ASCO 2012

Combining the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib dramatically delays metastatic melanoma progression without the skin toxicities associated with vemurafenib therapy.

Median progression-free survival reached 10.8 months in the subset of 24 patients given the recommended dose of the two oral experimental agents in the dose-escalation portion of a phase I/II trial involving 77 patients without prior therapy targeting the BRAF kinase gene. The median for the entire cohort was 7.4 months, which was said to be comparable to results from past trials of single-agent vemurafenib.

Moreover, there were fewer dermatologic side effects than with any BRAF inhibitor alone seen to date, Dr. Jeffrey S. Weber said during a press briefing in advance of the upcoming annual meeting of the American Society of Clinical Oncology.

"Obviously, we have to be cautious. It’s only a cohort of 24 patients, but it looks extremely encouraging," he said.

Overall, cutaneous squamous cell carcinoma occurred in 3% of patients, which compares favorably with a 15%-20% incidence with dabrafenib and other BRAF inhibitors, said Dr. Weber, director of the Donald A. Adam Comprehensive Melanoma Research Center at the Moffitt Cancer Center in Tampa.

Similarly, actinic keratosis occurred in 5% of patients and skin papilloma in 2%, compared with a 20%-40% incidence seen with BRAF-targeted monotherapy. Skin rashes occurred in 22%, but the acneform rash often seen with MEK (MAP/ERK kinase) inhibitors was essentially absent in these patients, he said.

Notably, grade 3 or worse squamous cell carcinoma was reported in 12% of patients given the oral BRAF inhibitor vemurafenib (Zelboraf) in the pivotal BRIM-3 (BRAF Inhibitor in Melanoma-3) trial. Vemurafenib was approved last August for the first-line treatment of both metastatic and unresectable melanomas with V600E mutations in the BRAF gene, a mutation that occurs in roughly half of melanomas.

(Data to be presented at ASCO will show that median overall survival reached 13.2 months with vemurafenib vs 9.6 months with dacarbazine chemotherapy, according to Emmy Wang, senior manager, corporate relations at Genentech. Overall, up to 24% of patients in clinical trials experienced squamous cell carcinoma, which was easily treated, she noted.)*

The dramatic reduction in dermatologic toxicity observed in the current trial was offset, however, by a corresponding increase in pyrexia. Grade 3 or 4 pyrexia, which is relatively uncommon with a BRAF inhibitor alone, was observed in 8% of patients and led to dose reductions or delays in 23% of those patients, Dr. Weber acknowledged.

Other grade 3/4 events included nausea in 34% of patients, fatigue in 37%, and chills in 38% of patients, leading to dose reductions in 10%.

The investigators were initially surprised that combining BRAF and MEK inhibition reduced skin toxicity. But as evidence began to accumulate on BRAF inhibition in normal cells, Dr. Weber said they and other researchers realized there is a paradoxical activation of the MAP (mitogen-activated protein) kinase pathway through promotion of c-Raf signaling, which then leads down that pathway. If activation can be blocked with a MEK inhibitor, however, that would lead to a decrease in the off-target effects on normal cells that occur with a BRAF inhibitor, he explained.

ASCO president-elect Dr. Sandra M. Swain, who comoderated the press conference, said the findings show that researchers are finding more creative ways to effectively treat one of the most challenging cancers.

05/17/12  

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FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY

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