New Prescribing Options in Metastatic Melanoma | Page 4
Published Online: October 11, 2013
John A. Thompson, MD
The high response rates of vemurafenib are tempered with the development of resistance to the agent.41,44 Varying mechanisms of resistance have been postulated, including bypass of the oncogenic pathway (eg, through activation of alternative pathways) or activation of a downstream target kinase (via secondary mutation and/or amplifi cation), both of which allow for continued signaling through the pathway with resultant disease progression.44,45 Recent data suggest that resistance to RAF inhibitors may be mediated by the expression of splicing isoforms of BRAFV600E that dimerize in a RAS-independent manner.46 Other data suggest that reactivation of the RAS/ RAF pathway and activation of an alternative pathway may be key mechanisms of disease relapse while on vemurafenib treatment, and these results support furtherclinical studies in which an inhibitor of downstream kinases such as MEK is added to vemurafenib treatment to overcome resistance.47 Recent data have suggested that the heat shock protein-90 inhibitor XL888 is able to overcome vemurafenib resistance through a number of mechanisms.48 Future studies will need to focus on mechanisms of overcoming acquired resistance.
EFFICACY IN PATIENTS WITH BRAIN METASTASES AND POTENTIAL COMBINATION THERAPY
Ipilimumab has been tested in clinical trials involving highly selected subjects with melanoma that has metastasized to the brain, and in this carefully monitored environment, there appear to be cases of antitumor activity in the brain metastases.49 The safety profile of ipilimumab in patients with advanced melanoma and brain metastases was similar to that in patients without brain lesions, with no increase in central nervous system–related toxicities and no unique toxicities observed, provided patientsmet the inclusion criteria and there was adherence to the clinical protocol. The most common irAEs in this subset of patients included diarrhea, rash, and pruritus.50,51
A phase 1 study of patients with incurable solid tumors with brain metastases, of whom 156 had metastatic melanoma, evaluated the safety of and response to treatment with dabrafenib, an inhibitor of BRAF kinase activity.52 The most common treatment-related AEs were cutaneous squamous cell carcinoma (20 patients, 11%), fatigue (14 patients, 8%), and pyrexia (11 patients, 6%). Responses were reported in patients at the dose of 150 mg twice daily, and of the patients with melanoma and untreated brain metastases, 9 of 10 had reductions in the size of brain lesions.52
Preliminary data from an open-label pilot study of vemurafenib in previously treated, BRAFV600E-mutant metastatic melanoma patients with brain metastases indicates that this agent may also have activity against brain metastases.53 A single-arm, phase 2 study specifically looking at use of vemurafenib in patients with brain metastases is ongoing.54
Preclinical studies indicate that vemurafenib, at concentrations equivalent to those achieved in patients receiving standard doses, does not inhibit activation of T cells. Lymphocytes exposed to high concentrations of vemurafenib maintained their viability and function.55 Furthermore, vemurafenib was able to enhance T-cell recognition of melanoma, again without negatively impacting lymphocyte function.56 These data indicate the potential for the combination of immunotherapy and BRAF inhibition for the treatment of patients with BRAFV600E-mutant melanoma, and clinical trials are under development that will investigate the use of vemurafenib in combination with ipilimumab in patients with BRAFmutant metastatic melanoma. How best to combine or sequence these therapies remains unknown, but studies are ongoing.57
EMERGING TREATMENT OPTION: MEK INHIBITION
Preclinical data suggest that that possession of a BRAF mutation may sensitize tumors to MEK inhibition; moreover, because MEK lies downstream of BRAF in the MAPK signaling pathway, inhibition of MEK may reverse resistance to BRAF inhibition.58 As such, various agents targeted to MEK are currently in the early stages of clinical development.
The dual MEK1 and MEK2 inhibitor GSK1120212 is currently in phase 2/3 clinical development with an allied predictive biomarker analysis program.59 At the recommended phase 2 dose of 2 mg orally once daily (n = 46), the most common AEs were rash (85% all grades; 2% grade ≥3) and diarrhea (48% all grades; 2% grade ≥3). GSK1120212 produced objective responses in phase 1/2 studies, with a response rate of 40% in patients with BRAF mutations (n = 20; this included 2 complete responses) and 9% in BRAF wild-type patients (n = 22; all were partial responses).60,61 In addition, 2 patients who had previously received vemurafenib experienced stable disease after GSK1120212. An ongoing trial is investigating the effectiveness of this MEK inhibitor in patients who have previously received treatment with a BRAF inhibitor.62
For decades, patients with advanced or metastatic melanoma had limited treatment options. Now, oncologists and patients have therapeutic options that have demonstrated clinical benefi ts in large, randomized studies. Ipilimumab has demonstrated long-term effi cacy in 2 phase trials, and is approved in the United States at a dose of 3 mg/kg for use in fi rst- and second-line advanced or metastatic melanoma. Vemurafenib, approved in the United States for use in patients that harbor the BRAFv600E mutation, is associated with high response rates in that patient subpopulation. More information is needed to fully address the question of how to best sequence the newer agents, and how or whether to incorporate existing agents, into the treatment paradigm for advanced melanoma.
The choice of therapy for patients with advanced, unresectable melanoma may be based on the patient’s molecular characteristics (eg, presence or absence of oncogenic mutations), the presence or absence of tumorrelated symptoms, and the tempo of disease. For subjects whose tumors express BRAF that is wild type, the choice of therapy will emphasize ipilimumab, IL-2 (for patients able to tolerate the toxicities of high-dose IL-2), or a clinical trial (if available). For BRAF wild-type patients with symptomatic, rapidly progressing disease, cytotoxic chemotherapy such as dacarbazine- or taxane-based therapymay be used in an effort to cytoreduce the tumor.
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