A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic <i>BRAF</i> -Mutant Colorectal Cancer
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- Robin M.J.M. van Geel
- 1The Netherlands Cancer Institute, Amsterdam, the Netherlands.
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- Josep Tabernero
- 2Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
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- Elena Elez
- 2Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
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- Johanna C. Bendell
- 3Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.
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- Anna Spreafico
- 4Princess Margaret Cancer Centre, Toronto, Canada.
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- Martin Schuler
- 5West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany, and German Cancer Consortium (DKTK), partner site University Hospital Essen, Essen, Germany.
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- Takayuki Yoshino
- 6National Cancer Center Hospital East, Chiba, Japan.
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- Jean-Pierre Delord
- 7Institut Claudius Regaud, Toulouse, France.
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- Yasuhide Yamada
- 8National Cancer Center Hospital, Tokyo, Japan.
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- Martijn P. Lolkema
- 9University Medical Center Utrecht, Utrecht, the Netherlands.
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- Jason E. Faris
- 11Massachusetts General Hospital, Boston, Massachusetts.
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- Ferry A.L.M. Eskens
- 10Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
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- Sunil Sharma
- 12Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
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- Rona Yaeger
- 13Memorial Sloan-Kettering Cancer Center, New York, New York.
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- Heinz-Josef Lenz
- 14Keck School of Medicine at the University of Southern California, Los Angeles, California.
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- Zev A. Wainberg
- 15UCLA Medical Center, Santa Monica, California.
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- Emin Avsar
- 16Novartis Pharmaceutical Corporation, East Hanover, New Jersey.
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- Arkendu Chatterjee
- 16Novartis Pharmaceutical Corporation, East Hanover, New Jersey.
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- Savina Jaeger
- 17Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
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- Eugene Tan
- 16Novartis Pharmaceutical Corporation, East Hanover, New Jersey.
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- Kati Maharry
- 18Array BioPharma Inc., Boulder, Colorado.
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- Tim Demuth
- 19Novartis Pharma AG, Basel, Switzerland.
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- Jan H.M. Schellens
- 1The Netherlands Cancer Institute, Amsterdam, the Netherlands.
書誌事項
- 公開日
- 2017-06-01
- DOI
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- 10.1158/2159-8290.cd-16-0795
- 公開者
- American Association for Cancer Research (AACR)
この論文をさがす
説明
<jats:title>Abstract</jats:title> <jats:p>Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAFV600E colorectal cancer models. Patients with refractory BRAFV600-mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with (n = 28) or without (n = 26) a PI3Kα inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase II dose. Dose-limiting toxicities were reported in 3 patients receiving dual treatment and 2 patients receiving triple treatment. The MTD was not reached for either group and the phase II doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib. Combinations of cetuximab and encorafenib showed promising clinical activity and tolerability in patients with BRAF-mutant mCRC; confirmed overall response rates of 19% and 18% were observed and median progression-free survival was 3.7 and 4.2 months for the dual- and triple-therapy groups, respectively.</jats:p> <jats:p>Significance: Herein, we demonstrate that dual- (encorafenib plus cetuximab) and triple- (encorafenib plus cetuximab and alpelisib) combination treatments are tolerable and provide promising clinical activity in the difficult-to-treat patient population with BRAF-mutant mCRC. Cancer Discov; 7(6); 610–9. ©2017 AACR.</jats:p> <jats:p>See related commentary by Sundar et al., p. 558.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 539</jats:p>
収録刊行物
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- Cancer Discovery
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Cancer Discovery 7 (6), 610-619, 2017-06-01
American Association for Cancer Research (AACR)
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キーワード
- Male
- Medizin
- Cetuximab
- Taverne
- Antineoplastic Combined Chemotherapy Protocols
- 80 and over
- Cancer
- Phosphoinositide-3 Kinase Inhibitors
- Aged, 80 and over
- Sulfonamides
- COLON-CANCER
- Middle Aged
- Clinical Trial
- Colo-Rectal Cancer
- Multicenter Study
- 6.1 Pharmaceuticals
- Female
- Colorectal Neoplasms
- Adult
- Proto-Oncogene Proteins B-raf
- Maximum Tolerated Dose
- EGFR
- Clinical Sciences
- Oncology and Carcinogenesis
- BIOMARKERS
- INHIBITION
- Antineoplastic Agents
- Disease-Free Survival
- Phase I
- SDG 3 - Good Health and Well-being
- Clinical Research
- MAPK PATHWAY
- Journal Article
- KRAS
- Humans
- WILD-TYPE
- Protein Kinase Inhibitors
- Aged
- Biomedical and Clinical Sciences
- Evaluation of treatments and therapeutic interventions
- Oncology and carcinogenesis
- RAF
- FLUOROURACIL
- Thiazoles
- EMC MM-03-86-08
- Biochemistry and cell biology
- Mutation
- GENE COPY NUMBER
- Carbamates
- Phosphatidylinositol 3-Kinase
- Digestive Diseases
詳細情報 詳細情報について
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- CRID
- 1363388846264945280
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- ISSN
- 21598290
- 21598274
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- PubMed
- 28363909
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