ALT-803 + Nivolumab Found Safe, Effective in Metastatic NSCLC
A study recently published in Lancet Oncology found ALT-803 + nivolumab safe and with early signs of efficacy in patients with mNSCLC considered PD-1-treatment resistant.
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.
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.
“I think we’ll see renewed interest in cytokine combination treatments for other cancers given our study results,” says Dr. Velcheti.