Combination approach could overcome mechanisms that previously led to poor outcomes with single-agent checkpoint inhibition.
Combination immune checkpoint therapy with nivolumab (Opdivo) and ipilimumab (Yervoy) showed early promise in men with metastatic castration-resistant prostate cancer (mCRPC), according to findings from the phase 2 CheckMate 650 trial published in Cancer Cell.1
Among patients who were chemotherapy-naïve, the combination led to a median objective response rate (ORR) of 25% and a median overall survival (OS) of 19 months. The corresponding results were 10% and 15.2 months among patients with prior chemotherapy.
There were 4 complete responses, 2 in the chemotherapy-naïve group and 2 among the men with prior chemotherapy. The disease control rates were 46.9% and 13.3%, respectively.
Padmanee Sharma, MD, PhD
"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 in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center stated 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," added Sharma, who is also co-director of MD Anderson's immunotherapy platform, part of the institution's Moon Shots Program.
The ongoing open-label, multicenter phase 2 CheckMate 650 trial (NCT02985957) is examining the PD-1 inhibitor nivolumab plus the CTLA-4 inhibitor ipilimumab in patients with mCRPC, ongoing ADT (must have testosterone level ≤1.73 nmol/L [50 ng/dL]),and an ECOG performance status ≤1.
The data published in Cancer Cell included 90 patients enrolled in the CheckMate 650 trial, 45 who were chemotherapy-naïve and 45 who progressed after receiving chemotherapy for mCRPC. Overall, 77.8% of the patients were White, 10% were Black/African-American, and 12.2% were other races. All patients were treated every 3 weeks with nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg.
The median radiographic progression-free survival was 5.5 months in the chemotherapy-naïve arm and 3.8 months in the post-chemotherapy arm. The PSA response rates were 17.6% and 10%, respectively.
Regarding safety, grade 3/4 treatment-related adverse events (TRAEs) were reported in 53.3% of the patients who had prior chemotherapy and in 42.2% of the chemotherapy-naïve group. The TRAEs that occurred most frequently were colitis, pneumonitis, increased lipase, and diarrhea. Thirty-four percent (n = 31) of the patients discontinued treatment due to a TRAE. There were 4 deaths related to treatment, 2 in the chemotherapy-naïve group and 2 in the post-chemotherapy group.
"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," said Sharma.
The initial data from these 90 patients led to an expansion of the trial to over 400 patients, which now includes cohorts exploring different schedules and doses to identify a dosage that will maximize efficacy while limiting adverse events.
The researchers noted in their findings that early exploration of biomarkers indicated that patients with high tumor mutational burden may reach a greater benefit with the nivolumab/ipilimumab regimen.
Sumit Subudhi, MD, PhD
"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 MD Anderson, stated in the press release.2 "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 [published online September 10, 2020]. Cancer Cell. doi: 10.1016/j.ccell.2020.08.007
2. Combination immunotherapy benefits subset of patients with advanced prostate cancer. Published September 10, 2020. https://bit.ly/3hcW3DK. Accessed September 10, 2020