LAUSR

Background: Despite the unprecedented efficacy of immunotherapy with PD-1/PD-L1 blockade in non-small cell lung cancer, treatment failure is common and an area of unmet clinical need. IL-2/IL-15Rbg agonists, which potently augment the activity of CD8+ T and NK cells, have shown the ability to induce complete and durable responses in select cancers. However, this class of drugs has been neither combined with PD-1 targeted immunotherapies nor examined extensively in NSCLC. We hypothesized that the addition of an IL-15 superagonist (ALT-803) would be safe and improve the efficacy of anti-PD-1 mAb (nivolumab) in metastatic NSCLC patients in second-line therapy. Methods: In this phase Ib trial, patients with metastatic NSCLC who were eligible to initiate or to continue receiving nivolumab (anti-PD-1 mAb) after first-line therapy were enrolled to trial, including patients with disease relapsed on or refractory to PD-1 blockade. Nivolumab was administered in combination with ALT-803 at four dose levels. The primary objective of the study was to define safety and tolerability and a recommended phase II dose of ALT-803 in combination with nivolumab, with secondary objectives including immune correlates and clinical parameters including response rate. Results: In a first-in-human combination, 21 NSCLC patients were treated at 4 dose levels of ALT-803 in combination with the approved dose of nivolumab. No dose-limiting toxicities were observed, and the most common adverse events were fever, flu-like symptoms, and injection site reactions. The recommended phase II dose (RP2D) of therapy is weekly subcutaneous ALT-803 at 20 mcg/kg in combination with intravenous nivolumab 240 mg every 14 days. Multiple objective responses were observed, including when ALT-803 was added to a failing PD-1 mAb regimen. Discussion: The recommended phase II dose of ALT-803 plus nivolumab was determined and the regimen can safely be administered in the outpatient setting. Responses among patients with PD-1 mAb relapsed disease with the addition of ALT-803 to their regimen demonstrate for the first time evidence of antitumor activity for a new class of agents for NSCLC and in patients with disease progression on PD-1/PD-L1 pathway blockade. This abstract is also being presented as Poster B34. Citation Format: John Wrangle, Vamshidar Velchetti, Manish Patel, Samantha Suriano, Marzena Swiderska-syn, Kate Anderton, James Ravenel, Elisabeth Hill, Amy Rock, Hing Wong, Mark Rubinstein. Safety and activity of the IL-15/sIL-15Rα complex ALT-803 in combination with the anti-PD1 mAb nivolumab in metastatic non-small cell lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr PR05.