fexagratinib (ABSK091)

P1, N=117, Active, not recruiting, AstraZeneca | Trial completion date: Jun 2024 --> Mar 2025

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.

Fexagratinib exhibited acceptable toxicity but limited efficacy in recurrent FGFR3-TACC3 + HGGs. Patients treated at first recurrence appeared more likely to benefit, yet additional evidence is required.

P2, N=423, Active, not recruiting, University of Birmingham | Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

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.

We have previously documented that vitamin D and its low-calcaemic analogues enhance the anticancer activity of drugs including a classic chemotherapeutic-dacarbazine-and an antiangiogenic VEGFRs inhibitor-cediranib. In this study, we explored the response of A375 and RPMI7951 melanoma lines to CPL304110 (CPL110), a novel selective inhibitor of fibroblast growth factor receptors (FGFRs), and compared its efficacy with that of AZD4547, the first-generation FGFRs selective inhibitor...Interestingly, 1,25(OH)2D3 and CPL304110 co-treatment resulted in activation of the ERK1/2 pathway in A375 cells. Our results strongly suggested possible crosstalk between vitamin D-activated pathways and activity of FGFR inhibitors, which should be considered in further clinical studies.

The upregulation of lncRNA AFAP1-AS1, which increases TSCC cell viability, migration, proliferation and invasion via the AFAP1-AS1/miR-133a-5p/ZIC2 axis, aids in the progression of TSCC.

This study showed that AZD4547 has significant anti-cancer effects in drug-sensitive cells and PDX models but not in drug-resistant EOC cells. In drug-resistant cells, the expression level of c-Met or FGF19/FGFR4 may be a predictive biomarker for AZD4547 treatment response, and a combination strategy of drugs targeting c-Met or FGF19/FGFR4 together with AZD4547 may be an effective therapeutic strategy for EOC.

P2, N=1460, Active, not recruiting, UNICANCER | Trial completion date: Dec 2023 --> Dec 2024

P2, N=999, Completed, UNICANCER | Active, not recruiting --> Completed

P1, N=156, Active, not recruiting, AstraZeneca | Phase classification: P1b --> P1 | Trial completion date: Sep 2023 --> Jun 2024

Bortezomib and Axitinib exhibited high efficacy on the patient's sample...Other FGFR inhibitors, including Olverematinib, AZD4547, Axitinib, Cediranib, Dovitinib, and Lenvatinib, also demonstrated exquisite sensitivity. Despite extensive screening, no other single agents or drug combinations exhibited increased effectiveness in the ZMYM2: : FGFR1 transformed BaF3 cells except for Trametinib, a MEK inhibitor, and the combination of Belvarafenib (RAF inhibitor) and Gilteritinib (FLT3 inhibitor)... Ex vivo drug sensitivity assays demonstrated the highly selective efficacy of FGFR inhibitors in ZMYM2: : FGFR1 fusion-positive leukemia cells and a fusion-expressing BaF3 cell line. Mutations in the FGFR1 kinase domain (ZMYM2: : FGFR1 F1171L) could contribute to Ponatinib insensitivity. These ex vivo drug screening results provide further support for ongoing clinical trials which are investigating the use of single agent Pemigatinib and other FGFR1 inhibitors for the treatment of patients with FGFR1-fusion positive leukemias.

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).

overall, tolerance was acceptable. The study did not meet the predetermined objective of PFS6 ≥ 35% and was stopped. A molecular characterization is ongoing to identify potential markers associated with prolonged stabilizations.

In this study, we showed that cabozantinib activated the innate immune system, and lenvatinib and AZD4547, which commonly inhibit FGFR signaling, altered TIME to a hot immune state by downregulating lipid metabolism-related genes. These findings support the therapeutic use of combination immunotherapies.

Endothelium-dependent TNBC-VM formation was prevented by AZD4547 or LY294002, strongly suggesting the involvement of the FGFR/PI3K/Akt axis in this process. Given that VM is associated with poor clinical prognosis, targeting FGFR/PI3K/Akt pharmacologically may hold promise for treating and preventing VM in TNBC tumors.

