New Prescribing Options in Metastatic Melanoma | Page 3
Published Online: October 11, 2013
John A. Thompson, MD
Immune-related AEs and their management have been characterized during the clinical development of ipilimumab.30 Although most irAEs were of mild to moderate severity, they can arise and/or escalate rapidly in severity. The median time to onset for any irAE grade 2 to 4 is 7 weeks (95% CI, 4.1-8.4 weeks) after initiation of treatment.10,30 While most irAEs occur during the induction phase of treatment, some irAEs arise months after therapy has been completed, although such late-onset irAEs are rare. In clinical studies, AEs were managed by close adherence to guidelines, which emphasize vigilance and early use of corticosteroids as appropriate.10 Importantly, the use of corticosteroids in the management of safety events does not appear to negatively impact ipilimumab efficacy.15,31 Treatment guidelines have been developed to assist healthcare professionals in managing ipilimumab- related safety events. These guidelines emphasize that unless an alternative etiology has been identifi ed, signs or symptoms of infl ammation should be considered immune mediated and appropriate treatment should be initiated.32 The importance of patient education cannot be overstated, and tools such as a patient wallet card can be useful.32
CLINICAL DEVELOPMENT OF VEMURAFENIB (PLX4032)
The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway is an intracellular signaling cascade involved in the regulation of cell proliferation, differentiation, and survival.33 In normal cells with unmutated BRAF, response to extracellular stimuli is achieved through binding of ligand to a relevant cell surface kinase receptor, which triggers phosphorylation and activation of Ras, a GTPase. Ras activation then induces dimerization and phosphorylation of RAF kinases—ARAF, BRAF and CRAF. These activated dimers drive phosphorylation of MAP-ERK-kinase (MEK), which in turn phosphorylates and activates ERK. Activated ERK is then able to enter the nucleus, where it acts as a transcription factor to activate genes involved in cell proliferation and survival (Figure 2A).34,35
BRAF mutations involving the valine residue at position 600 (V600) have been described in approximately 8% of all solid tumors, including 50% of melanomas, 30% to 70% of papillary thyroid carcinomas, and 5% to 8% of colorectal adenocarcinomas.36 The most common BRAF mutation in melanoma is a mutation in which V600 is replaced with glutamic acid (BRAFV600E). When this mutation is present, the MAPK pathway is inappropriately activated (approximately 500-fold) and becomes independent of upstream signaling.13,33,34,37,38 Of note, cells carrying the BRAFV600E mutation lack activated Ras; therefore, RAF kinases remain in the monomeric rather than the dimeric form; this hasimportance in the specifi city of BRAF inhibitors.39
These observations provided a strong rationale for development of therapies targeting the MAPK pathway for cancer treatment. Vemurafenib binds to BRAFV600E and inhibits ERK phosphorylation in BRAFV600E-bearing cells but not in cells with wild-type unmutated BRAF (Figure 2B). In BRAFV600E-dependent tumor xenograft models, vemurafenib caused tumor regression or growth delay, without evidence of signifi cant cellular toxicity.35
In a phase 1 dose-escalation trial in patients with metastatic melanoma, objective responses were seen in 11 of 16 patients (69%), while in an extension phase evaluating the maximum dose that could be administered without adverse effects, 26 of 32 patients (81%) achieved an objective response.40 In a phase 2 study of vemurafenib in 132 patients with previously treated BRAFV600E-mutant metastatic melanoma (BRIM-2), 53% of patients achieved objective responses, 29% experienced stable disease, and 14% had disease progression. At a median followup of 12.9 months, median duration of response was 6.7 months, median PFS was 6.8 months, and median OS was 15.9 months.41 In this study, AEs observed in >25% of patients were arthralgia, rash, photosensitivity, fatigue, alopecia, pruritus, and skin papilloma, mostly grade 1 to 2. However, 26% of patients developed cutaneous squamous cell carcinoma (grade 3), the majority being keratoacanthoma type (Table 2).42,43
A 6-month interim analysis of a large phase 3 study (BRIM-3) of vemurafenib in previously untreated patients with BRAFV600E-positive metastatic melanoma has been reported.13 A total of 2107 patients were screened, and 675 were randomized to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m2 intravenously every 3 weeks). Overall survival at 6 months was 84% (95% CI, 78%-89%) with vemurafenib compared with 64% (95% CI, 56%-73%) with dacarbazine; the corresponding median PFS was 5.3 months compared with 1.6 months. Patients receiving vemurafenib had a 63% relativereduction in the risk of death compared with patients receiving dacarbazine and a 74% relative reduction in the risk of either death or disease progression compared with patients receiving dacarbazine (P <.001 for both comparisons). In addition, response rates were significantly higher with vemurafenib compared with dacarbazine (48% vs 5%; P <.001) (Table 1). The OS benefit of vemurafenib over dacarbazine was observed across all patient subgroups regardless of age, sex, performance status, tumor stage, and lactate dehydrogenase level, although the study did not include patients with brain metastases.13
The most common AEs associated with vemurafenib therapy were cutaneous events, arthralgia, and fatigue. Keratoacanthoma, cutaneous squamous cell carcinomas, or both developed in 18% of patients who received vemurafenib, with all lesions treated by excision. Photosensitivity skin reactions of grade 2 or 3 were seen in 12% of the patients. In total, 38% of patients receiving vemurafenib and 16% of patients receiving dacarbazine required dose modifi cations or interruptions (Table 1). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended.13 The approved dose of vemurafenib is 960 mg (four 240-mg tablets) twice daily.21 For patients experiencing grade 2 to 3 AEs, interruption and/or dose modifi cations may be required and, in the case of grade 4 events, permanent discontinuation may be required.
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