Background
Open-label, phase 1b, multicenter expansion cohort (KEYNOTE-029) of 153 patients with treatment-naive advanced melanoma, evaluating standard-dose pembrolizumab combined with reduced-dose ipilimumab to improve tolerability of dual checkpoint blockade.
Interventions and follow up
Arm A: pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg every 3 weeks x4 doses, then pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or until disease progression (single-arm cohort)
Primary endpoint: safety and tolerability
Secondary endpoints: ORR and OS
mFollow up: 17 months
Primary endpoint: safety and tolerability
Secondary endpoints: ORR and OS
mFollow up: 17 months
Results
ORR: 61%
CR rate: 15%
1-yr PFS: 69%
1-yr OS: 89%
CR rate: 15%
1-yr PFS: 69%
1-yr OS: 89%
Adverse events
Grade 3-4 treatment-related: 45% of patients
Most common grade 3-4: elevated lipase 16%, autoimmune hepatitis 6%, colitis 5%, elevated amylase 4%; no treatment-related deaths reported
Most common grade 3-4: elevated lipase 16%, autoimmune hepatitis 6%, colitis 5%, elevated amylase 4%; no treatment-related deaths reported
Conclusions
Standard-dose pembrolizumab with reduced-dose ipilimumab showed a manageable safety profile and robust antitumor activity in treatment-naive advanced melanoma, suggesting an alternative dosing strategy to reduce toxicity while preserving efficacy of combination checkpoint blockade.
Key Limitations
Single-arm, non-randomized phase 1b cohort without a direct comparator; relatively small sample (n=153) and short follow-up; efficacy estimates not directly comparable to the registrational ipilimumab/nivolumab combination regimen.
Clinical Context
KEYNOTE-029 provided proof-of-concept for pembrolizumab plus low-dose ipilimumab as a potentially less toxic combination in advanced melanoma, though the FDA-approved combination remains nivolumab plus ipilimumab. ESMO guidelines recognize combination checkpoint blockade as a first-line option, with dose-optimization strategies an area of ongoing investigation.