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.
Adult
Aged
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Cetuximab
/ pharmacology
Chemotherapy-Induced Febrile Neutropenia
/ epidemiology
Colorectal Neoplasms
/ drug therapy
Drug Eruptions
/ epidemiology
Drug Resistance, Neoplasm
/ drug effects
ErbB Receptors
/ antagonists & inhibitors
Fatigue
/ chemically induced
Female
Follow-Up Studies
Gene Amplification
Gene Expression Regulation, Neoplastic
Humans
Italy
/ epidemiology
Male
Middle Aged
Panitumumab
/ pharmacology
Progression-Free Survival
Proto-Oncogene Proteins c-met
/ genetics
Proto-Oncogene Proteins p21(ras)
/ genetics
Pyrrolidinones
/ pharmacology
Quinolines
/ pharmacology
Advanced colon cancer
Anti-EGFR
Molecular selection
New therapeutic strategy
Journal
Clinical colorectal cancer
ISSN: 1938-0674
Titre abrégé: Clin Colorectal Cancer
Pays: United States
ID NLM: 101120693
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
03
09
2018
revised:
28
01
2019
accepted:
04
02
2019
pubmed:
9
3
2019
medline:
3
4
2020
entrez:
9
3
2019
Statut:
ppublish
Résumé
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. 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. 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%). 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.
Sections du résumé
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.
Identifiants
pubmed: 30846365
pii: S1533-0028(18)30425-0
doi: 10.1016/j.clcc.2019.02.004
pii:
doi:
Substances chimiques
ARQ 197
0
KRAS protein, human
0
Pyrrolidinones
0
Quinolines
0
Panitumumab
6A901E312A
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
MET protein, human
EC 2.7.10.1
Proto-Oncogene Proteins c-met
EC 2.7.10.1
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Cetuximab
PQX0D8J21J
Types de publication
Clinical Trial, Phase II
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
125-132.e2Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.