Nivolumab/Ipilimumab Combo Shows Modest OS Benefit in Advanced Melanoma in Updated Phase III Findings


The PD-1 and CTLA-4 inhibitor combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was associated with a 12% reduction in the risk of death versus nivolumab monotherapy in patients with treatment-naïve advanced melanoma.

James Larkin, PhD, FRCP

The PD-1 and CTLA-4 inhibitor combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was associated with a 12% reduction in the risk of death versus nivolumab monotherapy in patients with treatment-naïve advanced melanoma, according to descriptive analyses from the phase III CheckMate-067 trial presented at the 2017 AACR Annual Meeting.1

The median overall survival (OS) was not reached in the nivolumab/ipilimumab arm or for patients who received nivolumab alone, and was 20 months for those who were treated with ipilimumab. The combination showed a 2-year OS rate of 64%; the 2-year OS rates for nivolumab and ipilimumab alone were 59% and 45%, respectively.

This is the first phase III clinical trial to evaluate OS with the combination of PD-1/CTLA-4 therapies, according to lead study author James Larkin, PhD, FRCP. While the study was not powered to compare between nivolumab-containing arms, descriptive analyses were presented.

“CheckMate-067 was a positive study that met both of its co-primary endpoints,” said Larkin, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust, when reporting the findings. “Descriptively, the combination showed better overall OS, progression-free survival (PFS), and more durable response outcomes than with nivolumab alone with consistent results seen across the clinically relevant subgroups, such as those with low PD-L1 expression, elevated LDH, and those with tumors that were BRAF-mutated.”

In the randomized, double-blind phase III study, 945 patients with unresectable or metastatic previously untreated melanoma were randomized 1:1:1 to nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 doses followed by nivolumab at 3 mg/kg bi-weekly (n = 314), nivolumab at 3 mg/kg bi-weekly plus ipilimumab-matched placebo (n = 316), or ipilimumab at 3 mg/kg every 3 weeks for 4 doses plus nivolumab-matched placebo (n = 315).

Patients were also stratified by BRAF status, American Joint Committee on Cancer M stage, and PD-L1 expression <5% versus ≥5%. The coprimary endpoints were PFS and OS, with secondary endpoints being overall response rate (ORR) by RECIST v1.1 criteria, correlation of PD-L1 expression with efficacy, and safety. The OS analysis was conducted after all patients had 28 months of follow-up.

Additional descriptive OS findings showed that the combination was associated with a 45% reduction in the risk of death versus ipilimumab (HR, 0.55; 98% CI, 0.42-0.72; P <.0001) and was 12% versus nivolumab (HR, 0.88; 95% CI, 0.69-1.12). There was also a 37% reduction in the risk for disease progression or death in the nivolumab monotherapy arm versus the ipilimumab arm (HR, 0.63; 95% CI, 0.48-0.81; P <.0001).

Sixty-two percent of patients in the ipilimumab cohort received subsequent systemic therapies with a median time of 8 months until their next treatment, versus 44% and 27 months for those on the nivolumab arm. In the combination arm, 32% of patients went on to receive subsequent treatment, and the median time to next treatment was not reached. Furthermore, 66% of combination-treated patients remain free of treatment at 2 years, Larkin added.

In BRAF wild-type tumors, the OS benefit was less significant, with the 2-year OS rates 61%, 57%, and 42% for nivolumab/ipilimumab, nivolumab, and ipilimumab, respectively. The median OS was not reached in the combination arm (95% CI, 27.6-NR) and the nivolumab arm (95% CI, 25.8-NR) and was 18.5 months in the ipilimumab arm (95% CI, 14.8-23.0). The hazard ratio for the combination when compared with nivolumab was 0.97 (95% CI, 0.74-1.28).

In BRAF-mutant tumors, the median OS was not reached in the combination or nivolumab arm and was 24.6 months in the ipilimumab cohort (95% CI, 17.9-31.0), with a descriptive hazard ratio between nivolumab and nivolumab/ipilimumab of 0.71 (95% CI, 0.45-1.13). The 2-year OS rate was 71% with the combination, 62% with nivolumab alone, and 51% with ipilimumab alone.

When stratified for PD-L1 expression with a 5% cutoff, OS was improved with the combination versus nivolumab (HR, 0.84; 95% CI, 0.63-1.12) in patients with PD-L1 <5%, as well as the ORR (56.2% vs 42.3%). The 2-year OS rates were 63%, 55%, and 41% for nivolumab/ipilimumab, nivolumab, and ipilimumab, respectively.

