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Dirk Schadendorf

Dr. Schadendorf was interviewed during the 10th EADO Congress in Vilnius, Lithuania

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Dr. Schadendorf was interviewed during the 10th EADO Congress in Vilnius, Lithuania, on Dabrafenib and Trametinib combination therapy, present status and perspective.

Impression of interview content

Prof. dr. Dirk Schadendorf, Director and Chair of the University Hospital Essen, Clinic for Dermatology (Germany), was interviewed during the 10th EADO Congress in Vilnius (Lithuania) on Dabrafenib and Trametinib combination therapy, present status and perspective.

BRAF detection in melanoma is a new era in research and science. That BRAF, an oncogene that is required for tumor growth, is mutated in melanoma is already known for more than a decade. A specific interaction with mutant BRAF which drives the MAP-Kinase pathway is important to stop tumor cell proliferation. For this purpose BRAF-inhibitors as Dabrafenib have been developed. This drug can recognize mutant BRAF and inhibit the hyper-activated pathway. Similarly, MEK inhibitor Trametinib has a preference for a mutant BRAF and cells that have a mutation in the MAP-Kinase pathway respond by slowing down proliferation. In the clinic the effects are seen as reduced tumor growth and longer progression-free survival.

Dabrafenib is the second available BRAF-inhibitor to treat melanoma in Europe. The two drugs are very similar. Discriminatory are mainly the side-effects, as Dabrafenib lacks photosensitivity as side-effect.

The combination of Dabrafenib and Trametinib has a lower toxicity than the two individual drugs. Both drugs target a different part in the MAP-Kinase pathway, thus hitting this essential pathway for tumor proliferation extra hard.

The clinical effects of Dabrafenib are prolongation of progression free survival time up to 7 months, and a significant improvement of overall survival time up to 18 months. This drug therefore significantly improves the treatment options for melanoma patients.

Brain metastases are often seen with melanoma, and prognosis for these patients is extremely poor. Dabrafenib can reach the brain and has significant clinical effects in the brain of patients with a BRAF mutated melanoma. In 80% of such patients the tumor was controlled, in 40% tumor shrinkage was seen, and survival time was almost doubled.

Monotherapy with BRAF-inhibitors has thus been shown to be effective. Trials with a combination of BRAF en MEK inhibitors are currently recruiting patients. A first clinical trial comparing Dabrafenib monotherapy with Dabrafenib – Trametinib combination treatment is ongoing, and the preliminary data communicated show that progression free survival has been achieved. The data will be presented at this year’s ASCO. Other, partly similar studies are underway. Prof. Schadendorf expects that by the end of the year the BRAF – MEK-inhibitor combination therapy will have become the new standard for treating melanoma patients with a BRAF-mutation.

Other new developments involve studies targeting nRAS mutants. Also here MEK-inhibitors are being studies and the trials are currently recruiting patients. Immune-oncology is another exciting field with all the PD1 antibodies currently being tested in registration studies. We are looking forward to data showing if such treatment is also effective for patients with metastatic melanoma. First results are expected to be presented at this year’s ASCO.

General recommendations: Metastatic melanoma patients should be tested for BRAF mutation status. As Dabrafenib and Trametinib are registered in Europe, off-label use should be considered. Also, the Novartus trial testing the combination treatment is still open for recruitment, so that could also be a route to consider. The combination is approved in the US, but not in Europe – this approval is expected by the end of next year.

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