{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:36:49Z","timestamp":1760236609978,"version":"build-2065373602"},"reference-count":31,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T00:00:00Z","timestamp":1638835200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011645","name":"Kaohsiung Medical University Chung-Ho Memorial Hospital","doi-asserted-by":"publisher","award":["KMUH109-9R32, KMUH109-9R33, KMUH109-9R34, KMUH109-9M30, KMUH109-9M31, KMUH109-9M32, KMUH109-9M33, KMUHSA10903,  KMUHSA11013, KMUH-DK(C)110010, KMUH-DK(B)110004-3"],"award-info":[{"award-number":["KMUH109-9R32, KMUH109-9R33, KMUH109-9R34, KMUH109-9M30, KMUH109-9M31, KMUH109-9M32, KMUH109-9M33, KMUHSA10903,  KMUHSA11013, KMUH-DK(C)110010, KMUH-DK(B)110004-3"]}],"id":[{"id":"10.13039\/501100011645","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Backgroundand objectives: Patients with BRAF-mutated metastatic colorectal cancer have considerably poorer responses to conventional systemic treatment. The real-world effects of triplet therapy with BRAF, mitogen-activated protein kinase kinase, and epidermal growth factor receptor inhibitors in Asia have not been well-reported. Materials and Methods: This single-center case series included patients with BRAF-mutated metastatic colorectal cancer undergoing triplet therapy after failure of prior systemic treatment from 2016 to 2020. The primary outcome was progression-free survival, and secondary outcomes were overall survival, response rate, disease control rate, and adverse events. Results: Nine eligible patients with BRAF-mutated metastatic colorectal cancer receiving triplet therapy were enrolled, with a median follow-up time of 14.5 months (range, 1\u201326). Most patients (88.8%) had two or more prior systemic treatments, and the triplet regimen was mainly dabrafenib, trametinib, and panitumumab. The overall response rate and disease control rate were 11.1% and 33.3%, respectively. Median progression-free survival and overall survival were 2.9 and 7.4 months, respectively, and a trend toward better overall survival was found with left-sided metastatic colorectal cancer compared with right-sided disease (9.2 vs. 6.9 months, p = 0.093). Adverse events were mostly Grade 1\u20132, including nausea, hypertension, gastrointestinal symptoms, and skin disorders. Conclusions: In this single-center case series, triplet therapy with BRAF, mitogen-activated protein kinase kinase, and epidermal growth factor receptor inhibitors in BRAF-mutated metastatic colorectal cancer had an acceptable safety profile and reasonable efficacy.<\/jats:p>","DOI":"10.3390\/medicina57121339","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T11:00:23Z","timestamp":1638874823000},"page":"1339","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["BRAF, MEK, and EGFR Triplet Inhibitors as Salvage Therapy in BRAF-Mutated Metastatic Colorectal Cancer\u2014A Case Series Study Target Therapy of BRAF-Mutated mCRC"],"prefix":"10.3390","volume":"57","author":[{"given":"Jen-Hao","family":"Yeh","sequence":"first","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-DA Dachang Hospital, Kaohsiung 80794, Taiwan"},{"name":"Department of Medical technology, College of Medicine, I-Shou University, Kaohsiung 82445, Taiwan"},{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-DA Hospital, Kaohsiung 82445, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsiang-Lin","family":"Tsai","sequence":"additional","affiliation":[{"name":"Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yen-Cheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ching-Chun","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ching-Wen","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9760-5070","authenticated-orcid":false,"given":"Tsung-Kun","family":"Chang","sequence":"additional","affiliation":[{"name":"Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Chih","family":"Su","sequence":"additional","affiliation":[{"name":"Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Po-Jung","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2716-0050","authenticated-orcid":false,"given":"Yu-Peng","family":"Liu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7705-2621","authenticated-orcid":false,"given":"Jaw-Yuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Center for Liquid biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Pingtung Hospital, Ministry of Health and Welfare, Pingtung 90054, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1001\/jama.2021.0106","article-title":"Diagnosis and Treatment of Metastatic Colorectal Cancer: A Review","volume":"325","author":"Biller","year":"2021","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer Statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"37","DOI":"10.7326\/0003-4819-154-1-201101040-00006","article-title":"Systematic review: Anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer","volume":"154","author":"Dahabreh","year":"2011","journal-title":"Ann. Intern. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1093\/annonc\/mds620","article-title":"Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer","volume":"24","author":"Tougeron","year":"2013","journal-title":"Ann. Oncol. Off. J. Eur. Soc. Med. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2207","DOI":"10.1056\/NEJMoa2017699","article-title":"Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer","volume":"383","author":"Shiu","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_6","first-page":"2196703","article-title":"Low Level of Microsatellite Instability Correlates with Poor Clinical Prognosis in Stage II Colorectal Cancer Patients","volume":"2016","author":"Kashfi","year":"2016","journal-title":"J. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Yuan, Z.X., Wang, X.Y., Qin, Q.Y., Chen, D.F., Zhong, Q.H., Wang, L., and Wang, J.P. (2013). The prognostic role of BRAF mutation in metastatic colorectal cancer receiving anti-EGFR monoclonal antibodies: A meta-analysis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0065995"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4599","DOI":"10.1158\/1078-0432.CCR-20-1024","article-title":"Population-based Screening for BRAF (V600E) in Metastatic Colorectal Cancer Reveals Increased Prevalence and Poor Prognosis","volume":"26","author":"Chu","year":"2020","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1093\/annonc\/mdw261","article-title":"Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: Pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group","volume":"27","author":"Modest","year":"2016","journal-title":"Ann. Oncol. Off. J. Eur. Soc. Med. