ASCO 2018: BMS-986205, an IDO1 Inhibitor, in Combination with Nivolumab: Updated Safety Across all Tumor Cohorts and Efficacy in Patients with Advanced Bladder Cancer

Chicago, IL ( Over the last few years, several immunotherapy agents have been tested in the advanced/metastatic bladder cancer setting, with encouraging results. Nivolumab is an anti–PD-1 immunotherapy agent that has shown durable responses (ORR 19.6%) and manageable safety (grade 3‒4 treatment-related AEs 18%) in patients with advanced bladder cancer [1]. However, prolonging survival in more patients requires additional approaches to overcome tumor evasion mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1) allows tumor escape through kynurenine production, which stimulates the development of regulatory T cells and suppresses effector T-cell proliferation. Anti─PD-1 therapy can upregulate IDO1, supporting the rationale for combining nivolumab with an IDO1 inhibitor (IDO1i). BMS-986205 is a selective, potent, once-daily, oral IDO1i that works early in the IDO1 pathway to reduce kynurenine production. BMS-986205 + nivolumab has previously demonstrated a favorable safety profile and antitumor activity in heavily pretreated patients with select solid tumors [2]. Josep Tabernero, MD, Ph.D and colleagues presented updated safety data across all tumor cohorts, in addition to efficacy outcomes among patients with advanced bladder cancer. 

A previous dose-escalation study (phase 1/2a) tested BMS-986205 (25-200 mg) orally once daily for 2 weeks, followed by BMS-986205 + nivo 240 mg IV every 2 weeks, finding that BMS-986205 was well tolerated up to at least 200 mg in combination with nivolumab [3]. During the expansion phase of the study, patients received BMS-986205 100 or 200 mg once daily + nivolumab 240 mg IV every 2 weeks or 480 mg IV every 4 weeks. The objectives of this study included safety and ORR by RECIST v1.1. Patients with advanced bladder cancer were permitted to have received prior immunotherapy before enrollment. 

Overall, there were 434 patients that received BMS-986205 + nivolumab, of which 29 patients had advanced bladder cancer. Overall, treatment-related AEs were reported in 51% of patients (grade 3‒4, 12%), the most common being fatigue (13%) and nausea (10%). There were only 16 patients (4%) that discontinued therapy secondary to treatment-related AEs. For patients with advanced bladder cancer, over a median follow-up of 17 weeks (range 4‒53), the ORR was 34% (1 complete response, 9 partial responses), and the disease control rate was 48%. Among these patients, 26 (89.7%) had no prior immunotherapy, and ORR in these patients was 38% (1 complete response, 9 partial responses), with a disease control rate of 54%. The ORR in patients with tumor PD-L1 ≥ 1% (n = 15) vs < 1% (n = 11) was 47% vs 27%.

This study provides important safety and efficacy results when combining therapy with immunotherapy agents, undoubtedly the next wave of clinical trials forthcoming. Tabernero concluded noting that BMS-986205 + nivolumab was well tolerated, with a safety profile similar to that of nivolumab monotherapy. Furthermore, preliminary evidence of efficacy was observed in advanced bladder cancer, supporting further evaluation of BMS-986205 + nivolumab, which is also being assessed in a BCG-unresponsive non-muscle-invasive bladder cancer trial (NCT03519256). Clinical trial information: NCT02658890

Presented by: Josep Tabernero, MD, Ph.D., Vall d’Hebron University Hospital, Barcelona, Spain
Co-Authors: Jason J. Luke, Anthony M. Joshua, Andrea I. Varga, Victor Moreno, Jayesh Desai, Ben Markman, Carlos Alberto Gomez-Roca, Filippo G. De Braud, Sandip Pravin Patel, Matteo S. Carlino, Lillian L. Siu, Giuseppe Curigliano, Zhaohui Liu, Yuko Ishii, Penny Phillips, Megan Wind-Rotolo, Paul Andrew Basciano, Alex Azrilevich, Karen A. Gelmon; Vall d’Hebron University Hospital, Barcelona, Spain; University of Chicago Medical Center, Chicago, IL; St Vincent’s Hospital, Sydney, Australia; Gustave Roussy Cancer Campus, Villejuif, France; START Madrid-FJD, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain; Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia; Monash Health and Monash University, Melbourne, Australia; Institut Universitaire du Cancer de Toulouse - Oncopole, Toulouse, France; Istituto Nazionale dei Tumori, Milan, Italy; University of California San Diego Moores Cancer Center, La Jolla, CA; Westmead and Blacktown Hospitals, Melanoma Institute Australia, and The University of Sydney, Sydney, Australia; Princess Margaret Cancer Centre, Toronto, ON, Canada; University of Milan, Istituto Europeo di Oncologia, Milano, Italy; Bristol-Myers Squibb, Princeton, NJ; University of British Columbia, BC Cancer Agency, Vancouver, BC, Canada

1. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2 trial. Lancet Oncol 2017;18(3):312-322.
2. Luke JJ, Gelmon K, Pachynski RK, et al. Preliminary antitumor and immunomodulatory activity of BMS-986205, an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, in combination with nivolumab in patients with advanced cancers. SITC 2017, abstr O41.
3. Siu LL, Gelmon K, Chu Q, et al. BMS-986205, an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, is well tolerated with potent pharmacodynamic (PD) activity, alone and in combination with nivolumab (nivo) in advanced cancers in a phase 1/2a trial. AACR 2017, abstr CT116.

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA