P2, N=83, Completed, Incyte Corporation | Active, not recruiting --> Completed

Genetic testing revealed FGFR2-TXLNG-fusion, and the patient was treated with pemigatinib in combination with tislelizumab and SBRT for the BM, resulting in significant tumor shrinkage. Our study was the first to report the application of the treatment strategy combining pemigatinib with ICI and SBRT in this specific case. The combined therapy proved effective and well-tolerated, providing new insights for future treatment considerations.

P2, N=25, Suspended, M.D. Anderson Cancer Center | Not yet recruiting --> Suspended

Studies have shown that the clinical efficacy of the EGFR tyrosine kinase inhibitor gefitinib alone in treating HCC is limited...Among them, the best complex 6g exhibits significant antiproliferative activity against Huh7 cells and Huh7R (lenvatinib-resistant) cells...In addition, complex 6g causes a significant increase in the accumulation of reactive oxygen species (ROS), disrupts mitochondrial membrane potential (MMP), arrests the cell cycle in the G0/G1 phase, and induces apoptosis. Collectively, our findings demonstrate that complex 6g exhibits potential anti-HCC effects via dual-targeting of EGFR and TrxR.

P1, N=30, Recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Sep 2025 | Trial primary completion date: Oct 2024 --> Sep 2025

P=N/A, N=32, Recruiting, Sun Yat-sen University

P2, N=28, Recruiting, RenJi Hospital | Trial completion date: Jul 2026 --> Oct 2026

Several FGFR inhibitors have been studied or are in development, and erdafitinib is the sole inhibitor to achieve regulatory approval...In this review, we describe known mechanisms of FGFR inhibitor resistance, including gatekeeper mutations, domain mutations, and the development of new mutations. In addition, we discuss management strategies, including ongoing clinical trials evaluating FGFR inhibitors, antibody-drug conjugates, and combination therapies with immune checkpoint inhibitors that may provide additional treatment options for localized and metastatic urothelial carcinoma.

In this largest and most systematic analysis of acquired resistance to an FGFR inhibitor from prospective clinical trials, emergence of secondary FGFR2 kinase domain mutations was observed in most patients receiving clinical benefit to futibatinib. ctDNA analysis shows clinically relevant potential as a noninvasive method for assessing genomic profiles, identifying patients who may benefit from FGFR inhibitor treatment, and exploring acquired resistance mechanisms.

Improvements in ORR and PFS for L+P versus sunitinib in aRCC were observed consistently across a range of biomarker subgroups defined using RCC driver mutations, PD-L1, gene expression signatures, and molecular subtypes.

Our study elucidated a previously unidentified mechanism of lenvatinib action and identified the RRP15-KBTBD8 axis as a novel therapeutic target in HCC, offering new avenues for treatment strategies in combating HCC.

P2, N=38, Not yet recruiting, Mehmet Akce

P=N/A, N=146, Recruiting, Tianjin Medical University Cancer Institute and Hospital | N=80 --> 146

P3, N=252, Recruiting, Sun Yat-sen University

AXIN1-deficient patients have a lower response to lenvatinib, which may be associated with suppression of p15 mediated by WNT pathway activation. KDM5B inhibitors can restore p15 levels, resulting in efficient killing of resistant cells in HCC.

P2, N=33, Not yet recruiting, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

P2, N=51, Active, not recruiting, Institut Curie | Recruiting --> Active, not recruiting | Trial completion date: Sep 2028 --> Nov 2026 | Trial primary completion date: Jan 2027 --> May 2025

The patient was treated with pemigatinib (a selective FGFR inhibitor) in combination with Gemcitabine and Cisplatin at our hospital. To the best of our knowledge, this is the first reported rare case of unresectable cHCC-CCA with FGFR2-PRDM16 fusion in a child successfully treated with a combination of pemigatinib and chemotherapy as a first-line regimen. This treatment combination may be effective and safe for patients with unresectable cHCC-CCAs.

P2, N=168, Completed, Taiho Oncology, Inc. | Active, not recruiting --> Completed

P=N/A, N=50, Recruiting, Regina Elena Cancer Institute | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Jul 2024 --> Dec 2024

P2, N=60, Recruiting, University College, London | Trial completion date: Jul 2026 --> Jul 2030 | Trial primary completion date: Jul 2026 --> Jul 2028

P1, N=112, Recruiting, Janssen Research & Development, LLC | Trial completion date: Mar 2028 --> Jun 2029

P2, N=6, Active, not recruiting, Providence Health & Services | Recruiting --> Active, not recruiting | N=30 --> 6 | Trial primary completion date: Jun 2025 --> Dec 2024

Currently, pemigatinib and futibatinib are FDA approved FGFR-targeted therapies that have demonstrated remarkable responses. Additionally, unique side effects of FGFR inhibitors may limit their efficacy in clinical practice and can have detrimental effects on quality of life. Several novel FGFR inhibitors are currently being investigated to overcome resistance mechanisms and reduce toxicities.

