Chicago, IL—At the 2012 American Society of Clinical Oncology meeting, attendees flocked to sessions on the treatment of melanoma to hear about the next generation of agents that are building on the success achieved with the BRAF inhibitor vemurafenib (Zelboraf), and the immunotherapy drug ipilimumab (Yervoy), which have added new treatment options where, not long ago, none existed.
In two phase 3 studies, the investigational BRAF inhibitor dabrafenib and the first-in-class MEK inhibitor trametinib, as single agents, led to encouraging outcomes in advanced disease. In a phase 1/2 dose-finding study, the combination of the 2 inhibitors was especially impressive.
As Single Agents, Drugs Were Effective
The global BREAK-3 trial of 250 previously untreated BRAF-positive patients showed median progressionfree survival (PFS) of 5.1 months with dabrafenib and 2.7 months with standard dacarbazine (DTIC) treatment, representing a 70% reduction in risk (P <.001), reported Axel Hauschild, MD, Professor of Dermatology, Uni - versity Hospital in Kiel, Germany.
In a related phase 2 study of dabrafenib in 172 patients with brain metastases, other investigators reported an unprecedented overall intracranial disease control rate of 81% in patients with no prior treatment and 89% for previously treated patients.
In the METRIC study of 322 patients previously treated with chemotherapy (but not vemurafenib), after treatment with the MEK inhibitor trametinib, the median PFS was 4.8 months with trametinib compared with 1.5 months with chemotherapy, a 55% reduction in risk (P <.001), reported Caroline Robert, MD, PhD, Professor of Dermatology at the Institut Gustave Roussy, Paris, France.
“This is the first in a new class of targeted drugs that could benefit patients with melanoma who have BRAF mutations. The findings show that targeting the MEK molecular pathway is a viable strategy. Trametinib is likely to become another first-line treatment option for patients with advanced melanoma,” Dr Robert said.
Dual Inhibition May Work Even Better When both dabrafenib and trametinib were combined to create dual inhibition of 2 related molecular pathways (MEK is downstream of BRAF), an even more powerful effect was observed, other investigators reported.
The combination was tested in varying doses in 125 advanced melanoma patients with the BRAF mutation. The current efficacy analysis focused on 77 patients who had not received prior BRAF-targeted therapy and thus had demonstrated no resistance to vemurafenib.
The results included complete responses in 8% of patients, partial responses in 49%, and stable disease in 38%, for an overall disease control rate of 95%. However, among the 24 patients who received twice-daily 150-mg dabrafenib plus 2 mg/day of trametinib (assumed to be the optimal dose), 100% of patients achieved disease control or better, and no patients progressed on therapy, reported Jeffrey S. Weber, MD, PhD, Director, Donald A. Adam Comprehensive Research Center, Senior Member at Moffitt Cancer Center, Tampa, and Professor and Associate Chair, De - partment of Oncologic Sciences, University of South Florida.
The median PFS was 7.4 months, which rose to 10.8 months in patients who were optimally dosed. It is important to note that these outcomes were achieved with far less dermatologic toxicity (14%) than is normally observed with single-agent vemurafenib or with either of the investigational agents alone, he said.
“Certainly this is an impressive record by any assessment,” Dr Weber suggested. “It’s fascinating to find such promising effects with this combination regimen.”
“Not only are the 2 drugs causing shrinkage of the cancer, but we’re seeing that a second anticancer therapy may actually suppress the side effects of the first,” he explained. “There is a significant diminution of the dermatologic toxicities, such as just 3% squamous cell carcinomas, which can favorably be compared to 15% to 25% seen with this drug alone or other BRAF inhibitors.”
In discussing the exciting new re - search, Michael B. Atkins, MD, Deputy Director of Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, said that BREAK-3 establishes dabrafenib as the second BRAF inhibitor with proven efficacy, and he suggested that “competition is good” in the field of oncology.
“Despite recent advances, metastatic melanoma is still a bad disease,” he concluded. “We need to pause to celebrate, but then begin work to raise the bar higher.”
