Type of information: Granting of a Market Authorisation in the US
Product name: Opdivo®
Therapeutic area: Cancer - Oncology
- monoclonal antibody. Nivolumab is an investigational, fully-human PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 (programmed death-1) expressed on activated T-cells. PD-1, a receptor expressed on the surface of lymphocytes, plays a role in a regulatory pathway that suppresses activated lymphocytes in the body. Available evidence suggests that cancer cells exploit this pathway to escape from immune responses. Opdivo® is thought to provide benefit by blocking PD-1-mediated negative regulation of lymphocytes (i.e., the interaction of PD-1 with its ligands PD-L1 and PD-L2), thereby enhancing the ability of the immune system to recognize cancer cells as foreign and eliminate them. Opdivo® is the world’s first approved drug targeting PD-1.
- This monoclonal antibody has been generated under a research collaboration entered into in May 2005 between Ono and Medarex. When Medarex was acquired by BMS in 2009, it also granted BMS its rights to develop and commercialize the anti-human PD-1 monoclonal antibody in North America. Through the collaboration agreement entered into in September 2011 between Ono and BMS, Ono granted BMS exclusive rights to develop and commercialize Opdivo® in the rest of the world, except in Japan, Korea and Taiwan where Ono has retained all rights to develop and commercialize the compound.
Company: BMS (USA - NY)
- previously untreated patients with unresectable or metastatic melanoma
- previously treated advanced melanoma
- adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection
- • On December 21, 2017, the FDA has approved Opdivo® (nivolumab) injection for intravenous use for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection. The purpose of adjuvant therapy is to reduce the risk of recurrence following surgical removal of the tumor and lymph nodes that contain cancer.
- In the Phase 3 CheckMate -238 trial, Opdivo® significantly improved recurrence-free survival (RFS) versus an active comparator, Yervoy® (ipilimumab), in patients with stage IIIB/C or stage IV melanoma after surgery. This benefit was observed across important subgroups, including in both BRAF mutant and BRAF wild-type patients.
Opdivo® demonstrated an 18-month RFS rate of 66.4% [95% confidence interval (CI): 61.8 to 70.6] compared with 52.7% for Yervoy (95% CI: 47.8 to 57.4), with the median RFS not yet reached in either group. Opdivo® reduced the risk of disease recurrence by 35% versus Yervoy® [hazard ratio (HR): 0.65; 95% CI: 0.53 to 0.80; p <0.0001].
- Opdivo® received Breakthrough Therapy Designation from the FDA for the adjuvant treatment of patients with high-risk, fully resected melanoma in September 2017. Approximately three in every 10 patients with stage III melanoma currently receive adjuvant therapy after surgery. Even with available treatment options, the majority of stage IIIB and IIIC melanoma patients (71% and 85%, respectively) experience disease recurrence within five years.
- • On January 23, 2016, BMS announced that the FDA has expanded the use of Opdivo® as a single-agent to include previously untreated BRAF mutation-positive advanced melanoma patients. The use of Opdivo® as a single-agent in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.1 Opdivo® was approved by the FDA in November 2015, for use in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma.
- • On June 19, 2015, BMS announced that the European Commission has approved Opdivo®, a PD-1 immune checkpoint inhibitor, for the treatment of advanced (unresectable or metastatic) melanoma in adults, regardless of BRAF status. This 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 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 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 (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 (99.79% CI, 0.25-0.73; P<0.0001). 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 (AEs) (11.7% vs. 17.6%), which were managed using established safety algorithms. The most common Opdivo 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%), 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 OS. 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 mutuation 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 (AEs) were Grade 1/2 and managed using recommended treatment algorithms. Grade 3/4 drug-related AEs were less frequent for the Opdivo® arm (9% vs. 31% of patients treated with chemotherapy). Discontinuations due to drug-related AEs 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 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 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.
- * On April 29, 2015, BMS announced that the FDA has accepted for filing and review the supplemental Biologics License Application (sBLA) for Opdivo® (nivolumab) for the treatment of previously untreated patients with unresectable or metastatic melanoma. The FDA also granted Priority Review for this application. The projected FDA action date is August 27, 2015. Opdivo® was first approved by the FDA in December 2014 for patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. This initial indication was approved under accelerated approval based on tumor response rate and durability of response from CheckMate -037 clinical trial results.
- This new sBLA accepted by the FDA includes data from CheckMate -066, which evaluated Opdivo® in treatment naïve patients with BRAF wild-type advanced melanoma as compared to dacarbazine chemotherapy (DTIC). In the trial, safety and tolerability were well-characterized with fewer treatment-related Grade 3/4 adverse events observed with Opdivo® than dacarbazine.
- • On April 23, 2015, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for Opdivo®, intended for the treatment of advanced (unresectable or metastatic) melanoma in adults. Opdivo® will be available as a 10 mg/ml concentrate for solution for infusion. The benefits obtained with Opdivo® are an increase in overall survival over dacarbazine (HR = 0.42; 99.79%CI: 0.25, 0.73; p-value < 0.0001) in patients with advanced (unresectable or metastatic) melanoma in adults who have not received prior therapy and an improvement in overall response rate for nivolumab compared to investigator’s choice of treatment (31.7% versus 10.6%, respectively) in adults who had received previous therapy. The most common side effects are fatigue, pruritus, nausea, diarrhoea, and rash. Nivolumab is associated with immune-related adverse reactions including endocrine abnormalities, diarrhoea/colitis, hepatitis, pneumonitis, nephritis and rash.
