The combination of the programmed death receptor 1 (PD-1) inhibitor nivolumab at a reduced dose (1 mg/kg) with the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab at standard dose (3 mg/kg) for four doses followed by standard-dose nivolumab alone is a standard of care for patients with advanced, previously untreated melanoma. This is based on results from the phase III CheckMate-067 trial that confirmed combination therapy is significantly more effective than single-agent nivolumab or ipilimumab. However, improvement in efficacy is associated with increased treatment-related grade 3/4 adverse events and treatment discontinuation in nearly 40% of patients.
In an attempt to reduce the toxicity of the anti-CTLA-4 plus anti-PD-1 combination, the phase Ib Keynote-029 trial examined use of a reduced dose of ipilimumab (1 mg/kg) in combination with the standard dose of pembrolizumab (2 mg/kg) every 3 weeks for four doses, followed by pembrolizumab every 3 weeks for up to 2 years, in 153 patients with advanced melanoma.
At a median 17 months follow-up, 72% of patients received all four doses of pembrolizumab plus ipilimumab and 42% of patients remained on pembrolizumab monotherapy. The combination of standard-dose pembrolizumab with reduced-dose ipilimumab resulted in an impressive objective response rate of 61%, with 82% of patients having a decrease from baseline tumor size. The proportion of patients having an objective response was similar across patient subgroups, including PD-L1 expression and BRAF mutation. Estimated 1-year progression-free survival and overall survival were 69% and 89%, respectively.
Grade 3/4 treatment-related adverse events (AEs) occurred in 45% of patients, including grade 3/4 immune-mediated AEs in 27% of patients. The most common treatment-related AEs of any grade were fatigue (48%), rash (42%), and pruritis (41%). The most common immune-mediated AEs were hypothyroidism (16%) and hyperthyroidism (10%). AEs led to discontinuation of both treatments in 14% of patients, while 8% discontinued ipilimumab only and 9% discontinued pembrolizumab only. There were no treatment-related deaths.
The study investigators concluded that in patients with advanced melanoma, four doses of standard-dose pembrolizumab plus reduced-dose ipilimumab followed by standard-dose pembrolizumab is highly active and associated with a manageable toxicity profile. They noted that these results compare favorably with the results from the CheckMate-067 trial and that the pembrolizumab and ipilimumab combination warrants further investigation. An additional cohort of this trial examining a flat-dosing strategy is currently enrolling.
In an accompanying commentary, Michael Postow, MD (Memorial Sloan Kettering Cancer Center, New York, New York), highlighted that while this combination seems to result in reduced rates of grade 3/4 toxicities, it is still associated with much higher rates of grade 3/4 AEs than single-agent pembrolizumab. He noted that while the response rate with the combination is much higher than with pembrolizumab monotherapy, longer-term follow-up and randomized data are needed to assess the true impact of the reduced dose of ipilimumab in combination with an anti-PD-1 on survival.