PIVOT IO 009: A phase 3, randomized study of neoadjuvant and adjuvant nivolumab (NIVO) plus bempegaldesleukin (BEMPEG; NKTR-214) versus NIVO alone versus standard of care (SOC) in patients (pts) with muscle-invasive bladder cancer (MIBC) who are cisplatin (cis)-ineligible.
Authors: Grivas Petros , Van Der Heijden Michiel Simon , Necchi Andrea , Siefker-Radtke Arlene O. , Cutuli Hernan , Qureshi Anila H. , Kreiser Stephanie , Hodari Moana , Ravimohan Shruthi , Zakharia Yousef 
Published: February 2022

TPS596 Background: Radical cystectomy (RC) without neoadjuvant chemotherapy remains SOC for cis-ineligible pts (and those refusing cis) with MIBC and T1-T4aN1 disease. Yet, many pts progress to incurable, metastatic disease. Preventing disease recurrence for these pts remains an unmet need. Immune checkpoint inhibitors (ICIs) are approved in Bacillus Calmette-Guérin-unresponsive carcinoma in situ, in the adjuvant and metastatic urothelial cancer (UC) settings, and are being actively explored in the perioperative setting. In phase 2 single-arm trials, neoadjuvant ICIs showed promising pathologic complete response (pCR) rates (approximately 30%–40%). The phase 3 CheckMate 274 study showed improved disease-free survival with adjuvant NIVO vs placebo in MIBC. BEMPEG, an immunostimulatory interleukin-2 (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 natural killer cells over immunosuppressive regulatory T cells. The combination of BEMPEG + NIVO demonstrated deep responses and a tolerable safety profile in pts with metastatic UC in the phase 1/2 PIVOT-02 trial and is being further explored in the phase 2 PIVOT-10 (NCT03785925) study. The PIVOT IO 009 study, presented here, aims to evaluate the hypothesis that perioperative treatment with BEMPEG + NIVO will provide higher pCR and longer event-free survival (EFS) vs SOC in cis-ineligible pts with MIBC and T1-T4aN1 disease. Methods: PIVOT IO 009 (NCT04209114) is an open-label, phase 3 trial of 540 cis-ineligible pts with MIBC and T1-4aN1 disease, who will be randomized 1:1:1 to receive SOC, neoadjuvant and adjuvant BEMPEG + NIVO, or neoadjuvant and adjuvant NIVO alone. Stratification factors include clinical stage (T2N0 vs T3-T4aN0 vs T1-T4aN1) and tumor cell PD-L1 status. Key inclusion criteria: adults with MIBC and T1-T4aN1 disease deemed eligible for RC and ECOG PS 0–1. Cis-ineligibility is defined as one of the following: glomerular filtration rate ≥30 but < 60 mL/min, or ≥grade 2 hearing loss or peripheral neuropathy. Key exclusion criteria: clinical evidence of ≥N2 or metastatic disease or UC in the upper urinary tract; prior systemic therapy, radiation therapy, or prior surgery for bladder cancer other than TURBT or biopsies. Primary endpoints: pCR rate (pT0N0) of neoadjuvant BEMPEG + NIVO vs no neoadjuvant therapy (SOC), and EFS of neoadjuvant and adjuvant BEMPEG + NIVO vs SOC. Secondary endpoints: pCR rate of neoadjuvant NIVO vs SOC; EFS of neoadjuvant and adjuvant NIVO vs SOC; overall survival and safety in each treatment arm vs SOC. The study is currently recruiting pts. Clinical trial information: NCT04209114.