The CheckMate 511 phase IIIb/IV trial investigated raising the nivolumab dose to 3 mg/kg and lowering the ipilimumab dose to 1 mg/kg.
Among advanced melanoma patients in the CheckMate 511 phase IIIb/IV trial, raising the nivolumab dose to 3 mg/kg and lowering the ipilimumab dose to 1 mg/kg leads to a better safety profile without compromising efficacy. The trial results, recently published in the Journal of Clinical Oncology, may offer patients with advanced melanoma a safer dosing regimen of nivolumab and ipilimumab.
“This study is an important step towards optimizing combination immunotherapy with ipilimumab plus nivolumab,” Shailender Bhatia, MD, a medical oncologist at Seattle Cancer Care Alliance, told Cancer Network. He was not involved in the CheckMate 511 trial. “Using a lower dose of ipilimumab at 1 mg/kg appears to lower the risk of severe toxicity, while retaining the efficacy of the combination.”
The CheckMate 511 trial included 360 adult patients with treatment-naÃ¯ve, unresectable stage III or IV melanoma. Patients were randomly assigned treatment with either the standard approved dosing of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or the alternative dosing of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks for four doses. The primary trial endpoint was the comparison of the incidence of treatment-related grade 3 to 5 adverse events (AEs) between groups.
The trial met its primary endpoint, showing a statistically significant lower incidence of treatment-related grade 3 to 5 AEs in the alternative dosing group compared with the standard dosing group at a minimum follow-up of 12 months (33.9% vs 48.3%; P = .006). Only 1 patient in the alternative dosing group reported treatment-related grade 5 AEs. The incidence of treatment-related AEs overall was also lower for the alternative dosing group (85.6% vs 93.8%), and treatment-related AEs that lead to treatment discontinuation occurred at a lower incidence in the alternative dosing group (23.9% vs 33.1%).
The alternative dosing of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg did not appear to compromise clinical benefit; however, the study was not designed to formally show noninferiority of the alternative dosing compared with the standard dosing. Between the alternative dosing and standard dosing groups, the response rates were similar (45.6% vs 50.6%); complete response rates were also similar (15.0% vs 13.5%). Median progression-free survival (9.9 vs 8.9 months), median time to response (2.83 vs 2.79 months), and proportion of responders (76.8% vs 75.6%) were similar between groups. For both groups, median overall survival and median duration of response were not yet reached.
“The results of [the] CheckMate 511 study should be discussed with the patients who desire aggressive immunotherapy with the combination, as compared to anti-PD1 monotherapy, but are wary of the high rate of severe toxicity with the traditional doses of the combination,” Bhatia said. “In my practice, I routinely discuss [nivolumab 3 mg/kg plus ipilimumab 1 mg/kg] as an alternative option to [nivolumab 1 mg/kg plus ipilimumab 3 mg/kg] and anti–PD-1 monotherapy, so that my patients can make an informed decision based on their desire for aggressive immunotherapy and risk tolerance.”
The study investigators noted that longer follow-up may be needed to “better characterize efficacy outcomes.” Bhatia expressed a similar view, saying, “Longer follow-up on the efficacy data will certainly be important to ensure that the two regimens are equally efficacious on long-term survival.”