A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer
| العنوان: | A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer |
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| المؤلفون: | Sunil Sharma, Emin Avsar, Kati Maharry, Jan H.M. Schellens, Anna Spreafico, Rona Yaeger, Martin Schuler, Jason E. Faris, Takayuki Yoshino, Arkendu Chatterjee, Savina Jaeger, Ferry A.L.M. Eskens, Johanna C. Bendell, Tim Demuth, Josep Tabernero, Martijn P. Lolkema, Zev A. Wainberg, Yasuhide Yamada, Jean Pierre Delord, Robin M.J.M. van Geel, Eugene Tan, Elena Elez, Heinz-Josef Lenz |
| المساهمون: | MUMC+: DA KFT Medische Staf (9), RS: FHML non-thematic output, Medical Oncology |
| المصدر: | Cancer Discovery, 7(6), 610-619. American Association for Cancer Research Inc. Cancer discovery, vol 7, iss 6 Cancer Discovery, 7(6), 610. American Association for Cancer Research Inc. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Oncology, Male, Colorectal cancer, Medizin, Cetuximab, Raf Kinase Inhibitor, Pharmacology, 0302 clinical medicine, Encorafenib, Antineoplastic Combined Chemotherapy Protocols, 80 and over, Phosphoinositide-3 Kinase Inhibitors, Cancer, Aged, 80 and over, Sulfonamides, COLON-CANCER, Middle Aged, Clinical Trial, Colo-Rectal Cancer, 3. Good health, Multicenter Study, Tolerability, 6.1 Pharmaceuticals, 030220 oncology & carcinogenesis, Female, Colorectal Neoplasms, medicine.drug, Adult, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, Maximum Tolerated Dose, EGFR, Oncology and Carcinogenesis, BIOMARKERS, INHIBITION, Antineoplastic Agents, Disease-Free Survival, Clinical Trial, Phase I, 03 medical and health sciences, Phase I, SDG 3 - Good Health and Well-being, Clinical Research, Internal medicine, MAPK PATHWAY, medicine, Journal Article, KRAS, Humans, WILD-TYPE, neoplasms, Protein Kinase Inhibitors, Aged, business.industry, Evaluation of treatments and therapeutic interventions, RAF, medicine.disease, digestive system diseases, FLUOROURACIL, Clinical trial, Thiazoles, 030104 developmental biology, Concomitant, Mutation, GENE COPY NUMBER, Carbamates, Phosphatidylinositol 3-Kinase, Digestive Diseases, business |
| الوصف: | 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.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.See related commentary by Sundar et al., p. 558.This article is highlighted in the In This Issue feature, p. 539 |
| وصف الملف: | application/pdf |
| تدمد: | 2159-8274 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1a74efca771fba8318569827a37a712fTest https://hdl.handle.net/1765/108310Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....1a74efca771fba8318569827a37a712f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 21598274 |
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