Metastatic melanoma was long considered untreatable and incurable. The FDA approval of ipilimumab (Yervoy) and vemurafenib (Zelboraf) ushered in a new era for this disease, and now additional treatment options are in late stages of clinical development. Dabrafenib, a novel oral BRAF inhibitor, and trametinib, a novel oral MEK inhibitor, achieved significant improvements in progression-free survival in patients with BRAF V600 mutation–positive metastatic melanoma in two separate phase III studies presented at the 2012 ASCO Annual Meeting.
BREAK-3 Trial
Interim results of the BREAK-3 trial demonstrated a 70% decrease in risk of progression or death with dabrafenib compared with standard dacarbazine chemotherapy in patients with previously untreated BRAF V600E mutation–positive metastatic melanoma.1 Significant antitumor responses were observed in at least 50% of patients, whether assessed by independent review or investigators. Both dabrafenib and dacarbazine resulted in few serious adverse events and treatment discontinuations.
“We have had no new treatments for metastatic melanoma for decades, but now that is changing with the approval of ipilimumab and vemurafenib. Dabrafenib approval could be on the horizon,” stated principal investigator Axel Hauschild, MD, Professor of Dermatology at the University Hospital in Kiel, Germany. “This study forms the foundation for further studies of dabrafenib in combination with other drugs.”
Adverse events of interest with dabrafenib included secondary squamous cell carcinoma/keratoacanthoma (7%) and phototoxicity (3%). This represents fewer skin cancers than are seen with vemurafenib, the first BRAF inhibitor to gain FDA approval for metastatic melanoma.
The BREAK-3 study randomly assigned 250 patients with unresectable stage III or IV melanoma with or without central nervous system metastasis in a 3:1 ratio to dabrafenib at 150 mg twice daily or dacarbazine at 1,000 mg/m2 IV every 3 weeks; 68% of patients who were randomly assigned to standard dacarbazine crossed over at radiologically demonstrated disease progression.
Investigator-assessed progression-free survival (the primary endpoint) was a median of 5.1 months with dabrafenib vs 2.7 months with dacarbazine (P < .0001). Best confirmed independently reviewed response (complete plus partial response) was 50% for dabrafenib vs 6% for dacarbazine. The benefit of dabrafenib was seen in all subgroups. Treatment discontinuation, dose reduction, and dose interruptions were almost identical for the two treatment arms.
Dr. Hauschild noted that the survival data are not yet mature, but crossover will make it difficult to assess survival in the dabrafenib arm.
METRIC Trial
Trametinib, a novel MEK inhibitor, delayed disease progression and prolonged survival compared with standard chemotherapy in patients with BRAF-mutated metastatic melanoma, according to an interim analysis of the phase III METRIC trial.2 This is the first phase III trial evaluating a MEK inhibitor. (See page 82 for more on this study.) Both BRAF and MEK are involved in the MAP kinase signaling pathway; MEK exerts its effect downstream from BRAF.
“This study shows that targeting the MEK molecular pathway is a viable strategy for treatment of BRAF-mutant melanoma patients,” said lead investigator Caroline Robert, MD, PhD, Head of Dermatology at the Institute Gustave Roussy in Paris. “Trametinib provides an alternative first-line option for patients with BRAF-mutated melanoma.”
Investigator-assessed median progression-free survival was significantly greater in the trametinib group: 4.8 vs 1.5 months with standard chemotherapy (P < .0001), representing a 55% risk reduction in the risk of progression. Interim overall survival was also longer in the trametinib-treated group: 81 patients (74%) were alive after 6 months of treatment vs 67 patients (56%) treated with standard chemotherapy (P = .0136). The overall confirmed response rate was 22% vs 8% for those who received chemotherapy.
METRIC enrolled 322 patients with advanced BRAF V600E/K–mutated melanoma treated with up to one prior chemotherapy regimen. Patients were randomly assigned in a 2:1 ratio to trametinib at 2 mg daily (214 patients) or standard chemotherapy with dacarbazine or paclitaxel (108 patients). Patients who progressed on chemotherapy were allowed to cross over to trametinib; about 50% crossed over. Similar to the BREAK-3 trial, crossover will compromise interpretation of overall survival in the trametinib arm.
Adverse events were generally manageable. The most commonly reported (≥ 20%) adverse events in the trametinib arm included rash (57%), diarrhea (43%), fatigue (26%), and peripheral edema (26%). Grade 3 or 4 adverse events with trametinib included skin rash (7%), chorioretinopathy (< 1%), hypertension (12%), and reduced left-ventricular ejection fraction (7%). No treatment-induced squamous cell cancers were reported.
Dr. Robert said she welcomed these new drugs for melanoma. “For 50 years, we had nothing. Very recently we had two drugs on the market, an immunotherapy agent and a BRAF inhibitor; hopefully we will have others. The future will tell us how to use these drugs, and we are looking forward to studies of BRAF and MEK inhibitors.”
Preliminary Study of Combination
A separate phase I/II trial3 reported at the Annual Meeting evaluated the combination of dabrafenib plus trametinib in treatment-naive patients with metastatic melanoma (see The ASCO Post, June 15, page 10). The rationale for combining these drugs is that they provide dual inhibition of the MAP kinase pathway.
In this preliminary trial, the data were extremely promising for the combination, producing an overall response of 56%. The confirmed response rate for dabrafenib at 75 mg twice daily plus trametinib at 1 mg once daily was 67%; median progression-free survival at that dose level was 8.7 months. Only 2% of patients developed squamous cell carcinoma, which is a lower rate than reported with vemurafenib. Phase III studies of the combination of dabrafenib and trametinib are ongoing. ■
Disclosure: Drs. Hauschild and Robert reported no potential conflicts of interest.
References
1. Hauschild A, Grob JJ, Demidov LV, et al: Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAF V600E-mutated melanoma. 2012 ASCO Annual Meeting. Abstract LBA8500. Presented June 4, 2012.
2. Robert C, Flaherty KT, Hersey P, et al: METRIC phase III 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. 2012 ASCO Annual Meeting. Abstract LBA8509. Presented June 4, 2012.
3. Weber JS: Updated safety and efficacy data from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK inhibitor trametinib (GSK 1120212) in patients with BRAFi-naive metastatic melanoma. 2012 ASCO Annual Meeting. Abstract 8510. Presented June 4, 2012.
