Though some studies suggest that tissue-based TMB correlates with clinical outcomes for pembrolizumab treatment, “plasma TMB has not really been evaluated for pembrolizumab-based therapy,” nor for chemotherapy in combination with pembrolizumab, Charu Aggarwal, MD, MPH, Leslye M. Heisler assistant professor for lung cancer excellence at the Perelman Center for Advanced Medicine at the University of Pennsylvania, told this publication.3

The study enrolled 66 patients with metastatic NSCLC due to receive treatment with pembrolizumab-based therapy as standard of care, who were followed for at least 6 months (ClinicalTrials.gov Identifier: NCT03047616); 31 patients received pembrolizumab monotherapy and 35 received the immunotherapy in combination with platinum/permetrexed-based chemotherapy.

Plasma was obtained prior to therapy, and a 500-gene next-generation sequencing panel was used to quantify plasma TMB levels. The researchers succeeded in evaluating plasma tumor mutations in nearly 80% of patients, but failed to produce results for 14 individuals due to reasons that included low tumor shedding of DNA. Some outside research groups who have quantified plasma TMB have reported that 70% patients were evaluable, whereas certain other groups have reported figures of 41% and 58% when evaluating TMB based on tissue samples.4


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In Dr Aggarwal’s study, the median TMB across patients was 16.8 mutations per megabase, and TMB levels were associated with several clinical outcomes. For instance, among patients who experienced a durable clinical benefit (DCB), the researchers documented a median TMB of 21.3 mutations per megabase, compared with 12.4 mutations for those patients who saw no durable benefit.

Twenty-eight patients who had plasma TMB of 16 mutations or more had a median progression-free survival (PFS) of 14.1 months compared with 4.7 months for 14 individuals who had fewer than 16 mutations. “We were intrigued to find that patients with a high tumor mutational burden benefited from immunotherapy, including that with chemoimmunotherapy, which was surprising, since we have not seen this association with … chemoimmunotherapy before,” Dr Aggarwal said.

Interestingly, she and her colleagues found no correlation between plasma TMB and tissue PD-L1 status, consistent with some other studies that have investigated plasma TMB levels in patients with lung cancer.4

Six patients who had high plasma TMB values did not achieve DCB, a finding also consistent with some other research.5  Based on mutational profiling, Dr Aggarwal and her colleagues found that mutations in ERBB2, STK11, KEAP1, and PTEN were more common among patients who saw no DCB. Such mutations could “help identify plasma TMB-high patients unlikely to respond,” they wrote.