Biopsy- and Biology-driven Optimization of Targeted Therapy in Subjects With Advanced Melanoma

In this open-label, multi-center, clinical phase II study melanoma patients in stage III (non-resectable) and stage IV are sorted into Cohort A or B according to their previous BRAF-treatment: Cohort A (BRAFi naïve): Patients who have not received prior BRAFi or MEKi-therapy. Dabrafenib (BRAFi) and trametinib (MEKi) will be administered orally at their recommended doses for combination therapy of 150 mg twice daily (BID) and 2 mg daily (QD). Clinical endpoint is clinical response at week 8. Metabolic response will be assessed at week 2 and 8. Treatment will continue until disease progression, death, unacceptable toxicity, or withdrawal of consent. Cohort B (BRAFi / MEKi rechallenge): Patients with CR/PR as best response to previous BRAFi / MEKi combination therapy, discontinuation of this therapy after progression and different therapy for \> 3 months prior to enrollment. These patients will receive dabrafenib and trametinib at their recommended combination therapy doses of 150 mg twice daily (BID) and 2 mg daily (QD). Treatment will continue until disease progression, death, unacceptable toxicity, or withdrawal of consent. Survival will be assessed every 3 months after the final dose of BRAFi / MEKi until the end of the follow-up phase for the individual patient. Follow up phase for each subject is 1 year following first treatment dose. End of study will be at recruitment finished plus 1 year post start of treatment of last patient thus ensuring that 1 year survival rate can be estimated. Biopsies taken before start of treatment, after 2 weeks (+/- 4 days) and after progressive disease will be analyzed by Next generation sequencing (NGS), immunohistochemistry (IHC), phosphorplex Luminex as well as by reverse phase protein array in order to determine the magnitude of suppression of downstream signaling as well as reactivation of adaptative mechanisms. Rebiopsy is mandatory after 2 weeks and in case of progressive disease in order to determine mechanisms of adaptation of the signaling pathway downstream. The experimental molecular data will be analyzed in correlation with clinical response at week 8 (defined as partial or complete response according to RECIST) and metabolic responses at weeks 2 and 8 (responders are defined as those patients with changes of \>66% in the Standard Uptake value (SUVmax) between interim PET and baseline PET.