P1/2, N=0, Withdrawn, Tel Aviv Medical Center | N=47 --> 0 | Not yet recruiting --> Withdrawn

Considering the great difficulty in establishing AM cell culture lines, these findings suggest that AM may be more sensitive to microenvironment perturbations than CM. In conclusion, dual FGFR/VEGFR inhibition may be a viable therapeutic strategy that targets the unique biology of AM.

The predictive performance of the combined model established by integrating ultrasomics features and clinical baseline characteristics was improved, with the AUC, sensitivity, specificity, and accuracy of the RF machine learning combined model for the training and test dataset reaching 0.937 (95%CI, 0.884-0.971), 0.822 (95%CI, 0.702-0.909); 0.857, 0.833; 0.857, 0.800; 0.857, 0.817, respectively. To predict the status of EGFR expression in HCC patients, the ultrasomics model and combined model created by five machine learning algorithms can be utilized as efficient and noninvasive techniques, and the ultrasomics model and combined model established by RF classifier have the best predictive performance.

P1, N=72, Active, not recruiting, Eisai Co., Ltd. | Trial completion date: Dec 2024 --> Mar 2026 | Trial primary completion date: Dec 2024 --> Mar 2026

Our findings revealed that triple therapy is an effective, well-tolerated regimen for HCC patients with EM. AFP level and NLR are prognostic risk factors for triple therapy in this patient population.

P2, N=63, Active, not recruiting, Eisai Co., Ltd. | Trial completion date: Sep 2024 --> Mar 2026 | Trial primary completion date: Sep 2024 --> Mar 2026

P3, N=131, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed

P3, N=674, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed

Although these Kampo medicines are reported to inhibit drug-metabolizing enzymes and drug transporters, the risk of drug interactions for patients receiving lenvatinib therapy is low. Patients should feel confident that they can receive Kampo medicines as supportive care for lenvatinib therapy without a risk of drug interactions that could affect treatment efficacy.

The metabolites accounting for >10% of infigratinib were BHS697 and CQM157. The PK profiles of infigratinib and its metabolites in Chinese patients with GC or GEJ were largely consistent with known PK profiles of infigratinib from global populations.

The MDS consistently demonstrated the formation of stable protein-ligand complexes between FGFR3 and Cycloartobiloxanthone/Desoxylimonin throughout the trajectory. Based on these results, it can be inferred that Cycloartobiloxanthone and Desoxylimonin can potentially serve as valuable scaffolds in developing drugs targeting FGFR3 for cancer therapeutic after required validation.

It is found that although 5-fluorouracil, cisplatin, pemigatinib, and gemcitabine all inhibit ICC-TRCs, sulfarotene demonstrates superior efficacy. These actions collectively inhibit ICC-TRCs via destroying PSGL1-regulated cytoskeleton. The findings provide a strategy of inhibiting P-selectin/PSGL1 interaction and altering PSGL1 glycosylation pattern to compromise the cytoskeletal integrity and eliminate ICC-TRCs.

In addition, both morphological and molecular subtypes are associated with immunological and other molecular characteristics that could be relevant for modern immunotherapies or antibody-drug conjugates, e.g. in the form of PD-L1 and NECTIN-4 status. With the pending approval of erdafitinib (FGFR3 inhibitor), molecular tumour boards for patients with metastatic urothelial carcinoma will also become more important in the future.

In conclusion, HBV infection increases resistance to both sorafenib and lenvatinib in hepatoma cells by influencing the cell cycle regulatory genes and critical signaling pathways. However, the resistance mechanisms likely differ between the two medications.

P2, N=11, Active, not recruiting, Washington University School of Medicine | Trial completion date: Feb 2027 --> Dec 2025 | Trial primary completion date: Jul 2025 --> Jul 2024

Our study revealed that lenvatinib-induced NETs inhibited the cuproptosis of HCC cells, suggesting that targeting the IL33/PADI4/NET axis represents a promising therapeutic strategy for ameliorating lenvatinib resistance in HCC.

For example, erdafitinib is approved for treating locally advanced or metastatic urothelial cancer patients with FGFR2/FGFR3 mutations, and pemigatinib is approved for treating cholangiocarcinoma with FGFR2 fusion/rearrangement. Various detection methods, such as polymerase chain reaction, next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry, are available, and their selection should be based on diagnostic and treatment decision-making needs. Our developed expert consensus aims to standardize the diagnosis and treatment process for FGFR gene mutations and facilitate the practical application of FGFR inhibitors in clinical practice.

P1/2, N=30, Active, not recruiting, National Taiwan University Hospital | Trial completion date: Jun 2023 --> Dec 2024