Nivolumab/Ipilimumab Combo Gains NICE Approval for Melanoma Treatment

James Larkin, MD

The National Institute for Health and Care Excellence (NICE) has approved the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for patients with metastatic melanoma, which allows the combination to be used within the National Health Service (NHS).

The decision arrived just 2 months following a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP) and 1 month following an approval from the European Commission. The decision was based upon a collection of data from the CheckMate-067 and -069 studies.

In the phase III CheckMate-067 and the CheckMate-069 trials, the combination significantly improved objective response rates (ORR) and progression-free survival (PFS) versus monotherapy with ipilimumab for patients with advanced melanoma. In CheckMate-067, the combination demonstrated a 58% reduction in the risk of progression or death versus ipilimumab monotherapy in previously untreated patients with advanced melanoma (HR, 0.42; 99.5% CI, 0.32-0.56;P<.0001).

When the combination was approved in Europe, lead author of the CheckMate-067 study, James Larkin, MD, from The Royal Marsden, said, &ldquo;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.&rdquo;

In the 3-arm phase III CheckMate-067 trial,¹945 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. Single-agent nivolumab reduced the risk of progression by 45% versus ipilimumab (HR, 0.55; 00.5% CI, 0.42-0.73;P<.0001). The ORR with the combination was 58% versus 19% with ipilimumab. The median duration of response with the combination was not yet met.

Outcomes were similar regardless of BRAF mutation status. In the study, ORRs were higher for the combination versus nivolumab monotherapy across tumor PD-L1 expression levels. Additionally, 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,²142 treatment-na&iuml;ve 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). The ORR was 61% with the combination versus 11% with ipilimumab alone in patients with BRAF wild-type advanced melanoma. The estimated 12-month OS rate with the combination was 79% versus 62% with ipilimumab alone. At 18 months, the OS rate was 73% with the combination versus 56% with ipilimumab.

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. Grade 3/4 AEs were reported in 55%, 16.3%, and 27.3% of the combination, nivolumab, and ipilimumab groups, respectively.

In a pooled dataset from 3 studies exploring nivolumab and ipilimumab, the most common all-grade AEs with the combination were rash (51%), fatigue (43%), diarrhea (42%), pruritus (35%), nausea (25%), pyrexia (19%), decreased appetite (15%), hypothyroidism (15%), vomiting (14%), colitis (14%), abdominal pain (13%), anthralgia (11%), and headache (11%).

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.

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.

Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma. N Engl J Med. 2015;372:2006-2017.