{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:50:46Z","timestamp":1791571846304,"version":"4.3.4"},"reference-count":22,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":2,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Bayer Pharmaceuticals"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Regorafenib and anti-EGFR monoclonal antibodies are standard therapies for RAS\/BRAF wild-type (WT) metastatic colorectal cancer (mCRC) in the refractory setting, but the optimal sequencing remains unknown. Herein, we report results from REVERCE II, a randomized phase II trial evaluating the efficacy and safety of sequencing these therapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patients with RAS WT mCRC previously treated with fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive (R-E) regorafenib followed by anti-EGFR therapy\u2009\u00b1\u2009irinotecan or (E-R) anti-EGFR therapy\u2009\u00b1\u2009irinotecan, followed by regorafenib sequentially. The primary endpoint was overall survival (OS). Key secondary endpoints included progression-free survival (PFS) with initial (PFS1) and second treatment (PFS2), sequential treatment PFS (stPFS), objective response rate (ORR), and safety. Exploratory endpoints included serial biomarker analyses. Unfortunately, the trial was closed prematurely due to slow enrollment and lack of funding.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Twenty-two patients were enrolled (R-E: n\u2009=\u200912; E-R: n\u2009=\u200910) with sequential treatment initiated in 33% (4\/12) and 80% (8\/10) of patients in R-E and E-R, respectively. Median OS for R-E and E-R was 21.9 and 13.3\u2009months, respectively (one-sided P\u2009=\u2009.114). PFS1 was 2.5 (R-E) vs 5.6\u2009months (E-R) (one-sided P\u2009=\u2009.998), while PFS2 was 3.7 vs 2.0\u2009months (one-sided P\u2009=\u2009.086). stPFS was similar (9.3 vs 9.6\u2009months; one-sided P\u2009=\u2009.358). ORR for initial treatment was 0% in R-E and 20% (2\/8) in E-R. Sequential treatment ORR was 25% (n\u2009=\u20091\/4) in R-E and 0% in E-R. No significant differences were observed adverse effects between arms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>While the study was closed prematurely prior to completion, the sequence of regorafenib before to anti-EGFR therapy suggested a possible survival benefit. Further studies may help better determine the optimal treatment sequencing strategy in refractory mCRC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/oncolo\/oyag307","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T11:51:46Z","timestamp":1790855506000},"source":"Crossref","is-referenced-by-count":0,"title":["REVERCE II: a phase II trial of regorafenib followed by anti-EGFR therapy versus reverse sequencing in refractory metastatic colorectal cancer"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5666-6085","authenticated-orcid":false,"given":"Oluseyi B","family":"Abidoye","sequence":"first","affiliation":[{"name":"Division of Hematology and Medical Oncology, Mayo Clinic , Phoenix, AZ 85054,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1267-8735","authenticated-orcid":false,"given":"Fang-Shu","family":"Ou","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic , Rochester, MN 55905,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Ulrich","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic , Rochester, MN 55905,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaylene","family":"McCue","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic , Rochester, MN 55905,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad B","family":"Sonbol","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Mayo Clinic , Phoenix, AZ 85054,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald","family":"Wender","sequence":"additional","affiliation":[{"name":"UnityPoint Health \u2013 St. Luke's June E. Nylen Cancer Center , Sioux City, IA 51101,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey","family":"Klute","sequence":"additional","affiliation":[{"name":"University of Nebraska Medical Center Division of Medical Oncology, , Omaha, NE 986840,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7844-5833","authenticated-orcid":false,"given":"Zhaohui","family":"Jin","sequence":"additional","affiliation":[{"name":"Mayo Clinic Division of Hematology and Medical Oncology, , Rochester, MN 55905,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heinz-Josef","family":"Lenz","sequence":"additional","affiliation":[{"name":"University of Southern California, Norris Comprehensive Cancer Center Division of Medical Oncology, , Los Angeles, CA 90033,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John H","family":"Strickler","sequence":"additional","affiliation":[{"name":"Duke University Division of Medical Oncology, , Durham, NC 27710,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanios","family":"Bekaii-Saab","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Mayo Clinic , Phoenix, AZ 85054,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0161-4018","authenticated-orcid":false,"given":"Daniel H","family":"Ahn","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Mayo Clinic , Phoenix, AZ 85054,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,10,3]]},"reference":[{"key":"2026100914064250700_oyag307-B1","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.1016\/S1470-2045(19)30272-4","article-title":"Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study","volume":"20","author":"Bekaii-Saab","year":"2019","journal-title":"Lancet Oncol"},{"key":"2026100914064250700_oyag307-B2","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"2026100914064250700_oyag307-B3","author":"NCCN","year":"2025"},{"key":"2026100914064250700_oyag307-B4","doi-asserted-by":"publisher","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":"2026100914064250700_oyag307-B5","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1056\/NEJMc0904160","article-title":"BRAF mutation in metastatic colorectal cancer","volume":"361","author":"Tol","year":"2009","journal-title":"N Engl J