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Is Tumor Mutational Burden Alone Sufficient to Predict Response to Immunotherapy?


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In a letter to the editor published in The New England Journal of Medicine, Benoit Rousseau, MD, and colleagues presented evidence that high tumor mutational burden (TMB) alone is not sufficient to predict improved outcomes with immune checkpoint inhibitor therapy in patients with solid tumors.

As stated by the investigators, “The [U.S. Food and Drug Administration] recently approved pembrolizumab for patients who have treatment-refractory cancers with a TMB greater than 10 mutations per megabase. This approval, for [the] treatment of any type of solid tumor, was based on retrospective evidence from a study showing that high TMBw as 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

Benoit Rousseau, 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 Memorial Sloan Kettering Cancer Center. Median overall survival was 43.1 months (95% confidence interval [CI] = 14.14 months–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 with TMB < 10 mut/Mb (low TMB; hazard ratio [HR] = 0.40, 95% CI = 0.24–0.65) after immune checkpoint inhibitor treatment.

On multivariate analysis stratifying the cohort by DNA repair status according to mismatch repair (MMR) status or presence of pathogenic mutations in pol-d, there was no significant difference in median overall survival between 13 patients with MMR-proficient tumors with high TMB (10.6 months, 95% CI = 4.41–22.2 months) compared with that in 84 patients with MMR-proficient tumors with low TMB (12.1 months, 95% CI = 9.61–15.3 months), 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–not estimable) among four patients with pathogenic pol-d mutation (HR = 0.29, 95% CI = 0.15–0.54, vs MMR-proficient/low TMB) and not reached (95% CI = 34.28 months–not estimable) among 34 with MMR-deficient tumors (HR = 0.18, 95% CI = 0.02–1.37, vs MMR-proficient/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 validation cohort of 1,661 patients with metastatic disease treated with checkpoint inhibitors between 2015 and 2019.

Among patients with MMR-proficient and non–pol-d–mutant tumors, high vs low TMB was associated with improved overall survival among patients with non–small cell lung cancer (NSCLC; high = 111, low = 236; HR = 0.70, 95% CI = 0.52–0.95), melanoma (high = 148, low = 108; HR = 0.62, 95% CI = 0.41–0.94), and head and neck cancers (high = 26, low = 118; HR = 0.46, 95% CI = 0.22–0.95). Among these three tumor types combined (high = 285, low = 462), the hazard ratio for overall survival for high vs low TMB was 0.52 (95% CI = 0.41–0.64). Among a total of 11 patients in this group with MMR-deficient or pol-d–mutant tumors, the hazard ratio vs low-TMB, MMR-proficient tumors was 0.81 (95% CI = 0.34–1.97)

In contrast, no significant survival benefit was observed with high TMB vs low TMB among MMR-proficient tumors for patients with:

  • Esophageal or gastric cancer (high = 9, low = 107; HR = 0.97, 95% CI = 0.07–1.29)
  • Colorectal cancer (high = 13, low = 65; HR = 0.87, 95% CI = 0.34–2.25)
  • Urinary tract carcinoma (high = 77, low = 126; HR = 0.77, 95% CI = 0.50–1.18)
  • Brain cancer (high = 9, low = 108; HR = 0.74, 95% CI = 0.30–1.85)
  • Unknown primary tumor (high = 19, low = 44; HR = 0.72, 95% CI = 0.28–1.81)
  • Other tumors (including kidney, breast, mucosal melanoma, uveal melanoma, and neuroendocrine tumors; high = 11, low = 259; HR = 0.40, 95% CI = 0.10–1.62).

Among all these 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).   

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.
— Benoit Rousseau, MD, and colleagues

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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.”

Luis A. Diaz, Jr, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was supported by Nuovo Soldati, National Institutes of Health, and others. For full disclosures of the study authors, visit nejm.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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