Nivolumab in combination with ALT-803 is tolerable and achieves responses in patients with NSCLC.
Major finding: Nivolumab in combination with ALT-803 is tolerable and achieves responses in patients with NSCLC.
Concept: ALT-803 plus nivolumab has antitumor activity in patients who previously progressed on anti–PD-1 therapy.
Impact: Combination therapy with ALT-803 and nivolumab warrants further investigation in patients with NSCLC.
Immune checkpoint blockade with the anti–PD-1 antibody nivolumab achieves responses in a subset of patients with non–small cell lung cancer (NSCLC), but many of the patients who do respond eventually develop resistance. IL15 has been shown to promote the activation and proliferation of CD8+ T cells and natural killer cells, and preclinical studies have suggested that combining nivolumab with the IL15 superagonist ALT-803 may be beneficial. Thus, Wrangle and colleagues assessed the safety and efficacy of ALT-803 plus nivolumab in an open-label phase Ib trial, treating 21 patients with previously treated stage IIIB or stage IV NSCLC with escalating doses of ALT-803. The primary endpoint was to determine the safety and tolerability of ALT-803 plus nivolumab and to establish a recommended phase II dose for ALT-803. Secondary endpoints included progression-free survival and overall survival. ALT-803 treatment was safe and tolerable in combination with nivolumab; no dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. Further, no patients experienced grade 4–5 adverse events. The median progression-free survival was 9.4 months and the median overall survival was 17.4 months. Overall, 6 of 21 patients (29%) achieved objective responses, and an additional 10 patients (48%) achieved stable disease. Eleven patients had previously progressed after single-agent PD-1 monoclonal antibody treatment, and, of these patients, 3 (27%) achieved partial responses and 7 (65%) experienced stable disease, suggesting that treatment with ALT-803 plus nivolumab may be beneficial even in patients who have developed resistance to nivolumab monotherapy. In addition to indicating that ALT-803 can be safely administered with nivolumab, these findings suggest that ALT-803 has antitumor activity in patients with NSCLC and may resensitize resistant patients to nivolumab. These data support further investigation of ALT-803 plus nivolumab in patients with NSCLC, and phase II enrollment is under way.
Wrangle JM, Velcheti V, Patel MR, Garrett-Mayer E, Hill EG, Ravenel JG, et al. ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. Lancet Oncol 2018 Apr 5 [Epub ahead of print].
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