European Commission Approves Nivolumab, for Both First-Line and Previously Treated Patients With Advanced Melanoma

Approval follows accelerated assessment by the European Medicines Agency’s Committee for Medicinal Products for Human Use

On Friday, 19 June, 2015 the Bristol-Myers Squibb Company announced in a press release that 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 Opdivoin all 28 Member States of the EU.

It follows an accelerated assessment by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP), which was announced on 24 April, 2015. This accelerated assessment was given because Opdivoqualified 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.” Opdivois the only PD-1 immune checkpoint inhibitor to receive an accelerated assessment in Europe, andis the first approval given by the European Commission for a PD-1 inhibitor in any cancer.

Approval is based on CheckMate-066 trial demonstrating superior overall survival vs. dacarbazine in the first-line setting and CheckMate-037 trial showing improved response vs. chemotherapy in previously treated patients, both at a consistent and well-established dose. Opdivo safety profile is consistent with previously-reported trials.  

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 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 III clinical development programme for Opdivo.

CheckMate-066 is a phase III randomised, double-blind study comparing Opdivo (n=210) to the chemotherapy dacarbazine (DTIC) (n=208) in patients with treatment-naive 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 Opdivo versus 42% for DTIC, and there was a 58% decrease in the risk of death for patients treated with Opdivo based on a hazard ratio of 0.42 (p < 0.0001). The objective response rate (ORR) also was significantly higher for Opdivo 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 Opdivo and DTIC arms. Fewer discontinuations were observed with Opdivo than DTIC (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 events 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 III randomised, 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 ipilimumab(Yervoy), 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 Opdivo arm versus 11% in the investigator’s choice chemotherapy arm. A majority of responses (87%) were ongoing in those patients administeredOpdivo. 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 ICC (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 events were less frequent for the Opdivo arm (9% vs. 31% of patients treated with chemotherapy). Discontinuations due to drug-related adverse events of any grade occurred in 3% of Opdivo-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 Ib study (Study -003) in relapsed advanced or metastatic melanoma, which demonstrated the first characterisation of Opdivobenefit/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. The median PFS was 3.7 months. The median OS was 17.3 months, and the estimated OS rates were 63% at one year, 48% at two years, and 41% at three years.

Regulatory approval in other countries

Nivolumab became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on 4 July, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma.

On 22 December, 2014, the US Food and Drug Administration (FDA) granted its first approval forOpdivo for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.

On 4 March 4, 2015, Opdivoreceived its second FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer with progression on or after platinum-based chemotherapy.

Safety information: 

Immune-mediated pneumonitis

  • Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with Opdivo treatment. Across the clinical trial experience in 691 patients with solid tumours, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving Opdivo; no cases occurred in trial 1 or trial 3. In trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving Opdivo and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving Opdivo; one with grade 3 and five with grade 2. In trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving Opdivo, including, five grade 3 and two grade 2 cases.

Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for grade 2 or greater pneumonitis. Permanently discontinue Opdivo for grade 3 or 4 and withhold Opdivo until resolution for grade 2.

Immune-mediated colitis

  • In trial 1, diarrhoea or colitis occurred in 21% (57/268) of patients receiving Opdivo and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving Opdivo; five with grade 3 and one with grade 2. In trial 3, diarrhoea occurred in 21% (24/117) of patients receiving Opdivo. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients.

Monitor patients for immune-mediated colitis. Administer corticosteroids for grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold Opdivo for grade 2 or 3. Permanently discontinue Opdivo for grade 4 colitis or recurrent colitis upon restarting Opdivo.

Immune-mediated hepatitis

  • In trial 1, there was an increased incidence of liver test abnormalities in the Opdivo-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving Opdivo; two with grade 3 and one with grade 2. In trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%).

Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for grade 2 or greater transaminase elevations. Withhold Opdivo for grade 2 and permanently discontinue Opdivo for grade 3 or 4 immune-mediated hepatitis.

Immune-mediated nephritis and renal dysfunction

  • In trial 1, there was an increased incidence of elevated creatinine in the Opdivo-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. In trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (grade 2) occurred in 0.9% (1/117) of patients.

Monitor patients for elevated serum creatinine prior to and periodically during treatment. For grade 2 or 3 serum creatinine elevation, withhold Opdivo and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue Opdivo. Administer corticosteroids for grade 4 serum creatinine elevation and permanently discontinue Opdivo.

Immune-mediated hypothyroidism and hyperthyroidism

  • In trial 1, grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving Opdivo and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving Opdivo and 1% (1/102) of patients receiving chemotherapy. In trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving Opdivo. Hyperthyroidism occurred in 1.7% (2/117) of patients, including one grade 2 case.

Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Other immune-mediated adverse reactions

  • In trial 1 and 3 (n=385), the following clinically significant immune-mediated adverse reactions occurred in <2% of Opdivo-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of Opdivo administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome.

Based on the severity of adverse reaction, withhold Opdivo, administer high-dose corticosteroids, and, if appropriate, initiate hormone replacement therapy.

Embryofetal toxicity

  • Based on its mechanism of action, Opdivo can cause fetal harm when administered to a pregnant woman.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Opdivo and for at least 5 months after the last dose of Opdivo.

Lactation

  • It is not known whether Opdivo is present in human milk.

Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Opdivo, advise women to discontinue breastfeeding during treatment.

Serious adverse reactions

  • In trial 1, serious adverse reactions occurred in 41% of patients receiving Opdivo. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving Opdivo. The most frequent grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving Opdivo were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.
  • In trial 3, serious adverse reactions occurred in 59% of patients receiving Opdivo. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Common adverse reactions

  • The most common adverse reactions (≥20%) reported with Opdivo in trial 1 were rash (21%) and in trial 3 were fatigue (50%), dyspnoea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).