FDA Grants Nivolumab/Ipilimumab Combination Priority Review for Advanced Melanoma


The FDA has granted a priority review designation to a supplemental biologics license application for nivolumab plus ipilimumab in previously untreated patients with advanced melanoma.

Michael Giordano, MD

The FDA has granted a priority review designation to a supplemental biologics license application for nivolumab (Opdivo) plus ipilimumab (Yervoy) in previously untreated patients with advanced melanoma, according to a statement from the regimen's developer, Bristol-Myers Squibb.

The new application for nivolumab plus ipilimumab was based on findings from the phase III CheckMate-067 trial.1 At greater than 9 months of follow up, the median progression-free survival (PFS) was 11.5 months for the combination, 6.9 months for nivolumab monotherapy, and 2.9 months for single-agent ipilimumab. The combination reduced the risk of progression by 58% compared with ipilimumab (HR, 0.42; P <.0001).

A previous application for the nivolumab/ipilimumab combination was submitted in early 2015, based on data from the phase II CheckMate-069 trial.2 This application was granted a priority review, with an expected action date of September 30, 2015. The new entry has an FDA action date of January 23, 2016.

“Findings from CheckMate-067 provide additional evidence that the combination of two immuno-oncology agents, Opdivo and Yervoy, may provide improved outcomes for patients with advanced melanoma, and has the potential to become the basis for how this devastating disease is treated,” Michael Giordano, MD, senior vice president, head of Development, Oncology, Bristol-Myers Squibb, said in a statement. “We saw significant clinical benefit from the Opdivo plus Yervoy regimen in these patients, including an increase in the time patients lived without disease progression, and we look forward to working with the FDA to review this data.”

In the CheckMate-067 study, 945 patients with untreated unresectable or metastatic melanoma were randomized to receive nivolumab (n = 316), ipilimumab (n = 315), or nivolumab plus ipilimumab followed by nivolumab (n = 314). In the monotherapy arms, nivolumab was administered at 3 mg/kg every 2 weeks and ipilimumab was administered at 3 mg/kg every 3 weeks. In the combination arm, nivolumab at 1 mg/kg was administered with 3 mg/kg of ipilimumab every 3 weeks for 4 doses followed by 3 mg/kg of nivolumab every 2 weeks.

Patients were stratified by M-stage, PD-L1 status, and BRAF mutation status. Approximately a third of patients were BRAF mutation positive. The co-primary endpoints were PFS and overall survival (OS), with objective response rate (ORR), safety, and other measures as secondary endpoints.

In PD-L1—positive patients, the ligand was not found to be a biomarker for outcomes, with a PFS of 14 months in both nivolumab arms versus 3.9 months with ipilimumab. In PD-L1—negative patients, the combination was more effective compared with single-agent therapy, with a PFS of 11.2 months versus 5.3 and 2.8 months in the single-agent nivolumab and ipilimumab arms, respectively.

The ORR was 57.6% with the combination compared with 43.7% and 19% for single-agent nivolumab and ipilimumab, respectively. In the combination arm, the complete response rate was 11.5% versus 8.9% and 2.2% with single-agent nivolumab and ipilimumab.

Outcomes were similar regardless of BRAF mutation status. For those with BRAF-mutant melanoma treated with the combination of nivolumab and ipilimumab (n = 102), the median PFS was 11.7 months, representing a 53% reduction in the risk of progression versus ipilimumab (HR, 0.47; 95% CI, 0.32-0.68). For patients with BRAF wild-type disease (n = 212), the median PFS with the combination was 11.2 months (HR versus ipilimumab, 0.41; 95% CI, 0.32-0.53).

For those with BRAF mutations treated with single-agent nivolumab (n = 98), the median PFS was 5.6 months compared with 4.0 months with single-agent ipilimumab (n = 100; HR, 0.77; 95% CI, 0.54-1.09). In those with wild-type BRAF melanoma treated with nivolumab (n = 218), the median PFS was 7.9 versus 2.8 months with ipilimumab (HR, 0.50; 95% CI, 0.39-0.63).

