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Tumor Mutational Burden Predicts Who Will Respond to Immunotherapy

Jaime Rosenberg
Higher tumor mutational burden is associated with improved overall survival in patients with stage IV or metastatic disease being treated with immune checkpoint inhibitors.
The advent of immunotherapy has significantly shifted the treatment paradigm and prognosis for multiple advanced-stage cancers. In cancers like metastatic melanoma and non–small cell lung cancer (NSCLC), the treatment class has greatly improved survival rates.

However, not all patients respond to the treatments, highlighting the need for predictive biomarkers to determine which patients will benefit. Early reports and small cohorts have suggested high tumor mutational burden being associated with improved clinical response, and now a large study has confirmed the hypothesis.

“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,” explained the researchers of the study.

Looking at data from more than 1000 patients with stage IV or metastatic disease for which immune checkpoint inhibitors are approved, including NSCLC, melanoma, renal cell carcinoma, bladder cancer, and head and neck cancer, researchers found that higher somatic tumor mutational burden is associated with improved overall survival.

Patients were treated with atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, or tremelimumab. Tumor mutational burden was calculated by normalizing the number of somatic nonsynonymous mutations to the total number of megabases sequenced, and noting that mutational load varies across tumor types, the researchers defined tumor mutational burden within each cancer type.

The authors found that, across all cancers, more mutations translated into improved overall survival. The authors noted that the association remained even when removing NSCLC and melanoma from the analysis.

“Although the effect for some individual cancers did not reach statistical significance, possibly because of smaller sample size, the numerical trend of better overall survival was observed in nearly all cancer types, with glioma the clearest exception,” the authors wrote. These findings mirror real-world evidence, which has shown gliomas to be immunosuppressive and remain difficult to treat.

Of note, what constituted as high tumor mutational burden varied greatly by cancer type, which suggests that there is likely not a viable universal number that could define high tumor mutational burden and be predictive of response to immune checkpoint inhibitors across all cancers. While breast cancers and renal cell carcinomas only need 6 mutations per 1 million DNA to predictably respond well to immune checkpoint inhibitors, melanomas need 30.7 and colorectal cancers need 52.2.

According to the researchers, this can likely be explained by distinct tumor microenvironments as well as other factors that have shown to independently predict response, including clonality, immune infiltration, and immune cell exclusion.

Reference:

Samstein R, Lee C, Shoushtari A, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types [publihsed online January 14, 2019]. Nature. doi: 10.1038/s41588-018-0312-8.

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