CHICAGO – Two new oral targeted agents that have yielded positive results in phase III clinical trials are likely to change the treatment landscape for the half of patients with melanoma whose tumors have a mutation of BRAF driving their behavior.
The drugs – trametinib and dabrafenib – both interfere with signaling in the BRAF pathway and respectively reduced the risk of progression or death by 55% and 70% relative to chemotherapy in patients with advanced melanoma harboring common BRAF mutations, according to data presented at the annual meeting of the American Society of Clinical Oncology. These drugs also had good safety profiles.
Thus, trametinib and dabrafenib are likely to join vemurafenib (Zelboraf), the only targeted agent currently approved specifically for the treatment of BRAF-mutant melanoma.
The trials’ findings "show the promise of personalized medicine or precision medicine, using a patient-focused approach that targets treatment to the genetic abnormalities that drive cancer growth and metastatic behavior," Dr. Sylvia Adams of New York University Langone Medical Center commented in a press briefing that she moderated, where the findings were initially reported.
Dr. Sylvia Adams
In the first trial, known as METRIC, investigators led by Dr. Caroline Robert, head of the department of dermatology at the Institut Gustave Roussy in Villejuif, France, compared trametinib – an oral selective inhibitor of MEK, which lies downstream of BRAF – with chemotherapy (dacarbazine or paclitaxel) in 322 patients with V600E or V600K BRAF-mutant locally advanced or metastatic melanoma.
Patients in the trametinib group had a higher rate of grade 3 or worse hypertension (12% vs. 3%) and rash (8% vs. 0%). Cases of decreased ejection fraction or ventricular dysfunction (7%) and chorioretinopathy (less than 1%) with the drug were reversible. Of note – in contrast to what has been seen with vemurafenib – none of the patients developed cutaneous squamous cell carcinomas.
Median progression-free survival was longer with trametinib than with chemotherapy (4.8 vs. 1.5 months; hazard ratio, 0.45; P less than .0001), according to data reported at the meeting. (Full results are also being simultaneously published in the New England Journal of Medicine.)
Dr. Caroline Robert
Trametinib reduced the risk of death as well (HR, 0.54; P = .01). "Crossover was allowed," Dr. Robert noted. "That of course can blend the results of overall survival, but even in spite of this crossover in 47% of the patients [in the chemotherapy group], we still have a difference in overall survival.
"Trametinib is the first-in-class MEK inhibitor to show a statistically significant activity in progression-free survival, response rate, and overall survival benefit in a randomized trial and here in this population of BRAF-mutant melanoma patients. The safety profile is very manageable," she commented. "Thus, this phase III trial provides a really positive risk-benefit ratio of trametinib in patients with BRAF-mutant melanoma and delivers an alternate treatment option for these patients."
Dr. Robert said that she didn’t view it as problematic that oncologists may soon have to select among multiple drugs for this patient population. "Let me remind you, for 50 years, we had nothing. And very recently, we have one drug on the market, a BRAF inhibitor; now, hopefully we will have others. So we are very happy to have more than one drug. The future will tell us how to use these drugs, and we are looking forward to try[ing] the combination of BRAF and MEK inhibitors."
Dr. Adams, the press briefing moderator, characterized the findings as "exciting" for two reasons. "Number one, it shows that in metastatic melanoma, MEK pathway–targeted therapy, as seen here for MEK inhibition, is very effective. So there is tumor shrinkage; there is survival benefit for those patients. And second, it also opens the landscape of treatments for BRAF-mutant melanomas and provides patients with additional options."
In the second trial, known as BREAK-3, a team led by Dr. Axel Hauschild, professor of dermatology at the University Hospital in Kiel, Germany, compared dabrafenib, an oral inhibitor of BRAF, with chemotherapy (dacarbazine) in 250 patients with locally advanced or metastatic V600E BRAF-mutant melanoma. In this trial, 68% of patients in the chemotherapy group ultimately crossed over to the other group.
Compared with chemotherapy, dabrafenib improved median progression-free survival (5.1 vs. 2.7 months; HR, 0.30; P less than .0001). The rate of complete or partial response was more than double with the targeted therapy (53% vs. 19%).
"The data for overall survival are very immature; only 12% of the patients have died so far, and therefore the data are not presented here," Dr. Hauschild explained.