Dr. Goyal is a house officer in the Department of Internal Medicine and Dr. Silberstein is a professor and chief of Hematology/Oncology, both at CHI Health Creighton University Medical Center in Omaha, Nebraska. Dr. Silberstein is also the chief of oncology at VA Nebraska-Western Iowa Healthcare System in Omaha.
References
Another BRAF inhibitor, dabrafenib, was approved by the FDA for treatment of advanced melanoma with BRAF V600E mutation. It was tested in a phase 3 trial in which it was compared with dacarbazine in patients with advanced melanoma. Median OS in the dabrafenib arm was > 18 months and in dacarbazine arm > 15 months. 40 Fifty-seven percent of the patients in dacarbazine arm were crossed over to the dabrafenib arm, thereby confounding the survival data for the former group. Another multicenter, phase 2 trial showed dabrafenib to have activity in melanoma patients with brain metastases, irrespective of previous therapy for the brain metastases. 41 The long-term analysis of the BREAK-2 trial, which included 92 patients with metastatic melanoma treated with dabrafenib, showed a median OS of 12.9 months in BRAF V600K group and 13.1 months in BRAF V600E group. 42
Adverse effects associated with BRAF inhibition include fatigue, rash, arthralgia, and photosensitivity reactions. 43 Dermatologic complications may also include squamous cell carcinoma (SCC) (19%-26%), with keratoacanthoma being the most common subtype. 44 These are believed to be likely secondary to the paradoxical activation of the MAPK signaling, since most of these lesions are found to have mutations in the RAS molecule. 45 Other specific AEs of dabrafenib include hyperkeratosis (33%) and pyrexia (29%). 42
Most patients treated with a BRAF inhibitor eventually have disease progression, likely secondary to reactivation of the MAPK pathway. 46,47 This result has led to a heightened interest in combination therapies in an effort to improve outcomes. Combination therapy with ipilimumab and vemurafenib was studied and resulted in a higher incidence of hepatotoxicity (50%). 48 However, no hepatotoxicity was seen in a phase 1 trial of combined dabrafenib and ipilimumab. 49
Some studies have also suggested that extended BRAF inhibition after progression on a BRAF inhibitor may prolong survival. 50,51 The phase 2 trial NCT01983124 is being conducted to evaluate the survival benefit with a combination of vemurafenib and a nitrosourea alkylating agent, fotemustine, in patients who have progressed on vemurafenib alone.
MEK Inhibitors
The inhibition of MEK can halt cell proliferation and induce apoptosis. The phase 3 METRIC trial, which compared the oral MEK inhibitor (trametinib) with chemotherapy, was conducted in 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation. The PFS and 6-month OS were significantly better with trametinib (4.8 months vs 1.5 months, 81% vs 66%) despite the crossover between the 2 groups. 52 The AEs associated with trametinib included rash, diarrhea, and peripheral edema. Another phase 2 trial of trametinib including patients pretreated with a BRAF inhibitor showed no confirmed objective responses, 28% patients with stable disease, and minimal improvement in PFS (2 months). Among patients treated with prior chemotherapy and/or immunotherapy, trametinib showed significant improvement in complete responses, partial responses, stable disease, and the median PFS (2%, 23%, 51%, 4 months, respectively). 53
The second MEK inhibitor, binimetinib, was studied in a phase 2 trial of advanced melanoma cases harboring a BRAF V600E or NRAS. Bimetinib demonstrated a PR in 20% cases of both the BRAF and NRAS mutant melanomas. Durable disease control was seen in 43% of the NRAS group and 32% of the BRAF group.54 The AE profile was similar to that seen with trametinib. Bimetinib is being studied in phase 1 and 2 trials with the CDK4/6 inhibitor as well as in the phase 3 trial NCT01763164 compared with dacarbazine in NRAS mutation positive melanomas. 55
