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Brief Report
February 18, 2021

Response Rates to Anti–PD-1 Immunotherapy in Microsatellite-Stable Solid Tumors With 10 or More Mutations per Megabase

Author Affiliations
  • 1Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
  • 2Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
  • 3Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
  • 4Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
  • 5Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
  • 6Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, Ohio
  • 7Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
JAMA Oncol. 2021;7(5):739-743. doi:10.1001/jamaoncol.2020.7684
Key Points

Question  Is a universal cutoff value to define high tumor mutational burden (TMB) associated with tumor response to cancer immunotherapy?

Findings  In this cohort study of 1678 patients with tumors representing 16 cancer types who were treated with anti–programmed cell death 1 or programmed cell death ligand-1 immunotherapy, response rates were generally higher with high TMB (≥10 mutations per megabase). However, the proportion of tumors with high TMB and the association, if any, between high TMB and response rates varied widely across cancer types.

Meaning  These data validate the finding of higher response rates in tumors with high TMB (≥10 mutations per megabase), but the predictive value of a single cutoff value for TMB is limited and would likely be improved with cancer type–specific cutoffs.


Importance  In June 2020, the US Food and Drug Administration approved the anti–programmed cell death 1 drug pembrolizumab for patients with malignant solid tumors of any histologic type with high tumor mutational burden (TMB; ≥10 mutations per megabase). The predictive value of this universal cutoff for high TMB is not well understood.

Objective  To examine the performance of a universal definition of high TMB in an independent cohort of patients with solid tumors treated with immune checkpoint inhibitors.

Design, Setting, and Participants  This retrospective cohort study included 1678 patients at a single cancer referral center treated with immune checkpoint inhibitors from January 1, 2015, to December 31, 2018. Patients had 16 different cancer types and were treated with anti–programmed cell death 1 or programmed cell death ligand-1 immunotherapy. Tumors underwent next-generation sequencing.

Exposures  At least 1 dose of immune checkpoint inhibitors.

Main Outcomes and Measures  Best overall response to immune checkpoint inhibitor therapy. The hypothesis tested was formulated after data collection and prior to analysis.

Results  Of 1678 patients, 924 (55%) were male, and the median age was 64 years (interquartile range, 55-71 years). Using the universal cutoff of 10 mutations per megabase, 416 tumors (25%) were categorized as having high TMB. Across cancer types, the proportion of TMB-high tumors ranged from 0% of kidney cancers to 53% of melanomas (113 of 214). Tumors categorized as TMB-high had higher response rates compared with TMB-low tumors in only 11 of 16 cancer types. In the entire cohort, response rates increased with higher cutoffs for TMB-high categorization, reaching 41% (169 of 416) for TMB more than 10 and 56% (90 of 161) for TMB more than 18, the highest TMB decile. Response rates also increased with TMB percentile within cancer type. Using cancer-specific cutoffs, 457 tumors (27%) were categorized as TMB-high. Response rates within cancer type ranged from 4% for pancreatic cancer (1 of 26) to 70% for melanoma (46 of 66). Cancer-specific cutoffs were associated with numerically higher response rates for TMB-high compared with TMB-low tumors in 14 of 16 cancer types.

Conclusions and Relevance  The data from this cohort study validate the finding of generally higher response rates following immune checkpoint inhibitor therapy for tumors with TMB of 10 or more mutations per megabase, across multiple cancer types. However, the predictive value of a universal numerical threshold for TMB-high was limited, owing to variability across cancer types and unclear associations with survival outcomes. Further investigation will help define cancer type–specific TMB cutoffs to guide decision-making.

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    1 Comment for this article
    Treatment status of solid cancer of TMB (10 <) in Japanese cancer genomic medicine
    takuma hayashi, MBBS, DMSci, GMRC, PhD | National Hospital Organization Kyoto Medical Center
    In 2017, based on a common biomarker across cancer types, pembrolizumab was approved by the FDA for solid tumors with MSI-High or mismatch repair deficiency (dMMR). In the solid cancer of MSI-High, the value of the TMB has been found very high. Therefore, based on the results of the KEYNOTE-158 trial, an application for approval of pembrolizumab for TMB-H (10 <) solid tumors was submitted.

    On 16 June 2020, the US Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab for the treatment of ‘adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase
    (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

    During the period from December 2019 to December 2020, treatment methods for total of 576 cases (Ncc oncopanel test: 129 cases, F1CDx test: 447 cases) were examined in cancer genomic medicine at a national university in Japan.

    From the examination results, total of 33 cases (test with Ncc oncopanel: 8 cases, test with F1CDx: 25 cases) were determined to be MSI-H. In addition, a total of 25 cases (Ncc oncopanel test: 6 cases, F1CDx test: 19 cases) were determined to be TMB (10 <). There were 4 cases with TMB of 20 or more.

    Most of the cases determined to be MSI-H were solid tumors resistant to platinum. On the other hand, in cancer genomic medicine at a national university in Japan, treatment with Nivolumab or Atezolizumab was recommended for cases determined to be TMB (10 <).

    The following points have been pointed out as problems in future cancer genomic medicine.

    1. 10 / Mb is set as the cutoff value as the TMB value. Is this set value correct? The cut-off value of TMB should be examined based on future clinical data.

    2. DNA fragmentation is observed in specimens stored for long periods of time. In addition, the TMB value is affected by the tissue site from which the sample is collected. Specifically, the TMB value is higher in the irradiated tissue.

    In Japanese cancer medicine, as a therapeutic agent for solid tumors with pathogenic variants of BRCA1/2 and pathological variants of Homologous Recombination Deficiency (HRD) factors belonging to the mismatch repair function genes, new antitumor agents such as Poly (ADP-ribose) polymerase (PARP) inhibitors have been covered by insurance at the end of 2020. In the future, new antitumor agents will be developed and clinically applied. Further development of cancer genomic medicine is desired.