PIVOT-09: A phase III randomized open-label study of bempegaldesleukin (NKTR-214) plus nivolumab versus sunitinib or cabozantinib (investigator's choice) in patients with previously untreated advanced renal cell carcinoma (RCC).

Abstract

TPS763 Background: Bempegaldesleukin (BEMPEG; NKTR-214) is a first-in-class interleukin-2 (IL-2) receptor pathway agonist that activates and expands effector T cells and natural killer cells in the tumor microenvironment and increases tumor PD-L1 expression, making BEMPEG a promising agent for combination with immune checkpoint inhibitors. In a phase 1/2 study, BEMPEG plus nivolumab (NIVO) demonstrated an encouraging objective response rate (ORR) in first-line advanced RCC (46%) and a manageable safety profile. BEMPEG plus NIVO offers a potential novel immunooncology treatment option for patients with advanced RCC. Methods: A global, multicenter, randomized, open-label phase 3 study is evaluating the efficacy and safety of BEMPEG plus NIVO vs investigator’s choice of tyrosine kinase inhibitor (TKI; sunitinib [SUNI] or cabozantinib [CABO]) in patients with previously untreated advanced or metastatic RCC with a clear-cell component. Patients must not have had prior systemic therapy (including neoadjuvant, adjuvant or vaccine therapy) for RCC. Key exclusion criteria include active brain metastasis and autoimmune disease requiring systemic immunosuppressive agents. Approximately 600 patients will be randomized 1:1 to receive 0.006 mg/kg BEMPEG plus 360 mg NIVO intravenously every 3 weeks or TKI (50 mg SUNI [4 weeks on, 2 weeks off schedule] or 60 mg CABO; orally each day). Patients will be stratified by International Metastatic RCC Database Consortium (IMDC) prognostic score (0 [favorable risk] vs 1-2 [intermediate risk] vs 3-6 [poor risk]) and TKI choice (SUNI vs CABO). Primary objectives are ORR by blinded independent central review (BICR) and overall survival in the IMDC intermediate/poor risk population and the intention-to-treat (ITT) population. Secondary objectives are progression-free survival by BICR in the IMDC intermediate/poor risk population and the ITT population, safety, PD-L1 expression as a predictive biomarker, and quality of life. Enrollment is ongoing. Clinical trial information: NCT03729245.

Treatment Options for De Novo Metastatic Clear-cell Renal Cell Carcinoma: Current Recommendations and Future Insights

“…The results from two other ongoing phase 3 trials in the first-line setting should be available in the near future. The PIVOT-09 trial [42] will combine nivolumab + bempegaldesleukin and is expected to complete recruitment in 2021. Bempegaldesleukin is a first-in-class IL-2 receptor pathway agonist that increases PD-L1 expression, making it a promising agent to combine with ICIs.…”

Updates on Immunotherapy and Immune Landscape in Renal Clear Cell Carcinoma

“…Table 2 summarizes the ongoing phase III clinical trials that cover a wide range of critical issues, including the efficacy of newly developed ICIs, the role of immune checkpoint in the previously established experimental arms, the efficacy of ICI as adjuvant therapy on the rate of recurrence following nephrectomy [ 104 , 105 , 106 ], and the effect of salvage ICI following progression on ICI treatment [ 107 ]. In addition, other studies are also testing the role of small molecules inhibitors in combination immunotherapy [ 108 ], the effect of IL-2 in combination with ICI [ 109 ], the efficacy of ICI on brain metastasis [ 110 ], and the optimal sequence of ICIs [ 111 ].…”

New approaches to first-line treatment of advanced renal cell carcinoma

“…Ongoing phase III studies that are evaluating novel agents for first-line treatment of RCC include: PIVOT-09, which is assessing the pegylated interleukin-2 molecule bempegaldesleukin (NKTR-214) plus nivolumab versus sunitinib or cabozantinib; and the combination of pembrolizumab plus lenvatinib with or without the HIF-2α inhibitor belzutifan or the CTLA-4 inhibitor quavonlimab. 65 – 67 In the randomized phase II MERECA study, the dendritic cell vaccine ilixadencel followed by sunitinib was compared with sunitinib as a first-line treatment, with improved ORR but similar PFS and OS results. 68 …”