P2, N=239, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2023 --> Dec 2024

Gong et al present two NCI-MATCH tumor-agnostic trials evaluating erdafitinib for FGFR-altered cancers, marking steppingstones in precision oncology.

Compound 11 displayed a nanomolar potency against Huh7 cell lines and high selectivity over FGFR1-3 that were comparable to that of fisogatinib (8) as a reference standard. Additionally, compound 11 demonstrated remarkable antitumor efficacy in the Huh7 and Hep3B HCC xenograft mouse model. Moreover, bioluminescence imaging experiments with the orthotopic mouse model support that compound 11 can be considered a promising candidate for treating HCC.

The literature in the field is not definite, and so far, there has been no consensus on the best approach in this situation. At present, as it is described in this editorial, the decision is applied on a case-by-case basis.

This phenotype/genotype investigation suggests that the FGFR4 p.G388R variant may serve as a new marker for identifying patients who are responsive to TAS-102. A mechanistic hypothesis is proposed to interpret these findings.

P3, N=629, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Sep 2024 --> Nov 2026

This strategy resulted in the discovery of a potent inhibitor, 4c, with an IC50 of 33 nM and high selectivity among members of the FGFR family. Although further optimisation is required, our approach demonstrated the potential for discovering potent FGFR4 inhibitors for HCC treatment, and provides a useful method for obtaining hit compounds from small fragments.

P2, N=316, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Aug 2022 --> Dec 2023

Here, we provide an updated summary of the existing both pre- and clinical studies of the role of FGFR4 in BCa, with a special focus on its contribution to subtype switching during metastatic spread and/or induced by therapy. We also discuss a potential clinical benefit of targeting FGFR4 in the development of new treatment strategies.

Erdafitinib did not meet its primary end point of efficacy as determined by ORR in treatment-refractory solid tumors harboring FGFR1-4 amplifications. Our findings support that rearrangements and gene mutations, but not amplifications, of FGFR remain the established FGFR alterations with approved indications for FGFR inhibition.

This study met its primary end point in patients with several pretreated solid tumor types harboring FGFR1-3 mutations or fusions. These findings support advancement of erdafitinib for patients with fibroblast growth factor receptor-altered tumors outside of currently approved indications in a potentially tumor-agnostic manner.

P1, N=146, Completed, Blueprint Medicines Corporation | Active, not recruiting --> Completed

Key compounds showed low to subnanomolar potency, efficient covalent inactivation kinetics, and excellent selectivity against the other FGFRs, the kinases with an equivalent cysteine, and a representative subset of the kinome. Moreover, these compounds achieved nanomolar potencies in cellular assays and demonstrated good microsomal stability, highlighting the potential of SNAr-based approaches in covalent inhibitor design.

P2, N=35, Active, not recruiting, National Cancer Institute (NCI)

P2, N=35, Completed, Janssen Research & Development, LLC | Active, not recruiting --> Completed | Trial completion date: Jun 2024 --> Mar 2024

EFNA4, SLC3A2, and HNF1A share signaling pathways with FGFR4. Therefore, rs1966265 and rs351855 may be potential CRC risk factors.

P3, N=629, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Feb 2024 --> Sep 2024

The dysregulation of cellular ferrous iron concentrations and cell membrane peroxidation was rescued when knocking down HMOX1 with specific small interfering RNA. These findings shed light on the molecular mechanisms underlying FGFR4-targeting F30's anti-HCC effects and suggest that FGFR4 inactivation could be beneficial for HCC treatment involving ferroptosis.

No abstract available

The phase 3 THOR trial compared the efficacy of erdafitinib to chemotherapy or immunotherapy in FGFR3/2-altered advanced UC. THOR offers valuable data informing sequencing strategies, reinforcing the need for molecular testing in UC.

P2, N=35, Active, not recruiting, National Cancer Institute (NCI)

P1, N=73, Recruiting, Abbisko Therapeutics Co, Ltd

In this issue of Cancer Research, Hosni and colleagues discover a paracrine mechanism mediated by adipocyte precursor cells through which urothelial carcinomas become resistant to erdafitinib, a recently approved therapy inhibiting fibroblast growth factor receptors (FGFR)...The NRG1-mediated FGFR inhibitor resistance was amenable to intervention with pertuzumab, an antibody blocking the NRG1/HER3 axis...Because fibroblasts with the ASC/FAP signature are enriched in various carcinomas, it is possible that the paracrine signaling conferred by NRG1 is a pan-cancer mechanism of FGFR inhibitor resistance and tumor aggressiveness. See related article by Hosni et al., p. 725.

