Phase 1 dose‐escalation trial evaluating the combination of the selective MET (mesenchymal‐epithelial transition factor) inhibitor tivantinib (ARQ 197) plus erlotinib

• Published in: Cancer 2012-12, Vol.118 (23), p.5903-5911
• Main Authors: Goldman, Jonathan W., Laux, Isett, Chai, Feng, Savage, Ronald E., Ferrari, Dora, Garmey, Edward G., Just, Richard G., Rosen, Lee S.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; ARQ 197; Biological and medical sciences; carcinoma; Carcinoma, Non-Small-Cell Lung - drug therapy; erlotinib; Erlotinib Hydrochloride; Female; Humans; Lung Neoplasms - drug therapy; Male; Medical sciences; Middle Aged; Neoplasms - drug therapy; nonsmall cell lung cancer; Pneumology; Proto-Oncogene Proteins c-met - antagonists & inhibitors; proto‐oncogene proteins c‐MET; Pyrrolidinones - administration & dosage; Pyrrolidinones - adverse effects; Pyrrolidinones - pharmacokinetics; Quinazolines - administration & dosage; Quinolines - administration & dosage; Quinolines - adverse effects; Quinolines - pharmacokinetics; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Tumors; Tumors of the respiratory system and mediastinum
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.27575

BACKGROUND: Amplification of the mesenchymal‐epithelial transition factor (MET) gene can promote tumor resistance to epidermal growth factor receptor (EGFR) inhibition. Dual EGFR‐MET inhibition may overcome this resistance. Tivantinib (ARQ 197) is a selective, oral, non–ATP‐competitive, small‐molecule inhibitor of the MET receptor tyrosine kinase. This phase 1 trial assessed the safety, pharmacokinetics, and preliminary antitumor activity of tivantinib combined with the EGFR inhibitor erlotinib. METHODS: Patients with advanced solid malignancies were administered oral tivantinib at escalating doses of 120, 240, 360, and 480 mg twice daily (BID) plus 150 mg erlotinib once daily (QD). Single or multiple intrapatient dose escalation was planned in the absence of dose‐limiting toxicity in the first cycle of therapy (21 days). RESULTS: Thirty‐two patients received combination treatment. Tivantinib serum concentrations were not dose‐proportional. The most common (≥20%) adverse events (AEs) regardless of causality included rash (n = 17), fatigue (n = 12), nausea (n = 10), abdominal pain (n = 10), diarrhea (n = 9), bradycardia (n = 9), and anemia (n = 7). AEs considered related to study treatment occurred in 28 patients (87.5%), and 5 patients (15.6%) had treatment‐related serious AEs, including neutropenia, leukopenia, syncope, sinus bradycardia, and sick sinus syndrome. Fifteen of 32 patients (46.8%) had a partial response (n = 1) or stable disease (n = 14) as assessed by Response Evaluation Criteria in Solid Tumors. Six of 8 patients with nonsmall cell lung cancer achieved stable disease. The recommended phase 2 dose is tivantinib 360 mg BID plus erlotinib 150 mg QD. CONCLUSIONS: Tivantinib plus erlotinib was well tolerated with encouraging clinical activity, especially in patients with nonsmall cell lung cancer. Cancer 2012. © 2012 American Cancer Society. This phase 1 trial of dose‐escalated tivantinib (ARQ 197; a c‐MET inhibitor) in combination with fixed‐dose erlotinib enrolled patients with advanced solid malignancies. The maximum tolerated dose was not established, but tivantinib given at 360 mg twice daily plus erlotinib given at 150 mg once daily was considered safe and tolerable with promising clinical activity, especially in patients with nonsmall cell lung cancer.