CHICAGO—Treatment-naïve patients with advanced melanoma had significantly better clinical outcomes with nivolumab alone or in combination with ipilimumab compared with ipilimumab alone, a phase 3 study presented 2015 American Society of Clinical Oncology (ASCO) annual meeting concluded.

These findings confirm results of a phase 1 study of nivolumab plus ipilimumab in advanced melanoma and a phase 2 study of the combination in untreated melanoma, said Jedd D. Wolchok, MD, PhD, Chief of Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College in New York, NY. Also suggested is complementary clinical activity with nivolumab, a PD-1 checkpoint inhibitor, and ipilimumab, a CTLA-4 checkpoint inhibitor.

“Based on available evidence, the combination of nivolumab plus ipilimumab represents a means to improve outcomes versus nivolumab alone, particularly for patients whose tumors are low in PD-1 expression,” he said.

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“In the current era of precision medicine informed by biomarker data, the availability of markers such as PD-L1 expression level will allow meaningful discussions between patients and clinicians regarding the value of interventions, like the combination of nivolumab plus ipilimumab, based up on a real assessment of risk and benefit. Additional insights will be gained with the emergence of the overall survival data.”

The study remains blinded for overall survival until the planned number of events has been reached, a minimum of 22 months of follow-up.

The results were published simultaneously online in the New England Journal of Medicine.1

The CheckMate 0672 study randomly assigned 945 patients with previously untreated, advanced melanoma 1:1:1 to nivolumab 1 mg/kg every 2 weeks plus ipilimumab 3 mg/kg every 3 weeks for 4 doses followed by nivolumab 3 mg/kg every 2 weeks, nivolumab 3 mg/kg every 3 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for 4 doses plus placebo. Patients were treated until their disease progress of they experienced unacceptable toxicity.

Patients were stratified by PD-L1 status, BRAF mutation status, and M-stage. Coprimary end points were progression-free survival and overall survival. Secondary end points included objective response rate by RECIST v1.1 and safety. Predefined tumor PD-L1 expression level as a predictive biomarker of efficacy was also an end point.

The study was not designed for a formal statistical comparison between the nivolumab and the combination groups. However, exploratory analyses revealed more frequent responses and longer progression-free survival in the combination group compared with nivolumab alone.

Median progression-free survival was 11.5 months for the combination compared with 6.9 months for nivolumab alone and 2.9 months for ipilimumab alone.

Of the 314 patients receiving the combination, 57.6% had an objective response, measured as a significant reduction in tumor size. This compared with 43.7% of the 316 patients receiving nivolumab alone and 19% of the 315 patients receiving ipilimumab alone.

Average reductions in tumor burden were 51.9% with nivolumab plus ipilimumab and 34.5% with nivolumab alone. In contrast, patients who received ipilimumab alone experienced a 5.9% increase in tumor burden.

Grade 3/4 drug-related adverse events (AEs) occurred in 55.0% of patients in nivolumab plus ipilimumab arm, and 36.4% stopped the regimen because of any grade AEs.

In contrast, 16.3% of patients in the nivolumab alone arm had grade 3/4 AEs, with 7.7% discontinuing treatment, as did 27.3% in the ipilimumab alone arm, with 14.8% discontinuing treatment. There were no drug-related deaths in the combination arm, one death due to neutropenia occurred in the nivolumab alone group, and one death due to cardiac arrest occurred in the ipilumumab group.

The most common grade 3/4 AEs for each of the three arms—combination, nivolumab alone, and ipilumumab alone—were diarrhea (9.3%, 2.2%, and 6.1%, respectively),  increased alanine aminotransferase (8.3%, 1.3%, and 1.6%), and colitis (7.7%, 0.6%, and 8.7%). 

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In this trial, patients whose tumors expressed PD-L1 at a level of 5% or greater experienced a median progression-free survival of 14 months regardless of whether they received the combination or nivolumab alone.

However, for those whose tumors express PD-L1 at a level of less than 5%, the median progression-free survival was 11.2 on the combination arm and 5.3 months for nivolumab alone. In patients whose tumors have 5% or greater PD-L1 expression, the objective response rate for the combination was 72.1% (95% CI: 59.9, 82.3); for nivolumab alone, 57.5% (95% CI: 45.9, 68.5) and, for ipilimumab alone, 21.3% (95% CI: 12.7, 32.3).

“Immunotherapy drugs have already revolutionized melanoma treatment, and now we’re seeing how they might be even more powerful when they’re combined,” commented ASCO Expert Steven O’Day, MD, about the study in a press release.

“But the results also warrant caution—the nivolumab and ipilimumab combination used in this study came with greater side effects, which might offset its benefits for some patients. Physicians and patients will need to weigh these considerations carefully.”


  1. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. Published online June 1, 2015.
  2. Wolchok JD, Chiarion-Sileni C, Gonzalez R, et al. Efficacy and safety results from a phase III trial of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naive patients (pts) with advanced melanoma (MEL) (CheckMate 067). J Clin Oncol. 2015;33:(suppl; abstr LBA1).