Targeted Drug Shows Potential in Advanced Solid Tumors and Brain MetastasesResults from two early-phase studies of dabrafenib, given alone or combined with another targeted drug, show that the drug is safe and may be effective for patients with advanced melanoma, melanoma brain metastases, and other solid tumors with mutations in the BRAF gene.
The first study, a phase I trial published online May 17 in The Lancet, included 184 patients with melanoma or advanced solid tumors. Of these, 179 patients had BRAF mutations in their tumors. The patients received varying amounts of oral dabrafenib to establish a safe, tolerable dose for use in further studies.
Of the 36 patients with BRAF-mutated metastatic melanoma, but no brain metastases, who received 150 mg of dabrafenib twice a day (the recommended phase II dose), half had a partial or complete response, reported Dr. Gerald S. Falchook of the University of Texas MD Anderson Cancer Center and his colleagues. But most patients developed drug resistance, with a median time to disease progression of 5.5 months.
Dabrafenib at any dose led to partial responses in patients with papillary thyroid and non-small cell lung cancer, as well as in one patient with colorectal cancer. Seven other patients with colorectal cancer, a patient with ovarian cancer, and another with a gastrointestinal stromal tumor had stable disease.
The 150 mg dose of dabrafenib taken twice per day also shrank asymptomatic brain lesions in nine of ten patients with advanced melanoma, completely eliminating them in four of these patients. The median time to disease progression for patients with brain metastases was 4.2 months. All 10 patients were alive at 5 months, and two survived beyond a year. (Patients with brain metastases typically survive for fewer than 5 months.) The researchers suggested that dabrafenib may enter the brain when metastases disrupt the blood-brain barrier, which normally keeps drugs out of the brain.
The most common adverse effects of dabrafenib treatment were skin lesions, fatigue, and fever.
Further trials of dabrafenib, including a phase II study in patients with asymptomatic brain metastases and a phase III randomized controlled study of dabrafenib versus dacarbazine in patients with BRAF-mutant advanced or metastatic melanoma, are under way.
The second trial tested dabrafenib in combination with trametinib, which targets the MEK protein, in patients with BRAF-mutant metastatic melanoma. In preclinical studies, the combination was more effective than either drug alone. Dr. Jeffrey Weber of the H. Lee Moffitt Cancer Center discussed preliminary results of the phase I/II trial at a May 16 press briefing held prior to the American Society of Clinical Oncology annual meeting .
Of the 77 patients treated with any of four doses of the drug combination, 8 percent had a complete response, 49 percent had a partial response, and 38 percent had stable disease. Among the 24 patients taking 150 mg of dabrafenib twice a day and 2 mg of trametinib once a day (the dose that will be used in the phase II study), 8 percent of patients had a complete response, 54 percent a partial response, and 38 percent stable disease. In this subset of patients, the time to disease progression was 10.8 months.
Dr. Weber noted that only 3 percent of patients who received both drugs developed squamous cell cancers, compared with 15 to 25 percent of patients in previous studies who took dabrafenib or another BRAF inhibitor alone. Although 22 percent of patients who received both drugs developed a rash, there was an almost complete absence of the acneform rash usually seen with MEK inhibitors. However, high fever was more common among patients taking the combination than in patients in previous studies who took a single BRAF inhibitor, and in some cases high fever led to a dose reduction or treatment delay.
"Obviously, we have to be cautious—it's only a cohort of 24 patients—but [the finding] looks extremely encouraging," said Dr. Weber. A phase III trial testing the drug combination in patients with advanced melanoma has just begun.