{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T12:30:31Z","timestamp":1759667431382},"reference-count":10,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2018,8,17]],"date-time":"2018-08-17T00:00:00Z","timestamp":1534464000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Lessons Learned<\/jats:title>\n                  <jats:p>RAS- or BRAF-mutated metastatic colorectal cancers (mCRCs) progressing after first-line treatment have a poor prognosis. European and U.S. guidelines include the multikinase inhibitor regorafenib as a standard option for second-line therapy and beyond, based on the results of the randomized phase III CORRECT trial demonstrating improvement in survival. Although stopped prematurely for failing to accrue, the PREVIUM trial, the first prospective interventional study exploring regorafenib as second-line treatment for patients with mCRC bearing RAS or BRAF mutations, failed to demonstrate clinical activity in the population analyzed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Patients with RAS- or BRAF-mutated (mut) metastatic colorectal cancer (mCRC) progressing on first-line bevacizumab plus 5-FU\/irinotecan\/oxaliplatin (FOLFOXIRI) have a poor prognosis. We aimed to assess the efficacy and safety of regorafenib in this population.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Regorafenib was administered daily for 3 weeks of each 4-week cycle until disease progression or other reason. The primary endpoint was 6-month progression-free survival (PFS).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>KRAS, NRAS, or BRAF was mutated in mCRC samples in 60%, 20%, and 13% of patients, respectively. Median time from initial diagnosis of metastases to the start of regorafenib and treatment duration was 13.8 months and 7 weeks, respectively. Reasons for discontinuation included disease progression (80%), investigator decision (13%), and adverse events (AEs; 7%). Seven patients (47%) required dose reduction, mostly for asthenia (43%). The most common regorafenib-related grade 3 AEs were asthenia (33%), dysphonia (13%), and hypertension (13%) (Table 1). There were no grade 4 toxicities. No patient was progression-free at 6 months. Median PFS, time to progression (TTP), and overall survival (OS) were 2.2, 2.0, and 3.3 months, respectively.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Although stopped prematurely for failing to accrue, in the population analyzed, regorafenib failed to demonstrate clinical activity in KRAS- or BRAF-mutated mCRC with progression following first-line with FOLFOXIRI plus bevacizumab, although tolerability was acceptable. Our trial suggests that exploring regorafenib efficacy in an earlier line of therapy should not be undertaken without better population refinement.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1634\/theoncologist.2018-0316","type":"journal-article","created":{"date-parts":[[2018,8,17]],"date-time":"2018-08-17T11:58:04Z","timestamp":1534507084000},"page":"1271-e128","source":"Crossref","is-referenced-by-count":8,"title":["Single-Agent Regorafenib in Metastatic Colorectal Cancer Patients with Any RAS or BRAF Mutation Previously Treated with FOLFOXIRI plus Bevacizumab (PREVIUM Trial)"],"prefix":"10.1093","volume":"23","author":[{"given":"Pilar","family":"Garc\u00eda-Alfonso","sequence":"first","affiliation":[{"name":"Medical Oncology Department, Hospital General Universitario Gregorio Mara\u00f1\u00f3n, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Benavides","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital Universitario Regional y Virgen de la Victoria, M\u00e1laga, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esther","family":"Falc\u00f3","sequence":"additional","affiliation":[{"name":"Clinical Oncology Department, Hospital Son Llatzer, Palma de Mallorca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9s","family":"Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital General Universitario Gregorio Mara\u00f1\u00f3n, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Auxiliadora","family":"G\u00f3mez","sequence":"additional","affiliation":[{"name":"IMIBIC, Hospital Reina Sof\u00eda, University of C\u00f3rdoba, C\u00f3rdoba, Andalusia, Spain"},{"name":"CIBERONC Instituto de Salud Carlos III, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"Sastre","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital Universitario Clinico San Carlos, Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Hospital Clinico San Carlos (IdISSC), University Complutense, CIBERONC, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando","family":"Rivera","sequence":"additional","affiliation":[{"name":"Clinical Oncology Service, Hospital Universitario Marqu\u00e9s de Valdecilla, Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clara","family":"Montagut","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital del Mar, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mercedes","family":"Salgado","sequence":"additional","affiliation":[{"name":"Clinical Oncology Service, C.H. Universitario, Orense, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amelia","family":"L\u00f3pez-Ladr\u00f3n","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital Nuestra Senora de