However, in patients with ≥5% PD-L1 expression, the 2-year OS rate was higher in the nivolumab arm (72%) than the combination (68%); it was 54% with ipilimumab. The median OS was not reached in either the combination or nivolumab arm (HR, 1.05; 95% CI, 0.61-1.83) and was 28.9% in the ipilimumab cohort (95% CI, 18.1-NR). The ORR was 73.5% for nivolumab/ipilimumab and 58.8% for nivolumab, regardless of PD-L1 expression.

“In the roughly one-quarter of patients with PD-L1 expression greater than or equal to 5%, both nivolumab and nivolumab plus ipilimumab results in a similar prolongation of survival, although the response rate remains significantly higher with the combination,” explained Larkin.

With a minimum of 28 months of follow-up, the median PFS was 11.7 months with the combination (95% CI, 8.9-21.9) versus 6.9 months with nivolumab and 2.9 months with ipilimumab. Additionally, the ORR with the combination, nivolumab, and ipilimumab were 58.9%, 44.6%, and 19%, respectively. These included a 17.2% complete response (CR) rate with nivolumab/ipilimumab, a 14.9% CR rate with nivolumab, and a 4.4% CR rate with ipilimumab. The partial response rate was 41.7% with nivolumab/ipilimumab, 29.7% with nivolumab, and 14.6% with ipilimumab.

The median duration of response was not reached in the nivolumab/ipilimumab arm, 31.1 months in the nivolumab arm, and 18.2 months in patients who received ipilimumab. At the initial 18-month database lock, the CR rates for nivolumab/ipilimumab, nivolumab, and ipilimumab were 12.1%, 9.8%, and 2.2%, respectively.

Regarding safety, Larkin said that with an additional 19 months of follow-up, safety was consistent with the initial findings. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 58.5% of patients in the combination arm, 20.8% in the nivolumab arm, and 27.7% in the ipilimumab arm. All-grade TRAEs were reported in 95.8% of the nivolumab/ipilimumab patients, 86.3% in the nivolumab arm, and 86.2% in the ipilimumab arm. Thirty-one percent of patients in the combination arm had TRAEs that led to discontinuation of treatment, versus 7.7% and 14.1% in the nivolumab and ipilimumab arms, respectively.

Four treatment-related deaths were reported; 2 were included in the earlier reports. The 2 new deaths, both in the combination arm, were related to cardiomyopathy and liver necrosis and occurred more than 100 days following their last treatment.

“The safety profile of the combination is consistent with earlier experience with the majority of the AEs resolving in 3 to 4 weeks,” Larkin added. “Even in patients who discontinued the combination due to toxicity, an impressive survival benefit and responses over 70% were observed.”

The phase III findings coincide with earlier OS reports of the combination regimen; the phase II CheckMate-069 trial demonstrated a durable response rate of 61% and a 2-year OS rate of 64% in patients with advanced melanoma who were treated with nivolumab plus ipilimumab.2

“When used in combination, these drugs have a powerful antitumor effect in melanoma,” said program moderator Suzanne Topalian, MD, associate director, Bloomberg-Kimmel Institute for Cancer Immunotherapy, and professor of surgery and oncology at Johns Hopkins University School of Medicine. “This also carries with it an increased risk of toxicity. This combination is the first immunotherapy combination to be approved by the FDA. It reflects a very active area of research in immuno-oncology, with several hundred different clinical trials of various combinations ongoing.”

The FDA initially approved the combination of nivolumab and ipilimumab for patients with advanced melanoma for BRAF V600 wild-type disease, as well as those with unresectable or metastatic melanoma after treatment with ipilimumab or a BRAF inhibitor in October 2015. In January 2016, the agency expanded the combination’s indication to include patients with BRAF V600 mutations, based on the CheckMate-067 findings that demonstrated superiority in PFS and ORR with nivolumab/ipilimumab versus ipilimumab alone.

“Considering all of the study findings, first-line nivolumab plus ipilimumab may represent a means to improve outcomes versus nivolumab,” Larkin concluded. “Although the data by PD-L1 expression are intriguing, the role of PD-L1 as a predictive biomarker is not fully understood, and the data are still immature. Therefore, decisions about the optimal first-line treatment choice should be made on an individual patient basis with all factors taken into consideration.”


  1. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Overall survival results from a phase III trial of nivolumab combined with ipilimumab in treatment-naïve patients with advanced melanoma (CheckMate-067): press conference. In: Proceedings from the 2017 American Association for Cancer Research Annual Meeting; April 2 to 5, 2017; Washington DC. Abstract CT075.
  2. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma. N Engl J Med. 2015;372:2006-2017.


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