Conclusions In general, SHP099 can not only boost the tumor-cytotoxicity effect and overcome the drug resistance of AZD4547, but also activate cytotoxic T lymphocytes to kill tumor cells in FGFR2-alterated gastric cancers. Our results demonstrate the utility and feasibility of combining SHP2 to FGFR2 inhibitors for GC patients with FGFR2 alteration.

The sensitivity of the three chemotherapy drugs (AZD4547, Vincristine, and WEHI-539) varied among high- and low-risk patients, and was significantly negatively correlated with risk values, suggesting that they could be used as clinical treatment drugs for RCC. Our study not only obtained four potential biomarkers, but also provided guidance for immunotherapy and chemotherapy treatment of RCC, as well as new research strategies for the screening of other cancer biomarkers and sensitive drugs.

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.

In vivo experiments revealed that CYY292 inhibited U87MG tumor growth more effectively than AZD4547. CYY292 also efficiently reduced GBM cell proliferation and increased survival in orthotopic GBM models. This study further elucidates the function of FGFR1 in the GBM and reveals the effect of CYY292, which targets FGFR1, on downstream signaling pathways directly reducing GBM cell growth, invasion, and metastasis and thus impairing the recruitment, activation, and function of immune cells.

However, the T-ALL cells were resistant to FGFR1 inhibitors AZD4547 and PD-166866 even though FGFR1 signaling was specifically inhibited in the early stage...These results reveal that FGFR1 is a potential therapeutic target in human T-ALL, and ATF4-mediated amino acid metabolic reprogramming contributes to the FGFR1 inhibitor resistance. Synergistically inhibiting FGFR1 and mTOR can overcome this obstacle in T-ALL therapy.

P2, N=423, Active, not recruiting, University of Birmingham | Trial completion date: Mar 2023 --> Sep 2023 | Trial primary completion date: Mar 2023 --> Sep 2023

This study highlights the co-overexpression of FGFR1 and FGFR4 as a significant poor prognosis indicator in OSCC when combined with lymph node metastasis.

P1b, N=156, Active, not recruiting, AstraZeneca | Trial completion date: Mar 2023 --> Sep 2023

Of the HER inhibitors, neratinib and afatinib were more effective than erlotinib and lapatinib and inhibiting the growth of all HBCCLs at IC50 values below 700nM and 1.9 µM, respectively. Treatment with Src/Abl/c-kit inhibitor dasatinib, STAT3 inhibitor static, Abl/PDGFRα/VEGFR2/FGFR1 inhibitor Ponatinib and the TRK/ROS/ALK inhibitor entrecitinb also inhibited the growth of HBCCLs with IC50 value ranging from 0.06 - 2.96 µM, 1 - 3.8µM, 0.19- 0.42 μM and 2.85- 3.47μM, respectively...Finally, treatment with neratinib in combination with Palbociclib, AZD4547, trametinib and miransertib inhibited the growth of HBCCLs synergistically. Taken together, our results support further investigation on the therapeutic potential of irreversible pan HER in combination with the CDK inhibitor dinaciclib and other targeted agents in brain cancer.

A set of immuno-oncology reagents, including anti-PD-1/L1, CSF-1R inhibitor (ABSK021) and CD73 inhibitor (ABSK051) were also tested in combination with ABSK071 in vivo using mouse syngeneic models. ABSK071 demonstrated much stronger inhibitory activity than sotorasib and adagrasib against a variety of cell lines harboring KRASG12C, as well as significantly better in vivo anti-tumor efficacy in xenograft models that were less sensitive to sotorasib. Synergistic effects on cell growth inhibition were observed in vitro with ABSK071 in combination with several agents including cetuximab, afatinib, AZD4547, TNO-155, RMC-4630 and BI3406... ABSK071 is a next-generation KRASG12C inhibitor with greater activity and anti-tumor efficacy in vitro and in vivo. It also demonstrated broad synergistic effects with a large set of targeted agents and immuno-oncology agents, indicating its strong potential in combinatory therapy in treating a wider range of KRASG12C-dependent cancers.

