Which Target First?

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Despite uncertainty about the role of PD-L1 expression as a biomarker, it is still standard to evaluate for PD-L1 expression, according to Dr Gainor. It is, however, also standard for patients with non-squamous disease to undergo genetic evaluation for alterations in EGFR, ALK, ROS1, and BRAF, each of which has FDA-approved targeted therapies.

If a patient is positive for EGFR mutations or ALK rearrangements, nivolumab, atezolizumab, and pembrolizumab are all approved for use only after progression on an FDA-approved targeted treatment. Current evidence includes 4 randomized studies that showed no survival benefit with PD-1/PD-L1 inhibitors compared with docetaxel in EGFR-mutant disease. For patients with ALK-positive disease, there are no published examples of activity with checkpoint inhibitors.

Results from the recent ATLANTIC trial (ClinicalTrials.gov Identifier: NCT02087423) are, however, helping to fill this knowledge-gap. ATLANTIC was a phase 2 study that evaluated the immune checkpoint inhibitor, durvalumab, as a third-line or later treatment for advanced NSCLC.4 The trial had 3 cohorts: cohort 1 contained patients with EGFR-/ALK-positive NSCLC with at least 25%, or less than 25%, PD-L1 expression; cohort 2 contained patients with at least 25%, or less than 25%, PD-L1 expression; cohort 3 contained patients with at least 90% PD-L1 expression. The percentage of patients with EGFR– and ALK-negative disease achieving a response was higher than that of patients with EGFR-/ALK-positive disease.

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Among patients with at least 25% PD-L1 expression, 12.2% of patients in cohort 1, 16.4% of patients in cohort 2, and about one-third of patients in cohort 3 had an objective response.

Dr Gainor noted, however, that these data should be interpreted with caution. The patients in cohort 1 may not fully represent a typical patient with EGFR-/ALK-positive disease, because a number of them had a smoking history and had high levels of PD-L1 expression compared with the general cohort. Response rates were also very modest.

“With ATLANTIC, we see that even in the setting of high levels of PD-L1 expression, the activity of these agents in EGFR– and ALK-positive patients is quite low,” Dr Gainor said. “We need additional immune-based strategies for those patients.”