Abstract
ABSTRACT Introduction Combination therapy with cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, plus irinotecan is a standard treatment for previously treated, KRAS wildtype, metastatic colorectal cancer (mCRC); however, tumors generally develop resistance to cetuximab. The MET receptor tyrosine kinase has been implicated in tumor cell migration, invasion, proliferation, and angiogenesis, and is associated with resistance to EGFR inhibitors. Tivantinib is an oral, selective MET inhibitor currently in phase II and phase III trials in patients with non-small cell lung cancer and hepatocellular carcinoma. The current phase I/II study assesses the activity of tivantinib combined with irinotecan plus cetuximab in previously treated patients with mCRC. Methods Patients were required to have KRAS wildtype mCRC, ECOG performance status ≤ 1, and ≥ 1 previous lines of chemotherapy. Patient cohorts (n = 3) received escalating doses of tivantinib (120, 240, or 360 mg) twice daily (BID) and biweekly irinotecan (180 mg/m2) and cetuximab (500 mg/m2) in 28-day cycles. Patient plasma and tumor tissue samples were collected for pharmacokinetic and biomarker analyses. MET protein expression in tumor tissue was assessed via immunohistochemistry (IHC), with MET-positive samples defined as MET expression ≥ 2+ in ≥ 50% of tumor cells. Plasma biomarker levels were determined by ELISA. Radiographic response was assessed every 8 weeks by RECIST version 1.1. Results Nine patients (median age, 53 years; range, 30-76 years) with ECOG performance status 0 (n = 4) or 1 (n = 5) received treatment. Median number of previous therapies was 2 (range, 1-4), including 1 patient with previous cetuximab treatment (a protocol violation). No dose-limiting toxicities were observed during the first treatment cycle. Tivantinib 360 mg BID was the recommended phase II dose (RP2D). Median treatment duration was 7.3 months (range, 1.6-15.1 months), and all 9 patients have discontinued treatment. Reasons for discontinuation included disease progression (n = 5), adverse events (AEs; n = 2), withdrawal of consent (n = 1), and investigator decision (n = 1). Reported grade 3 and 4 AEs were grade 4 neutropenia (n = 1), grade 3 fatigue (n = 3), and grade 3 anemia, leukopenia, diarrhea, small intestine obstruction, vomiting, mucositis, pneumonia, syncope, acneiform rash, and skin fissure (n = 1 each). The objective response rate was 44%. Best response was complete response (n = 1), partial response (n = 3), or stable disease (n = 4). Archival tumor samples were available for 7 patients, 4 of which were MET-positive by IHC. In the 4 MET-positive patients best response was partial response (n = 2) and stable disease (n = 1). Mean plasma levels of MET and hepatocyte growth factor were unchanged and mean plasma VEGF levels decreased 40% in 5 patients with available samples. Conclusion The combination of tivantinib and irinotecan plus cetuximab was well tolerated and had antitumor activity in heavily pretreated patients with mCRC. The RP2D for tivantinib is 360 mg BID. The randomized, placebo-controlled phase II trial has completed enrollment (n = 122) and final results will be presented at a later date. Correlative studies are ongoing.
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