806
  • ClinicalTrials.gov/NCT02256436
  • ClinicalTrials.gov/NCT02255097
  • ClinicalTrials.gov/NCT02335411
  • ClinicalTrials.gov/NCT02370498
  • ClinicalTrials.gov/NCT02447003
  • ClinicalTrials.gov/NCT02674061
  • ClinicalTrials.gov/NCT02787005