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.

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.

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

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

P2, N=100, Not yet recruiting, BioMarin Pharmaceutical

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.

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

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

P1, N=60, Recruiting, Tyra Biosciences, Inc | N=36 --> 60 | Trial primary completion date: Jan 2024 --> May 2024

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)

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.

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

P1, N=36, Active, not recruiting, Oscotec Inc. | Recruiting --> Active, not recruiting

P1, N=14, Completed, Oscotec Inc. | Unknown status --> Completed | N=40 --> 14

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

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.

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.

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.

P1, N=36, Recruiting, Tyra Biosciences, Inc

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

P1/2, N=6, Terminated, Fusion Pharmaceuticals Inc. | Completed --> Terminated; Fusion announced that it is discontinuing this study as part of a portfolio prioritization and assessment; Fusion no longer plans to pursue development of FPI-1966.

Combination E + EV is feasible and preliminarily exhibits antitumor activity. Dose escalation is ongoing to identify the MTD or recommended dose for expansion of the trial. Clinical trial information: NCT04963153.

We showed longersurvival in pts with FGFR2/3 alt aUC who received both EV and E regardless of sequence, which may reflect guarantee-time bias. Additional limitations include retrospective nature, modest sample size, no central scan review, lack of data for pts who received E only, selection and confounding biases. Larger prospective studies are needed to determine optimal sequencing and putative biomarkers.

Background: Interest in FGFR-targeted (FGFRi) therapies for UC or pan-tumor use is growing (ongoing clinical studies include erdafitinib (NCT05316155; NCT04172675; NCT03390504; NCT04083976), LOXO-435 (NCT05614739), and pemigatinib (NCT03914794) following accelerated approval of erdafitinib in locally advanced/metastatic (m) post-chemotherapy UC patients with FGFR2/3 (i.e., DNA mutations and fusions) alterations (ALT). FGFR-PRS (+) captured most ALT (+) tumors and an additional 2X more with similar FGFR pathway activation. FGFR-PRS (+) tumors were associated with gene enrichments for ontologies linked to FGFR3 signaling. The correlation of FGFR-PRS score with in vitro FGFRi activity provided initial utility of the signature, which is undergoing clinical evaluation in the ALAMANCE retrospective study of UC patients treated with FGFRi or other standard-of-care therapies.

Background: In view of the efficacy of FGFR targeting in early and advanced bladder cancer, as has been shown for erdafitinib in the THOR and NORSE trial, molecular testing of FGFR mutations and fusions will soon become clinical routine worldwide... PCR-based FGFR assessment by Therascreen and UroTyper is highly concordant and enables fast, local FGFR assessment within few hours. FGFR3 mutations are associated with increased TROP2 & NECTIN4 expression indicating potential synergistic options which warrants further exploration as part of molecularly stratified clinical trials.

THOR trial showed a significant overall survival benefit with erdafitinib (FGFR inhibitor) vs (taxane or vinflunine) in patients (pts) with advanced UCB or UTUC. Although histologically similar, the genomic landscape of FGFR3mut+ UTUC has notable differences with FGFR3mut+ UCB. Limitations include lack of clinical data annotation. The findings may impact of clinical trial designs for UCB and UTUC, including evaluating combinations of anti-FGFR3 with other agents.

Cancer treatments using FGFRi are showing promising results but their ocular toxicity is not well reported nor fully understood. Oncologists should be aware of the potential risks associated with FGFRi and involve ophthalmologists for the follow-up of their patients. The toxicity of FGFRi seems to resolve after drug continuation, but a certain degree of infra clinical RPE impairment may persist. Longer term follow-ups are warranted to further understand the effects of FGFRi on the RPE.

P1, N=40, Recruiting, Tyra Biosciences, Inc

Although FGFRi treatments suppressed tumor growth across CRPC phenotypes, our analyses did not identify a single pathway or biomarker that would identify tumor response to FGFRi. This is very likely due to the array of FGFR1-4 expression and tumor phenotypes present in CRPC. Nevertheless, our data nominate the FGFR pathway as a clinically actionable target that promotes tumor growth in diverse phenotypes of treatment-refractory metastatic CRPC.

P3, N=629, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Apr 2024 --> Aug 2024 | Trial primary completion date: Oct 2023 --> Feb 2024

P2, N=35, Active, not recruiting, Janssen Research & Development, LLC | Phase classification: P2a --> P2

P2, N=107, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Oct 2024 --> Jul 2025