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6531","DOI":"10.1158\/1078-0432.CCR-12-0605","article-title":"Mutation profiling and microsatellite instability in stage II and III colon cancer: An assessment of their prognostic and oxaliplatin predictive value","volume":"18","author":"Gavin","year":"2012","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1056\/NEJMoa1908075","article-title":"Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer","volume":"381","author":"Kopetz","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4023","DOI":"10.1200\/JCO.2015.63.2471","article-title":"Combined BRAF and MEK Inhibition with Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer","volume":"33","author":"Corcoran","year":"2015","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1158\/1078-0432.CCR-14-2779","article-title":"Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients","volume":"21","author":"Yaeger","year":"2015","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1158\/2159-8290.CD-17-1226","article-title":"Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAF(V600E)-Mutant Colorectal Cancer","volume":"8","author":"Corcoran","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"S242","DOI":"10.1016\/j.annonc.2020.04.080","article-title":"LBA-5 ANCHOR CRC: A single-arm, phase 2 study of encorafenib, binimetinib plus cetuximab in previously untreated BRAF V600E-mutant metastatic colorectal cancer","volume":"31","author":"Grothey","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6686517","DOI":"10.1155\/2021\/6686517","article-title":"UGT1A1 Polymorphism for Irinotecan Dose Escalation in Patients with BRAF-Mutated Metastatic Colorectal Cancer Treated with First-Line Bevacizumab and FOLFIRI","volume":"2021","author":"Hsieh","year":"2021","journal-title":"J. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.3892\/ol.2020.11795","article-title":"Effect of KRAS and NRAS mutations on the prognosis of patients with synchronous metastatic colorectal cancer presenting with liver-only and lung-only metastases","volume":"20","author":"Chuang","year":"2020","journal-title":"Oncol. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s10897-010-9325-x","article-title":"Genetic counseling considerations in the evaluation of families for Lynch syndrome\u2014A review","volume":"20","author":"Weissman","year":"2011","journal-title":"J. Genet. Couns."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1093\/jnci\/92.3.205","article-title":"New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada","volume":"92","author":"Therasse","year":"2000","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"viii201","DOI":"10.1093\/annonc\/mdy281.152","article-title":"BIG BANG study: A multicenter phase II study of the MEK inhibitor binimetinib + BRAF inhibitor encorafenib + anti-EGFR antibody cetuximab in patients with BRAF non-V600E mutated metastatic colorectal cancer (EPOC 1703)","volume":"29","author":"Kotani","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.ejca.2019.06.008","article-title":"A validated prognostic classifier for V600EBRAF-mutated metastatic colorectal cancer: The \u2018BRAF BeCool\u2019 study","volume":"118","author":"Loupakis","year":"2019","journal-title":"Eur. J. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1016\/j.ejca.2015.03.015","article-title":"Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17","volume":"51","author":"Jonker","year":"2015","journal-title":"Eur J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ulivi, P., Scarpi, E., Chiadini, E., Marisi, G., Valgiusti, M., Capelli, L., Gardini, A.C., Monti, M., Ruscelli, S., and Frassineti, G.L. (2017). Right- vs. Left-Sided Metastatic Colorectal Cancer: Differences in Tumor Biology and Bevacizumab Efficacy. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18061240"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3504","DOI":"10.1200\/JCO.2016.34.15_suppl.3504","article-title":"Impact of primary (1\u00ba) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB\/SWOG 80405 (Alliance)","volume":"34","author":"Venook","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3502","DOI":"10.1200\/JCO.2021.39.15_suppl.3502","article-title":"Randomized study to investigate FOLFOXIRI plus either bevacizumab or cetuximab as first-line treatment of BRAF V600E-mutant mCRC: The phase-II FIRE-4.5 study (AIO KRK-0116)","volume":"39","author":"Stintzing","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7089","DOI":"10.1158\/1078-0432.CCR-19-2004","article-title":"Response to Anti-EGFR Therapy in Patients with BRAF non-V600\u2013Mutant Metastatic Colorectal Cancer","volume":"25","author":"Yaeger","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.clcc.2014.06.001","article-title":"Progression-free survival remains poor over sequential lines of systemic therapy in patients with BRAF-mutated colorectal cancer","volume":"13","author":"Morris","year":"2014","journal-title":"Clin. Colorectal Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1200\/JCO.18.02459","article-title":"Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients with BRAF V600E-Mutant Metastatic Colorectal Cancer: Safety Lead-in Results from the Phase III BEACON Colorectal Cancer Study","volume":"37","author":"Huijberts","year":"2019","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s12935-020-1117-2","article-title":"The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer","volume":"20","author":"Fanelli","year":"2020","journal-title":"Cancer Cell Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.1158\/1078-0432.CCR-19-3579","article-title":"BRAF-Mutant Transcriptional Subtypes Predict Outcome of Combined BRAF, MEK, and EGFR Blockade with Dabrafenib, Trametinib, and Panitumumab in Patients with Colorectal Cancer","volume":"26","author":"Middleton","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1758835920944359","DOI":"10.1177\/1758835920944359","article-title":"Risk factors for MEK-associated retinopathy in patients with advanced melanoma treated with combination BRAF and MEK inhibitor therapy","volume":"12","author":"Booth","year":"2020","journal-title":"Ther. Adv. Med. Oncol."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/57\/12\/1339\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:42:46Z","timestamp":1760168566000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/57\/12\/1339"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,7]]},"references-count":31,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["medicina57121339"],"URL":"https:\/\/doi.org\/10.3390\/medicina57121339","relation":{},"ISSN":["1648-9144"],"issn-type":[{"type":"electronic","value":"1648-9144"}],"subject":[],"published":{"date-parts":[[2021,12,7]]}}}