The safety data were consistent with outcomes previously reported for the drugs. All grade adverse-events (AEs) were 95.5%, 82.1%, and 86.2%, in the combination, nivolumab, and ipilimumab arms, respectively. Rates of treatment-related discontinuations with the combination and single-agent nivolumab and ipilimumab arms were 36.4%, 7.7%, and 14.8%, respectively.

The most common any-grade AEs in the combination arm versus the nivolumab and ipilimumab arms were diarrhea (44.1%, 19.2%, 33.1%), rash (40.3%, 25.9%, 32.8%), fatigue (35.1%, 34.2%, 28.0%), pruritus (33.2%, 18.8%, 35.4%), and nausea (25.9%, 13.1%, 16.1%). Grade 3/4 AEs were reported in 55%, 16.3%, and 27.3% of the combination, nivolumab, and ipilimumab groups, respectively. The most frequent grade 3/4 toxicities reported in the ipilimumab/nivolumab arm compared with nivolumab and ipilimumab were diarrhea (9.3%, 2.2%, 6.1%) colitis (7.7%, 0.6%, 8.7%), increased lipase (8.6%, 3.5%, 3.9%), increased ALT levels (8.3%, 1.3%, and 1.6%) and increased AST levels (6.1%, 1.0%, 1.6%).


Assessment of the CheckMate-067 study remains ongoing for the co-primary endpoint of OS, which is expected to reach maturity at an approximate median follow-up of 22 months, according to lead investigator Jedd D. Wolchok, MD, PhD.


“Nivolumab alone and nivolumab with ipilimumab significantly improved progression-free survival compared to ipilimumab alone in patients with previously untreated melanoma," Wolchok, chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center, said when the results were presented at the 2015 ASCO Annual Meeting. “[OS is not expected to be reported until 22 months of follow-up, so we’re quite a ways away from that.”


In the double-blind CheckMate-069 trial, 142 treatment-naïve patients with stage III/IV melanoma were randomized in a 2:1 ratio to 3 mg/kg of ipilimumab plus 1 mg/kg of nivolumab (n = 95) or placebo (n = 47) once every 3 weeks for four doses, followed by nivolumab at the same dose or placebo every 2 weeks until disease progression or unacceptable toxicity.  Median patient age was 65 years, two-thirds of patients were males, and all but two patients had an ECOG performance status of 0 or 1.


Among patients with BRAF wild-type tumors (n = 109), PFS was not yet reached in the nivolumab/ipilimumab group (n = 72) versus 4.4 months in the ipilimumab arm (n = 37; HR, 0.40; 95% CI, 0.23-0.68; P <.001). Similar PFS data were observed among patients with BRAF-positive melanoma (n = 33), at 8.5 versus 2.7 months in the combination (n = 23) and control (n = 10) arms, respectively (HR = 0.38; 95% CI, 0.15-1.00).


Forty-four patients with BRAF wild-type tumors (61%) receiving the combination had objective responses, including complete responses in 22% of patients (odd ratio, 12.96; 95% CI, 3.91-54.49; P <.001). There were no complete responses and four partial responses with single-agent ipilimumab. The ORR in BRAF wild-type tumors receiving the combination was independent of PD-L1 status; however, response rates with ipilimumab alone were higher in patients with PD-L1—positive tumors (18% vs 4%).


“These data are unprecedented in advanced melanoma, showing efficacy results that have not previously been observed with Immuno-Oncology agents,” lead study author F. Stephen Hodi, MD, associate professor of Medicine at Dana-Farber Cancer Institute, said in a statement when the data were presented at the 2015 AACR Annual Meeting. “With the Opdivo plus Yervoy regimen, we observed much higher response rates which were sustained, as well as significant reduction in tumor burden than with Yervoy. These responses seen in CheckMate-069 demonstrate the potential of this regimen in patients with metastatic melanoma.”


Nivolumab is currently FDA-approved for the treatment of patients with unresectable or metastatic melanoma following treatment with ipilimumab or a BRAF inhibitor. In addition to melanoma, the FDA approved nivolumab in March 2015 as a treatment for patients with metastatic squamous non-small cell lung cancer following a platinum-based chemotherapy, based on the open-label CheckMate-017 study.


  1. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373:23-34.
  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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