To Lynette Sholl, MD, an associate professor of pathology at Harvard Medical School and associate pathologist at Brigham and Woman’s Hospital in Massachusetts, the results add to the literature supporting the utility of TMB in predicting clinical outcomes for immunotherapies.

For instance, one study in patients with NSCLC found that PFS was greatly improved with first-line nivolumab plus ipilimumab compared with chemotherapy alone for individuals who had a high tissue TMB, irrespective of PD-L1 measures.Another study reported a positive correlation between tissue TMB and objective response, DCB, and PFS in NSCLC patients treated with pembrolizumab.3

And interestingly, the US Food and Drug Administration (FDA) recently granted a Priority Review designation to pembrolizumab for the treatment of unresectable or metastatic solid tumors with a TMB of more than 10 mutations per megabase for individuals who have progressed on prior treatment who have no alternative treatment options.7

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Nevertheless, evidence of the clinical utility of TMB in informing treatment selection for NSCLC is contradictory. One disappointing outcome, Dr Sholl said, was that of AstraZeneca’s NEPTUNE study ( Identifier: NCT02542293), which examined the combination of the anti–PD-L1 therapy durvalumab in combination with tremelimumab in patients with metastatic NSCLC with high blood TMB. According to a recent press release, the trial did not meet the primary endpoint, which could indicate that the therapy combination was not sufficiently efficacious, or that TMB, using a cutoff of 20 mutations per megabase, was not a good predictor of clinical benefit.8  

In addition, preliminary results from the KEYNOTE 021 study ( Identifier: NCT02039674), examining the efficacy of first-line pembrolizumab plus platinum-based chemotherapy for nonsquamous NSCLC patients,  showed no correlation between tissue TMB and objective response rate, PFS, or overall survival.

“There’s just a lot of contradictory evidence in the TMB space right now, so it’s not entirely clear that it’s going to be adopted widely,” Dr Sholl said.9

The pressing question is whether employing TMB-based biomarkers will actually lead to survival benefits, Dr Sholl noted. “We’re seeing TMB being predictive of, say, response and progression-free survival with immunotherapy in lung cancer patients, but not necessarily with overall survival, which I think is going to be a persistent challenge for this as a biomarker in terms of integrating it into routine clinical care.”

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“It would have to be demonstrated that employing [TMB] routinely leads to better outcomes than our current algorithm that is based on tumor-based testing for PD-L1 expression,” Dr West added.   

Dr West and Dr Sholl noted that TMB could potentially add to the predictive value of PD-L1 testing by helping identify a subpopulation of patients who have low or negative PD-L1 but who may still benefit from immunotherapy, or patients who are less likely to do well with immunotherapy despite high PD-L1, Dr West explained.

In addition, there’s the FDA’s recent approval of pembrolizumab as a single-agent for first-line treatment of patients with stage 3 NSCLC whose tumors lack EGFR/ALK mutations but have PD-L1 expression anywhere above 1%.10 However, data suggest that the likelihood of response is lower among low expressers, so clinicians have the option of combining pembrolizumab with chemotherapy for this group, Dr Sholl noted. TMB markers may help with such decisions among this group of patients. “There may be a space, or a niche, for TMB to help with some of these decisions, but I don’t think the data [are] mature enough yet for us to actually use it in that way just yet,” Dr Sholl said.

In the meantime, Dr Aggarwal hopes to continue to investigate the clinical utility of plasma-based TMB testing. “We are interested in conducting larger studies to validate these findings and also apply these in a prospective clinical trial.”


  1. Aggarwal C, Thompson JC, Chien AL, et al. Baseline plasma tumor mutation burden predicts response to pembrolizumab-based therapy in patients with metastatic non-small cell lung cancer. Clin Cancer Res. 2020. doi: 10.1158/1078-0432.CCR-19-3663
  2. Gandhi L, Rodríguez-Abreu D, Gadgeel, et al. Pembrolizumab plus chemotherapy in metastatic non-small cell lung cancer. N Engl J Med. 2018;378(22):2078-2092.
  3. Rizvi NA, Hellman MD, Snyder A, et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124-128.
  4. Gandara DR, Paul SM, Kowanetz M, et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med. 2018;24(9):1441-1448.
  5. Wang Z, Duan J, Cai S, et al. Assessment of blood mutational burden as a potential biomarker for immunotherapy in patients with non-small cell lung cancer with use of a next-generation sequencing cancer gene panel. JAMA Oncol. 2019;5(5):696-702.
  6. Hellman MD, Ciuleanu T, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high mutational burden. N Enl J Med. 2018;378(22):2093-2104.
  7. Merck. Merck receives priority review from FDA for second application for KEYTRUDA® (pembrolizumab) based on biomarker, regardless of tumor type press release]. Published April 7, 2020. Accessed April 23, 2020.
  8. AstraZeneca. Update on the Phase III NEPTUNE trial of Imfinzi plus tremelimumab in stage IV non-small cell lung cancer [press release]. Published August 21, 2019. Accessed April 23, 2020.
  9. International Association for the Study of Lung Cancer. New KEYNOTE 021 data shows no association with tumor mutational burden. Published September 8, 2019. Accessed April 23, 2020.
  10. Food and Drug Administration. FDA expands pembrolizumab indication for first-line treatment of NSCLC (TPS ≥1%) [press release]. Published April 11, 2020. Accessed May 05, 2020.