The aim of this trial is to evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib and trametinib (BRAF and MEK inhibitor respectively) to allow radical surgical resection in patients with unresectable BRAF-mutated, locally advanced stage III or oligometastatic stage IV melanoma.
A total of 25 patients with BRAF-mutated, unresectable locally advanced stage III or oligometastatic stage IV (≤3 metastases) melanoma will be treated with dabrafenib and trametinib for 8 weeks. Response evaluation by positron emission tomography/computed tomography (PET/CT) will occur at 2 and 8 weeks. If sufficient downsizing occurs, surgical resection will be performed. Biopsies for translational research will be taken at baseline and 2 weeks. The dissection specimen will be stored at 8 weeks.
Currently 17 patients have been included. Of these, 2 patients showed PD upon treatment and did not proceed to surgery. In 14/15 (93%) patients resection was possible after neoadjuvant treatment, of which 13 (93%) were R0 resections. Median follow-up time is 22 months with a median recurrence free survival of 9 months in patients undergoing surgery. The 1-year overall survival (OS) was 88% and 2-year OS 59%. Median OS was not reached. Metabolic response rates (RR) on PET/CT at 8 weeks were: 4 (24%) CR, 11 (65%) PR, 0 (0%) SD, 2 (12%) PD. Pathologic RR differed: 6 (35%) CR, 5 (29%) PR, 3 (19%) SD, 0 (0%) PD and in 3 patients (18%) no pathologic response was measured, since no resection was performed. Most patients (82%) experienced any toxicity, of which the majority (64%) was grade 1 and the most common reported toxicity was fever. Grade 3 toxicity occurred in 2 patients (12%).
Neoadjuvant dabrafenib and trametinib shows to be a potent cytoreductive treatment, allowing radical resection of metastases in 13/17 (76%) patients with prior unresectable locally advanced melanoma. Patients with no recurrence remained disease-free for a prolonged period of time. If there was recurrent disease, this usually occurred within months after surgery and this may present an opportunity for further tailored adjuvant therapy.
Clinical trial identification
Legal entity responsible for the study
Netherlands Cancer Institute, Amsterdam, The Netherlands.
Netherlands Cancer Institute and Novartis.
D. Peeper: Research support: BMS. A.C.J. van Akkooi: Consulting or advisory role: Amgen, Novartis, MSD Oncology, Merck Research funding: Amgen, Novartis; Travel, accomodations, expenses: Amgen, Novartis, MSD Oncology, Merck. J.B.A.G. Haanen: Compensation to NKI for advisory roles: BMS, Merck, Roche, Neon Therapeutics, Pfizer, Ipsen; Grants to NKI: BMS, Merck, Novartis, Neon Therapeutics. All other authors have declared no conflicts of interest.