Date: 2016-02-25
Type of information: Positive opinion for the granting of a Market Authorisation in the EU
Product name: Opdivo®
Compound: nivolumab
Therapeutic area: Cancer - Oncology
Action mechanism: monoclonal antibody/immune checkpoint inhibitor. 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)
Disease: non-small cell lung cancer
Latest news: * On 25 February 2016, the Committee for Medicinal Products for Human Use (CHMP) has adopted two positive * On October 9, 2015, BMS announced that the FDA has approved Opdivo® (nivolumab) injection, for intravenous use, for the treatment of patients with metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy. Patients with EGFR mutation or ALK translocation should have disease progression on appropriate targeted therapy prior to receiving Opdivo®. This approval is the third for Opdivo® in the United States this year, and is based on the results of the CheckMate -057 trial, a Phase 3 trial which demonstrated superior overall survival benefit for Opdivo® vs. docetaxel in previously treated metastatic NSCLC. Biomarker testing is not required for Opdivo®. CheckMate -057 is a landmark, comparative study designed with the goal of demonstrating survival. Clinical results from CheckMate -057 were recently presented at the 2015 European Cancer Congress with simultaneous publication in the New England Journal of Medicine. This study included patients regardless of their PD-L1 (programmed death ligand-1) expression status. The primary endpoint of this trial was OS. The median OS was 12.2 months in the Opdivo arm (95% CI: 9.7, 15.0) and 9.4 months in the docetaxel arm (95% CI: 8.0, 10.7).1 The hazard ratio (HR) was 0.73 (95% CI: 0.60, 0.89; p=0.0015), which translates to a 27% reduction in the risk of death with Opdivo compared to docetaxel.1 The prespecified interim analysis was conducted when 413 events were observed (93% of the planned number of events for final analysis).1 Additional secondary endpoints include investigator-assessed objective response rate (ORR) and progression-free survival (PFS). The ORR in the Opdivo arm was 19% (56/292; 4 complete responses, 52 partial responses) (95% CI: 15, 24) and 12% with docetaxel (36/290; 1 complete response, 35 partial responses) (95% CI: 9, 17) p=0.02. The median duration of response was 17 months in the Opdivo arm and 6 months in the docetaxel arm. Median PFS was 2.3 months in the Opdivo arm vs. 4.2 months with docetaxel; HR=0.92 (95% CI:0.77, 1.11, p=0.39). The safety profile of Opdivo® in CheckMate -057 was consistent with prior studies. Serious adverse reactions occurred in 47% of patients receiving Opdivo. The most frequent serious adverse reactions in at least 2% of patients receiving Opdivo were pneumonia, pulmonary embolism, dyspnea, pleural effusions and respiratory failure. Opdivo® was discontinued in 13% of patients and was delayed in 29% of patients for an adverse reaction. The most common adverse reactions (reported in ?20% of patients) were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%) and constipation (23%). BMS has partnered with Dako, an Agilent Technologies company, to develop PD-L1 IHC 28-8 PharmDx, a test which was used to assess PD-L1 expression in the CheckMate -057 trial. This test is now approved by the FDA as a complementary diagnostic, which will provide additional information for physicians. These tests are distinct from companion diagnostics, which are essential for safe and effective use of a drug. Biomarker testing is not required for Opdivo®. Earlier this year, the FDA approved Opdivo® to treat patients with advanced squamous NSCLC whose disease progressed during or after platinum-based chemotherapy. This new approval expands the use of Opdivo® to also treat patients with non-squamous NSCLC. While patients who received Opdivo® lived longer than those who received docetaxel across the study, an evaluation of samples from a subgroup of patients’ tumors suggests that the level of PD-L1 expression in NSCLC tumors may help identify patients who are more likely to live longer due to treatment with Opdivo®. Therefore, the FDA also approved the PD-L1 IHC 28-8 pharmDx test to detect PD-L1 protein expression levels and help physicians determine which patients may benefit most from treatment with Opdivo®. The most common side effects of Opdivo® are fatigue, musculoskeletal pain, decreased appetite, cough and constipation. Opdivo® also has the potential to cause serious side effects that result from the immune system effect of Opdivo® (known as “immune-mediated side effects”). These severe immune-mediated side effects involve healthy organs, including the lung, colon, liver, kidneys, hormone-producing glands and the brain. The FDA granted Opdivo® breakthrough therapy designation for this indication based on preliminary clinical evidence that suggested Opdivo® may offer a substantial improvement over available therapies. It also received priority review status, which is granted to drugs that, at the time the application was submitted, have the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition. The approval of Opdivo® occurred approximately three months ahead of the prescription drug user fee goal date of January 2, 2016, the date when the agency was scheduled to complete its review of the application. Another drug called Keytruda® (pembrolizumab), manufactured by Merck&Co, also targets the PD-1/PD-L1 pathway and was granted accelerated approval in October 2015 for treating NSCLC specifically