Chapter 15 – Vemurafenib

Vemurafenib (Zelboraf, Hoffmann-La Roche) is a selective serine/threonine kinase inhibitor that targets BRAF mutations, and in particular BRAFV600E (IC50 10 nM). Other BRAF mutations, such as V600K, V600D, V600R, V600G, V600M, and V600A, are also strongly inhibited (IC50 7–14 nM). It also exhibits IC50 values against SRMS (18 nM), ACK1 (19 nM), CRAF (48 nM), ARAF (48 nM), MAP4K5 (51 nM), and FGR (63 nM) at similar or moderately higher concentrations. BRAF mutations are constitutively activated, and frequently associated with a number of solid tumors, including melanoma. In 2011, the Food and Drug Administration (FDA) granted approval for the treatment of patients with malignant unresectable or metastatic melanoma (MM) with the BRAF-V600E mutation, as detected by a specific test (Cobas 4800 BRAF V600 Mutation Test). The European Medicines Agency (EMA) also granted accelerated approval in 2012 for the marketing of vemurafenib for the treatment of MM with any BRAFV600 mutation. The initial safety profile of vemurafenib was based on results from Studies PLX06-02, NP22657, and NO25026, and the ISS database of 524 patients treated with vemurafenib, including 500 subjects with MM. In the outcome of the EMA assessment report, the safety population was 866 patients who received at least one dose of vemurafenib (584) or dacarbazine (282). The typical safety profile, as depicted in MM patients, is generally considered moderate, and is characterized by arthralgia, fatigue, and cutaneous disorders including rash, photosensitivity reactions, and keratotic hyper/dysproliferative conditions, followed by diarrhea, other gastrointestinal disorders, and a number of constitutional signs. More concerning events were represented by squamous cell carcinoma (mostly cuSCC), other secondary malignancies including new melanocytic tumors, QT interval prolongation, and severe liver disorders.