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Combination of targeted therapies slowed advanced melanoma growth

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CHICAGO —   The combination of two targeted therapy drugs, dabrafenib and trametinib, prevented advanced melanoma from worsening while causing less severe side effects than the current standard targeted therapy drug.

Prior data has determined that approximately half of all melanomas harbor a V600E mutation in the BRAF gene, as well as a highly active MEK pathway. Due to the inevitable development of drug resistance to vemurafenib, researchers hypothesize that targeting the two active pathways — BRAF and MEK — concurrently could produce a more effective initial response to treatment and delay treatment resistance.

Based on results from preclinical models in which the drug combination demonstrated enhanced activity against BRAF-mutant cancer cells vs. either drug alone, Jeffrey S. Weber, MD, PhD, a senior member at H. Lee Moffitt Cancer Center and director of the Donald A. Adam Comprehensive Melanoma Research Center, and colleagues conducted a three-part study examining the dabrafenib/trametinib combination in 125 patients with V600 BRAF mutant solid tumors.

Of these patients, 77 were melanoma patients with no prior resistance to BRAF-targeted therapy.

Patients were separated into four cohorts with escalating dose levels of dabrafenib/trametinib: 75 mg/1 mg; 150 mg/1 mg; 150 mg/1.5 mg; or 150 mg/2 mg.

“There was only a 3% incidence of squamous cell cancers across the board in this study group, which is favorably compared to 15% to 25% with either dabrafenib BRAF-inhibitor alone or with other BRAF inhibitors,” Weber said during a press conference. “There was also a 5% incidence of actinic keratosis, and 2% incidence of skin papilloma — again very favorable compared to the 20% to 40% incidence seen with BRAF inhibitors alone.”

Among the 77 melanoma patients, confirmed response rate for each dose level was 67% (n=6) for 75 mg/1 mg; 64% (n=22) for 150 mg/1 mg; 48% (n=25) for 150 mg/1.5 mg; and 54% (n=24) for 150 mg/2 mg.  Median PFS was 8.7 months for the 75 mg/1 mg dose level; 8.3 months for 150 mg/1 mg; 5.5 months for 150 mg/1.5 mg; and 10.8 months for 150 mg/2 mg. Overall median PFS for the entire group was 7.4 months (95% CI; 5.5-9.2).

“I feel the most important cohort of this study would be the patients who received the recommended phase 2 dose, which turned out to be 150 mg twice daily of dabrafenib and 2 mg daily of trametinib. Of the 24 patients in this cohort, 100% of them had partial responses, complete responses or stable disease,” Weber said. “The median progression free survival for the cohort of patients at the recommended phase 2 dose was 10.8 months, which is superior to the PFS seen in any of the other cohorts, which ranged from 5.5 to approximately 7 months.”

For more information:

Weber J. Abstract #8510. Presented at: the 2012 American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago.

Disclosure: The researchers report holding consulting and advisory positions with, as well as receiving research funding from, GlaxoSmithKline and Bristol-Myers Squibb.