798P - NeoTrio – Optimal neoadjuvant (NAT) sequencing of anti-PD-1 and BRAF targeted therapy (TT) in BRAF mutant stage III melanoma: Results of histopathological analysis

Background

Anti-PD-1 and BRAF TT improve survival for metastatic and resected stage III melanoma. TT shows favourable immunomodulatory changes early during treatment and may have synergistic effects with anti-PD-1. Hyalinised fibrosis (HF) is associated with pathological complete response (pCR) with NAT. We examined longitudinal biopsies from the NeoTrio trial exploring the optimal combination of dabrafenib + trametinib (D+T) and pembrolizumab (pembro) (NCT02858921).

Methods

60 pts with resectable, RECIST measurable stage III BRAF^V600- mutant cutaneous melanoma were randomised 1:1:1 to 3 arms of 6 wks of NAT followed by therapeutic lymph node dissection (TLND): A) ALONE - pembro (200mg Q3W x 2); B) SEQ - D+T (150mg bd + 2mg od) for 1 wk followed by pembro (200mg x 2); C) CON - D+T+pembro (doses as SEQ). Primary endpoint was the pathological response rate and pCR at wk 6. Core biopsies were taken at baseline, wks 1 and 2 and TLND at wk 6 and examined for translational endpoints; lymphocyte density score (LDS), melanophages and HF.

Results

LDS significantly increased from baseline at wks 2 and 6 in SEQ and CON but not in ALONE. Melanophages significantly increased from baseline to wk 6 in ALONE, wk 2 and wk 6 in CON, but not in SEQ. All arms demonstrated a significant increase in HF at wk 6 from baseline. Across arms, HF was significantly increased in CON when compared to ALONE and SEQ while no significant difference was seen in HF in SEQ compared to ALONE. Increased melanophages were significantly associated with pCR in ALONE while increased HF was significantly associated with pCR in SEQ. LDS was not associated with pCR in any arm. Across all pts increased HF was significantly associated with pCR (Table). Table: 798P

*Pathological response; pCR vs no pCR **Wk 2 and 6; change from baseline

Conclusions

HF was significantly increased in CON when compared to SEQ or ALONE and was strongly associated with pCR across all patients. While melanophages and LDS demonstrated a temporal increase, these changes were not significantly associated with pCR.

Clinical trial identification

NCT02858921.

Editorial acknowledgement

Legal entity responsible for the study

Melanoma Institute of Australia, The University of Sydney.

Funding

Melanoma Institute of Australia, The University of Sydney, Merck Sharp & Dohme Corp., Novartis.

Disclosure

A.M. Menzies: Financial Interests, Personal, Advisory Board, advisory board: BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. M.S. Carlino: Financial Interests, Personal, Advisory Role: Amgen, Eisai, Ideaya, Nektar, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche; Financial Interests, Personal, Advisory Role, consultant advisor and honoraria: Bristol Myers Squibb, Merck Sharp and Dohme, Novartis. G. Au-Yeung: Financial Interests, Institutional, Research Grant, Research Funding: Roche/Genentech, AstraZeneca. R.P.M. Saw: Financial Interests, Personal, Invited Speaker: Bristol Myers Squib, Novartis; Financial Interests, Personal, Advisory Board: Novartis, MSD, Qbiotics; Financial Interests, Personal, Other, On Faculty, support of University of Sydney salary: Melanoma Institute Australia. D. Gyorki: Financial Interests, Personal, Advisory Board: Q biotics, Provectus, Amgen; Financial Interests, Personal, Sponsor/Funding, Honorarium: Bristol Myers Squibb, Merck. R.A. Scolyer: Financial Interests, Personal, Advisory Role, received fees for professional services: F Hoffmann-La Roche, Evaxion, Provectus, Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp and Dohme , NeraCare, Amgen, Bristol Myers Squibb, Myriad Genetics, GlaxoSmithKline. G.V. Long: Financial Interests, Personal, Other, Consultant Advisor: Agenus Inc, Amgen Inc, Array Biopharma Inc, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Merck Sharpe & Dohme (Australia) Pty Limited, Novartis Pharma AG, OncoSec Medical Australia, Pierre Fabre, Provectus Australia, Qbiotics Group Limited, Regeneron Pharmaceuticals Inc; Financial Interests, Personal, Advisory Board, Consultant Advisor: Highlight Therapeutics S.L. All other authors have declared no conflicts of interest.