The results of a phase I study in advanced melanoma suggested complementary clinical activity with Nivolumab ( Opdivo ), a PD-1 checkpoint inhibitor, plus Ipilimumab ( Yervoy ), a CTLA-4 checkpoint inhibitor.
Researchers have reported the results of a randomized, double-blind, phase III trial designed to evaluate Nivolumab combined with Ipilimumab or Nivolumab alone versus Ipilimumab alone in advanced melanoma.
Treatment-naïve patients ( N=945 ) were randomized 1:1:1 to Nivolumab 1 mg/kg Q2W plus Ipilimumab 3 mg/kg Q3W for 4 doses followed by Nivolumab 3 mg/kg Q2W, Nivolumab 3 mg/kg Q2W plus placebo, or Ipilimumab 3 mg/kg Q3W for 4 doses plus placebo, until progression or unacceptable toxicity.
Patients were stratified by PD-L1 status, BRAF mutation status, and M-stage.
Co-primary endpoints were progression-free survival ( PFS ) ( reported here ) and overall survival ( patients continue to be followed ).
Secondary endpoints include objective response rate ( ORR ) by RECIST v1.1 and safety.
At a minimum follow-up of 9 months, Nivolumab plus Ipilimumab and Nivolumab alone significantly improved median progression-free survival ( 11.5, 6.9, 2.9 months ) and ORR ( 57.6%, 43.7%, 19.0%; all P less than 0.00001 ) versus Ipilimumab alone.
Grade 3-4 drug-related adverse events occurred in 55.0%, 16.3%, and 27.3% of patients in the Nivolumab plus Ipilimumab, Nivolumab, and Ipilimumab arms, respectively ( most commonly diarrhea [ 9.3%, 2.2%, 6.1% ], increased lipase [ 8.6%, 3.5%, 3.9% ], increased alanine aminotransferase [ 8.3%, 1.3%, 1.6% ], and colitis [ 7.7%, 0.6%, 8.7% ] ).
Drug-related adverse reactions led to discontinuation in 36.4%, 7.7%, and 14.8% of patients in the Nivolumab plus Ipilimumab, Nivolumab, and Ipilimumab arms, with 0, 1, and 1 drug-related deaths, respectively.
In conclusion, Nivolumab plus Ipilimumab and Nivolumab alone had superior clinical activity versus Ipilimumab alone in advanced melanoma.
The results with Nivolumab plus Ipilimumab and Nivolumab alone further suggest complementary activity of the two agents.
There were no new safety signals or drug-related deaths observed with the combination. ( Xagena )
Wolchok JD et al, J Clin Oncol 33, 2015 (suppl; abstr LBA1)