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RESEARCH PRODUCT
Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer
Stephan BraunAndrés CervantesAmita PatnaikSusana RosellóRocio Garcia-carboneroAnthony W. TolcherRodrigo DienstmannRikke HaldBastiaan B J TopsMichael KraghNiels Jorgen Ostergaard SkartvedRachel S. Van Der PostGuillem ArgilesJosep TaberneroMikkel W. PedersenUlla H. HansenEric Van CutsemMarta BenaventIvan D. Horaksubject
AdultMaleProto-Oncogene Proteins B-rafClass I Phosphatidylinositol 3-KinasesColorectal cancerCancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2]Antineoplastic AgentsContext (language use)Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9]LigandsPhosphatidylinositol 3-Kinaseschemistry.chemical_compoundCell Line TumorHumansMedicinePanitumumabNeoplasm MetastasisAgedEGFR inhibitorsAged 80 and overDose-Response Relationship DrugCetuximabbusiness.industryGene AmplificationAntibodies MonoclonalCancerMiddle Agedmedicine.diseaseErbB ReceptorsClinical trialGenes rasTreatment OutcomeOncologychemistryMutationImmunologyCancer researchFemaleGrowth inhibitionColorectal Neoplasmsbusinessmedicine.drugdescription
Abstract Tumor growth in the context of EGFR inhibitor resistance may remain EGFR-dependent and is mediated by mechanisms including compensatory ligand upregulation and de novo gene alterations. Sym004 is a two-antibody mixture targeting nonoverlapping EGFR epitopes. In preclinical models, Sym004 causes significant EGFR internalization and degradation, which translates into superior growth inhibition in the presence of ligands. In this phase I trial, we observed grade 3 skin toxicity and hypomagnesemia as mechanism-based dose-limiting events during dose escalation. In dose-expansion cohorts of 9 and 12 mg/kg of Sym004 weekly, patients with metastatic colorectal cancer and acquired EGFR inhibitor resistance were enrolled; 17 of 39 patients (44%) had tumor shrinkage, with 5 patients (13%) achieving partial response. Pharmacodynamic studies confirmed marked Sym004-induced EGFR downmodulation. MET gene amplification emerged in 1 patient during Sym004 treatment, and a partial response was seen in a patient with EGFRS492R mutation that is predictive of cetuximab resistance. Significance: Potent EGFR downmodulation with Sym004 in patients with metastatic colorectal cancer and acquired resistance to cetuximab/panitumumab translates into significant antitumor activity and validates the preclinical hypothesis that a proportion of tumors remains dependent on EGFR signaling. Further clinical development and expanded correlative analyses of response patterns with secondary RAS/EGFR mutations are warranted. Cancer Discov; 5(6);598–609. ©2015 AACR. See related commentary by Stintzing and Heinemann, p. 578 This article is highlighted in the In This Issue feature, p. 565
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2015-01-01 |