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.

P2, N=47, Recruiting, Sun Yat-sen University

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.

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.

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.

P2, N=28, Active, not recruiting, Qilu Hospital of Shandong University | Recruiting --> Active, not recruiting | Trial primary completion date: May 2024 --> Dec 2024

Collaboration between nephrologists and oncologists is crucial for optimizing treatment benefits and managing side effects. Further research is warranted to refine management strategies and to understand the clinical implications of hyperphosphatemia.

Among these therapies, erdafitinib, a pan-fibroblast growth factor receptor (FGFR) inhibitor for specific FGFR2 and FGFR3 alterations, is the only targeted therapy approved till now...Ongoing investigations exist on its use in non-muscle-invasive BC and in combination with drugs such as enfortumab vedotin in mUC...This review emphasizes the importance of FGFR inhibition in UC and the optimization of its use in clinical practice. Moreover, it underscores the ongoing efforts to evaluate combination strategies and early treatment testing to enhance the effectiveness of targeted therapies for UC.

P1, N=35, Completed, Vanderbilt-Ingram Cancer Center | Active, not recruiting --> Completed | Trial completion date: Sep 2024 --> Mar 2024

On this basis, the present review aims at providing an overview of recently explored connections between the FGF/FGFR system and c-Myc oncoprotein, sustaining the therapeutic potential of targeting the FGF/FGFR/c-Myc axis in MM by using inhibitors targeting FGF ligands or FGF receptors. Importantly, the provided findings may represent the rationale for using FDA approved FGFR TK inhibitors (i.e. Pemigatinib, Futibatinib, Erdafitinib) for the treatment of MM patients presenting with an aberrant activation of this axis.

Erdafitinib (Erda) was nano-sized and encapsulated in PLTs to construct nano-Erda@PLT... PLTs-camouflaged nano-vehicles enable nano-Erda-mediated tumor immunotherapy through the induction of pyroptosis. These findings introduce a novel approach in exploring nanomaterial-mediated pyroptosis for cancer immunotherapy.

The characterization of metastatic tumour samples can improve response prediction to immunotherapy, the anti-NECTIN4 antibody-drug conjugate enfortumab vedotin and the FGFR inhibitor erdafitinib. Routine metastatic biopsy can thus improve the precision of identifying driver druggable alterations, thus improving treatment selection for patients with mUC.

P2, N=30, Not yet recruiting, Tianjin Medical University Cancer Institute and Hospital

P2, N=23, Not yet recruiting, Fujian Cancer Hospital

Mechanistically, TBK1 deletion or inhibition by amlexanox or GSK8612 reduced the expression of the transcription factor interferon-regulatory factor (IRF)4 and increased the level of IRF5 activation in macrophages stimulated with M-CSF, leading to an M1-like profile with highly proinflammatory factors. IRF5 deletion reversed the effect of TBK1 inhibition on M-CSF-mediated macrophage polarization. Our findings suggest that TBK1 contributes to the regulation of macrophage polarization in response to M-CSF stimulation partly through the IRF5/IRF4 axis.

Common adverse reactions observed during surufatinib treatment include hypertension, proteinuria, bleeding events, and hepatic lab test abnormal and diarrhea. Chinese multidisciplinary expert consensus on the rational use of surufatinib in clinical practice (2024 edition) aims to provide standardized guidance for its rational use and enhance patient compliance to maximize therapeutic benefits.

P2, N=34, Suspended, Zhejiang Cancer Hospital | Recruiting --> Suspended

With deepening understanding of the biology of bladder cancer, novel diagnostics, and improved drug delivery methods, we posit that FGFR inhibition will lead the way in advancing precision treatment of bladder cancer.

P1/2, N=40, Recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences | Not yet recruiting --> Recruiting

PAAD with high MCM3 expression was sensitive to c-75, brivanib, flavopiridol and VNLG/124 drugs, with stable molecular docking models. MCM3 is likely to be a critical element in promoting the initiation and growth of PAAD. Flavopiridol may exert its anti-PAAD effect through the interaction between MCM3, classic CDK1 targets in the cell cycle checkpoint and p53 pathway as well as related molecules in other pathways.

In vitro, the combination of nivolumab and OM-RCA-01 resulted in higher levels of interferon gamma and interleukin-2 release compared with nivolumab alone. In vivo, pembrolizumab in combination with OM-RCA-01 produced a greater inhibitory effect on tumor growth compared with vehicle and pembrolizumab alone...Combining an anti-FGFR1 antibody with a checkpoint inhibitor may enhance the efficacy of both drugs. However, further studies are needed to elucidate the mechanism of this interaction.

The drug may exert toxic effects on retinal pigment epithelium, which may be seen through interval OCTs and visualization of the interdigitation zone. Therefore, pronunciation of the ellipsoid and interdigitation zone on OCT may allow for surveillance of early manifestations of erdafitinib-induced retinal toxicity.

Molecular docking of 8m in the binding pockets of the VEGFR-2 and FGFR-1 proved its ability to occupy the binding pockets of both targets in type II inhibitor binding mode and to perform the essential interactions with the crucial amino acids in the binding pockets of both targets. Moreover, ADME prediction studies demonstrated the drug like properties of the synthesized benzimidazole-dioxoisoindolines 8a-o.

An anchored MAIC was conducted according to the National Institute for Health and Care Excellence Decision Support Unit guidance, with physician's choice of chemotherapy (docetaxel/paclitaxel and vinflunine) as the common comparator. The MAIC indicates comparable efficacy of erdafitinib vs EV for overall survival and progression-free survival, with erdafitinib showing a higher probability of achieving deep responses. While erdafitinib is associated with slightly more adverse events compared with EV, these events seem to be less severe.

