Two New BRAF-Targeted Therapies Reduce Disease Progression in Advanced Melanoma Patients

Targeted therapies and personalized medicine were a focus of the 2012 ASCO Annual Meeting

Trametinib and dabrafenib, two drugs designed specifically to inhibit pathways associated with BRAF-mutated melanoma, delayed disease progression and showed a trend toward improved survival in patients with advanced melanoma.

The results of two separate studies regarding these targeted therapies were presented on Monday at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

The mitogen-activated protein kinase (MAPK) pathway is associated with cellular growth and survival of tumors. Within the MAPK pathway are two genes, BRAF and MEK, that have been associated with disease progression in patients with melanoma. A specific mutation within the BRAF gene, V600E, is found in nearly 50% of melanoma patients. BRAF inhibitors represent a promising new class of drugs for melanoma patients, especially after one such drug, vemurafenib (Zelboraf, Genentech/Daiichi-Sankyo), was the first new major treatment option approved by the FDA in several years for advanced melanoma patients, receiving approval in August 2011.

However, patients who have received vemurafenib have been found to have an increased risk of developing a secondary malignancy— squamous cell carcinoma (SCC)—as a result of the treatment. Hence, researchers have been looking toward inhibiting the MEK gene as a means of preventing such malignancies from developing.

Trametinib

Two studies focused on how drugs designed to target each of these genes have shown improved outcomes in patients with advanced melanoma.A study presented on Monday showed some of the results from the phase III METRIC trial, which tested the efficacy of trametinib, a MEK inhibitor, to determine if it was capable of improving progression-free survival (PFS) in advanced or metastatic melanoma patients with the BRAF_V600E/K mutation.

Caroline Robert, MD, PhD

"Trametinib is a very potent and selective inhibitor of this protein and has already shown efficacy in phase I and phase II trials," said Caroline Robert, MD, PhD, head of dermatology at the Institute Gustave Roussy in Paris, France, and lead author of the study. "Because MEK is downstream from BRAF in the MAPK pathway, you have less risk to have another activated event further downstream."

The study enrolled 322 patients with advanced BRAF-mutated melanoma who had received up to one prior chemotherapy regimen. Those patients were randomized in a 2:1 ratio to receive either trametinib (214 patients) or a standard chemotherapy regimen of dacarbazine or paclitaxel (108 patients).

According to the results presented on Monday, patients in the trametinib group experienced a PFS period of 4.8 months compared with 1.5 months in the chemotherapy group, a 55% reduction in the risk of progression of the disease (hazard ratio[HR] = 0.44; 95% CI, 0.31-0.64, P < .0001). An interim analysis showed that there was also improvement in overall survival with a 46% reduced risk of death (HR = 0.53; 95% CI, 0.30-0.94; P = .0181). The overall response rate to trametinib was 22% compared with 8% in the chemotherapy group.

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Dr. Robert on the Trametinib METRIC Trial Results

Robert noted that the overall survival data could be affected by the fact that approximately 47% of patients in the chemotherapy group crossed over into the trametinib arm. Normally, crossover would show that the overall survival rates in both arms would be similar, but Robert said that despite this, there is still a difference observed, suggesting that the drug is effective early on in treatment.

Dabrafenib

"We have better PFS; we have a better response rate; and, what I would say is the ultimate goal of cancer treatment, we have significant prolonged survival," Robert said.Another trial presented on Monday discussed the results of the BREAK-3 trial, a multicenter phase III randomized, open-label study that compared the BRAF inhibitor dabrafenib to dacarbazine (DTIC) in metastatic melanoma patients with mutated BRAF.

Axel Hauschild, MD

"The dabrafenib trial has almost the same design as the BRIM-3 trial—the trial that investigated vemurafenib&mdash;although it is a 3:1 randomization simply because we knew that BRAF inhibitors are doing well in the patients from phase II data and from the randomized phase III data," said Axel Hauschild, MD, professor of Dermatology, University Hospital in Kiel, Germany, who was the lead author of the study.

In this study, 250 previously untreated, inoperable stage III or IV melanoma patients were randomized in a 3:1 ratio to receive either dabrafenib in a 150-mg oral dose twice daily (187 patients) or DTIC as standard chemotherapy (63 patients). The primary analysis of this study found that the median PFS was 5.1 months in patients who received dabrafenib compared with 2.7 months in the DTIC arm. The confirmed response rate was 53% of dabrafenib, compared with 19% for DTIC. Because of the early reporting of these results, the overall survival (OS) data were not mature and therefore not presented at the ASCO meeting. Likewise, patients in the DTIC arm were allowed to cross over as in the trametinib study, so the authors do not expect to see robust OS improvement in these particular results. In the dabrafenib arm, investigator-assessed review found that 99 patients (approximately 53%) achieved either complete or partial response.

Thirteen patients in this study developed SCC, and nine of those patients developed grade 3 SCC. No patients developed grade 4 SCC. However, no patients in the METRIC study of trametinib developed SCC.

Last month, ASCO released the interim results of a phase I/II study that explored the efficacy of combining dabrafenib and trametinib. The median PFS in patients who received the combination of both therapeutic agents was 7.4 months, although PFS was 10.8 months in patients who received a specific dose of 150 mg of dabrafenib twice daily and 2 mg of trametinib once daily. The ORR for that study was 56%, similar to what was observed in the phase III dabrafenib study. Although further studies need to be done, Hauschild said he believes that the combination of both therapies holds promise for advanced melanoma patients.

"It makes sense to believe that the combination of dabrafenib and trametinib produces better results, although superficially, the response rate appears to be the same," Hauschild said.

Robert C, Flaherty KT, Hersey P, et al. METRIC Phase 3 study: efficacy of trametinib, a potent and selective MEK inhibitor, in progression-free survival and overall survival, compared with chemotherapy in patients with BRAF_V600E/K mutant advanced or metastatic melanoma. J Clin Oncol. 2012:30(suppl; abstr LBA8509).

Hauschild A, Grob JJ, Demidov LV, et al. Phase III, randomized, open-label, multicenter (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine in patients with BRAF ^V600E-mutated melanoma. J Clin Oncol. 2012:30(suppl; abstr LBA8500).

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