Truseltiq (infigratinib)

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.

In a gastric cancer model containing FGFR2 amplified on ecDNA, BBI-2779 suppresses tumour growth and prevents ecDNA-mediated acquired resistance to the pan-FGFR inhibitor infigratinib, resulting in potent and sustained tumour regression in mice. Transcription-replication conflict emerges as a target for ecDNA-directed therapy, exploiting a synthetic lethality of excess to treat cancer.

Multi-kinase inhibition by fexagratinib in a well-tolerated dose of 1 mg·kg-1 in humans may be a promising approach to reduce inflammation and neurodegeneration, to slow down disease progression and support remyelination in patients.

This also resulted in significant synergy between BGJ 398 and VEGFR inhibitors (i.e., sunitinib and regorafenib) by enhancing their pro-apoptotic and anti-proliferative activities. Mechanistically, the FGF2-induced activation of the FGFR pathway turns on VEGFR signaling via the overproduction of VEGF-A, induces the interaction between FGFR1/2 and VEGFR1, and thereby renders cancer cells highly sensitive to the dual inhibition of the aforementioned RTKs. Thus, our data uncovers the novel mechanism of the cross-talk between the aforementioned RTKs in IM-resistant GISTs lacking secondary KIT mutations and suggests that the dual blockade of FGFR and VEGFR signaling might be an effective treatment strategy for patients with GIST-acquired IM resistance via KIT-independent mechanisms.

P2, N=6, Terminated, LianBio LLC | N=55 --> 6 | Trial completion date: Dec 2025 --> May 2024 | Recruiting --> Terminated | Trial primary completion date: Apr 2025 --> May 2024; Business Reason

Cell-based assays showed that triple therapy with osimertinib, ONO-7475, and the FGFR inhibitor BGJ398 significantly increased apoptosis by increasing expression of proapoptotic factor Bim and reduced cell viability compared with that observed for the osimertinib-ONO-7475 therapy. Xenograft models showed that triple therapy considerably suppressed tumor regrowth. A novel therapeutic strategy of additional initial FGFR1 inhibition may be highly effective in suppressing the emergence of osimertinib- and ONO-7475-resistant cells.

FGFR2-targeting drug BGJ-398 (infigratinib) in combination with the MEK inhibitor trametinib proved to be synergic and exceptionally active, both in vitro and in vivo. The effects of the combined treatment by single-cell gene expression analysis revealed a remarkable plasticity of tumor cells and the greater sensitivity of cells with epithelial phenotype. This study brings personalized therapy closer to CUP patients and provides the rationale for FGFR2 and MEK targeting in metastatic tumors with FGFR2 pathway activation.

P2, N=84, Active, not recruiting, QED Therapeutics, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: May 2023 --> Oct 2024

In contrast, CQM157 moderately inhibited both UGT1A1 and UGT1A4. Our findings provide novel insights into the metabolism of and potential DDIs implicating infigratinib.

The combination of infigratinib and PKI-402 showed a remarked synergistic suppression in cell viability in both CCA cell lines compared to treatment with single inhibitors...Notably, inhibition of autophagic flux by chloroquine prevented cell death induced by the combination treatment. This study demonstrated that concurrent inhibition of the key FGFR/PI3K/mTOR pathways in CCA carcinogenesis enhances the suppression of CCA cells. The present findings indicate potential clinical implications for using combination treatment modalities in CCA therapy.

P2, N=280, Enrolling by invitation, QED Therapeutics, Inc. | Recruiting --> Enrolling by invitation

The hepatic lipase (HL) and the membrane receptor CD36 are overexpressed in BGJ398-resistant ICC cells, while they are essential for lipid uptake, further enhancing lipid utilization in ICC...Additionally, the DDS strategically minimizes lipid uptake through the incorporation of the anti-HL drug, Orlistat, and anti-CD36 monoclonal antibody, reducing lipid-derived energy production...Upon in vivo experiments with this model, the DDS demonstrated exceptional capabilities in suppressing tumor growth, reprogramming lipid metabolism and improving immune response, thereby overcoming drug resistance. These findings underscore the mitochondria-targeted DDS as a promising and innovative solution in ICC drug resistance.

Currently, 3 targeted therapies are approved for use in CCA; Ivosidenib in patients with IDH1 mutations and Infigratinib/Pemigatinib in those with FGFR2 fusions. This is important, as it is thought up to 40 % of CCA patients harbour a potentially actionable mutation. In this review we provide an overview of the molecular pathogenesis of CCA and highlight currently available and potential future targeted treatments.

