Nivolumab/Ipilimumab Combo Approved in Europe for Advanced Melanoma

James Larkin, MD, PhD

The European Commission has approved the combination of ipilimumab (Yervoy) and nivolumab (Opdivo) as a treatment for patients with unresectable or metastatic melanoma regardless of BRAF status, based on data from the CheckMate-069 and -067 studies.

The combination significantly improved objective response rates (ORR) and progression-free survival (PFS) versus monotherapy with ipilimumab for patients with advanced melanoma, across the two studies. The two agents now comprise the first immunotherapy combination available in the European Union.

”Historically, advanced melanoma has been a very difficult-to-treat disease. Now, with this approval, patients in Europe will have a treatment option combining two Immuno-Oncology therapies, Opdivo and Yervoy, which in a phase III randomized trial has shown its ability to deliver superior efficacy versus Yervoy monotherapy in progression-free survival and response,” lead author of the CheckMate-067 study, James Larkin, MD, from The Royal Marsden, said in a statement. ”This is truly good news for healthcare providers and the patients they treat, as it represents an important new treatment option with the potential for improved outcomes.”

In the 3-arm phase III CheckMate-067 trial,¹ 945 patients with untreated unresectable or metastatic melanoma were randomized to receive nivolumab (n = 316), ipilimumab (n = 315), or nivolumab plus ipilimumab followed by nivolumab alone (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.

The median PFS was 11.5 months for the combination, 6.9 months for nivolumab monotherapy, and 2.9 months for single-agent ipilimumab. Compared with ipilimumab monotherapy, the combination of nivolumab and ipilimumab reduced the risk of progression by 58% (HR, 0.42; P <.0001). Single-agent nivolumab reduced the risk of progression by 43% versus ipilimumab (HR, 0.57; P <.0001). Outcomes were similar regardless of BRAF mutation status.

PD-L1 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 patients with tumors that expressed the ligand. In the PD-L1—negative group, 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.

In its opinion issued in April, Committee for Medicinal Products for Human Use (CHMP) noted that the combination improved PFS versus single-agent nivolumab, but only in patients with low tumor expression of PD-L1. Response rates were higher with the combination, regardless of PD-L1 expression.

In the phase II CheckMate-069 trial,² 142 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.

When compared with ipilimumab alone, the combination of nivolumab and ipilimumab reduced the risk of progression or death by 60% (HR, 0.40; 95% CI, 0.22-0.71; P <.002). ORR with the combination was found to be independent of PD-L1 status. In PD-L1—positive and –negative tumors, respectively, ORR was 58% and 55% with nivolumab/ipilimumab. In BRAF-mutant tumors, ORR was 52% versus 10% with the two-drug regimen versus monotherapy.

In the phase III study, all-grade adverse-events (AEs) occurred in 95.5%, 82.1%, and 86.2% of patients in the combination, nivolumab, and ipilimumab arms, respectively. Rates of treatment-related discontinuations with the combination, nivolumab, and ipilimumab arms were 36.4%, 7.7%, and 14.8%, respectively.

The most common all-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%).

"The Opdivo + Yervoy Regimen is the first and only approved Immuno-Oncology combination, and only Regimen to deliver superior efficacy compared to Yervoy, and we are thrilled to make this novel combination treatment available to patients with advanced melanoma in Europe," Emmanuel Blin, senior vice president, Head of Commercialization, Policy and Operations, Bristol-Myers Squibb, said in a statement.

A number of studies are assessing nivolumab in various combinations for patients with melanoma and other types of cancer. A phase I/II study is looking at nivolumab with the anti-CD27 antibody varlilumab (NCT02335918). Additionally, a phase II/III study is exploring nivolumab and ipilimumab with the GM-CSF agent sargramostim (NCT02339571).

In the United States, the combination of ipilimumab and nivolumab has already been approved for patients with advanced melanoma. In Europe, nivolumab is approved as a monotherapy for patients with advanced melanoma.

References

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.
3. Atkinson V, et al. Updated Survival, Response and Safety Data in a Phase 1 Dose-Finding Study (CA209-004) of Concurrent Nivolumab (NIVO) and Ipilimumab (IPI) in Advanced Melanoma. Presented at the Society for Melanoma Research 2015 International Congress; November 18-21, 2015; San Francisco, CA.