O-008 - Phase II study of tivantinib (ARQ 197) in combination with Cetuximab in EGFR Inhibitor-resistant, MET-High, KRAS Wild-Type (KRASwt) Metastatic Color...

Date 04 July 2015
Event WorldGI 2015
Session Oral and LBA abstracts
Topics Anticancer Agents
Colon and Rectal Cancer
Biological Therapy
Presenter L. Rimassa
Citation Annals of Oncology (2015) 26 (suppl_4): 108-116. 10.1093/annonc/mdv235
Authors L. Rimassa1, S. Lonardi2, A. Zaniboni3, S. Bozzarelli1, S. Cordio1, L. Toppo4, R. Bordonaro1, W. Liguigli4, V. Zagonel2, M.C. Tronconi1, L. Di Tommaso1, L. Giordano1, A. Santoro1
  • 1Istituto Clinico Humanitas IRCCS, Rozzano/IT
  • 2Istituto Oncologico Veneto - IRCCS, Padova/IT
  • 3Casa di Cura Poliambulanza, Brescia/IT
  • 4Istituti Ospitalieri di Cremona, Cremona/IT



MET overexpression could be associated with resistance to cetuximab in CRC. Tivantinib is a non-ATP-competitive, oral inhibitor of the MET receptor tyrosine kinase, well tolerated and active in MET-High, second/third line CRC (Eng C et al, j Clin Oncol 31, 2013; suppl, abstr 3508). Accordingly, combining tivantinib and cetuximab may benefit EGFR-resistant MET-High mCRC patients.


This is an investigator-initiated, multicenter, single-arm, Simon 2-stage, phase II study (NCT01892527) planning to enroll 41 patients. Eligibility criteria were: MET-High (≥ 2+ in ≥ 50% of tumor cells at immunohistochemistry), KRASwt, mCRC; ≥1 prior line of systemic therapy; stable disease (SD) or better response to last treatment regimen containing cetuximab or panitumumab; tumor progression on cetuximab or panitumumab within 3 months before enrollment; ECOG performance score ≤2; adequate bone marrow, liver, and kidney functions. Patients received tivantinib tablets 360 mg p.o. twice daily plus cetuximab 500 mg i.v. every 2 weeks and were evaluated by CT or MRI scan at 8-week intervals. Hematology testing was performed every week in the first 2 cycles, every 2 weeks in following cycles. Chemistry testing was performed every 2 weeks. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR); the secondary endpoints were progression-free survival (PFS), overall survival (OS), safety, and efficacy correlation with baseline tumor BRAF, EGFR, and PTEN status. To enter stage 2, ≥ 2 partial responses (PR) had to be observed among the 21 patients planned for stage 1.


Here we present results from the 21 patients enrolled in study stage 1. Of 42 consented patients, 22 (52.4%) had high MET expression, 1 screen failed due to early PS deterioration. As of March 1, 2015, 19 patients were evaluable for response. Two confirmed PR (lasting 18 and 2+ months, one patient alive after 21 months from enrolment, the other still on treatment 5 months after the enrolment) were observed, allowing the study to continue into stage 2. SD was observed in 8 patients, with median duration of 2 months. Overall disease control (PR + SD) was observed in 10 out of 19 patients (53%). Among 16 patients evaluable for PFS analysis, median PFS was 2.5+ months. Most common adverse events (AEs) were: fatigue and neutropenia (38%), maculopapular rash (33%); most common severe AEs was febrile neutropenia (10%). The most common tivantinib-related AEs were: fatigue and neutropenia (38%), anemia (28%). OS and efficacy correlations with baseline tumor markers will be available for presentation.


The combination in study is testing the hypothesis that resistance to EGFR inhibitors can be reverted by MET inhibition. The tivantinib and cetuximab regimen yielded encouraging initial results and was well tolerated. Stage 2 of this clinical trial is ongoing, with 33 patients enrolled as of March 1, 2015. Final results and analysis are expected by the end of 2015.