Melanoma, Vemurafenib and Ipilimumab.

Vemurafenib 

It has been approved in Europe for use in the treatment of patients with unresectable or metastatic melanoma whose tumors have a BRAF mutation. About 50% of patients with melanoma have this BRAF mutation. A companion diagnostic test, the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems), is already commercially available.A post hoc analysis showed that vemurafenib significantly improved median survival, compared with dacarbazine (13.2 vs 9.6 months): N Engl J Med 2011; 364: 2507-16.       

Potential adverse events include severe allergic reactions, severe skin reactions, cardiac events such as QT prolongation (which can be potentially life-threatening), abnormal liver function tests, eye problems, and new melanoma lesions. Common adverse effects include joint pain, rash, hair loss, tiredness, sunburn or sun sensitivity, nausea, itching, and warts.

Patients with advanced melanoma who are treated with vemurafenib should be tested for RAS mutations!! The testing is important because there is "potential for secondary tumor development" that arises from treatment with vemurafenib. Thus, patients with RAS mutations could also develop secondary cancers in organs beyond the skin, namely cutaneous squamous cell carcinoma and keratoacanthomas.

 Ipilimumab 

 

Ipilimumab is a fully human monoclonal antibody (IgG1) that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), an immune checkpoint molecule that downregulates pathways of T-cell activation. By inhibiting CTLA-4, ipilimumab acts to "release the brake" on the immune system. The role of CTLA-4 is to guard against unwanted and harmful self-directed activities (ie, autoimmunity). 

Treatment Arm	12 months (%)	18 months (%)	24 months (%)
Ipilimumab + gp100	43.6	30.0	21.6
Ipilimumab alone	45.6	33.2	23.5
gp100 alone	25.3	16.3	13.7

Hodi FS, O'Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363(8), 711–723 (2010).
•• First Phase III study to demonstrate the efficacy of ipilimumab in patients with advanced melanoma. 

 

A more recent Phase III trial comparing treatment with ipilimumab with dacarbazine versus dacarbazine alone has also provided evidence for efficacy of ipilimumab in melanoma patients with improved overall survival in the ipilimumab plus dacarbazine group (11.2 months vs 9.1 months) and durable responses in a small number of patients. Robert C, Thomas L, Bondarenko I et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364(26), 2517–2526 (2011).

The current dosing of ipilimumab is 3 mg/kg of body weight, administered by intravenous infusion over 90 minutes once every 3 weeks, for a total of 4 treatments. Disease regression has been reported 3-6 months following treatment initiation. In addition, a partial response followed by stable disease has been noted. Complete responses have been recorded approximately 1 year after receiving therapy.

The most common severe immune-mediated adverse reactions are: enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. These reactions often can be mitigated by withholding or permanently discontinuing ipilimumab, as well as by the administration of corticosteroids.