ASCO 2020: A Phase III Randomized Study of Neoadjuvant Chemotherapy Alone or in Combination with Nivolumab ± Linrodostat Mesylate, Followed by Adjuvant Postsurgical Nivolumab ± Linrodostat, in Cisplatin-Eligible Muscle Invasive Bladder Cancer

(UroToday.com) Immuno-oncology therapies have revolutionized the treatment of patients with advanced bladder cancer. For patients with cisplatin-eligible, muscle invasive bladder cancer, the recommended treatment is cisplatin-based neoadjuvant chemotherapy prior to radical cystectomy. However, since only ~30% of patients achieve a pathologic complete response translating to improved long-term outcomes with approved regimens,1 new therapies are needed. PD-L1 expression is associated with aggressive bladder cancer and has been shown to increase in tissue after neoadjuvant chemotherapy, supporting the therapeutic pursuit of the PD-1/PD-L1 axis. Additionally, the expression of indoleamine 2,3-dioxygenase (IDO) is higher in bladder cancer than in normal bladder tissue and is associated with advanced disease and poor clinical outcomes. Linrodostat mesylate, a selective, potent, once-daily oral IDO1 inhibitor that works to reduce kynurenine production, has demonstrated clinical activity in combination with nivolumab (anti–PD-1) in patients with immunotherapy treatment-naive advanced bladder cancer who had ≥ 1 prior line of therapy (ORR 37%).2



Preclinical data suggest a potential synergy between chemotherapy and immune checkpoint inhibitors. Gemcitabine promotes an inflammatory tumor microenvironment by depleting regulatory T cells and myeloid-derived suppressor cells and enhancing T-cell infiltration. Cisplatin induces CD8+ cytotoxic T lymphocyte-mediated killing and may increase tumor mutational burden, leading to an enhanced presentation of neoantigens and increased tumor recognition by the innate immune system. Taken together, these data provide a rationale for investigating neoadjuvant chemotherapy + nivolumab + linrodostat in muscle invasive bladder cancer. At the ASCO 2020 virtual meeting, Guru Sonpavde, MD, and colleagues describe CA017-078, a randomized, partially blinded, phase 3 study evaluating the efficacy and safety of neoadjuvant chemotherapy ± nivolumab ± linrodostat followed by radical cystectomy and continued immunotherapy treatment in patients with muscle invasive bladder cancer.

For this trial, patients aged ≥ 18 years with previously untreated muscle invasive bladder cancer (clinical stage T2-T4a, N0, M0), creatinine clearance ≥ 50 mL/min, and predominant urothelial carcinoma histology who are eligible for cisplatin-based neoadjuvant chemotherapy and radical cystectomy will be enrolled. Patients will be randomized to receive neoadjuvant chemotherapy (gemcitabine/cisplatin; arm A), neoadjuvant chemotherapy + nivolumab + oral placebo (arm B), or neoadjuvant chemotherapy + nivolumab + linrodostat (arm C) followed by radical cystectomy (all arms). Arms B and C will receive continued immunotherapy treatment. The trial schema for CA017-078 is as follows:

ASCO20__linrodostat.png

Patients with evidence of positive lymph node, metastatic bladder cancer, or prior systemic therapy, radiotherapy, or surgery for bladder cancer other than TURBT are not eligible. The primary endpoints include pathologic complete response after neoadjuvant treatment and radical cystectomy, and event-free survival (arms C vs A; arms B vs A) defined as the time from randomization to progression of disease that precludes radical cystectomy, or local or distant recurrence per blinded internal committee review, or death due to any cause. Secondary endpoints are overall survival and safety/tolerability of nivolumab +/- linrodostat in combination with gemcitabine/cisplatin.

This global study started on October 12, 2018 with a target enrollment of 1,200 patients in 28 countries. The estimated primary completion date for the study is November 28, 2023, and the estimated study completion date is December 30, 2026. The safety lead-in evaluating the tolerability of gemcitabine/cisplatin + nivolumab + linrodostat is underway, and the randomized phase of the trial will begin pending review of the data from the safety lead-in by the data monitoring committee.

Clinical trial information: NCT03661320.

Presented by: Guru Sonpavde, MD, Department of Genitourinary Oncology, Dana Farber Cancer Institute, Boston, MA

Co-Authors: Andrea Necchi, Shilpa Gupta, Gary D. Steinberg, Juergen Gschwend, Michiel Simon Van Der Heijden, Audrey Richiero, Alexandre Lambert, Bradley Raybold, Srikanth Gajavelli, Dimitrios Zardavas, Matt D. Galsky; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Cleveland Clinic Foundation, Cleveland, OH; NYU Langone Health, Perlmutter Cancer Center, New York, NY; Department of Urology, Technical University of Munich, Munich, Germany; Department of Medical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Bristol-Myers Squibb, Princeton, NJ; Department of Medicine, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY

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. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349(9):859-866.
  2. Tabernero, et al. J Clin Oncol2018;36(suppl) [abstr 4512]