Experimental Drug Brings Remission in Eighty Percent of Melanoma Patients

Results obtained in a multicenter clinical study have revealed that treatment of metastatic melanoma with the experimental oral drug PLX4032 (RG7204) in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in nearly 80% of patients.

The protein encoded by the BRAF gene plays a role in regulating the MAP kinase/ERKs signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene have been associated with various cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, thyroid carcinoma, non-small-cell lung carcinoma, and lung adenocarcinoma. The drug PLX4032 is a potent inhibitor of proliferation of the ERK pathway in melanoma cell lines expressing the BRAF-V600E mutation (at amino acid position number 600 on the BRAF protein, the normal valine is replaced by glutamic acid). About 60% of melanomas have the V600E mutation.

In the current study, researchers at Memorial Sloan-Kettering Cancer Center (New York, NY, USA) and their colleagues conducted a multicenter phase 1 dose-escalation trial of PLX4032 followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition.

Results published in the August 26, 2010, issue of the New England Journal of Medicine (NEJM) revealed that in the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and one had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and two had a complete response. The estimated median progression-free survival among all patients was more than seven months. The side effects of PLX4032 were relatively minor and included rash, nausea, photosensitivity, fatigue, and the formation of benign squamous cell skin tumors.

"We have never seen an 80% response rate in melanoma, or in any other solid tumor for that matter, so this is remarkable,” said senior author Dr. Paul Chapman, senior researcher in the melanoma and sarcoma service at the Memorial Sloan-Kettering Cancer Center. "The tumor responses induced by PLX4032 are not always long-lasting though, and we do not know if treatment really improves overall survival of melanoma patients. That is what we are trying to find out in the ongoing phase III trial. In the future, we hope to combine PLX4032 with other anti-melanoma drugs currently being developed.”

"Metastatic melanoma is a very challenging disease to treat and there have been no significant therapeutic advances in the past 20 years. What has changed is that we learned that half of melanomas are addicted to a mutated gene called BRAF; this new, targeted drug inhibits BRAF and shuts off these tumors. We have seen many tumors shrink rapidly and, in some patients, quality of life improved dramatically,” said Dr. Chapman. "This is the beginning of personalized medicine in melanoma.”

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Memorial Sloan-Kettering Cancer Center