GALNT6 is integral to the resistance mechanisms against lenvatinib in HCC by modulating autophagy and CAF activation. Targeting GALNT6 offers a promising strategy to enhance lenvatinib efficacy and improve therapeutic outcomes in HCC.

Its pharmacological inhibition with low concentrations of anticholinergic drugs, but not cholinomimetics, decreased anchorage-independent growth and anoikis, synergized with sorafenib and lenvatinib in HCC class 1 to 3 lines, yet not in primary human hepatocytes, and preserved mature hepatocyte functions. Hepatic neurons are likely the least studied liver cell type and mediate patients singularities from the ANS to the organ in real-time. Cholinergic inputs identified in this study as pathogenic may be targeted with the well charted pharmacopoeia of neurotropic drugs already available, for basic or clinical research purposes, with an expected high level of safety.

Combination of CDK2 inhibitors in clinical trials (Dinaciclib or PF-07104091) and lenvatinib markedly suppressed growth of xenograft tumors from the lenvatinib-resistant patient. The findings support the combination therapy strategy of lenvatinib and CDK2 inhibitor for lenvatinib-resistant ATC patients with high CDK2 expression.

The findings highlight the compound's therapeutic potential, emphasizing its mechanism of inducing apoptosis in active mutant RET cell lines by interacting with G-quadruplex structures. This novel insight opens avenues for a potentially effective treatment for MTC, potentially bypassing the challenges associated with current TKIs.

This article reviews the mechanisms of lenvatinib in treating liver cancer, the mechanisms and efficacy of its combination with immune checkpoint inhibitors, the causes of resistance, the exploration of biomarkers, and other novel combination therapy strategies for lenvatinib. We hope to provide insights into the use and research of lenvatinib in clinical and scientific settings, offering new strategies for the treatment of liver cancer.

To discover next-generation FLT3 inhibitors and gather additional structure-activity relationship (SAR) information, we performed structural modifications of G-749 (denfivontinib) utilizing structure simplification and scaffold hopping strategies...Furthermore, it significantly reduced reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP), and strongly inhibited FLT3-mediated signaling pathways. These findings, along with the obtained SAR information, provide valuable insights for the further development of FLT3 inhibitors.

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.

This analysis generated evidence supportive of the psychometric properties of the GP5 as a fit-for-purpose measure to assess treatment tolerability in patients with advanced/metastatic MTC. The definition of "high side-effect burden" was associated with the clinical feature of tolerability.

RET is responsible for activation of several signaling paths including PI3K/AKT and JAK/STAT. Those pathways are involved in the immune system. When reviewing current JAK inhibitors and PI3K inhibitors on the market, there is mixed data on HBV reactivation and CMV viremia, though theoretically possible. Therefore, this should be evaluated and addressed in further studies. The educational value of this case could provide valuable insights for baseline monitoring and management for similarly effected patients.

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

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

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.

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

No abstract available

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=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

Proteins were precipitated with acetonitrile, and selpercatinib and the internal standard (gefitinib) were separated via HPLC-UV. Thus, this study establishes a simple and sensitive method for quantifying selpercatinib in human plasma. Future studies will analyze plasma samples from patients treated with selpercatinib and utilize this method to explore the relationships among plasma concentration, efficacy, and adverse events to define the therapeutic concentration range.

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

To demonstrate the extent to which our findings reflect clinical results, we analyzed bulk-RNA sequencing data from 21 NSCLC patients undergoing anti-PD-1 immunotherapy. The NLRP3 inflammasome score influenced enhanced immune responses in patient data undergoing anti-PD-1 immunotherapy, suggesting a role for NLRP3 inflammasome in activating immune responses during treatment.

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

Patients were treated with selpercatinib (n = 13) or pralsetinib (n = 10), 57% (13/23) within a clinical trial. In patients with advanced hMTC, selective RETis appear safe and effective with outcomes similar to clinical trial cohorts, which mostly comprised patients with sMTC. Duration of response and AE profile was similar to sMTC, although longer follow-up and larger patient numbers are needed to confirm this.

Pralsetinib and selpercatinib have been approved as specific tyrosine kinase inhibitors (TKIs) for the treatment of patients with non-small cell lung cancer (NSCLC) harboring rearranged during transfection (RET) fusion and mutation. In this case, invasive aspergillosis that appeared concurrent with RET-TKI targeted therapy is proposed to be an additional adverse drug reaction (ADR) that was not mentioned in previous reports. Here, we describe the process of clinical diagnosis and treatment of invasive aspergillosis and attempt to explore its possible pathogenesis in association with RET-TKI targeted therapy, with the aim of providing clinicians a more in-depth understanding of the ADR associated with RET-TKIs, as well as to prevent serious outcomes caused by reduction or discontinuation of antitumor therapy.

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.

It is paramount to stay vigilant concerning the potential emergence of three newly identified AEs. Significant differences were found in selpercatinib-related AEs concerning reporter continent, sex, weight, dose, frequency, and onset time, which deserved clinical attention. These findings contribute to a broader understanding of the AE profiles of selpercatinib.

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.

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.

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.

P2, N=124, Active, not recruiting, SWOG Cancer Research Network | Trial completion date: Jan 2025 --> Dec 2025 | Trial primary completion date: Jan 2025 --> Jun 2025

Our pharmacovigilance analysis of real-world data from the FEARS database revealed the safety signals and potential risks of pralsetinib usage. These results can provide valuable evidence for further clinical application of pralsetinib and are important in enhancing clinical medication safety.

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.

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

In intermediate-to-advanced HCC, the BeSiIT and LeSiIT groups exhibited acceptable toxicities and comparable PFS, OS, and ORR.

We have first shown that doxorubizen has a potent antineoplastic effect in vitro in 8305C and in 5 different pATC, and that can synergize with lenvatinib. These results open the way to a future evaluation of the antineoplastic effect of doxorubizen in ATC patients.

These cases highlight the potential efficacy of selpercatinib in treating intracranial metastases in RET fusion-positive patients with NSCLC after pralsetinib-refractory progression. The key takeaway is that selpercatinib may offer a viable treatment option in such scenarios, although more extensive studies are needed to determine its role as a monotherapy or in combination with other treatments.