PMID- 32410080 OWN - NLM STAT- MEDLINE DCOM- 20210910 LR - 20230526 IS - 1573-0646 (Electronic) IS - 0167-6997 (Linking) VI - 38 IP - 6 DP - 2020 Dec TI - A phase 1b study of the MET inhibitor capmatinib combined with cetuximab in patients with MET-positive colorectal cancer who had progressed following anti-EGFR monoclonal antibody treatment. PG - 1774-1783 LID - 10.1007/s10637-020-00928-z [doi] AB - Background Overcoming resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) in patients with KRAS wildtype (WT) metastatic colorectal cancer (mCRC) could help meet the needs of patients with limited treatment options. Methods In this phase 1b study, patients with N/KRAS WT, MET-positive mCRC who had progressed following anti-EGFR mAb treatment received escalating oral doses of capmatinib (150, 300, and 400 mg) twice daily plus weekly intravenous cetuximab (at the approved dose). The primary objective was to establish a recommended dose for expansion (RDE) of capmatinib in combination with cetuximab. Safety, preliminary activity, pharmacokinetics, and pharmacodynamics were also explored. Results Thirteen patients were enrolled. No patients experienced a dose-limiting toxicity at investigated doses; the RDE was established as capmatinib 400 mg twice daily plus cetuximab. All patients experienced adverse events (AEs) suspected to be related to the study treatment. Five patients (38.5%) reported study-drug-related AEs of grade 3/4 in severity. No patients achieved a complete or partial response according to RECIST v1.1; however, tumor shrinkage of 29-44% was observed in 4 patients. Conclusions Capmatinib plus cetuximab was well tolerated. Preliminary signs of activity were observed. Further investigation is warranted to obtain efficacy data and refine predictive biomarkers of response. Clinical trial registration NCT02205398. FAU - Delord, Jean-Pierre AU - Delord JP AD - Department of Medical Oncology, Institut Universitaire du Cancer de Toulouse (IUCT) - Oncopole, 1 avenue Irene Joliot-Curie, 31059, Toulouse Cedex 9, France. delord.jean-pierre@iuct-oncopole.fr. FAU - Argiles, Guillem AU - Argiles G AD - Gastrointestinal Malignancies Division, Vall d'Hebron University Hospital, Barcelona, Spain. FAU - Fayette, Jerome AU - Fayette J AD - Centre Leon Berard, Lyon, France. FAU - Wirth, Lori AU - Wirth L AD - Hematology/Oncology Department, Massachusetts General Hospital, Boston, MA, USA. FAU - Kasper, Stefan AU - Kasper S AD - Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. FAU - Siena, Salvatore AU - Siena S AD - Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Department of Oncology and Hemato-Oncology, Universita degli Studi di Milano, Milan, Italy. FAU - Mesia, Ricard AU - Mesia R AD - Medical Oncology Department, Catalan Institut of Oncology - Hospitalet, IDIBELL, Barcelona, Spain. FAU - Berardi, Rossana AU - Berardi R AD - Medical Oncology, Universita Politecnica delle Marche-Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona, Ancona, Italy. FAU - Cervantes, Andres AU - Cervantes A AD - CIBERONC, Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain. FAU - Dekervel, Jeroen AU - Dekervel J AD - Department of Oncology, University Hospital Leuven, Leuven, Belgium. FAU - Zhao, Sylvia AU - Zhao S AD - Novartis Institutes for BioMedical Research, Shanghai, China. FAU - Sun, Yongjian AU - Sun Y AD - Novartis Institutes for BioMedical Research, Shanghai, China. FAU - Hao, Huai-Xiang AU - Hao HX AD - Novartis Institutes for BioMedical Research, Cambridge, MA, USA. FAU - Tiedt, Ralph AU - Tiedt R AD - Novartis Institutes for BioMedical Research, Basel, Switzerland. FAU - Vicente, Sergio AU - Vicente S AD - Novartis Institutes for BioMedical Research, Basel, Switzerland. FAU - Myers, Andrea AU - Myers A AD - Novartis Institutes for BioMedical Research, Shanghai, China. FAU - Siu, Lillian L AU - Siu LL AD - Princess Margaret Cancer Centre, Toronto, Ontario, Canada. LA - eng SI - ClinicalTrials.gov/NCT02205398 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20200514 PL - United States TA - Invest New Drugs JT - Investigational new drugs JID - 8309330 RN - 0 (Antineoplastic Agents) RN - 0 (Benzamides) RN - 0 (Imidazoles) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Triazines) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (MET protein, human) RN - EC 2.7.10.1 (Proto-Oncogene Proteins c-met) RN - EC 3.6.5.2 (ras Proteins) RN - PQX0D8J21J (Cetuximab) RN - TY34L4F9OZ (capmatinib) SB - IM MH - Adult MH - Aged MH - Antineoplastic Agents/*administration & dosage/adverse effects/pharmacokinetics MH - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/pharmacokinetics MH - Benzamides/*administration & dosage/adverse effects/pharmacokinetics MH - Cell Line, Tumor MH - Cetuximab/*administration & dosage/adverse effects/pharmacokinetics MH - Colorectal Neoplasms/*drug therapy/genetics/metabolism/pathology MH - Disease Progression MH - Drug Resistance, Neoplasm MH - ErbB Receptors/antagonists & inhibitors MH - Female MH - Head and Neck Neoplasms/drug therapy MH - Humans MH - Imidazoles/*administration & dosage/adverse effects/pharmacokinetics MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Protein Kinase Inhibitors/*administration & dosage/adverse effects/pharmacokinetics MH - Proto-Oncogene Proteins c-met/*antagonists & inhibitors/metabolism MH - Response Evaluation Criteria in Solid Tumors MH - Squamous Cell Carcinoma of Head and Neck/drug therapy MH - Triazines/*administration & dosage/adverse effects/pharmacokinetics MH - ras Proteins/genetics OTO - NOTNLM OT - Capmatinib OT - Cetuximab OT - Colorectal cancer OT - MET positive OT - Phase I EDAT- 2020/05/16 06:00 MHDA- 2021/09/11 06:00 CRDT- 2020/05/16 06:00 PHST- 2020/02/07 00:00 [received] PHST- 2020/03/19 00:00 [accepted] PHST- 2020/05/16 06:00 [pubmed] PHST- 2021/09/11 06:00 [medline] PHST- 2020/05/16 06:00 [entrez] AID - 10.1007/s10637-020-00928-z [pii] AID - 10.1007/s10637-020-00928-z [doi] PST - ppublish SO - Invest New Drugs. 2020 Dec;38(6):1774-1783. doi: 10.1007/s10637-020-00928-z. Epub 2020 May 14.