P1/2, N=15, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Dec 2025 --> Apr 2024 | Trial primary completion date: Dec 2025 --> Apr 2024

No abstract available

We initiated a biomarker-informed preoperative study of infigratinib, a Fibroblast Growth Factor Receptor (FGFR) inhibitor, in patients with localized upper tract urothelial carcinoma (UTUC), a population with high unmet needs and tumor with a high frequency of FGFR3 alterations...Renal preservation was enabled in a substantial proportion of participants. These data support the design of a biomarker-driven phase 2 trial of FGFR3 inhibition in this population with significant unmet clinical needs.

FDA has approved four anticancer agents such as erdafitinib, pemigatinib, infigratinib, and futibatinib, for clinical use in oncogenic FGFR-driven malignancies. Furthermore, futibatinib is the first-in-class covalent or irreversible pan-FGFR inhibitor that has received FDA approval for locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene aberrations. This review highlights the current clinical progress concerning the safety and efficacy of all the approved FGFR-TKIs (tyrosine kinase inhibitors) and their ongoing investigations in clinical trials for other oncogenic FGFR-driven malignancies.

For example, AZD4547 and BGJ398 are gradually entering the consumption cycle and are good options as combined treatments. Artificial intelligence and drug repositioning methods can help preselect suitable drug targets more successfully for future inhibition of carcinogenicity.

Various agents, including pan-FGFR inhibitors (erdafitinib and futibatinib), FGFR1/2/3 inhibitors (infigratinib and pemigatinib), as well as a range of more-specific agents, have been developed and several have entered clinical use. The next generation of small-molecule inhibitors, such as lirafugratinib and LOXO-435, and the FGFR2-specific antibody bemarituzumab are expected to have a reduced risk of hyperphosphataemia and the ability to overcome certain resistance mutations. In this Review, we describe the development and current clinical role of FGFR inhibitors and provide perspective on future research directions including expansion of the therapeutic indications for use of FGFR inhibitors, combination of these agents with immune-checkpoint inhibitors and the application of novel technologies, such as artificial intelligence.

P=N/A, N=4, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical-translational requirement for patient stratification.

P2, N=55, Recruiting, LianBio LLC

P1/2, N=15, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

P2, N=0, Withdrawn, Emory University | N=40 --> 0 | Not yet recruiting --> Withdrawn

Our failure to accrue sufficient patients to the current trial precludes any definitive conclusions around the role of infigratinib as adjuvant therapy for FGFR3-altered UC. In the process of study conduct, however, we garnered substantial insights that may aid in the development of future precision oncology trials for adjuvant UC. Clinical trial information: NCT04197986.

P3, N=110, Enrolling by invitation, QED Therapeutics, Inc.

Pemigatinib + cisplatin combination therapy (n = 5) resulted in significant TGI and prolonged survival in one of two p53abn PDXs. Seven-day treatment with BGJ398 revealed a significant reduction in angiogenesis and CD206 + M2 macrophages. These data collectively support the evaluation of FGFR inhibitors in a clinical trial.

Infigratinib showed a preliminary signal of efficacy in the first-line treatment of FGFR2-rearranged CCA, but due to early termination of the study, the power is insufficient to draw conclusions regarding its efficacy in comparison to gem/cis. This study highlights the challenge of performing confirmatory studies in biomarker-selected subpopulations of rare tumors and the importance of exploring alternative approaches to delivering confirmatory data for regulatory purposes. Clinical trial information: NCT03773302.

These findings suggest that gastrointestinal and skin toxicities are the most common adverse reactions for infigratinib. It is important to recognize skin exfoliation and dehydration in clinical practice, as they are unexpected AEs. Additionally, our study indicates that infigratinib dose may correlate with an increased risk of AE severity, highlighting the need for dose adjustment of infigratinib when exposure to the drug is increased due to internal or external factors.

This resulted in activation of both AKT- and MAPK-signaling pathways shown on mRNA and protein levels, and rendered cancer cells highly sensitive to pan-FGFR-inhibitors (BGJ 398, AZD 4547, and TAS-120). Collectively, our data illustrates that continuous inhibition of KIT signaling in IM-resistant GISTs lacking secondary KIT mutations induced clonal heterogeneity of GISTs and resulted in accumulation of cancer cells with overexpressed FGF-2 and FGFR1/2, thereby leading to activation of FGFR-signaling. This in turn rendered these cells extremely sensitive to the pan-FGFR inhibitors used in combination with IM, or even alone, and suggests a rationale to re-evaluate the effectiveness of FGFR-inhibitors in order to improve the second-line therapeutic strategies for selected subgroups of GIST patients (e.g., IM-resistant GISTs lacking secondary KIT mutations and exhibiting the activation of the FGFR-signaling pathway).

