Lorenza Rimassa1, Silvia Bozzarelli2, Filippo Pietrantonio3, Stefano Cordio4, Sara Lonardi5, Laura Toppo6, Alberto Zaniboni7, Roberto Bordonaro4, Maria Di Bartolomeo8, Gianluca Tomasello6, Vincenzo Dadduzio5, Maria Chiara Tronconi2, Chiara Piombo9, Laura Giordano10, Annunziata Gloghini11, Luca Di Tommaso12, Armando Santoro13. 1. Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy. Electronic address: lorenza.rimassa@cancercenter.humanitas.it. 2. Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy. 3. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Oncology and Hemato-oncology Department, University of Milan, Milan, Italy. 4. Medical Oncology Unit, Ospedale Garibaldi, Catania, Italy. 5. Medical Oncology Unit 1, Istituto Oncologico Veneto IRCCS, Padova, Italy. 6. Medical Oncology Unit, Istituti Ospitalieri, Cremona, Italy. 7. Medical Oncology Unit, Fondazione Poliambulanza, Brescia, Italy. 8. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 9. Pathology Unit, Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy. 10. Biostatistics Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy. 11. Pathology and Laboratory Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 12. Pathology Unit, Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy. 13. Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
Abstract
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.
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.
Authors: John H Strickler; Christel N Rushing; Hope E Uronis; Michael A Morse; Donna Niedzwiecki; Gerard C Blobe; Ashley N Moyer; Emily Bolch; Renee Webb; Sherri Haley; Ace J Hatch; Ivy P Altomare; Gary B Sherrill; David Z Chang; James L Wells; S David Hsu; Jingquan Jia; S Yousuf Zafar; Andrew B Nixon; Herbert I Hurwitz Journal: Oncologist Date: 2021-02-09