New Option in NSCLC With IL-15 Agonist Plus Immune Checkpoint Inhibition

The combination of nivolumab with an interleukin-15 (IL-15) agonist known as ALT-803 was well tolerated with no dose-limiting toxicities in a phase I trial of patients with metastatic non–small-cell lung cancer (NSCLC). The combination showed some promising activity in this setting.

“Although second-line treatment with anti–PD-1 immunotherapy can induce durable clinical responses, roughly 80% of unselected NSCLC patients will not respond to treatment, and nearly all of those who do initially respond will eventually develop resistant disease,” wrote study authors led by John M. Wrangle, MD, of the Medical University of South Carolina in Charleston. There is some evidence that targeting IL pathways along with immune checkpoint inhibitors may improve outcomes.

The new phase Ib trial included 21 patients treated with nivolumab and 1 of 4 dose levels of ALT-803, an IL-15 superagonist. All patients had previously treated stage IIIB or IV NSCLC, and an ECOG performance status of 0 or 1. The results were published in Lancet Oncology.

The median duration of follow-up was 6.9 months. The frequency and severity of adverse events observed did not increase as the dose levels rose, and a maximum tolerated dose was not reached. There were no dose-limiting toxicities observed. The recommended phase II dose was set at the highest of the 4 doses in the phase I trial, at 20 µg/kg.

The most frequent adverse event of any grade was injection site reaction; this occurred in 90% of patients, but there were no grade 3 or higher such events. Grade 1/2 flu-like symptoms occurred in 71% of patients, and fever and fatigue were also relatively common. The most common grade 3 adverse events were lymphocytopenia and fatigue; these occurred in 2 patients each. There was a grade 3 myocardial infarction observed in 1 patient.

A post-hoc analysis found that six patients (29%) achieved an objective response to the combination therapy; all were partial responses. Nine patients (43%) had a decrease in the size of target lesions, and 76% of the cohort had stable disease. The median progression-free survival was 9.4 months, with a median overall survival of 17.4 months. The authors noted that no dose-dependent response was seen.

There were 4 patients with PD-L1 expression higher than 50%, which was classified as PD-L1–positive, and 3 of those had an objective response; the fourth had stable disease and was receiving ongoing treatment at 6 months.

“In this study we show that ALT-803 is safe, tolerable, and can be conveniently administered in combination with an anti–PD-1 checkpoint antibody for patients with NSCLC in an outpatient setting,” the authors wrote, adding that the results suggest that agents in this class might help overcome resistance to anti–PD-1 therapies. If true, they wrote, this “could have implications in a wide range of cancers.”