Targeted NGS Helps Determine Likelihood of Immunotherapy Benefit in NSCLC


Targeted next-generation sequencing (NGS) may accurately estimate tumor mutation burden in non-small cell lung cancer (NSCLC), which may further shed light on the likelihood of benefit from immune checkpoint inhibitors in individual patients.

Treatment of advanced NSCLC with immune checkpoint inhibitors such as anti-programmed death 1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) agents has shown to provide durable responses and improve survival in a subset of patients. Targeted NGS has been used routinely for understanding the molecular determinants of response in this disease. However, its role in determining predictors of response to PD-1/PD-L1 therapy is not well known.

Hira Rizvi, MD, Memorial Sloan Kettering Cancer Center (New York, NY), and colleagues conducted a study to assess the applicability of targeted NGS in identifying predictors of response to immune checkpoint inhibitors in patients with advanced NSCLC. Researchers collected detailed clinical annotation and response data for patients with advanced disease who were treated with PD-1/PD-L1 therapy and profiled by targeted NGS (MSK-IMPACT; n = 240).  Efficacy was assessed by RECIST version 1.1, and durable clinical benefit was defined as partial response or stable disease that lasted at least 6 months.

Researchers further compared tumor mutation burden, fraction of copy number-altered genome, and gene alterations among patients with durable clinical benefit and those with no durable benefit. Whole-exome sequencing (WES) was performed in a subset of patients.

Results of the study were published in the Journal of Clinical Oncology (online January 16, 2018; doi:10.1200/JCO.2017.75.3384).


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Researchers reported that estimates of tumor mutation burden by targeted NGS correlated strongly with WES (P < .001). Tumor mutation burden was greater in patients with durable clinical benefit than in those with no durable benefit (P = .006). Furthermore, they noted that durable clinical benefit was more common and progression-free survival was longer in patients at increasing thresholds above vs below the 50th percentile of tumor mutation burden (38.6% vs 25.1%, respectively).

Researchers also acknowledged that tumor mutation burden and PD-L1 expression were independent variables, thus allowing a composite of tumor mutation burden plus PD-L1 to further enrich for the benefit of immune checkpoint inhibitors.

In their concluding remarks, Dr Rizvi and colleagues noted that targeted NGS accurately estimates tumor mutation burden and evaluating this burden improves the likelihood of benefit to immune checkpoint inhibitors in patients with advanced NSCLC.  The incorporation of both tumor mutation burden and PD-L1 expression into multivariable predictive models should result in greater predictive power,” they wrote.—Zachary Bessette