Philadelphia, PA—Combination immunotherapy with ipilimumab (Yervoy) plus nivolumab (Opdivo) was superior to ipilimumab monotherapy in previously untreated patients with advanced melanoma in a phase 2 randomized clinical trial, according to lead investigator F. Stephen Hodi, MD, Director of the Melanoma Center, Dana-Farber Cancer Institute, Boston, MA, who presented the study at the 2015 American Association for Cancer Research (AACR) annual meeting.
The study was published online in the New England Journal of Medicine (Postow MA, et al. 2015 April 20. Epub ahead of print) simultaneously with the presentation at the meeting.
“The combination of ipilimumab and nivolumab achieved durable responses and a substantially higher response rate, longer progression-free survival [PFS], and higher rates of complete response than ipilimumab monotherapy in patients with both wild-type BRAF and BRAF mutation–positive tumors,” Dr Hodi said.
Based on favorable phase 1 experience with the combination, the randomized phase 2 study was initiated to evaluate the combination of ipilimumab plus nivolumab versus ipilimumab alone (the standard of care) in previously untreated patients with advanced melanoma.
A total of 142 patients were randomized in a 2 to 1 manner to receive ipilimumab every 3 weeks for 4 cycles followed by nivolumab alone every 2 weeks versus ipilimumab monotherapy followed by placebo, and treated until disease progression or unacceptable toxicity. At randomization, patients were stratified according to BRAF mutation status (wild-type or mutationpositive).
The objective response rate (ORR) was 61% for the combination versus 11% for ipilimumab in patients with BRAF wild-type tumors (P <.001). Among these patients, the median duration of response was not reached in either treatment arm, with an ongoing response in 82% of the combination group and 75% of the ipilimumab monotherapy group.
In patients with the BRAF mutation, the ORR was 52% for the combination group, with a 22% complete response rate, which was similar to that in patients with BRAF wild-type tumors, versus 0% for ipilimumab alone.
More than 66% of the patients in the combination arm who discontinued therapy remained in complete response or partial response.
The median PFS was not reached in the BRAF wild-type group with the combination and was 4.4 months with ipilimumab monotherapy (P <.001).
Among patients with the BRAF mutation, the median PFS was 8.5 months with the combination and 2.7 months with ipilimumab monotherapy.
In patients discontinuing treatment as a result of toxicity, the ORR was 68% in the combination arm versus 10% in the ipilimumab monotherapy arm.
Treatment-related adverse events occurred in 91% of the combination therapy arm and in 93% of the patients who received ipilimumab monotherapy. Treatment-related events leading to discontinuation of therapy were observed in 47% of the combination arm and 17% of the ipilimumab-alone arm. The rate of grade 3 or 4 adverse events in the combination arm was 54% versus 24% in the ipilimumab-alone arm.
The most common grade 3 or 4 drug-related events associated with combination immunotherapy included colitis (17%), diarrhea (11%), and an elevated alanine aminotransferase level (11%). For ipilimumab, the most frequently reported grade 3 or 4 adverse events were diarrhea (11%) and colitis (7%). Steroids were used to manage the side effects, and most resolved.