Nivolumab Before Ipilimumab Has Greater Efficacy, Similar AEs

Two strategies of sequential immunotherapy for advanced melanoma showed similar safety and tolerability but substantially different efficacy.

F. Stephen Hodi, MD

Two strategies of sequential immunotherapy for advanced melanoma showed similar safety and tolerability but substantially different efficacy, according to a late-breaking abstract presented at the 2015 European Cancer Congress.1

Nivolumab followed by ipilimumab led to grade 3/4 adverse events (AEs) in half of patients during the first two induction cycles, whereas reversing the order of the drugs was associated with grade 3/4 AEs in 43%. However, beginning with nivolumab led to objective responses in 40% to 50% of patients, more than twice the rate observed with an ipilimumab-first strategy.

“The nature of adverse events was similar to those previously observed with either agent, alone and in combination, whereas the frequency of adverse events was consistent with previous reports for nivolumab followed by ipilimumab,” said F. Stephen Hodi, MD, director of immune-oncology at Dana-Farber Cancer Institute in Boston. “Consistent improvement in efficacy outcomes was demonstrated with nivolumab followed by ipilimumab as compared with ipilimumab followed by nivolumab.

A preliminary trial of sequential therapy showed an overall response rate of 19% with ipilimumab followed by nivolumab.2 A phase III trial involving patients with untreated melanoma showed an overall response rate of 58% with nivolumab followed by ipilimumab, 44% with nivolumab alone, and 19% with ipilimumab alone.3

To inform decision making about sequential treatment, Hodi and colleagues performed a randomized phase II trial to evaluate the safety and efficacy of 2 strategies of sequential therapy. Patients were randomized to nivolumab followed by ipilimumab followed by nivolumab maintenance therapy or ipilimumab-nivolumab and maintenance therapy with nivolumab.

The primary endpoint was the incidence of treatment-related grade 3-5 AEs during induction periods. Secondary endpoints included confirmed objective response rate at week 25 and progression rates at weeks 13 and 25. Eligible patients had unresectable stage III/IV melanoma, either untreated or that had progressed after first-line systemic therapy.

The final analysis included 138 randomized patients who had a median age of about 60 years. About 85%-90% of patients had no prior therapy. In the patients randomized to receive nivolumab first, 42% had PD-L1 expression greater than 5% as compared with 23% of the patients who received ipilimumab first.

The results showed a 52% incidence of treatment-related grade 3/4 AEs during induction periods 1 and 2 in the nivolumab-ipilimumab arm and 43% in the ipilimumab-nivolumab arm. No study drug-related deaths occurred in either group.

Hodi reported that 24% of patients in the nivolumab-ipilimumab group discontinued because of treatment-related grade 3/4 AEs versus 27% in the ipilimumab-nivolumab group.

Among patients who received nivolumab first, grade 3/4 AEs included diarrhea in 13%, colitis in 12%, and elevated liver enzymes (ALT) in 10%. No other grade 3/4 AE occurred in as many as 10% of the group. In patients who started with ipilimumab, the most common grade 3/4 AE was colitis, occurring in 21% of patients. No other grade 3/4 AE occurred in more than 7% of patients.

The efficacy summary showed an objective response rate at 25 weeks of 41.2% among patients who received nivolumab first versus 20.0% in those who started treatment with ipilimumab. The unconfirmed response rates were 47.7% with nivolumab first and 22.6% with ipilimumab first. At 25 weeks, 38.2% of patients had progressed in the nivolumab-first arm versus 60% with ipilimumab-first group.

The median change in tumor burden at 13 weeks was -27% in the patients who started treatment with nivolumab and +10% in those who started with ipilimumab. The median change from baseline to 25 weeks was -50% with nivolumab first and -17% with ipilimumab first.

“The data from this study, including planned correlative biomarker analyses that are underway, may help inform the choice of initial treatment approaches in advanced melanoma,” Hodi said.

Recent studies have demonstrated high response rates in advanced melanoma treated with nivolumab, as well as 10-year survival exceeding 20% in patients treated with ipilimumab. The activity of the two drugs stimulated interest in combination strategies to achieve even better outcomes.

The FDA is currently reviewing a supplemental biologics license application for nivolumab plus ipilimumab in previously untreated patients with advanced melanoma, based on phase III data. An earlier application was submitted based on phase II data, which was also being reviewed by the FDA. The agency will make a decision regarding the application by January 23, 2016.


  1. Hodi FS, Gibney G, Sullivan R, et al. An open-label, randomized, phase 2 study of nivolumab (NIVO) given sequentially with ipilimumab (IPI) in patients with advanced melanoma (CheckMate 064). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 23LBA.
  2. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-133.
  3. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34.


View more from the 2015 European Cancer Congress