Pichler R, van Creij N C H, Subiela J D, Cimadamore A, Caño-Velasco J, Tully K H, Mori K, Contieri R, Afferi L, Mari A, Soria F, Del Giudice F, D'Elia C, Mayr R, Mertens L S, Pyrgidis N, Moschini M, Gallioli A
Servicio de Urología, Universidad Médica de Innsbruck, Innsbruck, Austria.
Servicio de Urología, Universidad Médica de Innsbruck, Innsbruck, Austria.
Actas Urol Esp (Engl Ed). 2025 Jun;49(5):501719. doi: 10.1016/j.acuroe.2025.501719. Epub 2025 Feb 13.
FGFR3 mutations are among the most frequent genomic alterations in urothelial cancer (UC) being mainly associated with the luminal papillary (LumP) subtype. With the establishment of fibroblast growth factor receptor (FGFR) inhibitors, the treatment of UC is now shifting more and more towards personalized medicine. A systematic review using Medline and scientific meeting records was carried out according to the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines to assess the potential role of FGFR inhibitors in combination with additional therapies for the management of UC. Ongoing trials were identified via a systematic search on ClinicalTrials.gov. A total of eleven full-text papers, ten congress abstracts, and 5 trials on ClinicalTrials.gov were identified. Following the BLC2001 and THOR study, erdafitinib is the only approved FGFR1-4 inhibitor for metastatic UC with susceptible FGFR2/3 alterations following platinum-based chemotherapy. According to the THOR data of cohort 2, erdafitinib should not be recommended in patients who are eligible for and have not received prior immune checkpoint inhibitors (ICIs). One phase 3 trial is currently evaluating the intravesical device system (TAR210) in FGFR-altered intermediate non-muscle invasive bladder cancer (MoonRISe-1). Preclinical evidence suggests that combination-based approaches could be considered to improve the efficacy of FGFR inhibitors in patients with UC. Nine phase 1b/2 trials are focusing on the combination of FGFR inhibitors with ICIs, chemotherapy, or enfortumab vedotin. In metastatic disease, some preliminary analyses have reported promising results from these combinations (e.g. NORSE and FORT-2 trial). However, no phase 3 trial is terminated, so there is currently no level 1 evidence with long-term outcomes to support the combination of FGFR inhibitors with ICIs, chemotherapy, or targeted therapies. A better understanding of the different mechanisms of action to inhibit FGFR signaling pathways, optimal patient selection and treatment approaches is still needed.
成纤维细胞生长因子受体3（FGFR3）突变是尿路上皮癌（UC）中最常见的基因组改变之一，主要与腔乳头状（LumP）亚型相关。随着成纤维细胞生长因子受体（FGFR）抑制剂的出现，UC的治疗现在越来越朝着个性化医疗发展。根据系统评价和Meta分析的首选报告项目指南，利用Medline和科学会议记录进行了一项系统评价，以评估FGFR抑制剂联合其他疗法在UC治疗中的潜在作用。通过在ClinicalTrials.gov上进行系统检索，确定了正在进行的试验。共确定了11篇全文论文、10篇大会摘要和ClinicalTrials.gov上的5项试验。继BLC2001和THOR研究之后，erdafitinib是唯一获批用于治疗转移性UC且在铂类化疗后具有敏感FGFR2/3改变的FGFR1-4抑制剂。根据队列2的THOR数据，不建议在有资格且未接受过先前免疫检查点抑制剂（ICI）治疗的患者中使用erdafitinib。一项3期试验目前正在评估FGFR改变的中级非肌层浸润性膀胱癌的膀胱内装置系统（TAR210）（MoonRISe-1）。临床前证据表明，可以考虑采用联合治疗方法来提高FGFR抑制剂在UC患者中的疗效。9项1b/2期试验聚焦于FGFR抑制剂与ICI、化疗或恩杂鲁胺的联合应用。在转移性疾病中，一些初步分析报告了这些联合应用取得的有前景的结果（如NORSE和FORT-2试验）。然而，尚无3期试验结束，因此目前尚无支持FGFR抑制剂与ICI、化疗或靶向治疗联合应用的具有长期结果的1级证据。仍需要更好地了解抑制FGFR信号通路的不同作用机制、最佳患者选择和治疗方法。
