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Overcoming Resistance to Dabrafenib: Technical Summary
Overcoming acquired BRAF inhibitor resistance in melanoma by blocking MAPK pathway reactivation
A key advance in the treatment of metastatic melanoma came from the discovery of the importance of an activating oncogenic mutation in the BRAF gene, which codes for a critically important protein in a key signalling pathway (the MAPK pathway), controlling melanoma proliferation and spread. The BRAF single point mutation (V600) is typically found in around 50% of all melanoma patients, where a highly-activated form is produced. Mutation in BRAF activates a key signalling pathway in melanoma, the MAP kinase pathway (MAPK). The BRAF kinase activates target proteins of the MAPK. Its major role in a normal cell is to transduce external signals, such as growth factors, hormones and stress, from outside the cell to the nucleus (see Figure) via a complex cascade leading to regulation of genes involved in proliferation, differentiation and apoptosis. The MAPK pathway itself is an important driver in melanoma and comprises several potential drug targets.
Vemurafenib is a highly potent inhibitor of activated BRAF. A pivotal randomised trial comparing vemurafenib with standard chemotherapy showed a major benefit for vemurafenib in terms of significantly greater response rate, progression-free survival and overall survival. Vemurafenib was licensed in 2011 and approved by NICE in 2012. Dabrafenib, also a potent inhibitor of BRAF and with an efficacy similar to that of vemurafenib, has recently been licensed and is currently under review by NICE. A major weakness of both drugs is acquired resistance, which develops in the majority of patients after a median of approximately six months of treatment. In addition side effects can be serious, including developing new primary cutaneous malignancies and febrile drug reactions.
MEK is another important signalling protein in the MAPK pathway. It is further along in the pathway than BRAF and is always switched on. Trametinib is a potent inhibitor of MEK, although the response rates are lower than for BRAF inhibitors. MAPK pathway reactivation is important in acquired resistance to BRAF inhibitors.
Simplified view of the MAPK signalling pathway and the targets of dabrafenib and trametinib. Cell membrane in yellow, nuclear membrane in blue and a cell surface receptor in green.
The study tested the hypothesis that, by blocking the pathway in two places, combination treatment may be more effective. This ‘vertical blockade’ strategy is not without risk, in particular that both drugs will need to be given at a reduced dose and/or that side effects would be greater. The trial consisted of 247 patients from 16 centres, all with a BRAF mutation and late-stage melanoma, who had not received BRAF inhibitor therapy before. Patients were split into three groups and given either dabrafenib, dabrafenib plus trametinib at reduced dose, or both drugs at full dose. The study was open label, with the objectives of studying drug interactions, side effects and efficacy. The endpoints were toxicity, response and progression-free survival at various time points.
There were three main findings. When the two drugs were used in combination:
- The incidence of cutaneous squamous-cell carcinoma normally seen with dabrafenib was reduced by 12%.
- Other known dabrafenib side effects were reduced, including papilloma (benign epithelial tumours) (11% decrease) and hyperkeratosis (21% decrease). Acneiform dermatitis, a common dose-limiting toxic effect of trametinib, was also decreased in the combination therapy groups.
- Cases of pyrexia (45% increase) and chills (41% increase) were more frequent. It was concluded that these were related to dabrafenib; they were managed with antipyretic agents or – where they were recurrent – low doses of oral glucocorticoids. Some trametinib side effects were more frequent in the combination group compared with the dabrafenib only group, including peripheral oedema (12% increase) and hypertension (5% increase).
The patients participating in the efficacy part of the trial were followed for 14 months. The combination therapy group had progression-free survival of 9.4 months, compared with 5.8 months in the dabrafenib monotherapy group. The partial response rate rose from 50% to 67% with the combined therapy. At the one year assessment point 41% of the combination group were progression-free, compared with 9% of the dabrafenib-only group.
These results validate the authors’ hypothesis that inhibiting the MAPK pathway downstream of BRAF (via MEK) would suppress mechanisms of resistance and improve outcomes. The two drugs can be combined at full monotherapy doses. These results are still considered preliminary, with two larger randomised clinical trials to test this strategy now completed and the results awaited. In the meantime, the combination has just been approved by the FDA based on the results of this study.
The full paper (PubMed, ID-23020132) can be found at:
See also the Lay Summary of this paper