Ipilimumab for patients with metastatic melanoma

PICHON RIVIERE, A.; AUGUSTOVSKI, F.; GARCIA MARTI, S.; GLUJOVSKY, D.; ALCARAZ, A.; LOPEZ, A.; BARDACH, A.; CIAPPONI, A; REY-ARES, L.; CACCAVO, F

Documento de Evaluación de Tecnologías Sanitarias

IECS

Año: 2012 p. 1 - 30

1668-2793

Melanoma is the most aggressive form of skin cancer and it is generally fatal if not timely detected and treated. Its incidence is approximately three to five every 100,000 people. At the time of diagnosis, 10% of the cases already have metastases. Average survival of patients with metastatic melanoma is six to nine months, with a 15% 5-year survival. At present, there is no consensus on first or second line treatment; chemotherapy, radiotherapy and immunotherapy are some of the choices, all of them with very low efficacy. Ipilimumab is proposed as a therapeutic alternative for metastatic melanoma.TechnologyIpilimumab is a monoclonal human antibody that would interfere with the interaction between CTLA-4 and its ligand (B7) in the antigen presenting cell, blocking the immunomodulating function, increasing the number and activity of T lymphocytes which would attack the tumor.Treatment consists of intravenous administration of 3 mg/kg Ipilimumab, every three weeks. The complete scheme consists of 4 doses which should be administered based on tolerance and regardless of the presentation of new lesions or growth in the existing ones.PurposeTo assess the available evidence on the efficacy, safety and issues related to coverage policies for the use of ipilimumab in patients with metastatic melanoma.MethodsA bibliographic search was carried out on the main databases: DARE, NHS EED, on Internet general search engines, in health technology evaluation agencies and health sponsors. Priority was given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCTs); health technology assessments and economic evaluations; clinical practice guidelines and coverage policies of other health systems.ResultsIn this report, one systematic review, one randomized clinical trial (RCT) and coverage information from 7 health sponsors were used.In April 2011, one systematic review assessed 1 RCT, 1 quasi-experimental study and 3 Phase II studies. The RCT randomized 676 patients to 3 mg/kg ipilimumab and the gp100 vaccine, ipilimumab alone or the gp100 vaccine alone. Those patients who received ipilimumab and gp100 had a higher mean overall survival when compared with gp100 alone (10 vs. 6.4 months, RR = 0.68, p <0.01). It also showed benefits in overall survival in the group receiving ipilimumab as monotherapy in comparison with gp100 (10.1 vs. 6.4 months, RR=0.66, p<0.01). There was no significant difference in the overall survival between the groups receiving ipilimumab (RR = 1.04, p=0.76). More than 80% of the participants reported treatment related events (immune-related). The most common ones are mild (rash, itching, diarrhea) and with good response to the systemic administration of corticosteroids.In 2011, one RCT assessed 502 patients with treatment-naive unresectable or metastatic melanoma who received 10 mg/kg ipilimumab and 850 mg/m2 body surface dacarbazine or placebo and dacarbazine at the same dose. Mean survival rate for the ipilimumab-dacarbazine group was 11.3 months vs. 9.1 months in the dacarbazine group, with survival rates in both groups after 3 years of 20.8% and 12.2% respectively (RR for death with ipilimumab-dacarbazine: 0.72; P<0.01). Approximately 56.3% of the patients treated with ipilimumab plus dacarbazine experienced Grade 3 or 4 events, compared with 27.5% in the group treated with dacarbazine and placebo (P<0.001). There were no drug-related deaths or gastrointestinal perforations in the ipilimumab plus dacarbazine group.The health sponsors surveyed agreed to approve ipilimumab as first and second-line treatment for patients with unresectable and metastatic melanoma with a life expectancy longer than 4 months, in ambulatory conditions and capable of performing low intensity activities and who are not receiving immunosuppressive or glucocorticoid therapy.In Argentina, the cost of 50 mg ipilimumab is U$S 6.000 (VAT not included). The complete ipilimumab scheme is 4 doses of 3 mg/kg.ConclusionsThe ipilimumab use for the treatment of metastatic melanoma, both as first and second line therapy should be assessed considering that, currently, there is no standard treatment for this disease, although the use of dacarbazine is widespread.Even though the evidence found comes from RCTs, none of the studies directly compared ipilimumab versus dacarbazine or placebo. Ipilimumab as monotherapy proved to be better than the gp100 vaccine and in combination with dacarbazine, proved to be better than dacarbazine as monotherapy.Although its cost-effectiveness has not been evaluated, it should be considered that the cost of the ipilimumab therapy is approximately 40 times higher than that of dacarbazine therapy.