CHMP Recommends Approval of Nivolumab/Ipilimumab Combo for Melanoma

Jean Viallet, MD

The combination of ipilimumab (Yervoy) and nivolumab (Opdivo) has received a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP), which suggests that the treatment is likely to gain European approval for patients with advanced melanoma.

The positive opinion was based on the collection of data from the CheckMate-069 and -067 studies and a phase Ib trial. In the studies, the combination significantly improved objective response rates (ORR) and progression-free survival (PFS) versus monotherapy with ipilimumab for patients with advanced melanoma. In the CHMP opinion, the combination also improved PFS versus single-agent nivolumab, but only in patients with low tumor expression of PD-L1.

The company developing the combination, Bristol-Myers Squibb, noted that the European Commission, which is expected to make a decision within the coming months, was now reviewing the Marketing Authorization Application. If approved, nivolumab and ipilimumab would become the first immunotherapy combination available in the European Union.

“We are pleased the CHMP has recommended approval of Opdivo in combination with Yervoy in a broad melanoma patient population, and look forward to the European Commission’s decision,” Jean Viallet, MD, Global Clinical Research Lead, Oncology, Bristol-Myers Squibb, said in a statement.

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 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 Ib study that was also used as supporting evidence,³ the combination of nivolumab and ipilimumab was explored at various dosing schedules for patients with unresectable or metastatic melanoma. In 3 cohorts that received similar treatment schedules (n = 53), the ORR with the combination was 42% and the median duration of response was 22.3 months. Complete responses were seen in 21% of patients treated with the combination.

In another cohort that received the combination every 3 weeks for 12 weeks followed by nivolumab alone every 3 weeks for 12 weeks (n = 41), the 18-month OS rate was 68%. The ORR was 44%, with complete responses in 17% of patients. The median duration of response was 13.7 months.

In the phase III study,¹ 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%).

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.