The European Commission has approved nivolumab (Opdivo), a PD-1 immune checkpoint inhibitor, for the treatment of advanced (unresectable or metastatic) melanoma in adults, regardless of BRAF status.

The approval allows for the marketing of 'Opdivo' in all 28 Member States of the EU.

It follows an accelerated assessment by the Committee for Medicinal Products for Human Use (CHMP), which was announced on April 24, 2015.

This accelerated assessment was given because nivolumab qualified for the designation as a “medicinal product of major interest from the point of view of public health and in particular from the view point of therapeutic innovation.”

Nivolumab is the only PD-1 immune checkpoint inhibitor to receive an accelerated assessment in Europe, and is the first approval given by the European Commission for a PD-1 inhibitor in any cancer.

The incidence of melanoma has continued to increase in almost all European countries, with an estimated one in five patients expected to develop metastatic, or advanced, disease.

Historically, prognosis for late-stage metastatic melanoma has been poor: the average survival rate for stage IV is just six months with a one-year mortality rate of 75%.

About CheckMate -066, -037

The European Commission’s approval is based on data from two phase III studies (CheckMate -066, -037).

Together, the trials investigated nivolumab across treatment lines and mutational status with a consistent dose of 3 mg/kg every two weeks that has been well-established across the phase III clinical development program for nivolumab.

“The phase III data supporting the approval of nivolumab demonstrates both superior overall survival and response rate for treatment-naïve patients with advanced melanoma, against the standard of care,” said Dirk Schadendorf, M.D., professor, director and chair, Clinic for Dermatology, University Hospital, Essen, Germany.

“It is an important step forward in offering a new option for advanced melanoma patients in the European Union, especially considering that long-term benefits have largely been elusive in this treatment category.”

CheckMate -066 is a Phase 3 randomised, double-blind study comparing nivolumab (n=210) to the chemotherapy dacarbazine (DTIC) (n=208) in patients with treatment-naïve advanced melanoma.

It is the first phase III trial of a PD-1 immune checkpoint inhibitor to demonstrate superior overall survival (OS) in advanced melanoma, demonstrating a one-year survival rate of 73% for nivolumab versus 42% for DTIC, and there was a 58% decrease in the risk of death for patients treated with nivolumab based on a hazard ratio of 0.42 (99.79% CI, 0.25-0.73; P<0.0001).

Objective response rate (ORR) also was significantly higher for nivolumab than DTIC (40% vs. 14%, P<0.0001).

The primary endpoint of this trial was OS. Secondary endpoints included progression-free survival (PFS) and ORR by RECIST v1.1 criteria.

Safety was reported in all patients treated in the nivolumab and DTIC arms.

Fewer discontinuations were observed with nivolumab than DTIC (6.8% vs. 11.7%) as well as for treatment-related Grade 3/4 adverse events (AEs) (11.7% vs. 17.6%), which were managed using established safety algorithms.

The most common  nivolumab treatment-related AEs were fatigue (20%), pruritus (17%), and nausea (16.5%).

Common adverse events in the DTIC arm were consistent with those in previous reports and included nausea (41.5%), vomiting (21%), fatigue (15%), diarrhoea (15%) and haematological toxicities.

No deaths were attributed to study drug toxicity in either arm.

CheckMate -037 is a Phase 3 randomised, controlled open-label study of nivolumab (n=272) versus investigator’s choice chemotherapy (ICC) (n=133) - either single-agent dacarbazine or carboplatin plus paclitaxel - in patients with advanced melanoma who were previously treated with Yervoy (ipilimumab), and, if BRAF mutation positive, a BRAF inhibitor.

Co-primary endpoints of the study are ORR and OS. In a planned interim analysis of ORR, an improvement in ORR of 32% was seen in the nivolumab arm (95% CI, 23.5%-40.8%) versus 11% in the investigator’s choice chemotherapy arm (95% CI, 3.5%-23.1%).

A majority of responses (87%) were ongoing in those patients administered nivolumab.

Responses to nivolumab were demonstrated in both patients with or without BRAF mutuation and regardless of PD-L1 expression.

Safety was reported on all patients treated in the nivolumab (n=268) and ICC (n=102) arms.

The majority of nivolumab treatment-related adverse events (AEs) were Grade 1/2 and managed using recommended treatment algorithms.

Grade 3/4 drug-related AEs were less frequent for the nivolumab arm (9% vs. 31% of patients treated with chemotherapy).

Discontinuations due to drug-related AEs of any grade occurred in 3% of nivolumab-treated patients and 7% of patients administered ICC.

There were no deaths related to study drug toxicity.

The approval also was based on data from a phase 1b study (Study -003) in relapsed advanced or metastatic melanoma, which demonstrated the first characterisation of nivolumab benefit/risk in advanced melanoma.

Of the 306 previously-treated patients enrolled in the study, 107 had melanoma and received nivolumab at a dose of 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 10 mg/kg every two weeks for a maximum of two years.

In this patient population, objective response was reported in 33 patients (31%) with a median duration of response of 22.9 months (95% CI: 17.0, NR).

The median PFS was 3.7 months (95% CI: 1.9, 9.3).

The median OS was 17.3 months (95% CI: 12.5, 36.7), and the estimated OS rates were 63% (95% CI: 53, 71) at one year, 48% (95% CI: 38, 57) at two years, and 41% (95% CI: 31, 51) at three years.

Source: Business Wire