Expert Highlights Role of TMB in Evolving Immuno-Oncology Landscape

Published: Wednesday, Aug 08, 2018
Conor E. Steuer, MD
Conor E. Steuer, MD
Over the last year or so, the role of tumor mutation burden (TMB) has been debated as a biomarker for immunotherapy in solid tumors, most recently in non–small cell lung cancer (NSCLC).

The one FDA-approved immunotherapy biomarker is PD-L1; however, it has been called an imperfect biomarker with limitations, said Conor E. Steuer, MD. For example, the PD-1 inhibitor pembrolizumab (Keytruda) in combination with carboplatin/pemetrexed has demonstrated activity in the frontline setting for patients with NSCLC, regardless of PD-L1 expression.

Recent data have suggested that TMB can be useful as a predictor for immunotherapy response versus chemotherapy. For example, patients with high levels of TMB have typically responded better to immunotherapy combinations compared with chemotherapy, said Steuer.

Next-generation sequencing (NGS) has emerged as an important tool for measuring TMB. In contrast with the standard single-gene testing, NGS allows clinicians to get a broad understanding of a patient’s genomic profile with just 1 test. It is also more cost-effective, Steuer explained.

In an interview with OncLive, Steuer, assistant professor, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, discussed the pros and cons of TMB as a biomarker and the utilization of NGS.

OncLive: How would you characterize the role of TMB in the evolving immuno-oncology landscape?

Steuer: Tumor mutation burden is emerging as an important biomarker in the treatment of cancer, including NSCLC. PD-L1 expression is currently the only FDA-approved biomarker for NSCLC, with standard of care in the frontline setting for PD-L1–high NSCLC being the immune checkpoint inhibitor pembrolizumab [Keytruda]. However, this is rapidly changing, as recent data have shown success across the board for immunotherapy plus chemotherapy in a first-line setting.

Nonetheless, we know that PD-L1 is an imperfect biomarker. While many immunotherapy biomarkers are currently being explored, TMB’s ability to predict for immunotherapy response is demonstrating great promise. This is demonstrated most clearly by recent data showing that high TMB potentially serves as a biomarker for immunotherapy combinations and may help chose patients who benefit from immunotherapy versus chemotherapy. Numerous retrospective and prospective studies have also shown that this biomarker holds promise to aid in the selection of patients who will most benefit from immunotherapy.

Based on current data and trends, can you discuss next-generation sequencing (NGS) as a tool for measuring TMB from a clinical perspective?

Genomic testing has become an important tool in the NSCLC landscape. For nonsquamous NSCLC that is metastatic, the current standard of care now is to do genomic testing for the driver mutations EGFR, ALK, BRAF, [and] ROS1 at minimum, with other genes such as MET, RET, and NTRK demonstrating promise as targeted therapy options in clinical trials. Next-generation sequencing allows for the testing of all of those genes as well as other genes that might prove to be important to the treatment of NSCLC. NGS can be both cost- and tissue-use effective versus single gene testing. Because of this, NGS has become an approved testing method for NSCLC and is a more clinically practical test than whole exome sequencing, which was previously used to define TMB.

As the availability of NGS increases, what are the practical implications of its broader utilization as a biomarker for various cancers?

NGS testing can be more tissue- and cost-effective for determining the genes of interest in NSCLC than single gene testing. Using NGS tools to test for TMB would be a very clinically logical step and is already being done in some trials and institutions. Therefore, it would translate well to TMB given its established clinical familiarity. In addition, NGS, at least in NSCLC, is often covered by insurance carriers.


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