Reference Detail

Ref Type

Journal Article

PMID

(38297981)

Authors

Piha-Paul SA, Xu B, Dumbrava EE, Fu S, Karp DD, Meric-Bernstam F, Hong DS, Rodon JA, Tsimberidou AM, Raghav K, Ajani JA, Conley AP, Mott F, Fan Y, Fan J, Peng P, Wang H, Ni S, Sun C, Qiang X, Levin WJ, Ngo B, Ru QC, Wu F, Javle MM

Title

First-In-Human Phase I Study of Tinengotinib (TT-00420), a Multiple Kinase Inhibitor, as a Single Agent in Patients With Advanced Solid Tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
The oncologist			2024 Jan 31		Oncologist

URL

Abstract Text

This first-in-human phase I dose-escalation study evaluated the safety, pharmacokinetics, and efficacy of tinengotinib (TT-00420), a multi-kinase inhibitor targeting fibroblast growth factor receptors 1-3 (FGFRs 1-3), Janus kinase 1/2, vascular endothelial growth factor receptors, and Aurora A/B, in patients with advanced solid tumors.Patients received tinengotinib orally daily in 28-day cycles. Dose escalation was guided by Bayesian modeling using escalation with overdose control. The primary objective was to assess dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and dose recommended for dose expansion (DRDE). Secondary objectives included pharmacokinetics and efficacy.Forty-eight patients were enrolled (dose escalation, n = 40; dose expansion, n = 8). MTD was not reached; DRDE was 12 mg daily. DLTs were palmar-plantar erythrodysesthesia syndrome (8 mg, n = 1) and hypertension (15 mg, n = 2). The most common treatment-related adverse event was hypertension (50.0%). In 43 response-evaluable patients, 13 (30.2%) achieved partial response (PR; n = 7) or stable disease (SD) ≥ 24 weeks (n = 6), including 4/11 (36.4%) with FGFR2 mutations/fusions and cholangiocarcinoma (PR n = 3; SD ≥ 24 weeks n = 1), 3/3 (100.0%) with hormone receptor (HR)-positive/HER2-negative breast cancer (PR n = 2; SD ≥ 24 weeks n = 1), 2/5 (40.0%) with triple-negative breast cancer (TNBC; PR n = 1; SD ≥ 24 weeks n = 1), and 1/1 (100.0%) with castrate-resistant prostate cancer (CRPC; PR). Four of 12 patients (33.3%; HR-positive/HER2-negative breast cancer, TNBC, prostate cancer, and cholangiocarcinoma) treated at DRDE had PRs. Tinengotinib's half-life was 28-34 hours.Tinengotinib was well tolerated with favorable pharmacokinetic characteristics. Preliminary findings indicated potential clinical benefit in FGFR inhibitor-refractory cholangiocarcinoma, HER2-negative breast cancer (including TNBC), and CRPC. Continued evaluation of tinengotinib is warranted in phase II trials.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR2 C382R	cholangiocarcinoma	predicted - sensitive	Tinengotinib	Case Reports/Case Series	Actionable	In a Phase I trial, Tinengotinib (TT-00420) treatment was well tolerated and resulted in stable disease in 53.3% (23/43) and partial response in 16.3% (7/43) of patients with advanced solid tumors, including a partial response in a patient with cholangiocarcinoma harboring FGFR2 C382R (PMID: 38297981; NCT03654547).	38297981
FGFR2 rearrange	Her2-receptor negative breast cancer	predicted - sensitive	Tinengotinib	Case Reports/Case Series	Actionable	In a Phase I trial, Tinengotinib (TT-00420) treatment was well tolerated and resulted in stable disease in 53.3% (23/43) and partial response in 16.3% (7/43) of patients with advanced solid tumors, including a partial response in a patient with hormone receptor-positive, ERBB2 (Her2)-negative breast cancer harboring an FGFR2 rearrangement (PMID: 38297981; NCT03654547).	38297981
FGFR2 amp	prostate adenocarcinoma	predicted - sensitive	Tinengotinib	Case Reports/Case Series	Actionable	In a Phase I trial, Tinengotinib (TT-00420) treatment was well tolerated and resulted in stable disease in 53.3% (23/43) and partial response in 16.3% (7/43) of patients with advanced solid tumors, including a partial response in a patient with castration-resistant prostate adenocarcinoma with amplification of FGFR2 (PMID: 38297981; NCT03654547).	38297981