Safety Comparison of Two Dosing Regimens for Nivolumab Plus Ipilimumab in Advanced Melanoma


Key Points

  • NIVO3+IPI1 was associated with a significantly reduced incidence of treatment-related grade 3 to 5 adverse events compared with NIVO1+IPI3.
  • The incidence of treatment-related grade 3 to 5 adverse events was 33.9% vs 48.3%.

In the phase IIIb/IV CheckMate 511 study reported by Lebbé et al in the Journal of Clinical Oncology, a regimen of nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg (NIVO3+IPI1) was found to significantly reduce the incidence of treatment-related grade 3 to 5 adverse events compared with nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg (NIVO1+IPI3) in patients with advanced melanoma. The NIVO1+IPI3 regimen is approved for the first-line treatment of advanced melanoma in several countries, including the United States.

Study Details

In the trial, 360 patients with previously untreated unresectable stage III or IV melanoma were randomly assigned between April 2016 and March 2017 to receive NIVO3+IPI1 (n =180) or NIVO1+IPI3 (n = 180) every 3 weeks for 4 doses. After 6 weeks, all patients received nivolumab at 480 mg once every 4 weeks until disease progression or unacceptable toxicity.

The primary endpoint was the incidence of treatment-related grade 3 to 5 adverse events. Secondary endpoints included descriptive analyses of objective response rate, progression-free survival, and overall survival. The study was not designed to formally demonstrate noninferiority of NIVO3+IPI1 vs NIVO1+IPI3 for efficacy endpoints.

Results in the current analysis are from a database lock in June 2018, with minimum patient follow-up of 12 months. Median follow-up was 18.8 months in the NIVO3+IPI1 group and 18.6 months in the NIVO1+IPI3 group.

Treatment-Related Grade 3 to 5 Adverse Events

At a minimum follow-up of 12 months, the incidence of treatment-related grade 3 to 5 adverse events was 33.9% in the NIVO3+IPI1 group vs 48.3% in the NIVO1+IPI3 group (P = .006). One treatment-related grade 5 adverse event occurred in the NIVO3+IPI1 group. Serious adverse events of any grade and any cause occurred in 47.8% vs 63.5% of patients, and were of grade 3 or 4 in 33.9% vs 47.8% and grade 5 in 3.3% vs 1.7%. Treatment-related grade 3 or 4 adverse events led to treatment discontinuation in 16.7% vs 27.5%. The lower incidence of treatment-related grade 3 or 4 adverse events in the NIVO3+IPI1 group primarily reflected lower rates of hepatic (7.2% vs 16.3%), gastrointestinal (6.1% vs 10.7%), and endocrine (2.8% vs 7.3%) adverse events.

In descriptive analyses, objective response rates were 45.6% in the NIVO3+IPI1 group and 50.6% in the NIVO1+IPI3 group, with a complete response in 15.0% and 13.5%. Median progression-free survival was 9.9 months vs 8.9 months. Median overall survival was not reached in either group.

The investigators concluded, “The CheckMate 511 study met its primary endpoint, demonstrating a significantly lower incidence of treatment-related grade 3–5 adverse events with NIVO3+IPI1 vs NIVO1+IPI3. Descriptive analyses showed that there were no meaningful differences between the groups for any efficacy endpoint, although longer follow-up may help to better characterize efficacy outcomes.”

Celeste Lebbé, MD, PhD, of Saint-Louis Hospital, Institut National de la Santé et de la Recherche Médicale, Université Paris Diderot, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Bristol-Myers Squibb and ONO Pharmaceutical Company. The study authors' full disclosures can be found at

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®.