PIVOT IO 011: A phase 1/2 study of bempegaldesleukin (BEMPEG; NKTR-214) plus nivolumab (NIVO) and tyrosine kinase inhibitor (TKI) versus NIVO and TKI alone in patients (pts) with previously untreated advanced or metastatic renal cell carcinoma (mRCC).

TPS403 Background: The current standard of care for advanced RCC (aRCC) utilizes immune checkpoint inhibitors (ICIs) and targeted agents. Novel combinations of these agents, such as NIVO + TKIs, have demonstrated clinical benefit over TKI monotherapy. In CheckMate 9ER, NIVO + cabozantinib (CABO) in aRCC demonstrated clinically meaningful efficacy results and a favorable safety profile, and was FDA approved (01/2021). High-dose interleukin-2 (IL-2) was used historically for durable responses in mRCC but had unfavorable toxicity with complex inpatient treatment regimens. BEMPEG, an immunostimulatory IL-2 cytokine prodrug, is engineered to deliver a controlled, sustained, and preferential signal to the clinically validated IL-2 pathway. Preferential binding of BEMPEG to the IL-2 heterodimeric receptor (IL-2Rβγ) activates and expands CD8+ T cells and NK cells over immunosuppressive Tregs. In the phase 1/2 PIVOT-02 study, BEMPEG + NIVO displayed encouraging antitumor activity in pts with mRCC, with a tolerable safety profile. The clinical activity and the manageable, non-overlapping toxicity profiles of the individual agents in this combination warrants exploration of triplet regimens in previously untreated aRCC. Methods: PIVOT IO 011 (NCT04540705) is a 2-part, phase 1/2, randomized, open-label study assessing the safety and efficacy of BEMPEG + NIVO + TKI triplet in pts with untreated aRCC or mRCC. In Part 1, pts will receive BEMPEG + NIVO + TKI (Part 1A: axitinib [AXI] or Part 1B: CABO; n≈6–24 pts in each TKI arm). While BEMPEG + NIVO dosing will remain consistent across phases, each TKI will have 2 doses evaluated in Part 1, and results will determine the recommended phase 2 dose for AXI/CABO in Part 2. In Part 2, pts will be randomized 1:1 to receive either BEMPEG + NIVO + CABO or NIVO + CABO (N≈250), stratified by IMDC prognostic score and prior nephrectomy status. If the CABO triplet has an unacceptable toxicity profile, Part 2 may be amended to use the AXI triplet. Key inclusion criteria: aRCC or mRCC with clear cell component; no prior systemic therapy for RCC, except 1 prior adjuvant/neoadjuvant therapy for completely resectable RCC (must have included an anti–VEGF agent with recurrence ≥6 months after last dose); and Karnofsky PS ≥70%. Key exclusion criteria: active CNS brain/leptomeningeal metastases; active, known, or suspected autoimmune disease; and inadequately treated adrenal insufficiency. Primary endpoints in Part 1: dose-limiting toxicities and safety; and in Part 2: overall response rate per RECIST v1.1 by investigator. Secondary endpoints in Part 2: progression-free survival, overall survival, safety. Duration of BEMPEG + NIVO will be ≤2 years, and treatment with TKI will continue until disease progression. The study is currently recruiting. Clinical trial information: NCT04540705.