Cholangiocarcinoma remains one of the most challenging malignancies in GI oncology, with limited options beyond first-line therapy. Although selective FGFR2 inhibitors such as pemigatinib and futibatinib have transformed care for patients with FGFR2 fusions, acquired resistance—frequently driven by secondary FGFR2 mutations—remains a major barrier.Tinengotinib (TT-00420), a spectrum-selective kinase inhibitor with activity against multiple FGFR resistance mutations, has emerged as a promising candidate to address this unmet need.
A new multicentre phase 2 trial evaluated its activity across four genetically defined patient cohorts. The results of this multicentre phase 2 study were published online in The Lancet Gastroenterology & Hepatology on December 2, 2025, under the title “Tinengotinib for adults with advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 trial.”
Authors: Prof. Milind Javle; Christos Fountzilas; Chih-Yi Liao; Meredith Pelster; Daneng Li; Prof. Dustin Deming; Vaibhav Sahai; Lionel Kankeu Fonkoua; Allen Cohn; Parvez Mantry; Donald Richards; Edwin Kingsley; Frank Wu; Peng Peng; Katie Hennessy; Hui Wang; Caixia Sun; Shumao Ni; Jean Fan; Prof. Amit Mahipal.
What Is FGFR?
Fibroblast growth factor receptors (FGFRs) are a family of cell-surface tyrosine kinase receptors that play a critical role in normal cell growth, differentiation, tissue repair, and angiogenesis. The FGFR family includes FGFR1, FGFR2, FGFR3, and FGFR4, which are activated when they bind to fibroblast growth factors (FGFs). Under normal conditions, FGFR signaling is tightly regulated. When activated, FGFRs trigger downstream pathways such as MAPK, PI3K–AKT, and STAT, which control cell survival and proliferation. In cancer, however, genetic alterations in FGFR genes—including fusions, rearrangements, amplifications, or activating mutations—can lead to continuous pathway activation and uncontrolled tumor growth.
In cholangiocarcinoma, FGFR2 fusions or rearrangements are among the most clinically relevant FGFR alterations and represent a validated therapeutic target. These alterations are especially common in intrahepatic cholangiocarcinoma and have led to the development of multiple FGFR-targeted therapies. Despite initial responses, tumors often evolve resistance through secondary FGFR mutations, highlighting the need for next-generation inhibitors capable of overcoming this biological complexity.
What Is Tinengotinib and How Does It Work?
Tinengotinib (TT-00420) is a spectrum-selective small-molecule kinase inhibitor designed to retain activity against a broad range of FGFR1–3 mutations, including many known resistance mutations that limit the efficacy of first-generation FGFR inhibitors. Unlike highly selective FGFR2 inhibitors, tinengotinib demonstrates preclinical and clinical activity against multiple secondary FGFR alterations, allowing it to target heterogeneous resistance mechanisms within the same tumor.
In addition to FGFR inhibition, tinengotinib has broader kinase activity that might contribute to its antitumor effects, particularly in heavily pretreated disease. This pharmacologic profile formed the rationale for evaluating tinengotinib in patients with cholangiocarcinoma who progressed after prior FGFR-directed therapy.
Methods and Endpoints
This open-label, multicentre phase 2 trial was conducted across 32 U.S. medical centers. Adults (≥18 years) with advanced or metastatic cholangiocarcinoma, ECOG 0–1, and previous systemic therapy were eligible. Patients were assigned to four cohorts based on FGFR status:
- A1: FGFR2 fusions with primary FGFR inhibitor resistance
- A2: FGFR2 fusions with acquired FGFR inhibitor resistance
- B: Other FGFR alterations
- C: FGFR wild-type
Participants received tinengotinib 10 mg orally once daily in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. 
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Primary Endpoint
- Objective response rate (ORR) per investigator assessment (RECIST v1.1), confirmed and redocumented ≥4 weeks after initial response.
Secondary and Safety Endpoints
Secondary endpoints included duration of response, progression-free survival, and overall safety and tolerability. Safety was assessed in all patients who received at least one dose. The trial is registered as NCT04919642.
Results
Between Nov 19, 2021, and March 5, 2024, 55 patients were enrolled across the four cohorts. Median age was 61 years, and all patients had received prior systemic therapy. Median follow-up was 11.3 months. Objective responses differed markedly across FGFR-defined cohorts:
- ORR 6.3% in cohort A1 (primary FGFR inhibitor resistance; one confirmed partial response)
- ORR 30.0% in cohort A2 (acquired FGFR inhibitor resistance; three confirmed partial responses)
- ORR 23.1% in cohort B (other FGFR alterations; three confirmed partial responses)
- ORR 0% in cohort C (FGFR wild-type)
Safety observations Tinengotinib demonstrated a manageable safety profile. Grade 3 treatment-related adverse events most commonly included hypertension (31%), palmar-plantar erythrodysesthesia syndrome (13%), and stomatitis (11%). Grade 4 treatment-related adverse events occurred in 4% of patients, and no grade 5 treatment-related adverse events were reported. 
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Conclusion
Tinengotinib demonstrated notable antitumor activity in patients with FGFR2 fusion–positive cholangiocarcinoma who developed resistance to prior FGFR inhibitors, particularly in acquired resistance (cohort A2). Responses were also observed in patients with non-fusion FGFR alterations, while no activity was seen in FGFR wild-type disease. The safety profile was manageable and consistent with its kinase-inhibition mechanism.
These phase 2 findings supported the initiation of a phase 3 registration trial, marking an important step toward a potential new therapeutic option for patients with refractory FGFR-altered cholangiocarcinoma.
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