for patients whose tumors expressed PD-L1. * On 24 September 2015, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of the marketing authorisation for Opdivo®. The CHMP adopted a new indication as follows: “Non-Small Cell Lung Cancer (NSCLC) Opdivo® is indicated for the treatment of locally advanced or metastatic squamous non-small cell lung cancer (NSCLC) after prior chemotherapy in adults. * On September 2, 2015, BMS announced that the FDA has accepted for filing and review the supplemental Biologics License Application (sBLA) for Opdivo® for the treatment of previously treated patients with non-squamous (NSQ) non-small cell lung cancer (NSCLC). This sBLA seeks to expand the current indication for Opdivo® in patients with previously treated squamous (SQ) NSCLC. The projected FDA action date is January 2, 2016. The agency has also granted this application priority review, and Opdivo® Breakthrough Therapy Designation for this indication, underscoring the need for new treatments for this patient population, where currently a significant unmet medical need remains. According to the FDA, the criteria for Breakthrough Therapy Designation requires preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy. The submission is based on CheckMate -057, a Phase 3 study that evaluated the survival of patients with NSQ NSCLC who had progressed during or after one prior platinum doublet-based chemotherapy regimen. The positive results of a separate study, Checkmate -017, formed the basis of the current lung cancer indication; study -017 evaluated the survival of patients with SQ NSCLC who had progressed during or after one prior platinum doublet-based chemotherapy regimen. In both studies Opdivo demonstrated an overall survival benefit. * On July 23, 2015, BMS announced that the European Medicines Agency (EMA) has validated two of the company’s type II variation applications, which seek to extend the current indication for Opdivo®. Validation of the applications confirms that the submissions are complete and starts the EMA's centralized review process. In lung cancer, the proposed new indication addresses the non-squamous NSCLC population -- Opdivo® as monotherapy for the treatment of locally advanced or metastatic non-squamous NSCLC after prior chemotherapy in adults. The type II variation submitted to the EMA in non-squamous NSCLC is supported by data from the landmark, global Phase 3 study, CheckMate -057, which evaluated the survival of patients with advanced non-squamous NSCLC who had progressed during or after one prior platinum doublet-based chemotherapy regimen. * On July 20, 2015, BMS announced that the European Commission has approved nivolumab for the treatment of locally advanced or metastatic squamous (SQ) non-small cell lung cancer (NSCLC) after prior chemotherapy. This approval marks the first major treatment advance in SQ NSCLC in more than a decade in the European Union (EU). Nivolumab is also the first and only PD-1 immune checkpoint inhibitor to demonstrate overall survival (OS) in previously-treated metastatic SQ NSCLC. This approval allows for the marketing of nivolumab in all 28 Member States of the EU. Approval is based on the results of CheckMate -017 and -063. In the Phase III CheckMate -017 study, nivolumab demonstrated superior clinical benefit across all endpoints versus docetaxel, the standard of care, regardless of PD-L1 (programmed death ligand-1) expression status, including a 41% reduction in the risk of death, significantly superior OS rate of 42% versus 24% for docetaxel at one-year and superior durable antitumor activity. In the Phase II CheckMate -063 study, nivolumab showed an estimated 41% one-year survival rate and a median OS of 8.2 months. The safety profile of nivolumab is consistent with previously-reported trials, and in Checkmate -017, is also favorable compared to docetaxel. * On May 22, 2015, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending that nivolumab be granted approval for the treatment of locally advanced or metastatic squamous non-small cell lung cancer (NSCLC) after prior chemotherapy in adults. The CHMP positive opinion will now be reviewed by the European Commission, which has the authority to approve medicines for the European Union (EU). The CHMP positive opinion is based on data from CheckMate -017 and CheckMate -063, two trials that demonstrated the efficacy and safety of nivolumab in patients with advanced or metastatic squamous NSCLC who had progressed following previous chemotherapy treatment. CheckMate -017 was a Phase III, randomized, open-label trial that included patients who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. Results from a prespecified interim analysis of CheckMate -017, demonstrated significantly superior overall survival (OS) with nivolumab vs. docetaxel, with a 41% reduction in the risk of death (hazard ratio: 0.59 [95% CI: 0.44, 0.79; p=0.00025]). This benefit was observed regardless of PD-L1 expression status. The estimated one-year survival rate was nearly doubled with nivolumab (42% [95% CI: 34, 50]) compared to docetaxel (24% [95% CI: 17, 31]). The median OS was 9.2 months in the nivolumab arm (95% CI: 7.3, 13.3) and 6 months in the docetaxel arm (95% CI: 5.1, 7.3). A second study, CheckMate -063, was a Phase II single-arm, multinational, multicenter trial that included patients with metastatic squamous NSCLC who had progressed after receiving a platinum-based therapy and at least one additional systemic treatment regimen (65% of patients had received ? 