Valme, Sevilla, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital Cl\u00ednico de Santiago de Compostela, CIBERONC, La Coru\u00f1a, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inmaculada","family":"Ruiz de Mena","sequence":"additional","affiliation":[{"name":"Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD), Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gema","family":"Dur\u00e1n","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital Universitario Regional y Virgen de la Victoria, M\u00e1laga, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrique","family":"Aranda","sequence":"additional","affiliation":[{"name":"IMIBIC, Hospital Reina Sof\u00eda, University of C\u00f3rdoba, C\u00f3rdoba, Andalusia, Spain"},{"name":"CIBERONC Instituto de Salud Carlos III, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"on behalf of the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD)","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2018,8,17]]},"reference":[{"key":"2021122511132759700_onco12623-bib-0001","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1056\/NEJMoa1403108","article-title":"Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer","volume":"371","author":"Loupakis","year":"2014","journal-title":"N Engl J Med"},{"key":"2021122511132759700_onco12623-bib-0002","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.clcc.2011.06.013","article-title":"Outcome of second-line treatment after first-line chemotherapy with the GONO FOLFOXIRI regimen","volume":"11","author":"Fornaro","year":"2012","journal-title":"Clin Colorectal Cancer"},{"issue":"suppl 15","key":"2021122511132759700_onco12623-bib-0003","doi-asserted-by":"crossref","first-page":"3542a","DOI":"10.1200\/JCO.2017.35.15_suppl.3542","article-title":"Treatments (tx) after progression to first-line FOLFOXIRI plus bevacizumab (bev) in metastatic colorectal cancer (mCRC) patients (pts): A pooled analysis of TRIBE and MOMA studies by GONO group","volume":"35","author":"Rossini","year":"2017","journal-title":"J Clin Oncol"},{"key":"2021122511132759700_onco12623-bib-0004","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/S0140-6736(12)61900-X","article-title":"Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebo-controlled, phase 3 trial","volume":"381","author":"Grothey","year":"2013","journal-title":"Lancet"},{"key":"2021122511132759700_onco12623-bib-0005","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"},{"key":"2021122511132759700_onco12623-bib-0006","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1002\/cncr.29196","article-title":"RAS mutations affect pattern of metastatic spread and increase propensity for brain metastasis in colorectal cancer","volume":"121","author":"Yaeger","year":"2015","journal-title":"Cancer"},{"key":"2021122511132759700_onco12623-bib-0007","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1186\/s12885-016-2440-9","article-title":"Survival, safety, and prognostic factors for outcome with Regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: Results from a multicenter study (REBECCA) nested within a compassionate use program","volume":"16","author":"Adenis","year":"2016","journal-title":"BMC Cancer"},{"key":"2021122511132759700_onco12623-bib-0008","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1186\/1471-2407-14-976","article-title":"Relationship between circulating tumor cells and tumor response in colorectal cancer patients treated with chemotherapy: A meta-analysis","volume":"14","author":"Huang","year":"2014","journal-title":"BMC Cancer"},{"key":"2021122511132759700_onco12623-bib-0009","doi-asserted-by":"crossref","first-page":"3213","DOI":"10.1200\/JCO.2007.15.8923","article-title":"Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer","volume":"26","author":"Cohen","year":"2008","journal-title":"J Clin Oncol"},{"key":"2021122511132759700_onco12623-bib-0010","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/S1470-2045(15)00138-2","article-title":"Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: A retrospective, exploratory analysis of the CORRECT trial","volume":"16","author":"Tabernero","year":"2015","journal-title":"Lancet Oncol"}],"container-title":["The Oncologist"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1634\/theoncologist.2018-0316","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1634\/theoncologist.2018-0316","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/23\/11\/1271\/41914665\/oncolo_23_11_1271.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/23\/11\/1271\/41914665\/oncolo_23_11_1271.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,25]],"date-time":"2021-12-25T06:14:50Z","timestamp":1640412890000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/oncolo\/article\/23\/11\/1271\/6439839"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8,17]]},"references-count":10,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2018,8,17]]},"published-print":{"date-parts":[[2018,11,1]]}},"URL":"https:\/\/doi.org\/10.1634\/theoncologist.2018-0316","relation":{},"ISSN":["1083-7159","1549-490X"],"issn-type":[{"type":"print","value":"1083-7159"},{"type":"electronic","value":"1549-490X"}],"subject":[],"published-other":{"date-parts":[[2018,11,1]]},"published":{"date-parts":[[2018,8,17]]}}}