Phase 2 CheckMate 650 Trial Shows Promise for Nivolumab, Ipilimumab Combo in mCRPC

Researchers indicated that these early data support the rationale for further evaluation of immune-checkpoint inhibitor-based combinations in patients with metastatic castration resistant prostate cancer.

Results from a preliminary analysis of the phase 2 CheckMate 650 trial, published in Cancer Cell, suggested that the combination use of nivolumab (Opdivo) plus ipilimumab (Yervoy) demonstrated antitumor activity in chemotherapy-naïve and chemotherapy-experienced patients with metastatic castration resistant prostate cancer (mCRPC).1

Researchers indicated that these early data support the rationale for further evaluation of immune-checkpoint inhibitor-based combinations in patients with mCRPC, though questions still remain regarding the optimal dose and dose schedule.

“Historically, prostate cancer has been very resistant to checkpoint inhibitors because it is immunologically cold with few tumor-infiltrating T-cells,” principal investigator Padmanee Sharma, MD, PhD, professor of Genitourinary Medical Oncology and Immunology at The University of Texas MD Anderson Cancer Center, said in a press release.2 “These results suggest that a combination approach to increase T-cell infiltration and then block inhibitory pathways may be a useful strategy for treating these patients. Going forward, we plan to optimize the schedule and dosing to improve the safety profile.”

In this signal-seeking study, researchers used a dosing regimen of 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab administered every 3 weeks. In total, 90 patients with mCRPC were initially enrolled in the study, including 1 pre-chemotherapy cohort (n = 45) and 1 post-chemotherapy cohort (n = 45). As of the data cutoff of November 27, 2018, the median follow-up was 11.9 and 13.5 months in the pre-chemotherapy cohort and post-chemotherapy cohort, respectively.

At the data cutoff, 8 of 32 patients with measurable disease in the pre-chemotherapy cohort (25.0%) and 3 of 30 in the post-chemotherapy cohort (10.0%) achieved an investigator-assessed objective response, including 2 patients in the pre-chemotherapy cohort (6.3%) and 2 in the post-chemotherapy cohort (6.7%) with complete responses. Median time to response was 1.9 and 2.1 months in pre-chemotherapy cohort and post-chemotherapy cohort, and the median duration of response was not reached in either cohort. Further, overall disease control rate was 46.9% and 13.3%, respectively.

However, despite the positive responses observed, grade 3 and 4 treatment-related adverse events (TRAEs) occurred in 42.2% of pre-chemotherapy patients and 53.3% of post-chemotherapy patients. The most common of these events was diarrhea, pneumonitis, colitis and increased lipase in the pre-chemotherapy cohort (n = 3 for each, 6.7%); diarrhea and colitis were most commonly observed in the post-chemotherapy cohort (n = 5 for each, 6.7%). Moreover, TRAEs led to discontinuation of therapy in a total of 31 patients. There were 4 treatment-related deaths, including 2 in each cohort.

“There were patients who had clear benefit as a result of treatment, but there also were patients who had serious adverse events, which led us to amend the protocol to evaluate alternate schedules and doses and improve the safety of this approach,” Sharma explained.

Notably, the investigators also conducted analyses to identify possible biomarkers associated with clinical outcomes in patients with mCRPC. While this study only represents a small number of patients, the researcher’s findings suggest that the combination may be more effective in patients with a relatively high tumor mutational burden (TMB). This is in concurrence with previous findings that suggested certain patients with mCRPC may respond to checkpoint blockade despite having low TMB relative to other cancers, such as melanoma and lung cancer.

Moving forward, the trial has been expanded to include more than 400 patients, with different dosing and schedules being evaluated to identify strategies that can improve efficacy and minimize toxicities.

“The current study represents the first step in trying to identify mCRPC patients who would benefit from combination therapy with ipilimumab plus nivolumab based on chemotherapy exposure as well as preliminary biomarker analyses,” co-author Sumit Subudhi, MD, PhD, assistant professor of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, said in the release. “The data generated to date are encouraging, but we clearly have more work to do in the expansion cohort as we try to administer effective combination strategies with fewer toxicities.”


1. Sharma P, Pachynski RK, Narayan V, et al. Nivolumab Plus Ipilimumab for Metastatic Castration-Resistant Prostate Cancer: Preliminary Analysis of Patients in the CheckMate 650 Trial. Cancer Cell. doi: 10.1016/j.ccell.2020.08.007

2. Combination immunotherapy benefits subset of patients with advanced prostate cancer [news release]. Houston. Published September 9, 2020. Accessed September 11, 2020.