Med"},{"key":"2026100914064250700_oyag307-B6","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1038\/s41416-020-01140-9","article-title":"FOLFIRI plus cetuximab or bevacizumab for advanced colorectal cancer: final survival and per-protocol analysis of FIRE-3, a randomised clinical trial","volume":"124","author":"Heinemann","year":"2021","journal-title":"Br J Cancer"},{"key":"2026100914064250700_oyag307-B7","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1016\/S1470-2045(14)70330-4","article-title":"FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial","volume":"15","author":"Heinemann","year":"2014","journal-title":"Lancet Oncol"},{"key":"2026100914064250700_oyag307-B8","doi-asserted-by":"publisher","first-page":"2392","DOI":"10.1001\/jama.2017.7105","article-title":"Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial","volume":"317","author":"Venook","year":"2017","journal-title":"JAMA"},{"key":"2026100914064250700_oyag307-B9","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1093\/annonc\/mdx175","article-title":"Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials","volume":"28","author":"Arnold","year":"2017","journal-title":"Ann Oncol"},{"key":"2026100914064250700_oyag307-B10","doi-asserted-by":"publisher","first-page":"1812","DOI":"10.1001\/jama.2010.1535","article-title":"Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab","volume":"304","author":"De Roock","year":"2010","journal-title":"JAMA"},{"key":"2026100914064250700_oyag307-B11","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1056\/NEJMoa1305275","article-title":"Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer","volume":"369","author":"Douillard","year":"2013","journal-title":"N Engl J Med"},{"key":"2026100914064250700_oyag307-B12","doi-asserted-by":"publisher","first-page":"1346","DOI":"10.1093\/annonc\/mdu141","article-title":"Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer","volume":"25","author":"Douillard","year":"2014","journal-title":"Ann Oncol"},{"key":"2026100914064250700_oyag307-B13","doi-asserted-by":"publisher","first-page":"3504","DOI":"10.1200\/JCO.2016.34.15_suppl.3504","article-title":"Impact of primary (1\u00b0) 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":"JCO"},{"key":"2026100914064250700_oyag307-B14","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1001\/jama.2023.4428","article-title":"Panitumumab vs bevacizumab added to standard first-line chemotherapy and overall survival among patients with RAS wild-type, Left-Sided metastatic colorectal cancer: a randomized clinical trial","volume":"329","author":"Watanabe","year":"2023","journal-title":"JAMA"},{"key":"2026100914064250700_oyag307-B15","doi-asserted-by":"publisher","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":"2026100914064250700_oyag307-B16","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1093\/annonc\/mdy52","article-title":"REVERCE: a randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for previously treated metastatic colorectal cancer patients","volume":"30","author":"Shitara","year":"2019","journal-title":"Ann Oncol"},{"key":"2026100914064250700_oyag307-B17","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1002\/ijc.25864","article-title":"Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity","volume":"129","author":"Wilhelm","year":"2011","journal-title":"Int J Cancer"},{"key":"2026100914064250700_oyag307-B18","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17060969","article-title":"Sequential treatment with regorafenib and trifluridine\/tipiracil +\/- bevacizumab in refractory metastatic colorectal cancer in community clinical practice in the USA","volume":"17","author":"Ahn","year":"2025","journal-title":"Cancers (Basel)"},{"key":"2026100914064250700_oyag307-B19","doi-asserted-by":"publisher","first-page":"e245635","DOI":"10.1001\/jamanetworkopen.2024.5635","article-title":"Anti-EGFR rechallenge in patients with refractory ctDNA RAS\/BRAF wt metastatic colorectal cancer: a nonrandomized controlled trial","volume":"7","author":"Ciardiello","year":"2024","journal-title":"JAMA Netw Open"},{"key":"2026100914064250700_oyag307-B20","doi-asserted-by":"publisher","first-page":"1612","DOI":"10.1038\/s41591-022-01886-0","article-title":"Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial","volume":"28","author":"Sartore-Bianchi","year":"2022","journal-title":"Nat Med"},{"key":"2026100914064250700_oyag307-B21","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1038\/nm0715-827b","article-title":"Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients","volume":"21","author":"Siravegna","year":"2015","journal-title":"Nat Med"},{"key":"2026100914064250700_oyag307-B22","doi-asserted-by":"publisher","first-page":"LBA3515","DOI":"10.1200\/JCO.2025.43.17_suppl.LBA3515","article-title":"Panitumumab retreatment followed by regorafenib versus the reverse sequence in chemorefractory metastatic colorectal cancer patients with RAS and BRAF wild-type circulating tumor DNA (ctDNA): results of the phase II randomized PARERE trial by GONO","volume":"43","author":"Cremolini","year":"2025","journal-title":"JCO"}],"container-title":["The Oncologist"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/oncolo\/advance-article-pdf\/doi\/10.1093\/oncolo\/oyag307\/71581734\/oyag307.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/31\/11\/oyag307\/71581734\/oyag307.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/31\/11\/oyag307\/71581734\/oyag307.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:07:04Z","timestamp":1791569224000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/oncolo\/article\/doi\/10.1093\/oncolo\/oyag307\/8860752"}},"subtitle":[],"editor":[{"given":"Daniel H","family":"Ahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,10,3]]},"references-count":22,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2026,10,7]]}},"URL":"https:\/\/doi.org\/10.1093\/oncolo\/oyag307","relation":{},"ISSN":["1083-7159","1549-490X"],"issn-type":[{"value":"1083-7159","type":"print"},{"value":"1549-490X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,11]]},"published":{"date-parts":[[2026,10,3]]},"article-number":"oyag307"}}