BACKGROUND Infigratinib (BGJ398) is a potent and selective fibroblast grown factor receptor 1 to 3 (FGFR1-3) inhibitor with significant activity in patients with advanced or metastatic urothelial carcinoma bearing FGFR3 alterations. Given the distinct biologic characteristics of upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB), the authors examined whether infigratinib had varying activity in these settings. METHODS Eligible patients had metastatic urothelial carcinoma with activating FGFR3 mutations and/or fusions. Comprehensive genomic profiling was performed on formalin-fixed, paraffin-embedded tissues. Blood was collected for cell-free DNA analysis using a 600-gene panel. Patients received infigratinib at a dose of 125 mg orally daily (3 weeks on/1 week off) until disease progression or intolerable toxicity occurred. The overall response rate (ORR; partial response [PR] plus complete response [CR]) and disease control rate (DCR; CR plus PR plus stable disease [SD]) were characterized. RESULTS A total of 67 patients were enrolled; the majority (70.1%) had received ≥2 prior antineoplastic therapies. In 8 patients with UTUC, 1 CR and 3 PRs were observed (ORR, 50%); the remaining patients achieved a best response of SD (DCR, 100%). In patients with UCB, 13 PRs were observed (ORR, 22%), and 22 patients had a best response of SD (DCR, 59.3%). Notable differences in genomic alterations between patients with UTUC and those with UCB included higher frequencies of FGFR3-TACC3 fusions (12.5% vs 6.8%) and FGFR3 R248C mutations (50% vs 11.9%), and a lower frequency of FGFR3 S249C mutations (37.5% vs 59.3%). CONCLUSIONS Differences in the cumulative genomic profile were observed between patients with UTUC and those with UCB in the current FGFR3-restricted experience, underscoring the distinct biology of these diseases. These results support a planned phase 3 adjuvant study predominantly performed in this population.

中文翻译：

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Infigratinib 治疗上尿路尿路上皮癌与膀胱尿路上皮癌及其与综合基因组分析和/或无细胞 DNA 结果的关联。

背景 Infigratinib (BGJ398) 是一种有效的选择性成纤维细胞生长因子受体 1 至 3 (FGFR1-3) 抑制剂，在患有 FGFR3 改变的晚期或转移性尿路上皮癌患者中具有显着活性。鉴于上尿路尿路上皮癌 (UTUC) 和膀胱尿路上皮癌 (UCB) 的不同生物学特征，作者检查了 infigratinib 在这些情况下是否具有不同的活性。方法 符合条件的患者患有具有激活 FGFR3 突变和/或融合的转移性尿路上皮癌。对福尔马林固定、石蜡包埋的组织进行了全面的基因组分析。收集血液用于使用 600 基因面板进行无细胞 DNA 分析。患者每天口服 125 mg 的 infigratinib（服用 3 周/停药 1 周），直到出现疾病进展或无法耐受的毒性。表征了总体缓解率（ORR；部分缓解 [PR] 加完全缓解 [CR]）和疾病控制率（DCR；CR 加 PR 加稳定疾病 [SD]）。结果 共纳入 67 例患者；大多数 (70.1%) 之前接受过≥2 种抗肿瘤治疗。在 8 例 UTUC 患者中，观察到 1 例 CR 和 3 例 PR（ORR，50%）；其余患者达到 SD 的最佳反应（DCR，100%）。在 UCB 患者中，观察到 13 个 PR（ORR，22%），22 名患者的 SD 反应最佳（DCR，59.3%）。UTUC 患者和 UCB 患者之间基因组改变的显着差异包括更高频率的 FGFR3-TACC3 融合（12.5% 对 6. 8%) 和 FGFR3 R248C 突变（50% 对 11.9%），以及较低频率的 FGFR3 S249C 突变（37.5% 对 59.3%）。结论 在当前 FGFR3 限制性经验中，在 UTUC 患者和 UCB 患者之间观察到累积基因组谱的差异，强调了这些疾病的独特生物学特性。这些结果支持主要在该人群中进行的计划中的 3 期辅助研究。