Single-agent FGFRi's mediate selective, molecularly-targeted suppression of PDAC proliferation, and their effects are greatest in PDAC tumors expressing low- to-moderate FGFR1.

The first-line chemotherapeutic combination for the treatment of CCA are cisplatin and gemcitabine-based chemotherapies. While the side effect profile of infigratinib is minimal, particularly GI side effects, when compared with futibatinib and pemigatinib, the overall response rate (ORR) and median overall survival (mOS) for infigratinib (ORR=23.1%, mOS=3.8 months) was significantly lower than futibatinib (ORR=35.8%, mOS=21.1 months) and pemigatinib (ORR=35.5%, mOS=21.1 months). While there is ample promise for the use of infigratinib as molecular-directed therapy in the treatment of CCA harboring FGFR2 mutations, there is an appropriate concern for patient-acquired resistance. The heterogeneous nature of FGFR mutations and the emergence of different resistance mechanisms emphasize a need for more agents to inhibit FGFR rearrangements effectively.

In silico investigation revealed that larotrectinib, entrectinib, and infigratinib can target the key residues of the studied proteins. Therefore, these approved kinase inhibitors could be considered potential therapies for MDR cancers by targeting these transporters.Communicated by Ramaswamy H. Sarma.

These data support secondary FGFR2 mutations as the primary mode of acquired resistance to FGFR inhibitors-most commonly N550 and V565 mutations. Thus, development of combination strategies and next-generation FGFR inhibitors targeting the full spectrum of FGFR2 resistance mutations will be critical.

Ongoing trials are evaluating the use of erdafitinib in non-muscle invasive urothelial carcinoma as well as in combination with enfortumab vedotin in the metastatic setting, while other FGFR targeted agents such as infigratinib, AZD4547, rogaratinib and pemigatinib continue to be in development. Future challenges will include strategies to overcome FGFR acquired resistance and efficacy and safety of combination therapies with erdafitinib and other FGFR targeted agents.

Recent clinical studies showed promising data for FGFR-targeted therapy in reducing tumor volume and led to the United States Food and Drug Administration (FDA) approval of, e.g., pemigatinib, infigratinib, futibatinib, and erdafitinib...Pemigatinib (FIGHT-302) and futibatinib (FOENIX-CAA3) are being evaluated in phase III trials that compare these agents to current first-line gemcitabine and cisplatin in FGFR2-rearranged cholangiocarcinoma. However, complexity in targeting the FGFR signaling pathway is observed. Herein, we describe the characteristics of the FDA-approved and other investigational FGFR-targeted therapeutics, evaluate the most recent preclinical and clinical studies focusing on targeting FGFR genomic alterations in the treatment of cholangiocarcinomas and urothelial cancer, and provide insight into factors involved in response and (acquired) resistance to FGFR inhibition.

Dual FGFR and VEGFR inhibition inhibits lymphangiogenesis through suppression of c-MYC-dependent and HIF-1α-mediated HK2 expression, respectively. HK2 downregulation decreased glycolytic activity and further attenuated PD-L1 expression. Our findings suggest that dual FGFR and VEGFR blockade is an effective novel combination strategy to inhibit lymphangiogenesis and improve immunocompetence in iCCA.

P1, N=0, Withdrawn, M.D. Anderson Cancer Center | N=28 --> 0 | Trial completion date: Nov 2026 --> Aug 2023 | Initiation date: Feb 2024 --> Aug 2023 | Not yet recruiting --> Withdrawn | Trial primary completion date: Nov 2024 --> Aug 2023

However, comparison of the differences between pemigatinib and infigratinib in terms of the 33 PTs revealed no significant signals in each algorithm method. Some significant signals were detected between pemigatinib use and AEs. PTs with apparently strong signals and PTs not mentioned in the label should be taken seriously.

No drug-induced death was reported. Conclusions Infigratinib in GC/GEJ patients with FGFR2 gene amplification has shown an inspiring clinical improvement, with acceptable tolerance, which is a potential first TKI regimen that precisely targeting in this population.

No abstract available