Oral Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2021

Molecular correlates of clinical benefit in previously treated patients (pts) with BRAF V600E-mutant metastatic colorectal cancer (mCRC) from the BEACON study.   (#93)

Jayesh Desai 1 , Scott Kopetz 2 , Danielle A Murphy 3 , Jie Pu 3 , Fortunato Ciardiello 4 , Axel Grothey 5 , Eric Van Cutsem 6 , Harpreet Singh Wasan 7 , Rona Yaeger 8 , Takayuki Yoshino 9 , Lorraine Chantrill 10 , Niall Tebbutt 11 , Andrew Strickland 12 , Timothy Price 13 , Chris Karapetis 14 , Felicity Murphy 15 , Amber C Donahue 3 , Adele Golden 16 , Ashwin Gollerkeri 17 , Zhou Zhu 3 , Josep Tabernero 18
  1. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. MD Anderson Cancer Center, Houston, TX
  3. Pfizer, La Jolla, CA
  4. University of Campania Luigi Vanvitelli , Naples, Italy
  5. West Cancer Center, OneOncology, Germantown, TN
  6. University Hospital Gasthuisberg and University of Leuven, Leuven, Belgium
  7. Hammersmith Hospital, Division of Cancer, Imperial College London, London, United Kingdom
  8. Memorial Sloan Kettering Cancer Center, New York, NY
  9. National Cancer Center Hospital East, Kashiwa, Japan
  10. St Vincent’s Hospital, Sydney, NSW, Australia
  11. Austin Health – Medical Oncology, Melbourne, VIC, Australia
  12. Monash Health and Monash University, Melbourne, VIC, Australia
  13. Medical Oncology Unit, Queen Elizabeth Hospital and University of Adelaide, Adelaide, South Australia, Australia
  14. Flinders Medical Centre and Flinders University, Adelaide, SA, Australia
  15. The Mater Hospital, Brisbane, QLD, Australia
  16. Pfizer, Cambridge, MA, USA
  17. Pfizer, New York, NY
  18. Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), UVic-UCC, Barcelona, Spain

Background: In the BEACON study, encorafenib + binimetinib + cetuximab (enco/bini/cetux; triplet) and enco + cetux (doublet) improved OS and ORR vs standard of care in previously treated BRAF V600E-mutant mCRC pts. Molecular profiling of tumors from this study was performed to identify molecular correlates of outcome.

Methods: Baseline tumor samples were analysed by whole-exome sequencing (WES) and whole transcriptome sequencing (WTS). BRAF-mutant (BM) and consensus molecular subtypes (CMS) were determined and pathway activities evaluated with gene set variation analysis. Tumuor response was evaluated for each subtype. Additional association and interaction analyses between molecular features and outcomes by treatments are ongoing and will be presented.

Results: Baseline tumor samples were analysed by WES and/or WTS for 79.2% of pts. Of the 460 pts analysed by WTS (73.7% in the triplet arm, 66.4% in the doublet arm, 67.4% in the control arm), 84.6% were classified as CMS1 or CMS4. 32.2% of pts were classified as BM1 and the majority (84.5%) of these were CMS4. Many of those classified as BM2 (67.8%) were CMS1 (64.7%). In the BM1 and CMS4 tumors, expression of inflammatory response and epithelial mesenchymal transition genes were elevated, and expression of cell cycle genes was reduced. Response rate in pts with CMS4 and/or BM1 tumors was higher in the triplet arm (CMS4: 33.3% [95% CI: 21.7–46.7]; BM1: 33.3% [95% CI: 21.4–47.1]) vs the doublet arm (CMS4: 19.2% [95% CI: 9.6–32.5]; BM1: 14.9% [95% CI: 6.2–28.3]).

Conclusions: Molecular characteristics and biological properties observed in BRAF V600E-mutant mCRC suggest a subset of pts with specific molecular features may derive greater clinical benefit from triplet vs doublet therapy. These findings support further investigating the biological landscape in BRAF-mutant mCRC to enable potential hypotheses for pt selection to improve clinical outcome in future studies. Clinical trial information: NCT02928224.