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Molecular pathology selected abstracts

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Correlation between tumor mutation burden and efficacy of combination immunotherapy in nonsmall cell lung cancer

July 2018—Checkpoint inhibitor therapy has dramatically improved outcomes in many cancer types, with treatments including antibodies against cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), programmed cell death receptor-1 (PD-1), and its ligand (PD-L1). Combination immunotherapy using PD-1 plus CTLA-4 blockade has shown promising outcomes in nonsmall cell lung cancer (NSCLC).

However, the response is not universal in all patients, and it is difficult to predict those who will respond. Pathologist interpretation of the proportion of tumor cells showing membranous immunohistochemical staining with anti-PD-L1 antibody has been the mainstay for determining whether patients are eligible for treatment or clinical trials, or both. However, such interpretation shows interobserver variability, and more importantly, it is only modestly sensitive and specific for predicting response. Therefore, it is necessary to identify other predictive markers. There is increasing recognition of an association between tumor mutation burden (TMB) and response rates in multiple tumor types treated with checkpoint inhibitor monotherapy. In this study, the authors sought to determine whether this relationship between TMB and response rate also occurs in NSCLC treated with combination immunotherapy. They performed whole exome sequencing on tumor tissue and paired blood from 75 patients with advanced NSCLC treated with combination immunotherapy. A comparison of patients above and below the TMB median found that patients with a high TMB had significantly improved progression-free survival. To determine whether there were confounding variables, the authors compared the clinical characteristics between the two groups. Except for smoking status (patients with a high TMB were significantly more likely to be smokers), the clinical characteristics were similar. However, in a multivariate analysis that included smoking status, PD-L1 expression, histology, performance status, and amount of tumor, the authors confirmed that TMB was independently associated with overall response rate and progression-free survival. Finally, the authors examined whether other molecular features were associated with response to combination immunotherapy. They found that mutations in STK11 and PTEN were associated with resistance. It has been hypothesized in the medical literature, and by the authors, that immunotherapy is more effective in tumors with a high TMB because these tumors have increased numbers of neoantigens, mutated proteins specific to the tumor, that can be recognized by the immune system. Although determining mutation burden using whole exome sequencing would be difficult, especially given the short time frame in which it would need to be performed in patients with advanced NSCLC, some studies have shown that TMB correlates with the number of mutations seen in the targeted next-generation sequencing panels that are routinely used clinically. Overall, TMB appears to be a strong predictor of the efficacy of combination immunotherapy in NSCLC.

Hellmann MD, Nathanson T, Rizvi H, et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell. 2018;33:843–852.

Correspondence: Dr. Matthew D. Hellmann at hellmanm@mskcc.org

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