Immune checkpoint inhibitors shrink tumors in 26 to 38 percent of metastatic bladder cancer patients
Combination immunotherapy is producing response rates ranging from 26 to 38 percent among patients with metastatic bladder cancer in the early stages of a three-arm clinical trial presented Saturday at the 2016 Society for Immunotherapy of Cancer (SITC) Annual Meeting in National Harbor, Maryland.
“Until the first, recent approval of immune checkpoint therapy, patients with bladder cancer have not had new treatment options for over 30 years. We're quickly moving from immune checkpoint monotherapy to immune checkpoint combination therapies to improve outcomes for patients with bladder cancer,” said study principal investigator Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology at The University of Texas MD Anderson Cancer Center.
In the randomized phase I/II clinical trial known as CheckMate 032, patients who progress after platinum-based chemotherapy received either the anti-PD1 inhibitor nivolumab, or one of two combinations of nivolumab plus the CTLA4 inhibitor ipilimumab. One combination had a higher dose of ipilimumab, the other a higher dose of nivolumab, given every three weeks for four cycles, followed by nivolumab every two weeks. All patients were treated until disease progression or unacceptable toxicity.
Patients receiving the combination with the higher dose of ipilimumab had the highest objective response rate (38.5 percent), which is confirmed complete response (disappearance of tumors) plus confirmed partial response (at least a 30 percent shrinkage of tumors).
• Combination of 1 mg/kg infusion of nivolumab, 3 mg/kg infusion of ipilimumab, 10/26 (38.5 percent) overall response, 1/26 (4 percent) complete.
• Combination of 3 mg/kg of nivolumab, 1 mg/kg of ipilimumab, 27/104 (26 percent) overall response, 3/104 (3 percent) complete response rate.
• For nivolumab alone, 19/78 (24.4 percent) overall response, 5/78 complete (6 percent).
“These early results with the higher dose ipilimumab provide evidence for improved responses with combination immune checkpoint therapy, which is exciting news to help drive the field to develop and test combination treatment strategies as a new standard of care for patients with metastatic disease, as well as for patients with earlier stages of disease,” Sharma said.
Responses appear to be durable, with 70 and 80 percent of responding patients on the combinations still having ongoing responses at the time of database lock.
Sharma presented only the combination data at the SITC session. Single-agent nivolumab data were reported in a Lancet Oncology paper in October.
The two drugs target different proteins on T cells, white blood cells that act as the targeted soldiers of the immune system. Programmed cell death-1 (PD1) and cytotoxic T-lymphocyte associated protein 4 each act as brakes on T cells, shutting down immune response. Nivolumab blocks PD1, ipilimumab blocks CTLA4, freeing T cells to attack cancer.
• For the higher dose ipilimumab combination, 76.9 percent had at least one treatment-related adverse event of any grade, 30.8 percent had grade 3-4 events, the most serious categories, and 7.7 percent discontinued treatment.
• For the higher dose nivolumab combination, 84.6 percent had an event, 31.7 had grade 3-4 events and 13.5 percent stopped treatment.
• For nivolumab alone, 81.1 percent of patients had events, 22 percent had grade 3-4 events, and 3 percent had to discontinue treatment.
Median follow up was 15.2 months for the nivolumab group, 16.7 months for the higher dose nivolumab group and 7.8 months for the higher dose ipilimumab group.
Sharma said the trial sponsor, Bristol-Myers Squibb, expanded the higher-dose ipilimumab arm later in the course of the trial, which accounts for the lower patient accumulation and shorter follow-up.
The company had been exploring the two combinations in other trials and realized that response rates differed among them, Sharma said. She also advocated the change based on earlier immune monitoring research of presurgical bladder cancer treatment that showed higher-dose ipilimumab increases T cells that have high levels of the immune stimulating protein ICOS.
A third immunotherapy drug, atezolizumab, was approved for metastatic bladder cancer by the U.S. Food and Drug Administration in October, based on duration of response and an overall response rate of 14.8 percent in a single arm study. Atezolizumab blocks PD-L1, a ligand found on tumor cells and other cells that activates PD1, shutting down T cells.
As a phase I/II clinical trial, CheckMate 032 is assessing anti-tumor activity and remains under way. The trial is funded by Bristol-Myers Squibb, which makes both ipilimumab and nivolumab.
Sharma also is scientific director of MD Anderson’s immunotherapy platform and an investigator with the Parker Institute for Cancer Immunotherapy at MD Anderson. The platform is part of MD Anderson’s Cancer Moon Shots Program™ to reduce cancer deaths by accelerating development of therapies, prevention efforts and early detection based on scientific discoveries.
Co-investigators with Sharma are: Margaret Callahan, and Jonathan Rosenberg, Memorial Sloan Kettering Cancer Center, New York; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal, Madrid, Spain; Joseph Kim, Yale Cancer Center, New Haven, CT; Filipo de Braud, Istituto Nazionale dei Tumori-Università degli Studi di Milano, Milan, Italy; Patrick Ott, Dana-Farber Cancer Institute, Boston; Petri Bono, Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Rathi Pillai, Emory Winship Cancer Institute, Atlanta; Michael Morse, Duke University Medical Center, Durham, NC; Dung T. Le, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Matthew Taylor, Oregon Health and Science University, Portland, OR; Pavlina Spilliopoulou, Beatson West of Scotland Cancer Centre, Glasgow, UK; Johanna Bendell, Tennessee Oncology, Nashville, TN; Dirk Jaeger, Heidelberg University Hospital, Heidelberg, Germany; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Scott Antonia, Moffitt Cancer Center, Tampa, FL; Paolo Ascierto, Istituto Tumori Napoli Fondazione Pascale, Naples, Italy; Delphine Hennicken, Marina Tschaika and Alex Azrilevich, Bristol-Myers Squibb, Princeton, NJ.