Phase II Study of Tivantinib and Cetuximab in Patients With KRAS Wild-type Metastatic Colorectal Cancer With Acquired Resistance to EGFR Inhibitors and Emergence of MET Overexpression: Lesson Learned for Future Trials With EGFR/MET Dual Inhibition

Clin Colorectal Cancer. 2019 Jun;18(2):125-132.e2. doi: 10.1016/j.clcc.2019.02.004. Epub 2019 Feb 14.


Background: MET overexpression/amplification has been associated with resistance to anti- epidermal growth factor receptor therapies in patients with metastatic colorectal cancer (mCRC). Combining tivantinib, an inhibitor of the MET receptor tyrosine kinase, and cetuximab may be effective in patients with epidermal growth factor receptor-resistant MET-high mCRC.

Patients and methods: This multicenter, single-arm, Simon 2-stage, phase II study enrolled patients with MET-high, KRAS wild-type mCRC, who were treated with ≥ 1 prior systemic therapy, with at least stable disease on the last treatment regimen containing cetuximab or panitumumab. Patients were enrolled if they presented tumor progression on cetuximab or panitumumab within 3 months before enrollment. Patients received tivantinib (360 mg twice daily) plus cetuximab (500 mg intravenously every 2 weeks). The primary endpoint was objective response rate; secondary endpoints included progression-free survival, overall survival, and safety. The treatment would be considered effective if ≥ 5 confirmed partial responses were observed among 41 patients.

Results: In total, 41 patients were evaluated, 4 patients (9.8%) achieved an objective response, the median progression-free survival was 2.6 months (95% confidence interval, 1.9-4.2 months), and the median overall survival was 9.2 months (95% confidence interval, 7.1-15.1 months). Among 13 patients with tested MET amplification, 2 responding patients had MET amplification compared with none of the nonresponding patients. The most common grade ≥ 3 treatment-emergent adverse events were neutropenia (14.6%), skin toxicity (12.2%), and fatigue (9.8%).

Conclusion: Although the study did not meet its primary endpoint, efficacy results suggest some activity of the tested combination, with almost 10% of patients achieving objective response in a difficult-to-treat setting. Treatment-emergent adverse events were consistent with the known safety profile of tivantinib and cetuximab.

Keywords: Advanced colon cancer; Anti-EGFR; Molecular selection; New therapeutic strategy.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cetuximab / pharmacology
  • Cetuximab / therapeutic use*
  • Chemotherapy-Induced Febrile Neutropenia / epidemiology
  • Chemotherapy-Induced Febrile Neutropenia / etiology
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Drug Eruptions / epidemiology
  • Drug Eruptions / etiology
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • ErbB Receptors / antagonists & inhibitors
  • Fatigue / chemically induced
  • Fatigue / epidemiology
  • Female
  • Follow-Up Studies
  • Gene Amplification
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Italy / epidemiology
  • Male
  • Middle Aged
  • Panitumumab / pharmacology
  • Panitumumab / therapeutic use
  • Progression-Free Survival
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Pyrrolidinones / pharmacology
  • Pyrrolidinones / therapeutic use*
  • Quinolines / pharmacology
  • Quinolines / therapeutic use*


  • ARQ 197
  • KRAS protein, human
  • Pyrrolidinones
  • Quinolines
  • Panitumumab
  • EGFR protein, human
  • ErbB Receptors
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • Proto-Oncogene Proteins p21(ras)
  • Cetuximab