Immune checkpoint inhibitors have transformed the therapeutic landscape in lung cancer, yet some of the biomarkers currently used to guide therapy selection are imperfect, pushing researchers to explore new predictive biomarkers.

Some research has suggested that tumor mutational burden (TMB) — the number of nonsynonymous mutations in a tumor — correlates with clinical response to particular immunotherapies. However, tissue-based testing requires adequate samples, which can be challenging to obtain, particularly in the setting of lung cancer.

In a recent study, University of Pennsylvania researchers developed a plasma-based assay for TMB based on DNA shed from tumor tissue. They showed a significant correlation between plasma TMB levels and response to first-line pembrolizumab-based therapy in patients with metastatic non-small cell lung cancer (NSCLC). The findings were published in Clinical Cancer Research.1

“It’s one more proof of principle that we can obtain relevant information in terms of … tumor mutational burden derived from a blood sample,” noted Howard (Jack) West, MD, associate clinical professor of medical oncology and therapeutics research at City of Hope National Medical Center in Duarte, California, in an interview with Cancer Therapy Advisor. However, he agreed with the authors that “it would need to be tested in a much larger setting, and prospectively, to show that this variable has a place in clinical decision making.”

For patients with advanced NSCLC whose tumors have no actionable mutations, such as EGFR/ALK, tumor PD-L1 expression is used to inform treatment selection with the anti–PD-1 antibody pembrolizumab. Pembrolizumab monotherapy is indicated as a first-line treatment in patients with tumor PD-L1 expression of at least 50%. For patients with PD-L1 expression below 50%, pembrolizumab in combination with chemotherapy is standard.

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Yet tissue PD-L1 expression is an imperfect predictor of whether patients will respond to immunotherapy-based treatment, as evidenced by patients with high PD-L1 expression who don’t respond well to pembrolizumab as a monotherapy nor in combination, and patients with negative PD-L1 scores who show good responses to chemoimmunotherapy, Dr West explained. In addition, recent data from the KEYNOTE 189 study reported that patients with advanced nonsquamous NSCLC and without active EGFR/ALK mutations saw significant clinical benefits with pembrolizumab combination therapy compared with chemotherapy alone, irrespective of PD-L1 expression.2

Another limitation of PD-L1 as a biomarker is that it relies on sufficient tumor tissue for analysis, which is a challenge in lung cancer. One advantage of TMB — which typically correlates with a higher number of neoantigens on the tumor surface and therefore, a higher probability of response to immunotherapy — is that it can be detected through cell-free circulating DNA in the blood. Thus, it can be evaluated in a way similar to how actionable mutations are identified in many clinics — through plasma-based gene sequencing, or “liquid biopsies.”