A phase II, randomized study of nivolumab (NIVO), NIVO plus linrodostat mesylate, or NIVO plus intravesical bacillus Calmette-Guerin (BCG) in BCG-unresponsive, high-risk, nonmuscle invasive bladder cancer (NMIBC): CheckMate 9UT.
Noah M. Hahn, Sam S. Chang, Maxwell V. Meng, Neal D. Shore, Badrinath R. Konety, Gary D. Steinberg, Juergen E. Gschwend, Hiroyuki Nishiyama, Joan Palou, John A. Taylor, Alexandre Lambert, Li Zhu, Toshiki Maeda, Bradley Raybold, Bruce S. Fischer, Chandrika Jeyamohan, Dimitrios Zardavas, Fred Witjes
Abstract
TPS5090 Background: Immune checkpoint inhibitors, including NIVO (anti–PD-1), have demonstrated favorable tolerability and efficacy profiles, ushering in a new treatment (tx) paradigm for advanced bladder cancer (advBC). However, an unmet need exists for new effective tx options in earlier stages of disease, specifically for patients (pts) with BCG-unresponsive, high-risk NMIBC. Increased IDO and PD-L1 expression in NMIBC tumors (Inman, et al. Cancer 2007; Hudolin, et al. Anticancer Res 2017), support the combination of anti–PD-1 and IDO1 inhibition in NMIBC. Linrodostat mesylate, a selective, potent, once-daily IDO1 inhibitor, has demonstrated clinical activity in combination with NIVO in pts with immunotherapy-naive advBC who received ≥ 1 prior line of therapy (objective response rate, 37%; Tabernero, et al. J Clin Oncol 2018;36(suppl) [abstr 4512]). Furthermore, high levels of PD-L1 expression have been reported in patients not responding to BCG tx. These findings provide a rationale for investigation of NIVO ± linrodostat ± intravesical BCG therapy in BCG-unresponsive high-risk NMIBC. Here we describe a phase 2, randomized, open-label study assessing the safety and efficacy of NIVO ± linrodostat ± intravesical BCG in pts with BCG-unresponsive, high-risk NMIBC (NCT03519256). Methods: Pts aged ≥ 18 years with BCG-unresponsive (per February 2018 FDA guidance), high-risk NMIBC, defined as carcinoma-in-situ (CIS) with or without papillary component, any T1, or Ta high-grade lesions, will be enrolled. Pts must have urothelial carcinoma as the predominant histological component ( > 50%). Key exclusion criteria include locally advanced or metastatic BC, upper urinary tract disease within 2 years, prostatic urethral disease within 1 year, and prior immunotherapy. Using a novel adaptive-type design, pts will be randomized to 1 of 4 tx arms with NIVO ± linrodostat ± BCG. Primary endpoints include proportion of pts with CIS with complete response (CR) and duration of CR in pts with CIS. Secondary endpoints are progression-free survival and safety. This global study in 14 countries is underway, with a target enrollment of 436 pts. Clinical trial information: NCT03519256 .