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First PD-1 Inhibitor Approved in Europe

Silas Inman @silasinman
Published: Monday, Jun 22, 2015

Dirk Schadendorf, MD

Dirk Schadendorf, MD

The European Commission has approved nivolumab (Opdivo) as a treatment for patients with advanced melanoma in the first- and later-line setting regardless of BRAF mutation status, making it the first PD-1 inhibitor to gain approval in Europe.

The frontline decision was based on superior overall survival (OS) findings for nivolumab versus dacarbazine in the phase III CheckMate-066 trial. For previously treated patients, the European Commission based its decision on an improvement in objective response rates (ORR) seen in the phase III CheckMate-037 trial.

The approval follows an accelerated assessment from Committee for Medicinal Products for Human Use, and allows the medication to be marketed across 28 European Union member states.

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

In the CheckMate-066 trial,1 418 untreated patients were randomized in a 1:1 ratio to receive intravenous nivolumab at 3 mg/kg every 2 weeks (n = 210) or dacarbazine at 1000 mg/m2 IV every 3 weeks (n = 208). Of the patients enrolled, 61% had stage M1c disease.

According to findings published in The New England Journal of Medicine, the 1-year OS rate was 72.9% with nivolumab compared with 42.1% in the dacarbazine arm (HR = 0.42; 99.79% CI, 0.25-0.73; P <.001). The median PFS was 5.1 versus 2.2 months, in the nivolumab and dacarbazine arms, respectively (HR = 0.43; 95% CI, 0.34-0.56; P <.001). The ORR was 40% with nivolumab versus 13.9% with dacarbazine (odds ratio = 4.06; P <.001).

All-grade treatment-related adverse events occurred in 74.3% of patients with nivolumab versus 75.6% with dacarbazine. However, grade 3/4 adverse events were less common with nivolumab compared with dacarbazine (11.7% versus 17.6%, respectively). The most common nivolumab-related side effects were fatigue (19.9%), pruritus (17%), and nausea (16.5%).

In the CheckMate-037 trial,2 405 patients were randomized in a 2:1 ratio to receive nivolumab at 3 mg/kg every 2 weeks (n = 272) or investigators choice of chemotherapy (n = 133). The chemotherapy utilized in the study consisted of dacarbazine at 1000 mg/m2 every 3 weeks or paclitaxel at 175 mg/m2 in combination with carboplatin AUC 6 every 3 weeks. Patients in the trial were pretreated with ipilimumab or a BRAF inhibitor, if BRAF-mutation positive.

In this study, nivolumab demonstrated an ORR of 31.7% compared with 10.6% in patients treated with chemotherapy. The complete response rate with nivolumab was 3%, the partial response rate was 28%, and 23% of patients had stable disease. Of the 38 patients who responded to nivolumab, 82% experienced a greater than 50% reduction in target lesion burden compared with 60% in the 5 patients who responded to chemotherapy.

The median time to response in nivolumab-treated patients was 2.1 versus 3.5 months with chemotherapy. The majority of responses (95%) remained ongoing at the time of the analysis. A median duration of response was not yet reached in the nivolumab arm versus 3.6 months with chemotherapy.

Fewer serious adverse events were reported with nivolumab compared with chemotherapy (5% vs 9%, respectively). The most frequently reported grade 3/4 adverse events with nivolumab were increased lipase (1%), increased alanine aminotransferase, anemia, and fatigue (1% each). With chemotherapy, the most frequently occurring grade 3/4 adverse events were neutropenia (14%), thrombocytopenia (6%), and anemia (5%).

“We are pleased to bring the first PD-1 immune checkpoint inhibitor to the European Union for the treatment of advanced melanoma,” Emmanuel Blin, senior vice president, head of commercialization, policy and operations, Bristol-Myers Squibb, the company developing nivolumab, said in a statement. “We are working relentlessly and at record-breaking speed to build upon our Immuno-Oncology science to deliver new treatment options, with the goal of improving long-term survival for patients.”

In the United States, nivolumab is FDA-approved for the treatment of patients with unresectable or metastatic melanoma following treatment with ipilimumab or a BRAF inhibitor, based on data from the phase III CheckMate-037 trial. In late April 2015, the FDA granted a priority review to nivolumab as a frontline therapy for patients with previously untreated metastatic melanoma, based on data from the CheckMate-066 study. Under the expedited review process, the action date for the FDA’s decision is August 27, 2015.


View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Medical Crossfire®: Evolving Roles for Targeted Melanoma Therapies: Assessing Rapid Progress in the Field and Looking Toward Future CombinationsFeb 28, 20191.5
Advances in™ Melanoma: Exploring BRAF/MEK in Adjuvant and Neoadjuvant SettingsSep 28, 20191.5
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