Nivolumab plus ipilimumab shows benefit in advanced prostate cancer subset
Nivolumab plus ipilimumab induced durable responses among a subset of men with metastatic castration-resistant prostate cancer, according to results of the phase 2 CheckMate 650 study published in Cancer Cell.
However, nearly half of men who received the combination experienced grade 3 to grade 4 treatment-related adverse events, researchers noted. They are now evaluating alternate dosing regimens in an expanded trial to improve the safety profile.
“We had previously found that in response to ipilimumab [Yervoy, Bristol Myers Squibb] there was a significant increase in tumor-infiltrating T cells, as well as increased expression of compensatory inhibitory immune checkpoints, including PD-1 and PD-L1, within the prostate tumor microenvironment. The compensatory inhibitory pathways could account for the limited efficacy of ipilimumab in men with advanced prostate cancer,” Padmanee Sharma, MD, PhD, professor in the department of genitourinary medical oncology and immunology at The University of Texas MD Anderson Cancer Center, told Healio. “Based on these findings and other data in animal models, we designed CheckMate 650 to evaluate the safety and efficacy of nivolumab [Opdivo, Bristol Myers Squibb] plus ipilimumab in men with metastatic castration-resistant prostate cancer.”
Current treatments for metastatic castration-resistant prostate cancer often fail to induce durable long-term responses. However, combination strategies that include immunotherapy have the potential to provide long-term survival for this patient population.
For this reason, Sharma and colleagues conducted a multicenter, open-label study that included 90 men (77.8% white) with metastatic castration-resistant prostate cancer who received 1 mg/kg nivolumab, which targets PD-1, plus 3 mg/kg ipilimumab, which targets CTLA-4, every 3 weeks for four doses, followed by 480 mg nivolumab monotherapy every 4 weeks.
The analysis included two cohorts: men who had progressed after treatment with second-generation hormone therapy and had not received chemotherapy (cohort 1, n = 45; median age, 69 years; range, 48-85) and those who progressed after taxane-based chemotherapy (cohort 2, n =45; median age, 65 years; range, 46-84).
Investigator-assessed objective response rate and radiographic PFS served as co-primary endpoints. Secondary endpoints included OS and safety.
Median follow-up was 11.9 months in cohort 1 and 13.5 months in cohort 2.
Researchers presented early results of the trial at last year’s Genitourinary Cancers Symposium.
Final results showed ORRs of 25% among men in cohort 1 and 10% among men in cohort 2. Two men in each cohort had a complete response to therapy. Median duration of response had not been reached in either cohort.
Median radiographic PFS was 5.5 months (95% CI, 3.5-7.1) in cohort 1 vs. 3.8 months (95% CI, 2.1-5.1) in cohort 2, median OS was 19 months (95% CI, 11.5-not evaluable) vs. 15.2 months (95% CI, 8.4-not evaluable) and the disease control rate was 46.9% vs. 13.3%.
Grade 3 to grade 4 treatment-related adverse events occurred among 42.2% of men in cohort 1 and 53.3% in cohort 2. The most common of these included diarrhea, pneumonitis, colitis and increased lipase. Thirty-one men discontinued treatment due to adverse events, and two treatment-associated deaths occurred in each cohort.
“CheckMate 650 demonstrated a clinical efficacy signal in a subset of men with metastatic castration-resistant prostate cancer, which needs to be confirmed in a larger cohort of patients,” Sharma said. “The combination of ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) given every 3 weeks was too toxic for men with prostate cancer; therefore, we are evaluating different doses and schedules in an attempt to minimize toxicity while maintaining efficacy.”
For more information:
Padmanee Sharma, MD, PhD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: padsharma@mdanderson.org.
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