{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T05:07:43Z","timestamp":1751519263569,"version":"3.37.3"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T00:00:00Z","timestamp":1692403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Array Biopharma in collaboration with Novartis"},{"name":"National Institutes of Health Cancer Center","award":["P30 CA 008748"],"award-info":[{"award-number":["P30 CA 008748"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>Activating RAS gene mutations occur in approximately 55% of patients with metastatic colorectal cancer (mCRC) and are associated with poorer clinical outcomes due to epidermal growth factor receptor (EGFR) blockade resistance. Combined EGFR and mitogen-activated protein kinase (MEK) inhibition may extend response to EGFR inhibition and overcome acquired resistance. This phase Ib\/II dose escalation trial evaluated the safety and activity of dual inhibition with binimetinib (MEK1\/2 inhibitor) and panitumumab (EGFR inhibitor [EGFRi]) in patients with RAS mutant or BRAF wild type (WT)\/RAS WT mCRC.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Phase Ib dose escalation started with binimetinib 45 mg twice daily plus panitumumab 6 mg\/kg administered every 2 weeks. In the phase II study, patients with measurable mCRC were enrolled into 4 groups based on previous anti-EGFR monoclonal antibody therapy and RAS mutational status.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>No patients in the phase Ib portion (n\u2005=\u200510) had a response; 70% of patients had stable disease. In the phase II portion (n\u2005=\u200543), overall response rate (ORR, confirmed) was 2.3% with one partial response in the RAS WT group, DCR was 30.2%, and median progression-free survival was 1.8 months (95%CI, 1.6-3.3). All patients experienced \u22651 adverse event, with the most common being diarrhea (71.7%), vomiting (52.8%), nausea (50.9%), fatigue (49.1%), dermatitis acneiform (43.4%), and rash (41.5%). Most patients required treatment interruption or dose reduction due to difficulties tolerating treatment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The combination of binimetinib and panitumumab had substantial toxicity and limited clinical activity for patients with mutant or WT RAS mCRC, independent of EGFRi treatment history (Trial registration: NCT01927341).<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/oncolo\/oyad210","type":"journal-article","created":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T18:15:01Z","timestamp":1692468901000},"page":"e1209-e1218","source":"Crossref","is-referenced-by-count":3,"title":["Phase Ib\/II Study of the Efficacy and Safety of Binimetinib (MEK162) Plus Panitumumab for Mutant or Wild-Type <i>RAS<\/i> Metastatic Colorectal Cancer"],"prefix":"10.1093","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6372-1230","authenticated-orcid":false,"given":"Eric","family":"Van Cutsem","sequence":"first","affiliation":[{"name":"Digestive Oncology, University Hospitals Gasthuisberg , Leuven and KU Leuven, Leuven , Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7233-5454","authenticated-orcid":false,"given":"Rona","family":"Yaeger","sequence":"additional","affiliation":[{"name":"Department of Medicine, Memorial Sloan Kettering Cancer Center , New York, NY , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Pierre","family":"Delord","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Institut Claudius Regaud, IUCT-Oncopole , Toulouse , France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2495-8139","authenticated-orcid":false,"given":"Josep","family":"Tabernero","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Vall d\u2019Hebron Campus Hospital and Institute of Oncology (VHIO), IOB-Quiron, UVic-UICC , Barcelona , Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3500-0540","authenticated-orcid":false,"given":"Lillian L","family":"Siu","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network , Toronto, ON , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michel","family":"Ducreux","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology , Gustave Roussy, Cancer Campus, Universit\u00e9 Paris-Saclay, Villejuif , France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salvatore","family":"Siena","sequence":"additional","affiliation":[{"name":"Department of Oncology and Hemato-Oncology, Universit\u00e0 degli Studi di Milano , Milan , Italy"},{"name":"Department of Oncology , Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4653-6324","authenticated-orcid":false,"given":"Elena","family":"Elez","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Vall d\u2019Hebron Campus Hospital and Institute of Oncology (VHIO), Universitat Aut\u00f2noma de Barcelona (UAB) , Barcelona , Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Kasper","sequence":"additional","affiliation":[{"name":"West German Cancer Center, Department of Medical Oncology, University Hospital Essen , Essen , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Zander","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne, University of Cologne , Duesseldorf , Germany"},{"name":"Department of Internal Medicine I, Gastrointestinal Cancer Group Cologne (GCGC), University Clinic Cologne , Cologne , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neeltje","family":"Steeghs","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology and Clinical Pharmacology, Netherlands Cancer Institute , Amsterdam , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danielle","family":"Murphy","sequence":"additional","affiliation":[{"name":"Translational Oncology , Pfizer, La Jolla, CA , 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