CHICAGO—At the end of the last full day of this year's meeting of the American Society of Clinical Oncology, researchers presented persuasive evidence that a new class of targeted agents—MEK inhibitors—may warrant inclusion in the growing armamentarium for patients with advanced BRAF-mutated melanoma. Caroline Robert, MD, PhD, head of dermatology at the Institut Gustave Roussy in Paris, presented data from the phase III METRIC trial of the investigational MEK inhibitor trametinib. The data showed that monotherapy with trametinib resulted in a 55% reduction in the risk of progression compared with standard chemotherapy in patients with advanced BRAF-mutated disease.
In addition to their potential as a stand-alone therapy, MEK inhibitors may also produce added benefits when used in combination with a BRAF inhibitor. Jeffrey S. Weber, MD, PhD, director of the Donald A. Adam Comprehensive Melanoma Research Center at the H. Lee Moffitt Cancer Center, presented phase I/II data showing that the combination of trametinib and dabrafenib (a BRAF inhibitor) resulted in an impressive 10.8-month median progression-free survival in those BRAF-mutated patients who received the highest dose; in addition, the incidence of BRAF-related hyperproliferative skin lesions was noticeably lower than in patients who receive BRAF-inhibitor monotherapy.
MEK, a protein kinase immediately downstream of BRAF in the RAS/RAF/MAPK/ERK pathway, has been under investigation as a potentially useful target for over a decade. The early MEK inhibitors had problems with bioavailability and serious ocular adverse events. Now, these issues appear to have been resolved. In the METRIC trial, trametinib demonstrated both efficacy and tolerability. The MEK inhibitor showed a statistically significant progression-free survival benefit and a very significant overall survival benefit, despite the fact that crossover was allowed (overall survival at 6 months: 81% in the trametinib arm vs 67% in the chemotherapy arm). The agent also had what Dr. Robert described as “very manageable” toxicity: very few grade 3/4 adverse events were seen. The discussant at the clinical science symposium at which the MEK inhibitor data were presented, Patricia M. LoRusso, DO, of the Karmanos Cancer Institute, noted that the possibility of MEK-inhibitor monotherapy might be a welcome option for BRAF-mutated patients who cannot tolerate BRAF inhibitors.
Because it has been shown that restoration of MEK signaling can result in resistance to BRAF inhibitors, it had been postulated that simultaneous MEK inhibition and BRAF inhibition might be able to overcome resistance to selective BRAF inhibitors, a common and vexing problem in patients who receive BRAF-inhibitor monotherapy. This was the genesis of the trametinib plus dabrafenib combination trial. Dr. Weber offered the following analogy to explain the study’s rationale: “Think of yourself as a thief fleeing down a road. Up the road is a roadblock. If you’re a thief, you’re going to get off the road, bypass the roadblock, and get back on the road. But if you could not only have the roadblock up the road, but also block off all the exits, the thief couldn’t get off the road. The thief gets stopped. The tumor will be destroyed, and you will discourage resistance.” Although Dr. Weber urged caution because of the small numbers of patients involved, the data he presented did appear to confirm this hypothesis; the median progression-free survival seen in the combination study—10.8 months at the highest dose—was significantly greater than is seen with BRAF-inhibitor monotherapy (Dr. LoRusso noted that the latest progression-free survival data for vemurafenib, at 12.5 months, showed a median progression-free survival of 6.9 months). Dr. Weber predicted that eventually 2- and 3-year survivals would be seen, although the survival data are still not mature.
Along with reducing the development of resistance, it appears that adding a MEK inhibitor to BRAF-inhibitor therapy might also reduce the toxicity often seen with BRAF inhibitors. The rates of squamous cell carcinoma (2%) and actinic keratosis (2%) in the patients who received the combination therapy were significantly lower than rates typically observed in patients who receive BRAF-inhibitor monotherapy. Dr. LoRusso offered a possible explanation: BRAF inhibitors turn on ERK, a mechanism for skin toxicity, while MEK inhibitors inhibit activation of ERK.
At the beginning of her discussion, Dr. LoRusso posed the question, “Is it time for a MEK inhibitor as part of the melanoma armamentarium?” Her conclusion was unequivocal: “Absolutely! The oncology community is ready for a MEK inhibitor.”