FORT-1: Phase II/III Study of Rogaratinib Versus Chemotherapy in Patients With Locally Advanced or Metastatic Urothelial Carcinoma Selected Based on <i>FGFR1</i>/<i>3</i> mRNA Expression

Sternberg, Cora N.; Petrylak, Daniel P.; Bellmunt, Joaquim; Nishiyama, Hiroyuki; Necchi, Andrea; Lee, Jae‐Lyun; Heijden, Michiel S. van der; Rosenbaum, Eli; Penel, Nicolas; Pang, See-Tong; Li, Jian-Ri; Muro, Xavier García del; Joly, Florence; Pápai, Zsuzsanna; Bao, Weichao; Ellinghaus, Peter; Lu, Chengxing; Sierecki, Mitchell Robert; Coppieters, Sabine; Nakajima, Keiko; Ishida, Tatiane; Quinn, David I.

doi:10.1200/jco.21.02303

Cited by 44 publications

(27 citation statements)

References 22 publications

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“…Common adverse effects include diarrhea, decreased appetite, fatigue, and asymptomatic lipase elevation. 370 , 371 E7090 selectively inhibits FGFR1–3 and has been found to be effective in patients with cholangiocarcinoma with FGFR2 gene fusions and in patients with gastric cancer with FGFR2 gene amplification or increased expression, but more information is needed for a larger sample size. 372 Debio 1347 is an ATP‐competitive, highly selective FGFR1–3 inhibitor, and it is mainly used to treat breast cancer and cholangiocarcinoma.…”

Section: Fgfr Acts As a Therapeutic Targetmentioning

confidence: 99%

FGFR families: biological functions and therapeutic interventions in tumors

Liu,

Huang,

Yan

et al. 2023

MedComm

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There are five fibroblast growth factor receptors (FGFRs), namely, FGFR1–FGFR5. When FGFR binds to its ligand, namely, fibroblast growth factor (FGF), it dimerizes and autophosphorylates, thereby activating several key downstream pathways that play an important role in normal physiology, such as the Ras/Raf/mitogen‐activated protein kinase kinase/extracellular signal‐regulated kinase, phosphoinositide 3‐kinase (PI3K)/AKT, phospholipase C gamma/diacylglycerol/protein kinase c, and signal transducer and activator of transcription pathways. Furthermore, as an oncogene, FGFR genetic alterations were found in 7.1% of tumors, and these alterations include gene amplification, gene mutations, gene fusions or rearrangements. Therefore, FGFR amplification, mutations, rearrangements, or fusions are considered as potential biomarkers of FGFR therapeutic response for tyrosine kinase inhibitors (TKIs). However, it is worth noting that with increased use, resistance to TKIs inevitably develops, such as the well‐known gatekeeper mutations. Thus, overcoming the development of drug resistance becomes a serious problem. This review mainly outlines the FGFR family functions, related pathways, and therapeutic agents in tumors with the aim of obtaining better outcomes for cancer patients with FGFR changes. The information provided in this review may provide additional therapeutic ideas for tumor patients with FGFR abnormalities.

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Section: Fgfr Acts As a Therapeutic Targetmentioning

confidence: 99%

FGFR families: biological functions and therapeutic interventions in tumors

Liu,

Huang,

Yan

et al. 2023

MedComm

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“…Rogaratinib development provides a recent example. Although this drug was evaluated in patients selected according to FGFR 1-3 mRNA expression levels, in the FORT-1 study, testing rogaratinib monotherapy against investigator-choice chemotherapy as second-line therapy, the ORR increased from 20.7% to 52.4% in patients also harboring a FGFR3 GA ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

Derazantinib alone and with atezolizumab in metastatic urothelial carcinoma with activating FGFR aberrations

