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

• Published in: Investigational new drugs 2020-12, Vol.38 (6), p.1774-1783
• Main Authors: Delord, Jean-Pierre, Argilés, Guillem, Fayette, Jerôme, Wirth, Lori, Kasper, Stefan, Siena, Salvatore, Mesia, Ricard, Berardi, Rossana, Cervantes, Andrés, Dekervel, Jeroen, Zhao, Sylvia, Sun, Yongjian, Hao, Huai-Xiang, Tiedt, Ralph, Vicente, Sergio, Myers, Andrea, Siu, Lillian L.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Benzamides - administration & dosage; Benzamides - adverse effects; Benzamides - pharmacokinetics; Biomarkers; Cancer; Cell Line, Tumor; Cetuximab - administration & dosage; Cetuximab - adverse effects; Cetuximab - pharmacokinetics; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Disease Progression; Drug Resistance, Neoplasm; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; Female; Growth factors; Head and Neck Neoplasms - drug therapy; Humans; Imidazoles - administration & dosage; Imidazoles - adverse effects; Imidazoles - pharmacokinetics; Immunotherapy; Intravenous administration; Male; Maximum Tolerated Dose; Medicine; Medicine & Public Health; Metastases; Middle Aged; Monoclonal antibodies; Oncology; Patients; Pharmacodynamics; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Phase I Studies; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - metabolism; ras Proteins - genetics; Resistance factors; Response Evaluation Criteria in Solid Tumors; Squamous Cell Carcinoma of Head and Neck - drug therapy; Targeted cancer therapy; Toxicity; Triazines - administration & dosage; Triazines - adverse effects; Triazines - pharmacokinetics
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-020-00928-z

Summary 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.