PLX4032: does it keep its promise for metastatic melanoma treatment?

Importance of the field: Activating mutations in the BRAF kinase gene have been identified in 50% of all melanomas. PLX4032, a selective and potent inhibitor of BRAF V600E mutant tumor cells, has shown inhibition of tumor growth in cell lines harboring BRAF V600E mutations. Data from early clinical trials showed promising results in the treatment of patients with metastatic melanoma. Areas covered in this review: An extensive literature search was conducted that included published articles and abstracts on PLX4032 to evaluate the existing data in both preclinical and Phase I-II studies. What the reader will gain: The review comprises the rationale for choosing a selective BRAF inhibitor for certain types of melanoma, its mode of action, associated toxicities and potential pitfalls. Take home message: Despite the convincing response rates in Phase I trials, duration of tumor response is limited in some patients, and a cure cannot be expected. Intrinsic and acquired PLX4032 resistance still has to be investigated; signaling pathway switching is probably the most important factor for development of resistance. Combination therapy with simultaneous inhibition of different pathways might be more effective and warrants further investigation. The toxicity profile of PLX4032 is considerably low, and special attention is needed to address the development of keratoacanthomas and cutaneous squamous cell carcinomas.