Dr. Schindler is a research fellow at the Dermatology Service and Dr. Postow is the assistant attending physician at Melanoma and Sarcoma Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York.
Though targeting oncogenic BRAF directly has been incredibly successful for patients with BRAF-mutant metastatic melanoma, additional success has been observed by blocking the MAPK pathway at a downstream component, MEK. Trametinib is an MEK inhibitor that was approved by the FDA in June 2013 as a single agent for patients with BRAF V600E or V600K mutant melanoma. Trametinib is administered at a dose of 2 mg once daily and was shown to improve PFS and OS compared with dacarbazine and paclitaxel chemotherapies.47 Despite the improvement in PFS and OS compared with chemotherapy, the objective RR for trametinib was somewhat lower (22%) than that seen with BRAF inhibitors.
Trametinib also is associated with a different AE profile from BRAF inhibitors and includes diarrhea, peripheral edema, hypertension, and fatigue, typical of other MEK inhibitors as well.48 Asymptomatic and reversible reduction of the cardiac ejection fraction and ocular toxic effects also occur infrequently. Unlike with BRAF-inhibitor treatment, the development of cutaneous squamous-cell carcinomas or other hyperproliferative skin lesions was not noted.49
Despite the significant benefits of targeted therapy disrupting overly active MAPK signaling in patients with BRAF-mutant metastatic melanoma, almost all patients treated with these targeted inhibitors who achieve an initial response will ultimately progress. Several mechanisms of resistance have been proposed, and most relate to reactivation of the MAPK pathway.50,51 As a result, efforts to maintain suppression of the MAPK pathway have been pursued to delay the onset of resistance. In a phase 2 trial that combined dabrafenib with trametinib, there was a longer PFS than there was with dabrafenib monotherapy.52
Furthermore, the addition of trametinib to dabrafenib reduced the incidence of squamous-cell carcinoma, providing further evidence that reactivation of the MAPK pathway is involved in these hyperproliferative skin lesions arising under BRAF-directed therapy. A higher rate of febrile episodes was seen, however. An ongoing phase 3 study is looking at whether or not combining BRAF and MEK inhibitors results in improved OS compared with single-agent BRAF. It is premature at this juncture to recommend combining dabrafenib and trametinib until the results of the ongoing phase 3 studies more thoroughly describe the risks and benefits of this approach (Table 2).
KIT inhibitors
In a subset of melanomas, particularly those that arise from mucosal, acral, or chronically sun-damaged skin, mutations are found in the receptor-tyrosine kinase KIT.35 A number of agents directed against KIT, such as imatinib, have been tested in clinical trials. Initial phase 2 studies revealed poor RRs with KIT inhibition in molecularly unselected patients.53-55 Subsequent studies selected patients with KIT genetic aberrations, including mutations and amplifications, and some responses were seen.56-58
Importantly, not all KIT genetic aberrations are believed to be considered equal. Preliminarily, it appears that mutations in exon 11 (L576P) and exon 13 (K642E) appear to be most closely associated with response and may be true driver mutations. Other KIT mutations may have less functional significance but additional research is needed. Imatinib is a reasonable therapeutic choice in patients with a KIT mutation, particularly when an L576P or K642E mutation is present.
conclusions
Since 2011, 4 new drugs—ipilimumab, vemurafenib, dabrafenib, and trametinib—have been approved for the treatment of metastatic melanoma. Exciting early data from PD-1 clinical trials suggest that agents that disrupt PD-1 may also become important therapeutic modalities. Future studies will continue to evaluate combinations of these therapeutic modalities, but caution should be exercised in combining these drugs prior to data from ongoing clinical trials revealing the true benefits and risks of combination therapy. Excessive toxicity was seen in an early phase trial when vemurafenib was combined with ipilimumab.59
Additional research will also explore biomarkers that may help clinicians apply immunotherapy to the most appropriate patients and better understand mechanisms of resistance to targeted therapies. Clinical trials of novel agents or combinations should be considered at every treatment juncture to continue the rapid pace of developing the most innovative and tailored treatment approaches.
Author disclosures The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