The European Association of Urology (EAU), National Comprehensive Cancer Network, and European Society for Medical Oncology guidelines recommend PD-L1 and FGFR testing for patients with locally advanced bladder cancer or upper tract urothelial cancer (UTUC) according to specific eligibility criteria; positive results indicate therapy with immune checkpoint inhibitors or erdafitinib, respectively. The EAU guidelines recommend PD-L1 testing for subsequent adjuvant therapy in high-risk UC, and germline DNA sequencing in patients with UTUC positive for DNA mismatch repair alterations.

This study utilized pharmacokinetic methods to propose a new formulation of erdafitinib combined with sertraline or duloxetine. The findings suggest that this combination has potential for clinical co-administration based on a database analysis, thereby providing a novel strategy for anti-tumor treatment with fibroblast growth factor receptor (FGFR) inhibitors.

In conclusion, our study demonstrates that simply inhibiting TBK1 in all immune cells is not effective for the treatment of colitis. Further investigation the anti-inflammatory mechanism of ALX on dendritic cells and macrophages may provide a new strategy for the treatment of IBD.

Further molecular studies showed that such an effect of Erdafitinib and Stattic was associated with their concurrently inhibitory effect on FGFR1 and STAT3 signaling in LUSC cells. Therefore, the findings of this study indicated that the concurrent use of Erdafitinib and Stattic is a promising therapeutic approach for the treatment of FGFR1-positive LUSC.

We present the case of a patient with a FGFR3-TACC3 fusion-positive IDH-WT GB that at its second recurrence was treated with the FGFR inhibitor erdafitinib through a compassionate use program. Although no objective response was achieved, an overt deceleration in tumor growth was evidenced and the patient remained on treatment for 5.5 months.

Molecular docking simulation of 9a in the binding pocket of FGFR-1 confirms its capability to achieve the characteristic interactions of the type II FGFR-1 inhibitors. Exploration of the ADME properties of 9a-p by SwissADME web tool proved their satisfactory physicochemical properties for the discovery of new anticancer hits.

It showed a higher activity than sorafenib and staurosporine by 1.8- and 1.3-fold, respectively...Cell migration assay revealed that both compounds 6i and 6l have anti-migratory effects compared to control T-47D cells after 24, and 48 h. Molecular docking studies for compounds 6a-r on VEGFR-2 and FGFR1 binding sites showed that they exhibit an analogous binding mode in both target kinases which agrees with that of type II kinase inhibitors.

Furthermore, novel forms of application for instillation therapy, such as the TAR device, in combination with gemcitabine or erdafitinib are being investigated in clinical trials in order to extend the duration of action of the active substance on the urothelium. Thus, there are now many developments that could make bladder-preserving therapy with comparable survival data possible as an alternative to BCG or in the event of BCG failure. In the future, it will be necessary to clarify how BCG response can be predicted by using molecular markers and how to define risk groups that should primarily be given an alternative therapy to BCG.

P1, N=42, Active, not recruiting, 3D Medicines (Beijing) Co., Ltd. | Trial completion date: Jun 2024 --> Dec 2024 | Trial primary completion date: Jun 2024 --> Dec 2024

P2, N=37, Active, not recruiting, Bai-Rong Xia | N=20 --> 37

P2, N=74, Recruiting, Anhui Provincial Cancer Hospital | N=50 --> 74

Moreover, N5 demonstrated favorable pharmacokinetic characteristics with a bioavailability of 74.8% when administered intraperitoneally and effectively suppressed the growth of SNU16 xenograft tumors, exhibiting greater potency compared to the parental inhibitor Erdafitinib. This study lays the groundwork for developing and potentially applying therapeutic agents targeting FGFR2 degradation.

This writing highlights the initially promising yet transient efficacy of the FGFR inhibitor Erdafitinib on FGFR3-mutated BLCA, stressing the pressing need to unravel resistance mechanisms and identify co-targets for future combinatorial studies. A thorough analysis of recent preclinical and clinical evidence reveals resistance mechanisms, including secondary mutations, epigenetic alterations in pathway effectors, phenotypic heterogeneity, and population-specific variations within FGFR3 mutational status. Lastly, we discuss the potential of combinatorial treatments and concepts like synthetic lethality for discovering more effective targeted therapies against FGFR3-mutated BLCA.

Erdafitinib demonstrated efficacy in a population of Asian patients in selected advanced solid tumors, particularly in those with advanced FGFR-altered cholangiocarcinoma. Treatment was tolerable with no new safety signals.

The antibody was highly effective in suppressing growth of FGFR3-driven tumor models, providing efficacy comparable to that of the FDA-approved TKI erdafitinib. Thus, this bispecific antibody may provide an effective approach for broad and highly selective inhibition of oncogenic FGFR3 variants. Significance: Development of a bispecific antibody that broadly inhibits gain-of-function FGFR3 variants provides a therapeutic strategy to target tumors with oncogenic FGFR3 point mutations and fusions, a particularly difficult case for antibody blockade.

P2, N=80, Not yet recruiting, RenJi Hospital

In this article, we report a patient with uSRCS who responded to treatment with anti-VEGF inhibitor surufatinib and anti-PD-1 inhibitor camrelizumab after progression on first-line chemotherapy, second-line anlotinib combined with immunotherapy, and third-line chemotherapy...The patient received 4 cycles of the Ifosfamide and epirubicin hydrochloride regimen, and her best objective response was stable disease...Thus, a regimen of gemcitabine plus docetaxel was adopted...As of April 2023, the patient had a progression-free survival time of 26 months. Surufatinib in combination with camrelizumab could be effective in the treatment of advanced uSRCSs.

Adverse events were consistent with the known erdafitinib safety profile; no new safety signals emerged. Thus, repeated dosing of erdafitinib had no clinically meaningful effect on the pharmacokinetics of midazolam or metformin.