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Phase 2 study of neoadjuvant dabrafenib + trametinib (D+T) for resectable stage IIIB/C BRAF V600 mutant melanoma

2017; Elsevier BV; Volume: 28; Linguagem: Inglês

10.1093/annonc/mdx377.007

1569-8041

Alexander M. Menzies, Maria Gonzalez, Alex Guminski, Omgo E. Nieweg, Kerwin F. Shannon, John F. Thompson, Richard Kefford, Sydney Ch’ng, Jonathan R. Stretch, Andrew J. Spillane, J. Lee, H. Lee, Rony Kapoor, Louise Emmett, Helen Rizos, Robyn P.M. Saw, Richard A. Scolyer, Georgina V. Long,

Click Chemistry and Applications

Background: Combination D+T improves the overall survival (OS) of patients (pts) with BRAF V600 mutant advanced melanoma, and an adjuvant trial is in progress (NCT01682083). We sought to explore neoadjuvant D+T for pts with bulky but resectable stage III melanoma. Methods: In this phase 2 study, 35 pts received standard dose D+T for 12 wks prior to complete resection of the pre-therapy tumour bed (RES), then 40 wks of further D+T. Eligible pts had ECOG PS ≤ 1 with histologically confirmed resectable bulky AJCC v7 stage IIIB/C BRAF V600 mutant melanoma. CT and PET scans were performed at baseline and 12 wks just prior to RES for RECIST and metabolic complete response (rCR and mCR respectively). CT monitoring was continued 12 wkly thereafter to 2 yrs then 6 monthly to 3 yrs. Biopsies were taken at baseline and wk 1. The primary endpoints were the complete pathological response (pCR) and RECIST response rate (rRR) at wk 12. Secondary endpoints were surgical morbidity, mCR, relapse free survival (RFS), OS, toxicity and translational endpoints. Results: At data cut 18th April 2017, 35 had commenced D+T. 33 had reached RES (27 stage IIIC [8 in-transit only], 6 IIIB; 32 V600E, 1 V600K; 12 LDH >ULN). At RES, 17/33 (52%) had pCR, 16 (48%) had rCR (rRR 88%), and 16 (48%) had mCR. The pathologic response was discordant with RECIST response in 7 (21%) pts and metabolic response in 9 (27%) pts; only 11 (65%) pts with pCR had rCR and mCR. No pt discontinued D+T and no pt progressed during the neoadjuvant period, D+T did not make surgery more difficult in any pt, and in 16 (48%) surgery was deemed easier. Median F/U post RES was 12.1 mo (95% CI 8.8-14.8). 12 (36%) pts had recurred (median 12.9 mo), 4 while on D+T, 6 with prior pCR, 8 at distant sites, and 1 pt had died. 26 (79%) pts developed drug fever. 18 (55%) had ≥ 1 surgical complication post RES; 11 had a wound infection requiring antibiotics, 5 had a seroma, 2 bled. Updated data will be presented including tumour biopsy and and ctDNA biomarker data. Conclusions: Neoadjuvant D+T has a high response rate and high pCR rate in resectable stage III melanoma. Surgical complication rates were consistent with historic controls and stage of disease. Clinical trial identification: NCT01972347 Legal entity responsible for the study: Melanoma Institute Australia Funding: Novartis Disclosure: A.M. Menzies: Advisory board - MSD, Novartis, Chugai, Pierre Fabre. Honoraria - Bristol-Myers Squibb, Roche G.V. Long: Advisory board - Bristol-Myers Squibb, MSD, Novartis, Amgen, Pierre Fabre. All other authors have declared no conflicts of interest.