1099P - Long-term survival follow-up from the REDUCTOR trial: Neoadjuvant cytoreductive treatment with BRAF/MEK inhibition of prior unresectable regionally advanced melanoma to allow complete surgical resection

Background

The REDUCTOR trial demonstrated that neoadjuvant dabrafenib (D) plus trametinib (T) allowed radical (R0) resections in 81% of patients with prior unresectable locally advanced BRAF-mutated melanoma. Major pathologic responses were seen in 9/18 patients undergoing surgery. Recurrences were observed in 50% of patients and usually occurred shortly after surgery. Here, we present an update of long-term relapse-free survival (RFS), progression-free survival (PFS) and overall survival (OS).

Methods

In this single-arm phase II trial, 21 patients with unresectable, BRAF-mutated, locally advanced stage IIIC or oligometastatic stage IV melanoma were treated with neoadjuvant D+T for 8 weeks. PET/CT and physical examination were performed to evaluate response. If sufficient downsizing of the tumor was observed, surgical resection was performed. Adjuvant therapy was not routinely given. The primary endpoint was the percentage of patients achieving a R0 resection. Secondary endpoints were RFS, PFS and OS.

Results

At a median follow-up of 80.9 months (IQR 38.6-89.7 months), the median RFS in patients that underwent surgery was 15.4 months (95% CI 8.89-not reached). The median PFS in all patients was 12.4 months (95% CI 8.68-not reached). Recurrences were seen in 10/18 patients undergoing surgery, most of which occurred in the first year after resection (8/10). One patient recurred after 1 year and one after 5 years. The median OS was not reached. The 1-year, 2-year, 3-year and 4-year OS were 100%, 85% (95% CI 70.7-100.0), 85% (95% CI 70.7-100.0) and 75% (95% CI 58.2-96.6), respectively. In total, 1/6 patients (17%) with a pathologic complete response (pCR) developed recurrence, compared to 4/5 patients (80%) with a pathologic non-response (pNR). Late recurrences (after >1 year) were seen in a patient with a near-pCR and a patient with a pNR.

Conclusions

These data confirm favorable long-term survival rates after neoadjuvant D+T and surgical resection without adjuvant therapy in prior unresectable locally advanced BRAF-mutated melanoma patients. Most patients remain disease-free if no recurrence occurs in the first year after treatment.

Clinical trial identification

EudraCT: 2013-002616-28.

Editorial acknowledgement

Legal entity responsible for the study

Netherlands Cancer Institute, Amsterdam, The Netherlands.

Funding

Netherlands Cancer Institute and Novartis.

Disclosure

W. Van Houdt: Financial Interests, Institutional, Invited Speaker: Amgen; Financial Interests, Institutional, Advisory Board: Belpharma, Sanofi, MSD; Financial Interests, Personal, Other, travel grant: Novartis; Financial Interests, Institutional, Local PI: BMS. A.C.J. van Akkooi: Financial Interests, Institutional, Advisory Board: Amgen, Bristol Myers Squibb, Novartis, MSD - Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Sirius Medical, 4SC, Provectus; Financial Interests, Institutional, Research Grant, NIVEC study: Amgen; Financial Interests, Institutional, Research Grant: Merck-Pfizer. J.B.A.G. Haanen: Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb, Achilles Therapeutics, Ipsen, Merck Sharp & Dohme, Merck Serono, Pfizer, Molecular Partners, Novartis, Roche, Sanofi, Third Rock Venture, Iovance Biotherapeutics; Financial Interests, Institutional, Advisory Board, SAB member: BioNTech, Immunocore, Gadeta, Instil Bio, PokeAcel, T-Knife; Financial Interests, Personal, Advisory Board, SAB member: Neogene Therapeutics, Scenic; Financial Interests, Personal, Stocks/Shares: Neogene Therapeutics; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, BioNTech US, Merck Sharp & Dohme, Amgen, Novartis, Asher Bio; Non-Financial Interests, Member: ASCO, AACR, SITC; Other, Editor-in-Chief IOTECH: ESMO; Other, Editorial Board ESMO Open: ESMO; Other, Editorial Board: Kidney Cancer. All other authors have declared no conflicts of interest.