In a UK phase II trial (PRISM) reported in the Journal of Clinical Oncology, Vasudev and colleagues found that ipilimumab given every 12 weeks vs every 3 weeks in combination with nivolumab resulted in a significantly reduced rate of treatment-related grade ≥ 3 adverse events in treatment-naive patients with advanced clear cell renal cell carcinoma. However, the modified regimen did not reach the prespecified threshold for efficacy, but progression-free survival in the two groups was similar on informal comparison.
Study Details
In the multicenter open-label trial, 192 patients (70% at intermediate/poor risk) were randomly assigned 2:1 between March 2018 and January 2020 to receive four doses of ipilimumab at 1 mg/kg given every 12 weeks (modified group, n =128) or every 3 weeks (standard group, n = 64) in combination with nivolumab.
In the modified group, nivolumab was given in four doses of 3 mg/kg every 12 weeks with ipilimumab, with a 240-mg maintenance dose once every 2 weeks between the first and second combination doses, and a 480-mg maintenance dose once every 4 weeks between all other combination doses; thereafter, nivolumab was given at 480 mg every 4 weeks until disease progression or unacceptable toxicity. In the standard group, nivolumab was given at 3 mg/kg in combination with ipilimumab every 3 weeks; thereafter, it was given at 480 mg every 4 weeks until disease progression or unacceptable toxicity.
The primary endpoint was the incidence of grade ≥ 3 to 5 treatment-related adverse events. The key secondary endpoint was 12-month progression-free survival in the modified group; the threshold for efficacy was a lower limit of the 90% confidence interval (CI) in the modified group that excluded a rate of 39.7% from an historical sunitinib control group. The study was not designed to formally compare efficacy in the modified group vs standard group.
Key Findings
The incidence of grade ≥ 3 treatment-related adverse events was 32.8% in the modified group vs 53.1% in the standard group (odds ratio = 0.43, 90% CI = 0.25–0.72, P = .0075). The modified group had lower rates of colitis (3.9% vs 6.3%), arthralgia (1.6% vs 7.8%), increased serum lipase (1.6% vs 9.4%), and hypophysitis (0.8% vs 3.1%).
Median follow-up for progression-free survival was 21 to 22 months in both groups. Progression-free survival at 12 months in the modified group was 46.1% (90% CI = 38.6%–53.2%). Comparison of the lower limit of the confidence interval (38.6%) failed to exclude the historical control rate of 39.7%.
Progression-free survival at 12 months in the standard group was 44.8% (90% CI = 32.1%–56.7%). Exploratory analysis showed a post hoc unadjusted hazard ratio for the modified vs standard group of 0.95 (95% CI = 0.67–1.36). Median progression-free survival was 10.8 months (95% CI = 8.2–14.2 months) in the modified group and 9.8 months (95% CI = 6.6–13.3 months) in the standard group.
Objective response rate was 45.3% vs 35.9%. Overall survival rates were 88.3% and 84.1% at 12 months and 71.3% vs 73.7% at 24 months.
The investigators concluded: “Rates of grade 3–5 [treatment-related adverse events] were significantly lower in patients receiving modified versus standard [ipilimumab]. Although 12-month [progression-free survival] did not meet the prespecified efficacy threshold compared with historical control, informal comparison of treatment groups did not suggest any reduction in efficacy with the modified schedule.”
Naveen S. Vasudev, MD, PhD, of the University of Leeds & St James’s University Hospital, Leeds, is the corresponding author of the Journal of Clinical Oncology article.
Disclosure: The study was supported by Bristol Myers Squibb and Yorkshire Cancer Research. For full disclosures of the study authors, visit ascopubs.org.