- • On December 22, 2014, the FDA granted accelerated approval to nivolumab for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on objective response rate (ORR) and durability of response in the first 120 patients who were treated with nivolumab and had a minimum 6 months follow- up from an on-going, randomized, open-label trial in which 370 patients with unresectable or metastatic melanoma received nivolumab 3 mg/kg intravenously every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102). Chemotherapy included either dacarbazine or the combination of carboplatin plus paclitaxel. Patients were treated until disease progression or unacceptable toxicity. Patients with unresectable or metastatic melanoma were required to have disease progression following ipilimumab, and a BRAF inhibitor if BRAF V600 mutation positive. Patients were excluded from the trial if they had an autoimmune disease, a medical condition that required corticosteroids or immunosuppression, or a history of severe ipilimumab-related adverse reactions. Among these 120 patients, 65% were male, the median age was 58 years (68% less than age 65), 98% were White, and 58% and 42% had a baseline ECOG performance status of 0 or 1, respectively. Disease characteristics included BRAF V600 mutation -positive melanoma (22%), elevated lactate dehydrogenase (56%), M1c disease (76%), history of brain metastases (18%), and two or more prior therapies for advanced or metastatic disease (68%). The major efficacy endpoints were confirmed ORR according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and response duration. ORR was assessed by a blinded independent review committee. The ORR was 32% (95% CI: 23, 41) with four complete responses and 34 partial responses. Five responding patients have progressed, while the remaining 33 patients (87%) have ongoing responses (range 2.6+ to 10+ months). Thirteen patients have ongoing responses of 6 months or longer. The most common (greater than or equal to 20%) adverse reaction among the 268 patients receiving nivolumab was rash. The most frequent Grade 3 and 4 adverse drug reactions observed in 2% to less than 5% with nivolumab were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. Clinically significant immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, nephritis/renal dysfunction, hypothyroidism, and hyperthyroidism.
- As a condition of this accelerated approval, BMS is required to conduct a multicenter, randomized trial(s) establishing the superiority of nivolumab over standard therapy in adult patients with unresectable or metastatic melanoma to verify and describe the clinical benefit of nivolumab.The recommended dose of nivolumab is 3 mg/kg, administered as an intravenous infusion over 60 minutes, every 2 weeks. BMS expects to begin shipping Opdivo within one to two weeks of this approval.
- • On September 26, 2014, BMS announced that the FDA has accepted for priority review the Biologics License Application (BLA) for previously treated advanced melanoma and the Prescription Drug User Fee Act (PDUFA) goal date for a decision is March 30, 2015. The FDA also granted Opdivo® Breakthrough Therapy status for this indication.
- In the European Union, the European Medicines Agency (EMA) has validated for review the Marketing Authorization Application (MAA) for Opdivo® in advanced melanoma. The application has also been granted accelerated assessment by the CHMP. The U.S. BLA is based on data from CheckMate -037, a multinational, multicenter, randomized open-label Phase 3 trial evaluating Opdivo compared to the physician’s choice of either dacarbazine (DTIC) or carboplatin/paclitaxel in patients with unresectable or metastatic melanoma who have been previously treated with Yervoy and, if BRAF-mutation positive, a BRAF inhibitor. The MAA submitted to the EMA in advanced melanoma is also supported by data from CheckMate -037. Accelerated assessment procedure may be requested for medicinal products of major interest from the point of view of public health and, in particular, from the point of view of therapeutic innovation. The acceptance of accelerated assessment by the CHMP could shorten the review time of Opdivo in advanced melanoma by approximately two months.
- • On July 10, 2014, BMS announced that, following discussions with the FDA, the company is planning a third quarter submission of a Biologics Licensing Application (BLA) for Opdivo® (nivolumab) for previously treated advanced melanoma. This will mark the second tumor type for which Bristol-Myers Squibb has a regulatory submission underway for Opdivo® in the U.S. Another BLA has been submitted for the trearment of Hodgkin lymphoma after failure of autologous stem cell transplant and brentuximab. The advanced melanoma BLA is based on data from Checkmate -037, a multinational, multicenter, randomized open-label Phase 3 trial evaluating Opdivo® compared to dacarbazine (DTIC) or carboplatin/paclitaxel in patients with unresectable or metastatic melanoma who have been previously treated with Yervoy® (ipilimumab) and, if BRAF-mutation positive, a BRAF inhibitor regimen.
- In 2013, the FDA granted Fast Track designation for Opdivo® (nivolumab) in NSCLC, melanoma and RCC. In April 2014, the company initiated a rolling submission with the FDA for Opdivo® in third-line pre-treated squamous cell NSCLC and expects to complete the submission by year-end. The FDA granted Opdivo® Breakthrough Therapy Designation in May 2014 for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant and brentuximab.
- • On July 4, 2014, Ono Pharmaceutical announced that Opdivo® received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma, making Opdivo® the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Currently, only dacarbazine, anticancer drug, monotherapy is available as standard drug therapy for the treatment of advanced melanoma in Japan. To help people who need early treatment with Opdivo® based on ethical considerations, Ono will provide access to Opdivo® free of charge as soon as it is ready. This program will be offered until the product is listed on the national health insurance (NHI) price list and at some limited medical institutions where Phase II clinical trials of Opdivo® were performed and those are prepared to accept the drug access program. Because of the very limited number of patients treated with Opdivo® in Japanese clinical trials, Ono is required to perform a post-marketing use-results survey covering all cases until data on a certain minimum number of patients have been accumulated. Through these activities, Ono should identify the characteristics of patients to be treated with Opdivo® and collect safety and efficacy data as soon as possible, thereby taking actions necessary to ensure the proper use of Opdivo®.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2014-12-22/2017-12-21
UE authorization: 2015-06-19
Favourable opinion UE: 2015-04-23
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: