Lung Cancer: Predicting Response Checkpoint Inhibition

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Assessing tumor mutational burden may help to determine which patients will respond.
Assessing tumor mutational burden may help to determine which patients will respond.

Targeting PD-1 or its ligand, PD-L1, with immune checkpoint inhibitors is emerging as a promising treatment strategy for many solid tumor types, including non–small cell lung cancer (NSCLC). The majority of patients with advanced NSCLC will, however, not respond to checkpoint inhibitors, and identifying which patients will benefit most from this treatment remains a challenge.

The most common biomarker used to test for response to PD-1/PD-L1 inhibitors is currently PD-L1 expression.

“It is imperfect, but right now it is the best biomarker that we have, and it has been clinically validated,” said Justin F. Gainor, MD, of Massachusetts General Hospital in Boston.

According to Dr Gainor, one of the challenges of using PD-L1 expression as a biomarker is that clinical trials testing the 3 US Food and Drug Administration (FDA)-approved PD-1/PD-L1 inhibitors — nivolumab, atezolizumab, and pembrolizumab — defined “high” PD-L1 expression in different ways.

In the phase 3 CheckMate 057 study (ClinicalTrials.gov Identifier: NCT01673867) of nivolumab in patients with NSCLC, a predictive value of high PD-L1 expression — defined at a level of 1% or greater — was seen for overall survival, progression-free survival, and objective response rate. Yet PD-L1 expression analysis was done retrospectively and included only 78% of the patients in the study.1

Atezolizumab is approved for NSCLC regardless of the patient's PD-L1 status. The phase 3 OAK trial (ClinicalTrials.gov Identifier: NCT02008227) compared atezolizumab with docetaxel in patients unselected for PD-L1 expression.2 Although patients with the highest levels of expression had the most benefit, improvements in overall survival were seen even in those patient with minimal or no PD-L1 expression.

Right now, the most clinically relevant measure of PD-L1 expression is if it occurs in more than 50% of tumor cells, according to Dr Gainor.

“This cutoff is what clinicians use to decide between pembrolizumab monotherapy compared with chemotherapy,” he said.

Pembrolizumab was approved as a first-line treatment of patients with NSCLC with PD-L1 expression of 50% of greater, based on data from the KEYNOTE 24 study (ClinicalTrials.gov Identifier: NCT02142738).3 In this study, patients with high expression had significant improvement in progression-free and overall survival.

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