In a letter to the editor in The New England Journal of Medicine, Benoit Rousseau, MD, PhD, and Michael B. Foote, MD, of Memorial Sloan Kettering Cancer Center (MSK), and colleagues presented evidence that a high tumor mutational burden (TMB) threshold of 10 alone may not be sufficient to predict improved outcomes with immune checkpoint inhibitor therapy for some solid tumors.¹

As stated by the investigators: “The … FDA recently approved pembrolizumab … for patients who have treatment-refractory cancers with a [TMB] greater than 10 mutations per megabase…. This approval, for treatment of any type of solid tumor, was based on retrospective evidence from a study showing that high [TMB] was predictive of a favorable radiographic response to treatment with immune checkpoint inhibitors in patients with 10 different rare cancers…. Of note, high [TMB] did not predict improved overall survival after treatment with [immune checkpoint inhibitors], nor did the study evaluate other major tumor types or the cause of the high-mutation phenotype.”

Benoit Rousseau, MD, PhD

Michael B. Foote, MD

Assessment in Colorectal Cancer Cohort

Observing that the above approval would affect approximately 18% of cases of advanced colorectal cancer, the investigators evaluated 137 patients with advanced colorectal cancer treated with PD-1/PD-L1– or CTLA-4–targeted therapy prior to December 2019 at MSK. Median overall survival was 43.1 months (95% confidence interval [CI] = 14.14 months to not estimable) among 52 patients with TMB ≥ 10 mutations/megabase (mut/Mb) vs 12.1 months (95% CI = 9.61–15.3 months) among 85 patients with TMB < 10 mut/Mb (low TMB; hazard ratio [HR] = 0.40, 95% CI = 0.24–0.65) after immune checkpoint inhibitor treatment. 

On multivariable analysis stratifying the cohort by DNA repair status according to mismatch repair (MMR) status or presence of pathogenic mutations in pol-d (ie, in polymerase ε [POLE] or polymerase δ1 [POLD1]), there was no significant difference in median overall survival between 13 patients with MMR-proficient tumors with high TMB compared with that in 84 patients with MMR-proficient tumors with low TMB, with a hazard ratio of 1.17 (95% CI = 0.59–2.32) for high vs low TMB. 

Median overall survival was not reached (95% CI = 1.68 months to not estimable) among four patients with pathogenic pol-d mutation (HR = 0.29, 95% CI = 0.15–0.54, vs MMR-proficient with low TMB) and not reached (95% CI = 34.28 months to not estimable) among 34 with MMR-deficient tumors (HR = 0.18, 95% CI = 0.02–1.37) vs MMR-proficient tumors with low TMB.

Assessment in Validation Cohort of Multiple Tumor Types

The association of immune checkpoint inhibitor treatment with overall survival according to TMB status among patients with MMR-proficient tumors of multiple primary types was assessed in a publicly available cohort of 1,661 patients with metastatic disease treated with immune checkpoint inhibitors between 2015 and 2019.

Among patients with MMR-proficient and non–pol-d–mutant tumors, high (≥ 10 mut/Mb) vs low (< 10 mut/Mb) TMB was associated with improved overall survival among patients with non–small cell lung cancer (NSCLC; high TMB = 111, low TMB = 236; HR = 0.70, 95% CI = 0.52–0.95), melanoma (high TMB = 148, low TMB = 108; HR = 0.62, 95% CI = 0.41–0.94), and head and neck cancers (high TMB = 26, low TMB = 118; HR = 0.46, 95% CI = 0.22–0.95). Among these three “TMB-sensitive” tumor types combined (high TMB = 285, low TMB = 462), the hazard ratio for overall survival for high vs low TMB was 0.52 (95% CI = 0.41–0.64). 

In contrast, no significant survival benefit was observed with high TMB vs low TMB among MMR-proficient tumors for esophageal or gastric cancer (high TMB = 9, low TMB = 107; HR = 0.97, 95% CI = 0.07–1.29), colorectal cancer (high TMB = 13, low TMB = 65; HR = 0.87, 95% CI = 0.34–2.25), urinary tract carcinoma (high TMB = 77, low TMB = 126; HR = 0.77, 95% CI = 0.50–1.18), brain cancer (high TMB = 9, low TMB = 108; HR = 0.74, 95% CI = 0.30–1.85), unknown primary tumor (high TMB = 19, low TMB = 44; HR = 0.72, 95% CI = 0.28–1.81), and other tumors (including kidney, breast, mucosal melanoma, uveal melanoma, and neuroendocrine tumors; high TMB = 11, low TMB = 259; HR = 0.40, 95% CI = 0.10–1.62). Among all these “TMB-insensitive” tumor types combined (high TMB = 138, low TMB = 709), the hazard ratio for high vs low TMB was 0.84 (95% CI = 0.63–1.11). Among a total of 56 patients in this group with MMR-deficient or pol-d–mutant tumors, the hazard ratio vs low-TMB, MMR-proficient tumors was 0.34 (95% CI = 0.18-0.61).

As stated by the investigators: “Mismatch-repair deficiency is a well-established biomarker of improved overall survival after treatment with immune checkpoint inhibitors, and pol-d status may also predict benefit from immune checkpoint inhibitors…. We observed that other than patients with these two genetic subtypes, the only patients with hypermutated tumors who benefited from immune checkpoint inhibitors had cancers strongly associated with environmental carcinogens—chronic exposure to ultraviolet radiation or tobacco.”

They concluded: “The current FDA approval granted on the basis of tumor mutational burden may be too broad, and immune checkpoint inhibitors should be considered in the context of the cause of the high tumor mutational burden and not based solely on an absolute threshold. This approval, given purely on the basis of response rate, also neglects more meaningful clinical endpoints, including survival and quality of life, and slows the development of more effective therapies for this patient population.” 

DISCLOSURE: The study was supported by Nuovo Soldati, National Institutes of Health, Swim Across America, Stand Up to Cancer Colorectal Cancer Dream Team, Marie-Josee and Henry R. Kravis Center for Molecular Oncology, and Comprehensive Program of Cancer Immunotherapy and Immunology BBVA Foundation. Dr. Rousseau has served as an institutional consultant or advisor to Bayer and Roche; has participated in a speakers bureau for Bayer and Gilead Sciences; has received institutional research funding from Roche; and has been reimbursed for travel, accommodations, or other expenses by Astellas Pharma, Bayer, and Servier.

REFERENCE

1. Rousseau B, Foote MB, Maron SB, et al: The spectrum of benefit from checkpoint blockade in hypermutated tumors. N Engl J Med 384:1168-1170, 2021.