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.
Another PD-1 blocking antibody, MK-3475, has been evaluated in patients with advanced melanoma, and promising RRs have been described.32 In a small group of patients, the confirmed RR at a dose of 10 mg/kg every 2 weeks was 52% and appeared similar in patients who had and who had not been previously treated with ipilimumab. The AEs of MK-3475 seem to resemble nivolumab. MK-3475 is similarly being evaluated in large phase 2 and 3 trials for both patients with melanoma and additional malignancies.
In addition to antibodies targeting PD-1, clinical activity has also been observed with several different antibodies (BMS-936559, MPDL3280A, and MEDI4736) that target PD-L1. Though some data have been published for this therapeutic strategy,33 ongoing trials will continue to clarify the role of targeting PD-L1 in patients with advanced melanoma.
Targeted Therapies That Block Oncogenic Signaling Pathways
The mitogen-activated protein kinase (MAPK) pathway responds to extracellular growth signals and regulates cell proliferation and survival. In many patients with melanoma, the MAPK pathway is constitutively activated as a result of molecular alterations in genes encoding key regulators or components of the pathway such as BRAF, NRAS, and KIT.34,35 The most common mutation arising in melanoma is the BRAF mutation, occurring in nearly half of melanomas, and typically involves a missense mutation in which glutamic acid is substituted for valine at codon 600 (BRAF V600E mutation).36 Less frequent BRAF mutations include V600K, V600R, and K601E.37 Strategies that directly inhibit oncogenic BRAF or disable downstream elements such as MEK have recently shown dramatic results in patients with melanoma (Figure 2).
BRAF inhibitors
Vemurafenib is a potent inhibitor of mutated BRAF with marked antitumor effects against melanoma cell lines with the BRAF V600E mutation.38 The first striking results of tumor regression with this strategy in patients were seen in a phase 1 study in patients with melanoma characterized by a BRAF V600E mutation but not in patients whose melanomas did not have a BRAF mutation.39
Subsequent phase 3 trials confirmed the high RRs of this agent in patients with BRAF-mutant melanoma and demonstrated superiority in OS compared with dacarbazine chemotherapy.40 The results of this phase 3 trial led to the approval of vemurafenib by the FDA in August 2011 with treatment exclusively limited to patients with BRAF mutant melanoma. Updated OS data from this phase 3 study revealed a median OS of 13.2 months for vemurafenib, compared with 9.6 months for dacarbazine, with an overall RR in patients treated with vemurafenib of 57% and a median PFS of 6.9 months.41 General AEs with vemurafenib include arthralgia, fatigue, aminotransferase elevations, nausea and vomiting, and decreased kidney function. In general, toxicities are manageable with dose reduction or temporary drug cessation.
One characteristic of vemurafenib and other BRAF-targeted agents is the frequent development of hyperproliferative skin AEs. Skin lesions, including follicular and palmo-plantar hyperkeratosis, papillomas, and also cutaneous squamous-cell carcinomas and keratoacanthomas, have commonly been observed under treatment with vemurafenib, and close evaluation by a dermatologist is important.42 The mechanism of this phenomenon is believed to be a paradoxical activation of the MAPK pathway in nonmelanoma BRAF wild-type cells when systemic treatment with a BRAF inhibitor is administered.43
The phenomenon of hyperproliferation of non–BRAF-mutant tissues with ongoing BRAF-inhibitor therapy has also been seen in patients with lymphoproliferative disorders and may be a mechanism involved in the discovery that patients have a high rate of new primary melanomas while on therapy.44,45 These findings warrant special attention, particularly as BRAF inhibitors are undergoing evaluation as adjuvant therapy.
Another active BRAF kinase inhibitor with a similar efficacy profile as vemurafenib is dabrafenib, which was approved in May 2013 based on the demonstration of improved PFS in a phase 3 trial comparing dabrafenib 150 mg orally twice daily and dacarbazine 1,000 mg/m2 intravenously once every 3 weeks in previously untreated patients with BRAF V600E mutant melanoma. The median PFS times were 5.1 and 2.7 months in the dabrafenib and dacarbazine arms, respectively, with an objective RR of 52% in patients treated with dabrafenib.46 Follow-up time was too short to make a determination of the impact of dabrafenib on OS. In a separate study, dabrafenib was also shown to be effective for patients with brain metastases and remains an excellent therapeutic choice for this particular patient population.47
Generally, dabrafenib is believed to have similar efficacy to vemurafenib. Nevertheless, EAs with of dabrafenib differ somewhat from those observed with vemurafenib: The rate of proliferative skin lesions, including squamous cell carcinomas and keratoacanthomas appears to be lower for dabrafenib than vemurafenib. However, AEs particular to dabrafenib have been seen such as pyrexia, which were recorded in about 11% of patients.46