BALVERSA (erdafitinib), a selective pan-FGFR kinase inhibitor, has shown clinical activity against FGFR altered solid tumors in pts who exhausted standard treatment options... The large Chinese solid tumor cohort analysis showed comparable FGFR alts prevalence between Chinese and Western population. Differences in relationship between FGFR alts and PD-L1 expression across tumor types reflect the differential role of predominant FGFR types in each tumor type.

Moreover, CXF-007 exhibited significant antitumor activity in hepatocellular carcinoma cell lines and breast cancer cell lines through sustained inhibition of the FGFR4 signaling pathway. In summary, our study highlights a novel covalent FGFR4 inhibitor, CXF-007, which has the potential to overcome drug-induced FGFR4 mutations and might provide a new strategy for future anticancer drug discovery.

P2, N=108, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Jul 2025 --> Mar 2025

In surgical navigation, the TBR was 9.31 ± 1.36 and 8.57 ± 1.15 in HepG2 in situ tumor and HCC-PM models, respectively, indicating considerable tumor uptake. As a result, peptide I0 is an excellent clinical diagnostic reagent for HCC, as well as a tool for surgically resecting HCC peritoneal metastases.

P2, N=35, Recruiting, National Cancer Institute (NCI) | Initiation date: Jul 2024 --> Jan 2024

P2, N=316, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Sep 2024 --> Oct 2023

P1, N=35, Active, not recruiting, Vanderbilt-Ingram Cancer Center | Trial completion date: Dec 2023 --> Sep 2024

P1, N=78, Recruiting, BrodenBio Co., Ltd.

Furthermore, 8z displayed desirable microsomal stability and significant in vivo efficacy in the Huh7 HCC cancer xenograft model in nude mice. The study provides a promising new lead for anticancer drug discovery directed toward overcoming FGFR4 gatekeeper mutation mediated resistance in HCC patients.

In addition, we found that the low-risk subgroup exhibited greater infiltration by M1 macrophages, CD8+ T cells, CD4+ T cells, and activated NK cells. In conclusion, our findings provide evidence that seven immune-related hub genes can be considered as gene signatures to predict CRC prognosis and to differentiate CRC patient benefit, ultimately serving as a guide for individualized immunotherapy.

Downregulation of S100A11 plays a crucial role in enhancing the therapeutic response to Erdafitinib and reversing immunosuppressive tumor microenvironment.

Comparative analyses with FDA-approved FGFR inhibitors, erdafitinib and pemigatinib, revealed certain advantages of CPL304110 in both in vitro and in vivo assessments. Encouraging preclinical results led the way for the initiation of a Phase I clinical trial (01FGFR2018; NCT04149691) to further evaluate CPL304110 as a novel anticancer therapy.

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.

Combined erdafitinib and ICI resulted in high therapeutic efficacy. In aggregate, our work establishes that, in mice, co-alteration of FGFR3 and Trp53 results in high-grade, non-muscle-invasive UC and presents a previously underappreciated role for FGFR inhibition in blocking ICI-induced Treg expansion.

This review aims to provide an update on the clinical development of both analogs and antagonists targeting the FGF19-FGFR4 signaling pathway for patients with cholestatic, metabolic, and cancer diseases. We will also analyze potential safety and mechanistic concerns that should guide future research and advanced trials.

While both EPN patients did not respond to erdafitinib treatment, the FGFR1-ITD-harbouring tumour showed a significant decrease in tumour volume and contrast enhancement throughout treatment. The tumour remained stable 6 months after treatment discontinuation.

Pharmacological inhibition of the NRG1/HER3 axis using pertuzumab reversed erdafitinib resistance in tumor cells in vitro and prolonged survival of mice bearing bladder cancer xenografts in vivo. Remarkably, data from single-cell RNA-sequencing revealed that NRG1 was enriched in platelet-derived growth factor receptor-A (PDGFRA) expressing inflammatory cancer-associated fibroblasts, which is also expressed on adipocyte precursors. Together, this work reveals a paracrine mechanism of anti-FGFR resistance in bladder cancer, and potentially other cancers, that is amenable to inhibition using available targeted therapies.

Pharmacologic inhibition of FGFR4 using H3B-6527, or its knockdown, remarkably reduced the level of NRF2 with a reduction in the size and number of gastric cancer spheroids. Mechanistically, we detected binding between FGFR4 and P62 proteins, competing with NRF2-KEAP1 interaction, allowing NRF2 to escape KEAP1-dependent degradation with subsequent accumulation and translocation to the nucleus. These findings demonstrate a novel functional role of FGFR4 in cellular homeostasis via regulating the NRF2 levels in response to H. pylori infection in gastric carcinogenesis, calling for testing the therapeutic efficacy of FGFR4 inhibitors in gastric cancer models.

P1/2, N=125, Active, not recruiting, Janssen Research & Development, LLC | Phase classification: P1b --> P1/2 | Trial completion date: May 2024 --> Jun 2025