Researchers involved in a U.S.-Australian Phase I study have reported significant activity for PLX4032 in the treatment of patients with advanced melanoma. The details of this study were presented as a late-breaking abstract at the Joint ECCO 15-34^th ESMO Multidisciplinary Congress in Berlin, September 20-24, 2009.[1]

Patients with metastatic melanoma have a very poor outcome with current therapies. The median progression-free survival for a patient with metastatic melanoma is less than two or three months with an average survival of less than a year. Patients who develop metastatic melanoma are rarely cured with available treatments.

Chemotherapy, biological agents, or combinations of both have had little impact on survival of patients with metastatic melanoma. However, there has been recent interest in evaluating new targeted agents for the treatment of melanoma. For example, Nexavar® (sorafenib) has been shown to improve progression-free survival in patients with advanced melanoma receiving dacarbazine. More recently, researchers from Belgium have reported that Sutent® (sunitinib) benefits one-third of patients with advanced malignant melanoma who have previously failed dacarbazine-based chemotherapy.

PLX4032 is a novel, oral, and highly selective drug that targets the BRAFV600E cancer-causing mutation that occurs in 60% of melanomas and 10% of colorectal cancers. The current study included 55 patients with solid tumors including melanoma enrolled in the dose-escalation phase with 30 of these patients receiving “optimized doses.” Dose-limiting toxicities were pruritis, rash, and arthralgias. Squamous cell skin cancer occurred in four patients. The dose escalation part of the study included 16 patients with advanced melanoma with an activating BRAF mutation. Eleven of the 16 patients with BRAF mutations had a partial response (PR).

Thirty additional patients have been treated at the maximum tolerated dose, and 22 were evaluable for response. The PR rate in this second cohort of patients was 64% with an additional six patients having a response but not fulfilling the requirement for PR. Responses were observed in subcutaneous sites, liver, lung, GI, and bone. Responses were associated with resolution of symptoms. Disease control was reported to last up to 14 months with many patients still receiving treatment. The interim median progression-free survival of was six months with many responding patients still receiving treatment.

There were no responses observed in patients without the BRAF, and progression-free survival was less than two months. Side effects included primarily rash, fatigue, and joint pain and were seen at 1120 mg BID.

Comments: PLX4032 appears to be a very active drug in patients with melanoma and possibly other tumors that contain the oncogenic V600E mutant BRAF kinase. Other studies are apparently planned for selected patients with colorectal and thyroid cancer. The fact that four patients developed squamous cell skin cancer is of major interest, and there is concern about the development of other second malignancies.

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