455O - Efficacy and circulating tumor DNA (ctDNA) analysis of the BRAF inhibitor dabrafenib (D), MEK inhibitor trametinib (T), and anti-EGFR antibody pani...

Date 09 October 2016
Event ESMO 2016 Congress
Session Gastrointestinal tumours, colorectal 1
Topics Cytotoxic agents
Colon and Rectal Cancer
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Therapy
Biological therapy
Presenter Ryan Corcoran
Citation Annals of Oncology (2016) 27 (6): 149-206. 10.1093/annonc/mdw370
Authors R.B. Corcoran1, T. André2, T. Yoshino3, J.C. Bendell4, C.E. Atreya5, J.H.M. Schellens6, M.P. Ducreux7, A. McRee8, S. Siena9, G. Middleton10, M. Gordon11, Y. Humblet12, K. Muro13, E. Elez14, R. Yaeger15, R. Sidhu16, M. Squires17, S. Jaeger18, F. Rangwala19, E. Van Cutsem20
  • 1Cancer Center, Massachusetts General Hospital, 02114 - Boston/US
  • 2Oncologie Médicale, Hôpital Saint-Antoine, 75571 - Paris/FR
  • 3Gastroenterology & Gastrointestinal Oncology, National Cancer Center Hospital East, 277-8577 - Chiba/JP
  • 4Gi Oncology Research, Sarah Cannon Research Institute, 37203 - Nashville/US
  • 5Helen Diller Family Comprehensive Cancer Center, University of California, 94158 - San Francisco/US
  • 6Clinical Pharmacology, The Netherlands Cancer Institute, 1066CX - Amsterdam/NL
  • 7Medicine, Institute Gustave Roussy, 94805 - Villejuif/FR
  • 8Gi Medical Oncology, University of North Carolina - Chapel Hill, 27599-7305 - Chapel Hill/US
  • 9Ospedale Niguarda, Università Degli Studi Di Milano, Niguarda Cancer Center, 20162 Milano - Milano/IT
  • 10School Of Cancer Sciences, University of Birmingham, B15 2TT - Birmingham/GB
  • 11Division Of Arizona Center For Cancer Care, Pinnacle Oncology Hematology, Scottsdale/US
  • 12Medical Oncology Dept, St-Luc University Hosptial, 1200 - Brussels/BE
  • 13Department Of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya/JP
  • 14Medical Oncology, Vall d'Hebron University Hospital, 08015 - Barcelona/ES
  • 15Gastrointestinal Oncology, Memorial Sloan Kettering Cancer Center, New York/US
  • 16Hematology/oncology, Amgen Inc., Thousand Oaks/US
  • 17Global Oncology, Novartis Pharma AG, 4002 - Basel/CH
  • 18Biomarkers And Diagnostics Biometrics, Novartis Institute for Biomedical Research Inc., 02139 - Boston/US
  • 19Global Oncology, Novartis Pharmaceuticals Corporation, East Rutherford/US
  • 20Digestive Oncology, University Hospitals Leuven, 3000 - Leuven/BE

Abstract

Background

BRAF V600E mutations occur in 5% to 10% of mCRC and confer poor prognosis. Unlike in BRAF V600–mutated melanoma, BRAF and MEK inhibitors have minimal activity in BRAFm mCRC. Preclinical studies suggest combined inhibition of the EGFR and MAPK pathway may improve efficacy in BRAFm mCRC. This study evaluates the safety and efficacy of P with D and/or T in BRAFm mCRC with integrated biomarker analyses.

Methods

134 eligible pts with BRAFm mCRC received DP (n = 20), TP (n = 31), or DTP (n = 83) at up to full dose of each monotherapy agent. Pretreatment and on-treatment tumor biopsies were assessed for phosphorylated ERK (pERK) by IHC. Serial ctDNA samples were profiled for mutations in BRAF, KRAS, NRAS, and PIK3CA.

Results

120 pts had prior chemotherapy for mCRC; 14 were enrolled in the first line. Most common adverse events were dermatitis acneiform, diarrhea, fatigue, nausea and rash. Rates of confirmed CR/PR and SD, respectively, were 10% and 80% for DP, 0% and 53% for TP, and 18% and 67% for DTP. Median progression-free survival (PFS) for DP and TP was 3.4 and 2.8 months, respectively. Median PFS for DTP is not yet mature. Median reduction in pERK in on-treatment vs pretreatment biopsies was 23% for DP, 50% for TP, and 54% for DTP. To date, serial ctDNA analysis for pts in the DTP arm demonstrated >70% reduction in BRAF V600E mutant fraction (MF) in 12 of 14 pts (86%) by week 4, with 6 of these 12 pts having PR at week 6. BRAF V600E MF increased in 10 of these pts upon progression. Of 12 pts with CR/PR or SD as best response, 7 (58%) had detectable RAS mutations in ctDNA upon progression that were not detectable at baseline, with 3 pts developing multiple RAS mutations. 2 pts had co-occurring BRAF V600E and RAS mutations detectable at baseline. Updated clinical and integrated biomarker analyses will be presented.

Conclusions

DTP had acceptable tolerability and activity in BRAFm mCRC, with evidence of downstream target inhibition. CtDNA changes in BRAF V600E MF may allow for monitoring of disease response and progression. Preexisting and emerging RAS mutations are potential mechanisms of resistance.

Clinical trial identification

NCT01750918; first received by clinicaltrials.gov on December 6, 2012

Legal entity responsible for the study

Supported by GlaxoSmithKline. Dabrafenib and trametinib are assets of Novartis AG as of 2 March 2015.

Funding

Supported by GlaxoSmithKline. Dabrafenib and trametinib are assets of Novartis AG as of 2 March 2015.

Disclosure

R.B. Corcoran: Consultancy: Genentech, Merrimack, Astex, N-of-One, Avidity Nanamedicinces, Taiho T. André: Consultancy: Roche Honoraria: Roche, Amgen, Novartis. T. Yoshino: Research Funding: GlaxoSmithKline K.K., Boehringer Ingelheim GmbH. C.E. Atreya: Research Funding: GlaxoSmithKline, Novartis, Merck Membership on board of directors or advisory committees: Bayer Diagnostics, Genentech. M.P. Ducreux: Honoraria: Novartis, Roche, Merck, Amgen, Lilly, Servier Speakers Bureau: Novartis, Roche, Merck, Amgen, Lilly, Servier Membership on Board or Ad Committee: Novartis, Roche, Merck, Amgen, Lilly, Servier. A. McRee: Celegene: Membership on board of directors or advisory committee (Ad Board). S. Siena: Membership on Board or Ad Committee: Amgen, Roche, Bayer, Sanofi, Merck Serono, Eli Lilly. G. Middleton: Equity Ownership: PHX Immune Research Funding: Merck Shar Dhome, Kael Gemvax, Astra Zeneca Honoraria: BristolMeyersSquibb, Eli Lilly. K. Muro: Honoraria: Takeda, Chugai, Taiho, Yakult, MerckSerono Membership on Board/Ad Committee: Eli Lilly, Ono. R. Yaeger: Consultancy: GlaxoSmithKline Research Funding: GlaxoSmithKline, Novartis. R. Sidhu: Employment: Amgen Inc. M. Squires: Employment: Novartis Pharma AG. S. Jaeger, F. Rangwala: Employment: Novartis. E. Van Cutsem: Research Funding: Amgen, Bayer, Boehringer, Celgene, Lilly, Ipsen, Novartis, Merck, Roche, Sanofi. All other authors have declared no conflicts of interest.