New drugs in melanoma: it's a whole new world.
ABSTRACT Current developments in systemic therapies for melanoma are spectacular. Over the last 40 years no one drug or combination of drugs demonstrated any impact on survival in metastatic melanoma. In contrast, in 2011 a number of new drugs will be approved. In 2011 immunomodulation with ipilimumab, a monoclonal antibody targeting the ligand CTLA-4, has been approved for patients with advanced melanoma in first- and second-line treatment by the Food and Drug Administration (FDA) and in second-line treatment by the European Medicines Agency (EMA). Also in 2011, a significant survival benefit of the combination of ipilimumab with dacarbazine compared with dacarbazine alone for first-line treatment was reported. Other monoclonal antibodies targeting T-cell ligands, such as programmed death-1 (PD-1), also show promise. Various inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) yield high response rates in patients harbouring the BRAF-V600E mutation. A significant impact on both progression-free and overall survival was demonstrated for vemurafenib compared with dacarbazine in a phase-III trial. Approval is expected in 2011. Both drugs had only modest effects of 2-3 months on median survival, so combination therapies must be explored. BRAF inhibitors in combination with mitogen-activated protein kinase (MEK) inhibitors show great potential. Moreover, combinations of immunomodulators and pathway inhibitors are expected to be very active, and phase-III trials are planned. Pegylated interferon-α2b was approved in 2011 on the basis of the results of the European Organisation for Research and Treatment of Cancer (EORTC) 18991 phase-III trial demonstrating a sustained impact on relapse-free survival in patients with lymph-node-positive melanoma. The efficacy of adjuvant therapy with ipilimumab is assessed in the now fully accrued EORTC18071 trial. Adjuvant trials with BRAF and MEK inhibitors are in the planning phase. Never was there a more exciting period in the world of melanoma treatment.
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ABSTRACT: Metastatic melanoma (MM) presents a treatment challenge to oncologists worldwide. Dacarbazine is the first line chemotherapy treatment for MM, though the overall response rates are very poor. Recently, the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation was found to play a main role in MM. This mutation is present in 40-60% of melanoma patients. Vemurafenib is a BRAF kinase inhibitor that showed impressive results in phase I-III trials and was thus recently approved for the treatment of MM. This paper will briefly focus on vemurafenib in the treatment of MM and highlight concerns.Rare tumors 04/2012; 4(2):e31.
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ABSTRACT: BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naïve patients (BRIM-3). The study results showed a relative reduction of 63 % in risk of death and 74 % in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors.Journal of Translational Medicine 05/2012; 10:85. · 3.41 Impact Factor