Novel BRAF Inhibitor Yields Dramatic Responses in Metastatic Melanoma
Dramatic results in patients with advanced metastatic melanoma were reported for a compound that blocks the BRAF mutation in melanoma, which occurs in about 50% of melanomas and about 8% of other solid tumors.
At the ECCO 15 - ESMO 34 Joint Congress, Paul Chapman, MD, an attending physician at Memorial Sloan-Kettering Cancer Center, New York, reported the dramatic results of the phase I extension study of the novel targeted compound PLX4032 (Plexxikon, Inc) in patients with advanced metastatic melanoma. PLX4032 is a compound that blocks the BRAF mutation, which occurs in about 50% of melanomas and about 8% of other solid tumors. PLX4032 has recently entered a phase II trial in the US and Australia, and a worldwide phase III trial will commence in December 2009.
The study included 31 patients with advanced (mostly stage M1c) disease, who received 960 mg of PLX4032 twice daily until disease progression. Most patients had multiple metastatic sites and had received prior treatment.
Among 27 evaluable patients, 18 partial responses were noted and 1 complete response, for an overall response rate of 70%. After data cut-off an additional patient achieved a complete response. “Of the 27 patients, 25 had tumor shrinkage. Nineteen had shrinkage of more than 30% and 15 had shrinkage of more than 50%,” Dr Chapman reported at a press briefing. “To put this into context, with conventional chemotherapy we expect a response rate of only 13% to 15%.”
Many patients experienced rapid symptomatic improvement. On positron emission tomography, performed at baseline and on or around day 15, patients with extensive liver and bony metastases showed widespread disappearance of glucose uptake. “The tumors become metabolically quiet,” noted Dr Chapman. “In fact, they actually shrink.” Median progression-free survival has not been reached, and many patients are continuing on treatment.
PLX4032 was well tolerated, and the main side effects were fatigue, photosensitivity, and rash, virtually all grade 1 or 2; however, 23% of patients developed squamous cell carcinomas, which were treated by excision. The reason for this was unclear, he said.
Chris Twelves, MD, Professor of Clinical Cancer Pharmacology at the Institute of Cancer Therapeutics, University of Bedford, UK, who moderated the press briefing, commented, “These findings have never been seen in melanoma. If this pans out, it will be a once-in-a-generation type of drug. This is potentially remarkable data.”
Dr Chapman added that BRAF is only one of an emerging plethora of mutations in melanoma. “We are beginning to think in terms of genotypes in melanoma, with BRAF being the most common.” Screening for BRAF and other mutations will undoubtedly become universal in this disease, as it is in other tumor types. “We won’t be able to treat it effectively,” he explained, “without knowing mutation status.”
ECCO/ESMO Abstract 6BA