Therefore, it is essential the identification of new biomarkers that could help to predict more accurately those patients that could benefit from anti-FGFR therapy.Materials and We have treated 15 NSCLC PDX models with high FGFR1 expression levels and variable N-Cadherin expression levels, with the FGFR inhibitor (FGFRi) AZD4547... In conclusion, previous research had underlined N-Cadherin as a potential biomarker of response to FGFRi, while not successful in all contexts. Transcriptome study of PDXs classified as responder or non-responder to FGFRi revealed a differential gene expression pattern, with an upregulation of N-Cadherin pathway observed in the Responder group, while an enrichment of KRAS signaling and KRAS mutations in non-Responders. Furthermore, we validated our finding using a cell line repository that confirm that N-Cadherin could predict FGFR-targeted therapy efficacy but only in the KRAS wildtype context .

P2, N=1460, Active, not recruiting, UNICANCER | Trial completion date: Dec 2022 --> Dec 2023

P2, N=6452, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

P2, N=423, Active, not recruiting, University of Birmingham | Trial completion date: Oct 2022 --> Mar 2023 | Trial primary completion date: Oct 2022 --> Mar 2023

We have established an immune syngeneic orthotopic HCC mouse model inoculating Hep-55.1C cells into the left liver lateral lobe of C57BL/6 mice (n=5-6/group) and treated with the MTAs (lenvatinib (LEN), sorafenib (SORA), regorafenib, cabozantinib, DC101/an anti-mouse VEGFR-2 antibody)) for 2 weeks... In the orthotopic xenograft mice model for HCC, LEN and AZD4547, which commonly inhibit FGFR signaling, altered the TIME from cold to hot. The findings obtained from this study support the therapeutic concept in the era of multi-MTAs including ICIs.

P1b, N=156, Active, not recruiting, AstraZeneca | Trial completion date: Sep 2022 --> Mar 2023

Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in the current study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.

Drug resistance arises from FGF1-mediated differential activation of high-fidelity homologous recombination DNA damage repair. FGFR and ATM inhibitors reverse platinum drug resistance, highlighting novel combination chemotherapy approaches for future clinical trial evaluation.

We conducted a phase IIa, multi-centre, open label, single arm study (RADICAL; NCT01791985) of AZD4547 (a potent and selective inhibitor of Fibroblast Growth Factor Receptor (FGFR)-1, 2 and 3 receptor tyrosine kinases) administered with anastrozole or letrozole in estrogen receptor positive metastatic breast cancer patients who had become resistant to aromatase inhibitors. Eleven patients had retinal pigment epithelial detachments which was asymptomatic and reversible in all but one patient. Exploratory ribonucleic acid sequencing (RNA-Seq) analysis was done on patients' samples: 6 differentially-expressed-genes could distinguish those who benefited from the addition of AZD4547.

In conclusion, the drugs impaired self-aggregation capacity, reduced stemness features, induced cell-differentiation and when combined, synergistically inhibited cell proliferation. Overall, our results suggest that calcitriol, at low pharmacological doses, may be a suitable candidate to synergize AZD4547 effects in luminal B breast tumors, allowing to reduce dose and adverse effects.

P1b, N=156, Active, not recruiting, AstraZeneca | Trial completion date: Feb 2022 --> Sep 2022

Finally, mice treated topically with AZD4547 prior to UVB exposure showed decreased cSCC incidence and increased survival rate. Collectively, the current data supports the hypothesis that inhibition of FGFR in epidermis may provide a new strategy to prevent and/or treat UVB-induced cSCC.

FGFR1 is an actionable driver oncogene in NB and a promising therapy may consist in targeting FGFR1 mutations in patients with therapy-resistant NB.