First PD-1 Inhibitor Approved in Europe

The European Commission has approved nivolumab 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.

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.

In addition to melanoma, the FDA approved nivolumab in March 2015 as a treatment for patients with metastatic squamous non-small cell lung cancer (NSCLC) following a platinum-based chemotherapy, based on the open-label CheckMate-017 study. In addition to this indication, nivolumab improved OS by 27% in patients with non-squamous NSCLC in the CheckMate-057 study. An approval in this setting is anticipated.

In the CheckMate-017 study,3 the median OS in patients with squamous histology was 9.2 months with nivolumab versus 6.0 months with chemotherapy (HR = 0.59; 95% CI, 0.44-0.79; P = .00025), with a 1-year OS of 42% versus 24%, respectively. Nivolumab also improved median PFS by 38% versus docetaxel (3.5 vs 2.8 months; HR = 0.62; 95% CI, 0.47-0.81; P = .0004).

In the CheckMate-057 study,4 the median OS in those with non-squamous histology was 12.2 months with nivolumab versus 9.4 months with docetaxel (HR = 0.73; 96% CI, 0.59-0.89; P = .00155), with a 1-year OS of 50.5% versus 39.0%, respectively. The median PFS was 2.3 months in the nivolumab arm compared with 4.2 months with docetaxel (HR = 0.92; 95% CI, 0.77-1.11; P = .393).


  1. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320-330.
  2. Weber JS, D'Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial [published online March 17, 2015]. Lancet Oncol. 2015;16(4):375—384.
  3. Spigel DR, Reckamp KL, Rizvi NA, et al. A phase III study (CheckMate 017) of nivolumab (NIVO; anti-programmed death-1 [PD-1]) vs docetaxel (DOC) in previously treated advanced or metastatic squamous (SQ) cell non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33 (suppl; abstr 8009).
  4. Paz-Ares LG, Horn L, Borghaei H, et al. Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33 (suppl; abstr LBA109).