ASCO 2020: CheckMate 9UT: A Phase II, Randomized Study of Nivolumab, Nivolumab plus Linrodostat Mesylate, or Nivolumab plus Intravesical BCG in BCG-Unresponsive, High-Risk, NMIBC

(UroToday.com) Immune checkpoint inhibitors, including nivolumab (anti–PD-1), have demonstrated favorable tolerability and efficacy profiles, ushering in a new treatment paradigm for advanced bladder cancer. In patients with advanced bladder cancer whose disease has progressed or recurred following treatment with platinum-based chemotherapy, nivolumab has shown meaningful clinical benefit (objective response rate 20%) and manageable safety (grade 3/4 treatment-related adverse event rate 23%).¹ However, an unmet need exists for new effective treatment options in earlier stages of disease, specifically for patients with BCG-unresponsive, high-risk NMIBC. Increased IDO and PD-L1 expression in NMIBC tumors^2-3 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 nivolumab in patients with immunotherapy-naive advanced bladder cancer who received ≥ 1 prior line of therapy (objective response rate, 37%).⁴ Furthermore, high levels of PD-L1 expression have been reported in patients not responding to BCG treatment. These findings provide a rationale for investigation of nivolumab ± linrodostat ± intravesical BCG therapy in BCG-unresponsive high-risk NMIBC. At the virtual ASCO 2020 annual meeting, Noah M. Hahn, MD, and colleagues describe CheckMate 9UT, a phase 2, randomized, open-label study assessing the safety and efficacy of NIVO ± linrodostat ± intravesical BCG in patients with BCG-unresponsive, high-risk NMIBC.

In CheckMate 9UT, patients aged ≥ 18 years with BCG-unresponsive (per February 2018 FDA guidance), high-risk NMIBC, defined as carcinoma-in-situ with or without papillary component, any T1, or Ta high-grade lesions, will be enrolled. Patients must have urothelial carcinoma as the predominant histological component (> 50%). Using a novel adaptive-type design, patients will be randomized to one of four treatment arms with nivolumab ± linrodostat ± BCG.  The trial schema for CheckMate 9UT is as follows:

Key exclusion criteria include locally advanced or metastatic bladder cancer, upper urinary tract disease within 2 years, prostatic urethral disease within 1 year, and prior immunotherapy. Primary endpoints include the proportion of patients with carcinoma in-situ with complete response and duration of complete response in patients with carcinoma in-situ. Secondary endpoints are progression-free survival and safety.

This global study started on May 25, 2018, is underway in 14 countries (including the United States, Canada, Russia, Australia, and Brazil), with a target enrollment of 480 patients. The estimated primary completion date for the study is September 16, 2022 and the estimated study completion date is September 16, 2026.

Presented by: Noah M. Hahn, MD, Associate Professor of Medicine, Departments of Oncology and Urology, Johns Hopkins School of Medicine, Baltimore, MD

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md, at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020.

References:

1. Sharma P, et al. “Abstract CT178: Nivolumab monotherapy in patients with advanced platinum-resistant urothelial carcinoma: Efficacy and safety update and association between biomarkers and overall survival in CheckMate 275” AACR 2018. DOI: 10.1158/1538-7445.AM2018-CT178, Published July 2018
2. Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer 2007 Apr 15;109(8):1499-1505.
3. Hudolin T, Mengus C, Coulot J, et al. Expression of Indoleamine 2,3-Dioxygenase Gene is a feature of poorly differentiated non-muscle-invasive urothelial cell bladder carcinomas. Anticancer Res 2017 Mar;37(3):1375-1380.
4. Tabernero, et al. BMS-986205, an indoleamine 2,3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab (NIVO): Updated safety across all tumor cohorts and efficacy in pts with advanced bladder cancer (advBC). Journal of Clinical Oncology 36, no. 15_suppl (May 20, 2018) 4512-4512.