Neoadjuvant cytoreductive treatment with BRAF/MEK inhibition of prior unresectable regionally advanced melanoma to allow complete surgical resection, REDUCTOR trial

Background: 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. Methods: 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. Results: 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%). Conclusions: 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: EudraCT: 2013-002616-28 Legal entity responsible for the study: Netherlands Cancer Institute, Amsterdam, The Netherlands. Funding: Netherlands Cancer Institute and Novartis. Disclosure: 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.