Type of information: Positive opinion for the granting of a Market Authorisation in the EU
Product name: Yervoy®
Therapeutic area: Cancer - Oncology
- monoclonal antibody/immune checkpoint inhibitor. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of ipilimumab’s effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune responses.
Company: BMS (USA - NY))
- unresectable (inoperable) or metastatic melanoma
- pediatric patients 12 years of age and older who have unresectable or metastatic melanoma
- patients with stage 3 melanoma who are at high risk of recurrence following complete surgical resection
- • On December 14, 2017, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has recommended the approval of Yervoy® (ipilimumab) for pediatric patients 12 years of age and older who have unresectable or metastatic melanoma.
- Yervoy® was evaluated in two trials of pediatric patients: a dose-finding study in 33 patients aged two to 21 years with relapsed or refractory solid tumors and an open-label, single-arm trial in 12 adolescents (ages ranging from 12 to 16 years) with previously treated or untreated, unresectable Stage III or IV malignant melanoma. The FDA expanded the approval of Yervoy® to include pediatric patients 12 years and older in July 2017.
- • On October 28, 2015, the FDA expanded the approved use of Yervoy® (ipilimumab) to include a new use as adjuvant therapy for patients with stage III melanoma, to lower the risk that the melanoma will return following surgery. Yervoy®, administered intravenously, was originally approved in 2011 to treat late-stage melanoma that cannot be removed by surgery. The safety and effectiveness of Yervoy® for this new use were studied in 951 patients who received Yervoy or a placebo as adjuvant therapy following complete surgical removal of melanoma. The study measured the amount of time after treatment it took for the cancer to come back (“recurrence-free survival”) and overall survival. Forty-nine percent of participants taking Yervoy had their cancer return after an average of 26 months, compared to 62 percent of those receiving a placebo, whose cancer returned after an average of 17 months. The analysis of overall survival data has not yet occurred.
- Clinical data from the pivotal Phase 3 trial, CA184-029 (EORTC 18071 - NCT00636168) demonstrated Yervoy® 10 mg/kg significantly improved recurrence-free survival (RFS) vs. placebo in this setting, with a 25 percent reduction in the risk of recurrence or death. The median RFS was 26 months (95% CI: 19, 39) for Yervoy® vs. 17 months (95% CI: 13, 22) for placebo (hazard ratio [HR]=0.75; 95% CI: 0.64, 0.90; p<0.002). Yervoy® is the first and only FDA-approved immune checkpoint inhibitor in the adjuvant treatment for fully resected Stage III melanoma (lymph node >1 mm).
- Yervoy is associated with a Boxed Warning and can result in severe to fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. Please see below for additional Important Safety Information, including Boxed WARNING regarding immune-mediated adverse reactions.
- • On March 2, 2015, BMS announced that the FDA has accepted for filing and review the supplemental Biologics License Application (sBLA) for Yervoy® for the adjuvant treatment of patients with stage 3 melanoma who are at high risk of recurrence following complete surgical resection. The projected FDA action date is October 28, 2015. This filing acceptance is based on clinical data from a randomized, double-blind Phase III trial, CA184-029 (EORTC 18071), assessing the efficacy of Yervoy®, at the investigational dose of 10 mg/kg, in preventing or delaying recurrence after complete resection of high-risk stage 3 melanoma.
- •On November 8, 2013, Bristol-Myers Squibb has announced that the European Commission has approved Yervoy® (ipilimumab) for the first-line treatment of adult patients with advanced (unresectable or metastatic) melanoma. When initially approved in Europe in July 2011 for the treatment of adult patients with previously-treated advanced melanoma, ipilimumab represented the first major treatment advance in this disease in more than 30 years, providing the first overall survival benefit ever seen in the treatment of metastatic melanoma in a phase III study. The recommended treatment regimen of Yervoy® is 3 mg/kg administered intravenously over a 90-minute period every 3 weeks for a total of 4 doses. The types of adverse events attributed to ipilimumab are generally mechanism (immune-) based and are managed using protocol-specific guidelines. Immune-related adverse reactions, which can be severe or life-threatening, may involve the gastrointestinal, liver, skin, nervous, endocrine, or other organ systems. The safety profile of ipilimumab 3 mg/kg in chemotherapy-naive patients pooled across phase II/III clinical trials (N= 75) and in treatment naïve patients in a retrospective observational study (N= 120) was similar to that in previously-treated advanced melanoma.
The extension of the Marketing Authorisation was supported by data derived from phase 2 and 3 studies conducted in advanced melanoma patients, as well as from two retrospective observational studies in first-line advanced melanoma patients who were treated with ipilimumab 3mg/kg monotherapy. These observational data were presented at the European Cancer Congress (27 September - 1 October 2013). Overall survival (OS) of ipilimumab 3 mg/kg monotherapy in chemotherapy-naive patients pooled across phase 2 and 3 clinical trials (N= 78; randomised) and in treatment-naive patients in two retrospective observational studies (N= 120 and N= 61) were generally consistent.The estimated 1-year survival rates were 59.5% (95% CI: 50.1 - 67.8) and 49.3% (95% CI: 35.6 - 61.6) in the two retrospective observational studies. The estimated 1-year and 2-year survival rates for chemotherapy-naive patients (N= 78) pooled across phase 2 and 3 clinical trials were 54.1% (95% CI: 42.5 - 65.6) and 32% (95% CI: 20.7 - 42.9), respectively.
• On 19 September 2013
, the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending a variation to the terms of the marketing authorisation for Yervoy®. The CHMP adopted a change to the indication, extending the use of the medicine to previously untreated patients. The change adopted is as follows:“Yervoy® is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults."
• On March 25, 2011, BMS also announced that it has agreed with the FDA to conduct a post-marketing study comparing the safety and efficacy of the 3 mg/kg dose vs. an investigational 10 mg/kg dose in patients with unresectable or metastatic melanoma.
• On May 20, 2011, the CHMP has adopted a positive opinion recommending the granting of marketing autorisation for Yervoy® (ipilimumab), from Bristol-Myers Squibb Pharma EEIG, intended for the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy.
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: 2011-03-25/2015-10-28/2017-12-18
UE authorization: 2011-07-13
Favourable opinion UE: 2011-05-20/2017-12-14
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: