Combined BRAF, EGFR, and MEK Inhibition in Patients with <i>BRAF</i>V600E-Mutant Colorectal Cancer
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- Ryan B. Corcoran
- 1Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
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- Thierry André
- 2Hôpital Saint-Antoine, and Sorbonne Universités, Paris, France.
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- Chloe E. Atreya
- 3University of California, San Francisco, California.
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- Jan H.M. Schellens
- 4The Netherlands Cancer Institute, Amsterdam, the Netherlands.
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- Takayuki Yoshino
- 5National Cancer Center Hospital East, Chiba, Japan.
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- Johanna C. Bendell
- 6Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.
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- Antoine Hollebecque
- 7Institute Gustave Roussy, Villejuif, France.
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- Autumn J. McRee
- 8University of North Carolina, Chapel Hill, North Carolina.
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- Salvatore Siena
- 9Niguarda Cancer Center, Grande Osopedale Metropolitano Niguarda and Department of Oncology and Hemato-Oncollogy, Università degli Studi di Milano, Milan, Italy.
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- Gary Middleton
- 10University of Birmingham and University Hospital, Birmingham, United Kingdom.
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- Kei Muro
- 11Aichi Cancer Center Hospital, Nagoya, Japan.
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- Michael S. Gordon
- 12Pinnacle Oncology Hematology, Scottsdale, Arizona.
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- Josep Tabernero
- 13Vall d'Hebron University Hospital, Barcelona, Spain.
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- Rona Yaeger
- 14Memorial Sloan Kettering Cancer Center, New York, New York.
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- Peter J. O'Dwyer
- 15Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
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- Yves Humblet
- 16St-Luc University Hospital, Brussels, Belgium.
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- Filip De Vos
- 17Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
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- A. Scott Jung
- 18Amgen Inc., Thousand Oaks, California.
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- Jan C. Brase
- 19Novartis Pharma AG, Basel, Switzerland.
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- Savina Jaeger
- 20Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
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- Severine Bettinger
- 19Novartis Pharma AG, Basel, Switzerland.
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- Bijoyesh Mookerjee
- 21Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
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- Fatima Rangwala
- 21Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
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- Eric Van Cutsem
- 22University Hospitals Leuven and KU Leuven, Leuven, Belgium.
Description
<jats:title>Abstract</jats:title> <jats:p>Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only approximately 5% of patients with BRAFV600E colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in BRAFV600E colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAFV600E colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism.</jats:p> <jats:p>Significance: This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with BRAFV600E colorectal cancer. Our findings highlight the MAPK pathway as a critical target in BRAFV600E colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. Cancer Discov; 8(4); 428–43. ©2018 AACR.</jats:p> <jats:p>See related commentary by Janku, p. 389.</jats:p> <jats:p>See related article by Hazar-Rethinam et al., p. 417.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 371</jats:p>
Journal
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- Cancer Discovery
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Cancer Discovery 8 (4), 428-443, 2018-04-01
American Association for Cancer Research (AACR)
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Details 詳細情報について
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- CRID
- 1363670319544933376
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- ISSN
- 21598290
- 21598274
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- Data Source
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- Crossref