The European Medicines Agency review of ipilimumab (Yervoy) for the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy: summary of the scientific assessment of the Committee for Medicinal Products for Hum

On 13 July 2011 the European Commission issued a marketing authorisation valid throughout the European Union (EU) for ipilimumab for the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy. Ipilimumab is a monoclonal antibody that specifically blocks the inhibitory signal of cytotoxic T lymphocyte antigen 4 (CTLA-4), resulting in T cell activation, proliferation and lymphocyte infiltration into tumours, leading to tumour cell death. The recommended induction regimen of ipilimumab is 3mg/kg administered intravenously over a 90 min period every 3 weeks for a total of four doses. In a phase 3 trial in patients with advanced melanoma, median overall survival for ipilimumab was 10 months versus 6 months for gp100, an experimental melanoma vaccine (Hazard ratio (HR) 0.66; 95% confidence interval (CI): 0.51, 0.87; p = 0.0026). Ipilimumab was most commonly associated with adverse reactions resulting from increased or excessive immune activity. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of ipilimumab. The most common side-effects (affecting more than 10% of patients) were diarrhoea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite and abdominal pain. The objective of this paper is to summarise the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics (SmPC), are available on the European Medicines Agency (EMA) website (www.ema.europa.eu).

Hanaizi Z ，van Zwieten-Boot B ，Calvo G ，Lopez AS ，van Dartel M ，Camarero J ，Abadie E ，Pignatti F ... -  《-》

Ipilimumab: a novel immunostimulatory monoclonal antibody for the treatment of cancer.

Ipilimumab (Yervoy, developed by Medarex and Bristol-Myers Squibb) is a fully human monoclonal IgG1κ antibody against the cytotoxic T-lymphocyte antigen-4 (CTLA-4), an immune-inhibitory molecule expressed in activated T cells and in suppressor T regulatory cells. Interaction of the monoclonal antibody with CTLA-4 blocks inhibitory signals generated through this receptor and enhances T cell activation, leading to increased antitumor responses. Ipilimumab has been approved by FDA in March 2011 as monotherapy (3mg/kg every 3 weeks for 4 doses) for the treatment of advanced (unresectable or metastatic) melanoma both in pre-treated or chemotherapy naïve patients. Four months later, ipilimumab has received a rapid approval by the European Commission, after a positive opinion from the Committee for Medicinal Products for Human Use. However, the indication in the EU is limited to previously-treated patients with advanced melanoma. Ipilimumab is the first agent that has demonstrated to improve overall survival in patients with metastatic melanoma, which has a very poor prognosis, in randomized phase III clinical trials. The patterns of tumour response to ipilimumab differ from those observed with cytotoxic chemotherapeutic agents, since patients may have a delayed yet durable response and obtain long-term survival benefit despite an initial tumour growth. The major draw-back of ipilimumab is the induction of immune-related adverse effects; the latter can be life-threatening, unless promptly managed with immunosuppressive agents (most frequently corticosteroids) according to specific guidelines. Further development of ipilimumab includes its use in the neoadjuvant or adjuvant high-risk melanoma setting and for the treatment of other refractory and advanced solid tumours, either as single agent or in combination with additional immunostimulating agents or molecularly targeted therapies.

Graziani G ，Tentori L ，Navarra P 《-》

The European Medicines Agency review of vemurafenib (Zelboraf®) for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma: summary of the scientific assessment of the Committee for Medicinal Products for Huma

The applicant company Roche Registration Ltd. submitted to the European Medicines Agency (EMA) an application for marketing authorisation for vemurafenib. Vemurafenib is a low molecular weight, orally available, inhibitor of oncogenic V600 BRAF serine-threonine kinase. Mutations in the BRAF gene which substitute the valine at amino acid position 600 constitutively activate BRAF proteins, which will drive cell proliferation in the absence of growth factors. Results from a phase 3 trial (N=675) comparing vemurafenib 960 mg twice daily (taken either with or without food) to standard treatment dacarbazine (DTIC) in patients with BRAF V600E mutation-positive unresectable or metastatic melanoma were submitted. The study met its primary efficacy objective after an interim analysis of overall survival. Patients were allowed to cross-over to the experimental arm following disclosure of the study results after the first interim analysis. In the update of the analysis, the median overall survival (OS) was 9.9 months versus 13.2 months for DTIC and vemurafenib, respectively (HR=0.67; 95% confidence interval (CI): 0.54, 0.84; cut-off 3 October 2011). Based on the updated analysis, the CHMP concluded that a survival benefit over DTIC had been convincingly demonstrated, in the overall population. The follow-up was considered sufficiently mature with close to 50% of the events observed. The most common side effects (affecting more than 30% of patients) in vemurafenib treated patients included arthralgia, fatigue, rash, photosensitivity reaction, nausea, alopecia and pruritus. Some patients treated with vemurafenib developed cutaneous squamous cell carcinoma which was readily treated by local surgery. The objective of this paper is to summarise the scientific review of the application leading to regulatory approval in the European Union (EU). The full scientific assessment report and product information, including the Summary of Product Characteristics (SmPC), are available on the EMA website (www.ema.europa.eu).

da Rocha Dias S ，Salmonson T ，van Zwieten-Boot B ，Jonsson B ，Marchetti S ，Schellens JH ，Giuliani R ，Pignatti F ... -  《-》

The European Medicines Agency approval of axitinib (Inlyta) for the treatment of advanced renal cell carcinoma after failure of prior treatment with sunitinib or a cytokine: summary of the scientific assessment of the committee for medicinal products for

Axitinib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, and VEGFR-3. Based on the positive opinion from the European Medicines Agency (EMA), a marketing authorization valid throughout the European Union (EU) was issued for the treatment of advanced renal cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine. The demonstration of clinical benefit for axitinib was based on a phase III, randomized, open-label, multicenter study of axitinib compared with sorafenib in patients with advanced RCC after failure of a prior systemic first-line regimen containing one or more of the following agents: sunitinib, bevacizumab plus interferon-α, temsirolimus, or cytokines. In the primary analysis, a 2-month increase in median progression-free survival (PFS) was observed for axitinib compared with sorafenib (hazard ratio [HR]: 0.665; 95% confidence interval [CI]: 0.544-0.812; p < .0001). In the subgroup of patients with a prior cytokine-containing regimen, the increase in median PFS associated with axitinib was 5.4 months (updated analysis, HR: 0.519; 95% CI: 0.375-0.720; p < .0001). In the subgroup of patients with prior sunitinib treatment, the increase in median PFS was 1.4 months (updated analysis, HR: 0.736; 95% CI: 0.578-0.937; p = .0063). The analysis of overall survival showed no statistically significant survival benefit of axitinib over sorafenib in patients previously treated with cytokine-containing regimens (HR: 0.813; 95% CI: 0.556-1.191) or sunitinib (HR: 0.997; 95% CI: 0.782-1.270). The most common treatment-related adverse events associated with axitinib included diarrhea, hypertension, fatigue, nausea, decreased appetite, dysphonia, and palmar-plantar erythrodysesthesia. Most of these events were mild or moderate in severity. This paper summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu).

Tzogani K ，Skibeli V ，Westgaard I ，Dalhus M ，Thoresen H ，Slot KB ，Damkier P ，Hofland K ，Borregaard J ，Ersbøll J ，Salmonson T ，Pieters R ，Sylvester R ，Mickisch G ，Bergh J ，Pignatti F ... -  《-》

Ipilimumab: a guide to its use in advanced melanoma.

Lyseng-Williamson KA ，Sanford M 《-》