ALT-803 + Nivolumab Found Safe, Effective in Metastatic NSCLC

An IL-15 superagonist shows promise

A study recently published in Lancet Oncology found ALT-803, an IL-15 superagonist, in combination with nivolumab, an anti-PD-1 monoclonal antibody, to be safe and with early signs of efficacy in patients with metastatic non-small cell lung cancer (NSCLC) who are progressed on prior anti-PD1 immunotherapy.

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Vamsidhar Velcheti, MD, FACP, FCCP, Associate Director of Cleveland Clinic Cancer Center’s Center for Immuno-Oncology Research, was the principal investigator of the clinical trial and a coauthor of the study along with a team of collaborators across the United States.

ALT803 is a novel IL-15 superagonist complex consisting of an IL-15 mutant (IL-15N72D) bound to an IL-15 receptor α/IgG1 Fc fusion protein. In preclinical experiments in mouse models, ALT-803 augments both the innate and adaptive immune responses against cancer cells to elicit rapid and durable control of cancers, and the effects were enhanced in combination with anti-PD1.

A phase 1/1b clinical trial of patients with advanced stage NSCLC included those both anti-PD1 naïve or progressed on prior PD1 therapy. Twenty-one patients received the ALT-803 combination with nivolumab at four escalating dose cohorts of 6, 10, 15 or 20 mg/kg SC doses once per week in the first five of six-week cycles. The primary role of the study was to evaluate safety and tolerability of the combination and to determine the optimal dose of ALT803 in combination with nivolumab.

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Study results

There were no dose-limiting toxic effects in the study at any of the dose cohorts, and the maximum tolerated dose was not reached. Furthermore, higher doses of ALT-803 were not associated with an increase in the frequency and severity of adverse events. Injection-site reactions and flu-like symptoms were the most common adverse events reported in 90 percent and 71 percent of patients, respectively. Other commonly reported grade 1 or 2 events included fever, chills, fatigue, dizziness, pain and nausea. Lymphocytopenia and fatigue were the most common grade 3 adverse events, each occurring in 10 percent of patients. Grade 4 or 5 adverse events were not observed.

Based on the safety and biological activity, the recommended phase 2 dose of ALT-803 was determined as 20 mg/kg administered subcutaneously once per week + 240 mg nivolumab given weekly every two weeks. In this study, disease control was achieved in ten of 11 patients (91 percent) who previously received a single-agent PD-1 monoclonal antibody and were considered PD-1-treatment resistant. Three (27 percent) patients demonstrated partial responses, and seven (64 percent) patients achieved stable disease.

The ongoing phase 2 trial aims to “evaluate the efficacy of this exciting combination of ALT803 with nivolumab in patients who progress on anti-PD1 therapies,” says Dr. Velcheti. Some patients with solid tumors, particularly NSCLC, have impaired antigen presentation with downregulation of HLA class I antigens, and this appears to be playing a critical role in primary and acquired resistance to anti-PD1 therapies. Cytokine combination strategies with anti-PD1 therapies can potentially overcome these limitations.

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“I think we’ll see renewed interest in cytokine combination treatments for other cancers given our study results,” says Dr. Velcheti.