3 prior therapies). In CheckMate -063, confirmed objective response rate, the study’s primary endpoint, was 14.5% (17/117) (95% CI = 8.7, 22.2) with an estimated one-year survival rate of 40.8% (95% CI: 31.6, 49.7) and median overall survival of 8.2 months (95% CI: 6.1, 10.9). In both CheckMate -017 and -063, there was consistent nivolumab dosing of 3 mg/kg every two weeks. The safety profile of nivolumab has been evaluated in thousands of patients enrolled in the broader clinical program and treatment-related adverse events (AEs) were generally managed using established safety algorithms. In CheckMate -017, the safety profile of nivolumab was consistent with prior studies and favorable versus docetaxel. Treatment-related adverse events occurred less frequently with nivolumab than docetaxel (grade 3–4, 6.9% vs. 55%, respectively). * On March 4, 2015, the FDA expanded the approved use of Opdivo® (nivolumab) to treat patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. The approval is based on the results of CheckMate -017 and CheckMate -063. CheckMate -017 was a landmark Phase III, open-label, randomized, multinational, multicenter clinical trial that evaluated Opdivo® (3 mg/kg intravenously over 60 minutes every two weeks) (n=135) vs. standard of care, docetaxel (75 mg/m2 intravenously administered every 3 weeks) (n=137), in patients with metastatic squamous NSCLC who had progressed during or after prior platinum doublet-based chemotherapy regimen. This trial included patients regardless of their PD-L1 (programmed death ligand-1) status. The primary endpoint of this trial was overall survival (OS). On average, participants who received Opdivo® lived 3.2 months longer than those participants who received docetaxel. In January, the trial was stopped based on an assessment conducted by the independent Data Monitoring Committee (DMC), which concluded that the study met its endpoint, demonstrating superior OS in patients receiving Opdivo® compared to docetaxel. The prespecified interim analysis was conducted when 199 events (86% of the planned number of events for final analysis) were observed (86 in the Opdivo® arm and 113 in the docetaxel arm). The safety and efficacy of Opdivo® to treat squamous NSCLC was supported by a single-arm trial of 117 participants who had progressed after receiving a platinum-based therapy and at least one additional systemic regimen. The study was designed to measure objective response rate (ORR), or the percentage of participants who experienced partial shrinkage or complete disappearance of the tumor. Results showed 15 percent of participants experienced ORR, of whom 59 percent had response durations of six months or longer. The most common side effects of Opdivo® are fatigue, shortness of breath, musculoskeletal pain, decreased appetite, cough, nausea and constipation. The most serious side effects are severe immune-mediated side effects involving healthy organs, including the lung, colon, liver, kidneys and hormone-producing glands. Opdivo® for squamous NSCLC was reviewed under the FDA’s priority review program, which provides for an expedited review of drugs that treat serious conditions and, if approved, would provide significant improvement in safety or effectiveness in the treatment of a serious condition. Opdivo® is being approved more than three months ahead of the prescription drug user fee goal date of June 22, 2015, the date when the agency was scheduled to complete its review of the application. This approval is the second for Opdivo® in the United States within three months. Last December, 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. * On September 29, 2014, BMS announced that the European Medicines Agency (EMA) has validated for review the Marketing Authorization Application (MAA) for nivolumab in non-small cell lung cancer (NSCLC) – the first completed regulatory submission for a PD-1 immune checkpoint inhibitor in this tumor type. The MAA submitted to the EMA in lung cancer is based on data from the Phase 2 study of nivolumabin third-line pre-treated squamous cell NSCLC (Study -063).In addition to the MAA for lung cancer in the E.U., the company previously announced that it has 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. In April 2014, BMS 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 its first Breakthrough Therapy Designation for Opdivo in May 2014 for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant and brentuximab. On July 4, Ono Pharmaceutical Co. 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. On September 26, BMS announced that the FDA accepted for priority review the 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 E.U., the EMA has validated for review the MAA for Opdivo in advanced melanoma. The application has also been granted accelerated assessment by the EMA’s Committee for Medicinal Products for Human Use (CHMP).
opinions recommending changes to the terms of the marketing authorisation for Opdivo® (nivolumab) . The CHMP adopted an extension to an existing indication as follows: "Opdivo® is indicated for the treatment of locally advanced or metastatic squamous non-small cell lung cancer (NSCLC) after prior chemotherapy in adults.”
Patents:
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: 2015-03-04 /2015-10-09
UE authorization: 2015-07-20
Favourable opinion UE: 2015-05-22/2015-09-24
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: OTC status: Other news:
