Phase 1b/2 trial of tepotinib in sorafenib pretreated advanced hepatocellular carcinoma with MET overexpression.
Adult
Aged
Aged, 80 and over
Antineoplastic Agents
/ administration & dosage
Carcinoma, Hepatocellular
/ drug therapy
Drug Administration Schedule
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Liver Neoplasms
/ drug therapy
Male
Maximum Tolerated Dose
Middle Aged
Piperidines
/ administration & dosage
Proto-Oncogene Proteins c-met
/ genetics
Pyridazines
/ administration & dosage
Pyrimidines
/ administration & dosage
Sorafenib
/ therapeutic use
Survival Analysis
Treatment Outcome
Up-Regulation
/ drug effects
Young Adult
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
02
10
2020
accepted:
23
02
2021
revised:
05
02
2021
pubmed:
8
4
2021
medline:
15
12
2021
entrez:
7
4
2021
Statut:
ppublish
Résumé
This Phase 1b/2 study evaluated tepotinib, a highly selective MET inhibitor, in US/European patients with sorafenib pretreated advanced hepatocellular carcinoma (aHCC) with MET overexpression. Eligible adults had aHCC, progression after ≥4 weeks of sorafenib, and, for Phase 2 only, MET overexpression. Tepotinib was administered once daily at 300 or 500 mg in Phase 1b ('3 + 3' design), and at the recommended Phase 2 dose (RP2D) in Phase 2. Primary endpoints were dose-liming toxicities (DLTs; Phase 1b) and 12-week investigator-assessed progression-free survival (PFS; Phase 2). In Phase 1b (n = 17), no DLTs occurred and the RP2D was confirmed as 500 mg. In Phase 2 (n = 49), the primary endpoint was met: 12-week PFS was 63.3% (90% CI: 50.5-74.7), which was significantly greater than the predefined null hypothesis of ≤15% (one-sided binomial exact test: P < 0.0001). Median time to progression was 4 months. In Phase 2, 28.6% of patients had treatment-related Grade ≥3 adverse events, including peripheral oedema and lipase increase (both 6.1%). Tepotinib was generally well tolerated and the RP2D (500 mg) showed promising efficacy and, therefore, a positive benefit-risk balance in sorafenib pretreated aHCC with MET overexpression. ClinicalTrials.gov: NCT02115373.
Sections du résumé
BACKGROUND
This Phase 1b/2 study evaluated tepotinib, a highly selective MET inhibitor, in US/European patients with sorafenib pretreated advanced hepatocellular carcinoma (aHCC) with MET overexpression.
METHODS
Eligible adults had aHCC, progression after ≥4 weeks of sorafenib, and, for Phase 2 only, MET overexpression. Tepotinib was administered once daily at 300 or 500 mg in Phase 1b ('3 + 3' design), and at the recommended Phase 2 dose (RP2D) in Phase 2. Primary endpoints were dose-liming toxicities (DLTs; Phase 1b) and 12-week investigator-assessed progression-free survival (PFS; Phase 2).
RESULTS
In Phase 1b (n = 17), no DLTs occurred and the RP2D was confirmed as 500 mg. In Phase 2 (n = 49), the primary endpoint was met: 12-week PFS was 63.3% (90% CI: 50.5-74.7), which was significantly greater than the predefined null hypothesis of ≤15% (one-sided binomial exact test: P < 0.0001). Median time to progression was 4 months. In Phase 2, 28.6% of patients had treatment-related Grade ≥3 adverse events, including peripheral oedema and lipase increase (both 6.1%).
CONCLUSIONS
Tepotinib was generally well tolerated and the RP2D (500 mg) showed promising efficacy and, therefore, a positive benefit-risk balance in sorafenib pretreated aHCC with MET overexpression.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT02115373.
Identifiants
pubmed: 33824476
doi: 10.1038/s41416-021-01334-9
pii: 10.1038/s41416-021-01334-9
pmc: PMC8292404
doi:
Substances chimiques
Antineoplastic Agents
0
Piperidines
0
Pyridazines
0
Pyrimidines
0
tepotinib
1IJV77EI07
Sorafenib
9ZOQ3TZI87
MET protein, human
EC 2.7.10.1
Proto-Oncogene Proteins c-met
EC 2.7.10.1
Banques de données
ClinicalTrials.gov
['NCT02115373']
Types de publication
Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
190-199Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2021. The Author(s).
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