e-Poster Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2021

NeoTrio Trial; Optimal Neoadjuvant Sequencing of Anti-PD1 and BRAF targeting therapy in Resectable BRAF Mutant stage IIIB/C/D Melanoma: Results of Translational Investigations (#314)

Jorja Braden 1 , Alison J Potter 1 , Elizabeth Paver 1 , Alexander M Menzies 1 , Matteo S Carlino 1 , George Au-yeung 2 , Robyn P Saw 1 , Andrew J Spillane 1 , Jonathan R Stretch 1 , Kerwin F Shannon 1 , Thomas E Pennington 1 , Sydney Ch'ng 1 , David Gyorki 2 , Julie Howle 3 , Dariush Deneshvar 3 , Ines P Silva 1 , Richard A Scolyer 1 , James S Wilmott 1 , Georgina V Long 1
  1. Melanoma Institute of Australia, Sydney , NSW, Australia
  2. Medical Oncology , Peter MacCallum Department of Oncology , Melbourne, VIC, Australia
  3. Medical Oncology , Westmead Hospital, Sydney, NSW, Australia

BRAF/MEK targeted therapy and anti-PD-1 immunotherapy have significantly improved survival for both advanced-stage and resected stage III melanoma. Melanoma biopsies taken from patients early-during BRAF-targeted therapy have shown favourable immunomodulatory changes which may have synergistic effects when combined with immune checkpoint inhibition. In the metastatic setting, BRAF/MEK inhibitors combined with anti-PD-1 improved outcomes compared with BRAF/MEK alone, at the expense of increased toxicity. In this study we sought to ascertain the optimal combination or sequencing of these therapies in the neoadjuvant setting.

 

NeoTrio was a three-armed, randomized, multicentre, phase II study, including patients with histologically-confirmed, resectable and RECIST measurable stage III (no in-transit metastases allowed), BRAFV600-mutant melanoma. Patients were randomised to one of three treatment arms: A) Sequential: dabrafenib (150mg bd) plus trametinib (2mg od) for 7 days followed by pembrolizumab (200mg Q3W) days 8 and 22; B) Concurrent: dabrafenib plus trametinib with pembrolizumab (doses as per Sequential), C) Single Agent Pembrolizumab (doses as per Sequential). Core biopsies were performed at baseline, week 1 and 2, with complete lymphadenectomy at 6 weeks, followed by adjuvant pembrolizumab to week 52. The translational endpoint of this trial is to assess the longitudinal effects of neoadjuvant treatment on the tumour and its microenvironment. This trial is registered with ClinicalTrials.gov, NCT02858921. Follow-up is ongoing.

 

Between 27th July 2018 to 30th June 2021, 60 patients were randomised to one of three arms. Translational results of this study will report changes to the tumour microenvironment as analysed on representative haematoxylin and eosin stains. This analysis will include tumour regression/melanosis, degree/location of tumour-infiltrating lymphocytes, degree of inflammation and fibrosis. Changes will be compared across the treatment arms. The clinical results of this study will be reported in separately.