A Phase II cohort from the international PIVOT-02 study has shown the combination of interleukin-2 (IL-2) pathway agonist bempegaldesleukin (BEMPEG) plus nivolumab is safe and produces a deep, durable response in previously untreated metastatic melanoma patients by researchers from The University of Texas MD Anderson Cancer Center.
The Food and Drug Administration awarded Breakthrough Therapy designation to the combination of BEMPEG and nivolumab in 2019 for previously untreated metastatic melanoma.
The publication also includes an exploratory biomarker analysis that demonstrates early on-treatment blood biomarkers correlate with response and indicates that the combination of BEMPEG plus nivolumab may not only boost T cell numbers, but it also may improve T cell function.
“Immune checkpoint inhibitors have become standard of care for advanced melanoma patients, yet there is still an urgent, unmet need for patients whose disease does not respond to these therapies,” Diab said. “We sought to overcome some of the limitations of checkpoint inhibitors by adding an agent that leverages the IL-2 pathway to modulate the tumor microenvironment, without adding significant toxicity.”
The clinical trial enrolled 41 patients with previously untreated stage III or IV melanoma. Participants received intravenous BEMPEG and nivolumab once every three weeks for up to two years. A total of 38 patients were evaluable for response. Safety and objective response rates were the primary endpoints.
At a median follow-up of 29 months, the objective response rate was 52.6% and the complete response rate was 34.2%. Among responders, 90% saw a 100% reduction in their target lesions versus baseline. Median overall survival was not reached and the 24-month overall survival rate was 77%. Median progression-free survival was 30.9 months.
The majority of treatment-related adverse events were low grade and resolved without intervention or with standard management. Grade 3 or 4 treatment-related events were observed in 17.1% of patients, while 4.9% experienced immune-mediated adverse events. These rates were consistent with reported toxicity for PD-1 inhibitor monotherapy.
The median age of study participants was 63, and more than half (58.5%) were male. Consistent with overall melanoma incidence, 92.7% of participants were white and 7.3% were of other races.
The researchers also assessed baseline and on-treatment biomarkers. Baseline tumor biomarkers, including high IFN-y GEP, CD8+, tumor-infiltrating lymphocytes (TIL), CD74, and HLA-E, were associated with response. Based on these and the blood-based biomarker findings, the researchers theorize that adding BEMPEG to nivolumab increases the number of T cells, while also boosting their fitness and functional capacity.
The study was limited by the small cohort size and single-arm design. A randomized Phase III clinical trial now is underway to further investigate the preliminary findings.
“Our study shows that the combination of BEMPEG and nivolumab is safe and effective,” Diab said. “We are encouraged by the potential of a new treatment option for newly diagnosed patients with advanced melanoma, and we look forward to the results from the Phase III study, which is enrolling now.”