In the phase II cohort of a phase I/II trial (PIVOT-02) reported in the Journal of Clinical Oncology, Adi Diab, MD, and colleagues found that the combination of the interleukin-2 pathway agonist bempegaldesleukin and nivolumab produced high response rates and extended progression-free survival in the first-line treatment of patients with unresectable or metastatic melanoma.

Adi Diab, MD

Study Details

In the trial, 41 patients (intention-to-treat [ITT] population) enrolled from sites in the United States, Italy, and Poland between March 2017 and March 2018 received bempegaldesleukin at 0.006 mg/kg plus nivolumab at 60 mg once every 3 weeks until disease progression, unacceptable toxicity, or for up to 2 years. The response-evaluable population consisted of 38 patients with at least one postbaseline scan.

Efficacy Outcomes

Median follow-up for responses was 29.0 months. Objective response on blinded independent central review was observed in 20 (52.6%) of 38 response-evaluable patients, with complete response in 13 (34.2%); of these 13, 8 patients achieved complete response after eight or more treatment cycles, suggesting deepening of responses over time. At data cutoff (September 2020), 16 (80.0%) of 20 responders had ongoing response. Median duration of response was not reached (interquartile range = 29.0 months–not reached), with responses lasting for 6 months or longer in 90% and 12 months or longer in 80%. Median change in size of target lesions from baseline was 278.5%; 18 patients (47.4%) exhibited complete clearance of target lesions.

Increased polyfunctional responses in CD8-positive and CD4-positive T cells were observed in blood in association with production of cytokines with effector functions. Early on-treatment biomarkers, including CD8-positive polyfunctional strength difference and increased eosinophils (consistent with interleukin-2 signaling), were correlated with response to treatment.

At data cutoff in the ITT population, median progression-free survival was 30.9 months (95% confidence interval [CI] = 5.3 months–not estimable), with 1-, 2-, and 3-year rates of 56.2%, 53.1%, and 45.5%. Median overall survival was not reached, with 1-, 2-, and 3-year rates of 82.3%, 77.0%, and 70.9%.

Adverse Events

The most common treatment-related adverse events of any grade (incidence ≥ 40%) were flu-like symptoms, rash, fatigue, pruritus, arthralgia, and nausea. Grade 3 or 4 treatment-related adverse events occurred in 17% of patients, with the most common being atrial fibrillation and acute kidney injury (5% each).

Treatment-related adverse events led to discontinuation of treatment in 12% of patients. Immune-mediated adverse events occurred in 32% and were grade ≥ 3 in 5% (1 patient with nephritis and renal dysfunction, and 1 with hyperglycemia related to diabetes mellitus). The incidence of cytokine-related adverse events (flu-like symptoms, rash, pruritus, and hypotension) decreased with continued dosing. No cases of cytokine-release syndrome, hypereosinophilic syndrome, or treatment-related grade ≥ 3 hypotension were observed. No treatment-related deaths were reported.

The investigators concluded, “Bempegaldesleukin in combination with nivolumab was tolerated, with relatively low rates of grade 3 and 4 treatment-related and immune-mediated adverse events. The combination had encouraging antitumor activity in first-line metastatic melanoma, including an extended median progression-free survival. Exploratory analyses associated noninvasive, on-treatment biomarkers with response, before radiologic evidence was observed.”

Dr. Diab, of The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Nektar Therapeutics. For full disclosures of the study authors, visit ascopubs.org.