Sequential Nivolumab/Ipilimumab Appears More Active Than Reverse Sequence in Advanced Melanoma


Key Points

  • The sequence of nivolumab followed by ipilimumab resulted in an improved response rate vs ipilimumab/nivolumab in patients with advanced melanoma.
  • Treatment was more frequently discontinued due to adverse events in the nivolumab/ipilimumab group.

In the phase II CheckMate 064 trial reported in The Lancet Oncology, Weber et al found that sequential nivolumab (Opdivo)/ipilimumab (Yervoy) was more active than the reverse sequence (ipilimumab/nivolumab) in patients with advanced melanoma.

Study Details

In the open-label study, 138 patients (as-treated population) with unresectable stage III or IV melanoma from 9 U.S. sites who were treatment-naive or who had progressed after one previous systemic therapy were randomized to receive induction with nivolumab at 3 mg/kg every 2 weeks for six doses followed by a planned switch to ipilimumab at 3 mg/kg every 3 weeks for four doses (n = 68) or the reverse sequence (n = 70). After induction, both groups received nivolumab at 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was treatment-related grade 3 to 5 adverse events during the induction period at week 25, analyzed in the as-treated population.

Adverse Events

The frequencies of treatment-related grade 3 to 5 adverse events up to week 25 were 50% in the nivolumab/ipilimumab group and 43% in the ipilimumab/nivolumab group. During the whole study period (minimum follow-up of 15 months), grade 3 or 4 treatment-related adverse events occurred in 63% vs 50%.

Treatment-related grade 3 or 4 increases in alanine transaminase and aspartate transaminase were more common with nivolumab/ipilimumab. The most common treatment-related grade 3 or 4 adverse events during the whole study period were colitis (15% vs 20%), increased lipase (15% vs 17%), and diarrhea (12% vs 7%). Systemic corticosteroids were used in 84% vs 51% of patients. Discontinuation of treatment due to adverse events occurred in 35% vs 17%. No treatment-related deaths were observed.


At week 25, response rates were 41% in the nivolumab/ipilimumab group vs 20% in the ipilimumab/nivolumab group. Disease progression was observed in 38% vs 61% at week 13 and in 38% vs 60% at week 25.

After median follow-up of 19.8 months, median overall survival was not reached in the nivolumab/ipilimumab group, whereas median survival was 16.9 months over follow-up of 14.7 months in the ipilimumab/nivolumab group (hazard ratio = 0.48, 95% confidence interval = 0.29–0.80). Twelve-month survival was 76% vs 54%. A greater proportion of nivolumab/ipilimumab patients received subsequent systemic anticancer therapy (37% vs 20%).

The investigators concluded: “Nivolumab followed by ipilimumab appears to be a more clinically beneficial option compared with the reverse sequence, albeit with a higher frequency of adverse events.”

The study was funded by Bristol-Myers Squibb.

F. Stephen Hodi, MD, of the Dana-Farber Cancer Institute, is the corresponding author of The Lancet Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.