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Study Finds High Tumor Mutational Load Is a Predictor of Response to Immunotherapy in Some Cancers

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Key Points

  • Higher somatic tumor mutational burden was linked to better overall survival across a wide variety of cancer types, although improved survival was not seen in glioma.
  • The tumor mutational burden cutpoints associated with improved survival varied markedly among cancer types.
  • The number defining high tumor mutational burden appears to vary across cancer types and it is unlikely there is a universal number that defines the likelihood of benefit from checkpoint inhibitors across all histologies.

Although the emergence of immune checkpoint inhibitors over the last decade has revolutionized the treatment of patients with metastatic cancers, only a minority of patients experience long-lasting benefit from the therapy. A study investigating the association between tumor mutational burden and response to immune checkpoint inhibitors has found that while higher somatic tumor mutational burden was linked to better overall survival across a wide variety of cancer types, improved survival was not seen in glioma. In addition, the tumor mutational burden cutpoints associated with improved survival varied markedly among cancer types. The findings suggest that the number defining high tumor mutational burden appears to vary across cancer types and it is unlikely there is a universal number that defines the likelihood of benefit from checkpoint inhibitors across all histologies. The study was published by by Samstein et al in Nature Genetics.

Study Methodology

The researchers analyzed the clinical and genomic data of 1,662 patients with advanced cancer who had been treated with a U.S. Food and Drug Administration (FDA)-approved immune checkpoint inhibitor and 5,371 patients with advanced cancer who had not been treated with an immune checkpoint inhibitor. They examined the association between nonsynonymous somatic tumor mutational burden, as measured using the Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay, and overall survival after treatment with an immune checkpoint inhibitor. The cancer types included in the study were bladder, breast, colorectal, esophagogastric, head and neck, glioma, non–small cell lung, melanoma, renal cell, and unknown primary.

To calculate tumor mutational burden, the total number of somatic nonsynonymous mutations was normalized to the total number of megabases sequenced. Overall survival was measured from the date of the first immune checkpoint inhibitor treatment to time of death or most recent follow-up. The median follow-up was 19 months (range 0–80, with 830 [50%] patients alive and censored at the most recent follow-up).

Study Results

The researchers found that among all patients, higher somatic tumor mutational burden (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher tumor mutational burden and improved survival was observed. However, distinct from the other cancer types, there was no association between higher tumor mutational burden and improved survival in patients with glioma—in fact, the trend was toward poorer survival.

“The tumor mutational burden cutpoints associated with improved survival varied markedly between cancer types. These data indicate that tumor mutational burden is associated with improved survival in patients receiving immune checkpoint inhibitors across a wide variety of cancer types, but that there may not be one universal definition of high tumor mutational burden … given the potential toxicities of immunotherapy and the highly variable response to immune checkpoint inhibitors, as well as the significant economic cost of these agents, there is an urgent need for biomarkers that can predict immunotherapy response. Future studies that integrate other genomic or pathologic biomarkers may allow for the development of an even more optimized predictive test to inform clinical decisions on the use of immune checkpoint inhibitors,” concluded the study authors.

David B. Solit, MD; Timothy A. Chan, MD, PhD; and Luc G. T. Morris, MD, MSc, FACS, of Memorial Sloan Kettering Cancer Center, are the corresponding authors of this study.

Disclosure: The study authors’ full disclosures can be found at nature.com.

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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