As reported in the Journal of Clinical Oncology by Nizar M. Tannir, MD, FACP, and colleagues, the phase III PIVOT-09 trial has shown no objective response or overall survival benefit with bempegaldesleukin plus nivolumab vs tyrosine kinase inhibitor (TKI) treatment with sunitinib or cabozantinib in previously untreated patients with intermediate- or poor-risk advanced clear cell renal cell carcinoma.
As stated by the investigators, “Bempegaldesleukin is a pegylated interleukin (IL)-2 cytokine prodrug engineered to provide controlled and sustained activation of the clinically validated IL-2 pathway, with the goal of preferentially activating and expanding effector CD8+ T cells and natural killer cells over immunosuppressive regulator T cells in the tumor microenvironment.”
Nizar M. Tannir, MD, FACP
Study Details
In the open-label trial, 623 patients from sites in 10 countries were randomly assigned between December 2018 and January 2021 to receive bempegaldesleukin at 0.006 mg/kg plus nivolumab at 360 mg every 3 weeks (n = 311) or investigator’s choice of TKI (n = 312), consisting of sunitinib at 50 mg once daily for 4 weeks on/2 weeks off (n =225) or cabozantinib at 60 mg once daily (n = 87). A total of 514 patients had International Metastatic RCC Database Consortium (IMDC) intermediate- or poor-risk disease, including 256 in the bempegaldesleukin/nivolumab group and 258 in the TKI group.
The co-primary endpoints of the study were objective response rate on blinded independent central review and overall survival in patients with IMDC intermediate- or poor-risk disease.
Objective Response and Overall Survival
Among patients with IMDC intermediate- or poor-risk disease, objective response rates were 23.0% (95% confidence interval [CI] = 18.0%–28.7%) in the bempegaldesleukin/nivolumab group vs 30.6% (95% CI = 25.1%–36.6%) in the TKI group (difference = –7.7%, 95% CI = –15.2% to –0.2%, P = .0489). Median duration of response was 16.4 months vs 13.2 months, respectively.
Among patients with IMDC intermediate- or poor-risk disease, median overall survival was 29.0 months (95% CI = 25.6 months to not evaluable) in the bempegaldesleukin/nivolumab group vs not evaluable (95% CI = 25.6 months to not evaluable) in the TKI group (HR = 0.82, 95% CI = 0.61–1.10, P = .1915). Rates at 12 months were 78.9% vs 71.9%, respectively.
Among all patients, objective response rates were 23.5% in bempegaldesleukin/nivolumab group vs 34.9% in the TKI group (difference = –11.6%, 95% CI = –18.5% to –4.7%, P = .0013). Median duration of response was 16.4 vs 15.4 months, respectively. Median overall survival was not evaluable (95% CI = 29.0 months to not evaluable) in the bempegaldesleukin/nivolumab group vs not evaluable (95% CI = not evaluable to not evaluable) in the TKI group (HR = 0.90, 95% CI = 0.67–1.19, P = .4512).
Adverse Events
Among all patients, grade 3 or 4 treatment-related adverse events occurred in 25.8% of the bempegaldesleukin/nivolumab group vs 56.5% of the TKI group. The most commonly reported events in the bempegaldesleukin/nivolumab group included anemia (2.6%), eosinophilia (1.3%), fatigue (1.3%), and hypertension (1.3%); in the TKI group, the most common were hypertension (13.1%), neutropenia (10.8%), anemia (6.2%), and palmar-plantar erythrodysesthesia syndrome (6.2%). Treatment-related serious adverse events occurred in 13.2% vs 10.8% of patients. Treatment-related adverse events led to discontinuation of treatment in 7.7% vs 7.2% of patients. Treatment-related death occurred in three patients in the bempegaldesleukin/nivolumab group (due to generalized edema, colitis, and acute respiratory failure) and in three patients in the TKI group (due to gastrointestinal hemorrhage, cardiac arrest, and hepatic failure).
The investigators concluded, “First-line bempegaldesleukin plus nivolumab for advanced/metastatic clear cell renal cell carcinoma did not improve efficacy in patients with intermediate-/poor-risk disease but led to fewer grade 3/4 treatment-related adverse events vs TKI.”
Dr. Tannir, 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 and Bristol Myers Squibb. For full disclosures of the study authors, visit ascopubs.org.
