Opdivo, a PD-1 checkpoint inhibitor approved in Europe, for both first-line and previously-treated advanced melanoma patients
The European Commission has approved Opdivo ( Nivolumab ), a PD-1 immune checkpoint inhibitor, for the treatment of advanced ( unresectable or metastatic ) melanoma in adults, regardless of BRAF status.
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 Opdivo 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.
Opdivo 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%.
The European Commission’s approval is based on data from two phase 3 studies ( CheckMate -066, -037 ). Together, the trials investigated Opdivo 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 3 clinical development program for Opdivo.
CheckMate -066 is a phase 3 randomized, double-blind study comparing Opdivo ( n=210 ) to the chemotherapy Dacarbazine ( DTIC ) ( n=208 ) in patients with treatment-naïve advanced melanoma. It is the first phase 3 trial of a PD-1 immune checkpoint inhibitor to demonstrate superior overall survival in advanced melanoma, demonstrating a one-year survival rate of 73% for Opdivo versus 42% for Dacarbazine, and there was a 58% decrease in the risk of death for patients treated with Opdivo based on a hazard ratio of 0.42 ( 99.79% CI, 0.25-0.73; P less than 0.0001 ). Objective response rate ( ORR ) also was significantly higher for Opdivo than Dacarbazine ( 40% vs 14%, P less than 0.0001 ).
The primary endpoint of this trial was overall survival. Secondary endpoints included progression-free survival and ORR ( overall response rate ) by RECIST v1.1 criteria.
Safety was reported in all patients treated in the Opdivo and Dacarbazine arms. Fewer discontinuations were observed with Opdivo than Dacarbazine ( 6.8% vs. 11.7% ) as well as for treatment-related grade 3/4 adverse events ( 11.7% vs 17.6% ), which were managed using established safety algorithms.
The most common Opdivo treatment-related adverse reactions were fatigue ( 20% ), pruritus ( 17% ), and nausea ( 16.5% ).
Common adverse events in the Dacarbazine arm were consistent with those in previous reports and included nausea ( 41.5% ), vomiting ( 21% ), fatigue ( 15% ), diarrhea ( 15% ) and hematological toxicities.
No deaths were attributed to study drug toxicity in either arm.
CheckMate -037 is a phase 3 randomized, controlled open-label study of Opdivo ( 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 overall survival.
In a planned interim analysis of ORR, an improvement in ORR of 32% was seen in the Opdivo 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 Opdivo. Responses to Opdivo were demonstrated in both patients with or without BRAF mutation and regardless of PD-L1 expression.
Safety was reported on all patients treated in the Opdivo ( n=268 ) and investigator’s choice chemotherapy ( n=102 ) arms. The majority of Opdivo treatment-related adverse events were grade 1/2 and managed using recommended treatment algorithms. Grade 3/4 drug-related adverse effects were less frequent for the Opdivo arm ( 9% vs. 31% of patients treated with chemotherapy ). Discontinuations due to drug-related adverse effects of any grade occurred in 3% of Opdivo-treated patients and 7% of patients administered investigator’s choice chemotherapy. 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 characterization of Opdivo benefit/risk in advanced melanoma. Of the 306 previously-treated patients enrolled in the study, 107 had melanoma and received Opdivo 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 progression-free survival was 3.7 months ( 95% CI: 1.9, 9.3 ). The median overall survival was 17.3 months ( 95% CI: 12.5, 36.7 ), and the estimated overall survival 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. ( Xagena )
Source: BMS, 2015