title: A randomized, placebo-controlled, phase 1/2 study of tivantinib (ARQ 197) in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with wild-type KRAS who have received first-line systemic therapy.
abstract: Cetuximab in combination with an irinotecan-containing regimen is a standard treatment in patients with KRAS wild-type (KRAS WT), metastatic colorectal cancer (mCRC). We investigated the addition of the oral MET inhibitor tivantinib to cetuximab + irinotecan (CETIRI) based on preclinical evidence that activation of the MET pathway may confer resistance to anti-EGFR therapy. Previously treated patients with KRAS WT advanced or mCRC were enrolled. The phase 1, open-label 3 + 3, dose-escalation study evaluated the safety and maximally tolerated dose of tivantinib plus CETIRI. The phase 2, randomized, double-blinded, placebo-controlled study of biweekly CETIRI plus tivantinib or placebo was restricted to patients who had received only one prior line of chemotherapy. The phase 2 primary endpoint was progression-free survival (PFS). The recommended phase 2 dose was tivantinib (360 mg/m(2) twice daily) with biweekly cetuximab (500 mg/m(2)) and irinotecan (180 mg/m(2)). Among 117 patients evaluable for phase 2 analysis, no statistically significant PFS difference was observed: 8.3 months on tivantinib vs. 7.3 months on placebo (HR, 0.85; 95% confidence interval, 0.55-1.33; P = 0.38). Subgroup analyses trended in favor of tivantinib in patients with MET-High tumors by immunohistochemistry, PTEN-Low tumors, or those pretreated with oxaliplatin, but subgroups were too small to draw conclusions. Neutropenia, diarrhea, nausea and rash were the most frequent severe adverse events in tivantinib-treated patients. The combination of tivantinib and CETIRI was well tolerated but did not significantly improve PFS in previously treated KRAS WT mCRC. Tivantinib may be more active in specific subgroups.
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Cathy
authors.initials: C
authors.lastname: Eng
authors.affiliation: cCARE (California Cancer Associates for Research & Excellence), Encinitas, CA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bessudo
authors.affiliation: Florida Cancer Specialists/Sarah Cannon Research Institute, Fort Myers, FL.
authors.forename: Lowell L
authors.initials: LL
authors.lastname: Hart
authors.affiliation: The Central Clinical Hospital #1, Moscow, Russia.
authors.forename: Aleksey
authors.initials: A
authors.lastname: Severtsev
authors.affiliation: Chelyabinsk Regional Clinical Oncological Dispensary, Chelyabinsk, Russia.
authors.forename: Oleg
authors.initials: O
authors.lastname: Gladkov
authors.affiliation: Onkologie Untere Ems Leer-Emden-Papenburg, Leer, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Müller
authors.affiliation: Samara Regional Clinical Oncology Dispensary, Samara, Russia.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Kopp
authors.affiliation: Pyatigorsk Oncological Dispensary, Pyatigorsk, Russia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vladimirov
authors.affiliation: Nebraska Methodist Hospital Cancer Center, Omaha, NE.
authors.forename: Robert
authors.initials: R
authors.lastname: Langdon
authors.affiliation: Military Medical Academy, Saint Petersburg, Russia.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Kotiv
authors.affiliation: Azienda Ospedaliera Treviglio, Treviglio, BG, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Barni
authors.affiliation: Daiichi Sankyo, Inc, Edison, NJ.
authors.forename: Ching
authors.initials: C
authors.lastname: Hsu
authors.affiliation: Bayer HealthCare, Whippany, NJ, (Employed at Daiichi Sankyo, Inc. At Time of Manuscript Preparation).
authors.forename: Ellen
authors.initials: E
authors.lastname: Bolotin
authors.affiliation: Daiichi Sankyo, Inc, Edison, NJ.
authors.forename: Reinhard
authors.initials: R
authors.lastname: von Roemeling
authors.affiliation: ArQule, Inc, Burlington, MA.
authors.forename: Brian
authors.initials: B
authors.lastname: Schwartz
authors.affiliation: Tennessee Oncology/Sarah Cannon Research Institute, Nashville, TN.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011760:Pyrrolidinones / Q000008:administration & dosage*; D011804:Quinolines / Q000008:administration & dosage*
chemical_list: C551661:ARQ 197; C117307:KRAS protein, human; D011760:Pyrrolidinones; D011804:Quinolines; D000077146:Irinotecan; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab; D002166:Camptothecin
keywords: KRAS wild-type; MET inhibitor; irinotecan; metastatic colorectal cancer; tivantinib