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Efficacy and circulating tumor DNA (ctDNA) analysis of the BRAF inhibitor dabrafenib (D), MEK inhibitor trametinib (T), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E–mutated (BRAFm) metastatic colorectal cancer (mCRC)

Date

09 Oct 2016

Session

Gastrointestinal tumours, colorectal 1

Presenters

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

Author affiliations

  • 1 Cancer Center, Massachusetts General Hospital, 02114 - Boston/US
  • 2 Oncologie Médicale, Hôpital Saint-Antoine, 75571 - Paris/FR
  • 3 Gastroenterology & Gastrointestinal Oncology, National Cancer Center Hospital East, 277-8577 - Chiba/JP
  • 4 Gi Oncology Research, Sarah Cannon Research Institute, 37203 - Nashville/US
  • 5 Helen Diller Family Comprehensive Cancer Center, University of California, 94158 - San Francisco/US
  • 6 Clinical Pharmacology, The Netherlands Cancer Institute, 1066CX - Amsterdam/NL
  • 7 Medicine, Institute Gustave Roussy, 94805 - Villejuif/FR
  • 8 Gi Medical Oncology, University of North Carolina - Chapel Hill, 27599-7305 - Chapel Hill/US
  • 9 Ospedale Niguarda, Università Degli Studi Di Milano, Niguarda Cancer Center, 20162 Milano - Milano/IT
  • 10 School Of Cancer Sciences, University of Birmingham, B15 2TT - Birmingham/GB
  • 11 Division Of Arizona Center For Cancer Care, Pinnacle Oncology Hematology, Scottsdale/US
  • 12 Medical Oncology Dept, St-Luc University Hosptial, 1200 - Brussels/BE
  • 13 Department Of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya/JP
  • 14 Medical Oncology, Vall d'Hebron University Hospital, 08015 - Barcelona/ES
  • 15 Gastrointestinal Oncology, Memorial Sloan Kettering Cancer Center, New York/US
  • 16 Hematology/oncology, Amgen Inc., Thousand Oaks/US
  • 17 Global Oncology, Novartis Pharma AG, 4002 - Basel/CH
  • 18 Biomarkers And Diagnostics Biometrics, Novartis Institute for Biomedical Research Inc., 02139 - Boston/US
  • 19 Global Oncology, Novartis Pharmaceuticals Corporation, East Rutherford/US
  • 20 Digestive Oncology, University Hospitals Leuven, 3000 - Leuven/BE
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Abstract 2425

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.

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