Necchi,

Ramlau,

Falcón González

et al. 2024

JNCI Cancer Spectrum

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Background This Phase 1 b/2 study assessed the efficacy, in terms of objective response rate (ORR) of the FGFR1/2/3 kinase inhibitor derazantinib as monotherapy or in combination with atezolizumab in patients with metastatic urothelial cancer (mUC) and FGFR1-3 genetic aberrations (FGFR1-3GA). Methods This multicenter, open-label study comprised 5 substudies. In Substudies 1 and 5, patients with mUC with FGFR1–3GA received derazantinib monotherapy (300 mg QD in Substudy 1, 200 mg BID in Substudy 5). In Substudy 2, patients with any solid tumor received atezolizumab 1200 mg every 3 weeks plus derazantinib 200 or 300 mg QD. In Substudy 3, patients with mUC harboring FGFR1–3GA received derazantinib 200 mg BID plus atezolizumab 1200 mg every 3 weeks. In Substudy 4, patients with FGFR inhibitor-resistant mUC harboring FGFR1–3GA received derazantinib 300 mg QD monotherapy or derazantinib 300 mg QD plus atezolizumab 1200 mg every 3 weeks. Results The ORR for Substudies 1 and 5 combined was 4/49 (8.2%, 95% CI: 2.3, 19.6%), based on 4 partial responses. The ORR in Substudy 4 was 1/7 (14.3%, 95% CI: 0.4, 57.9%; 1 partial response for derazantinib 300 mg monotherapy, zero for derazantinib 300 mg plus atezolizumab 1200 mg). In Substudy 2, derazantinib 300 mg plus atezolizumab 1200 mg was identified as a recommended dose for Phase 2. Only 2 patients entered Substudy 3. Conclusions Derazantinib as monotherapy or in combination with atezolizumab was well-tolerated but did not show sufficient efficacy to warrant further development in mUC.

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“…Dysregulation of FGFRs has been implicated in various human malignancies, including UC, in which genetic alterations of FGFR1-3 have been implicated (17). Recent research on molecular subtypes and ICIs therapy has shown that UC of the bladder with FGFR3 mutation or high expression has a comparatively low immune signature and lower expression of PD-L1 (18,19). Inhibition of FGFR3 in FGFR3-activated bladder cancer has been shown to increase PD-L1 protein levels by changing its ubiquitination, which in turn regulates CD8+ T cells from engaging in antitumor activity (20).…”

Section: Discussionmentioning

confidence: 99%

Case Report: PD-L1-negative advanced bladder cancer effectively treated with anlotinib and tislelizumab: A report of two cases

Liu

et al. 2023

Front. Oncol.

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Second-line treatment for metastatic or locally advanced urothelial cancer (UC) is limited. Immunotherapy is approved as a second-line treatment for metastatic UC. Its use as a first-line agent is limited to patients who are ineligible for cisplatin-based treatments. The fibroblast growth factor receptor (FGFR) inhibitor, erdafitinib, can be applied as a third-line approach after the failure of these prior treatments in eligible patients. Therefore, it is especially important to combine limited drugs for second-line treatment of advanced or metastatic UC. Anlotinib is a multiple tyrosine kinase inhibitor agent with both anti-angiogenic and FGFR inhibitory effects. For two patients with advanced and metastatic UC, we combined anlotinib and tislelizumab therapy even though there is no indication of its use. We describe two patients with programmed death ligand-1 (PD-L1)-negative advanced bladder cancer, one with FGFR3 mutation and another with FGFR3 wild type. Both patients had progressed after first-line chemotherapy with gemcitabine and cisplatin. We selected anlotinib in combination with tislelizumab, a programmed death-1 (PD-1) immune checkpoint inhibitor, for second-line treatment. Responses were evaluated as partial remission in both cases, who achieved up to 12 months of progression-free survival with no significant adverse events. Two patients with PD-L1-negative UC underwent second-line therapy using tislelizumab in combination with anlotinib, and the efficacy was better than that of tislelizumab alone. These results suggest that anlotinib may act synergistically with tislelizumab in the treatment of UC.

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FORT-1: Phase II/III Study of Rogaratinib Versus Chemotherapy in Patients With Locally Advanced or Metastatic Urothelial Carcinoma Selected Based on FGFR1/3 mRNA Expression

Cited by 44 publications

References 22 publications

FGFR families: biological functions and therapeutic interventions in tumors

FGFR families: biological functions and therapeutic interventions in tumors

Derazantinib alone and with atezolizumab in metastatic urothelial carcinoma with activating FGFR aberrations

Case Report: PD-L1-negative advanced bladder cancer effectively treated with anlotinib and tislelizumab: A report of two cases

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