From Gustave Roussy, INSERM Unité 981, Université Paris-Sud, Université Paris-Saclay, Villejuif, France (Y.L.); Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (A.N.); Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Genitourinary and Gynecological Cancer Unit, Centro Integral Oncológico Clara Campal, Madrid (J.G.-D.), Hospital Clinic Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona (B.M.), and Hospital Universitario Marques de Valdecilla, Santander (I.D.) - all in Spain; the Institute of Cancer Research, Sutton, London (R.H.); the Levine Cancer Institute, Atrium Health, Charlotte, NC (E.B.); Virginia Oncology Associates, US Oncology Research, Norfolk (M.F.); Norton Healthcare, Louisville, KY (A.R.); the Altai Regional Cancer Center, Barnaul, Russia (S.V.); the Penn State Cancer Institute, Hershey (M.J.), and Janssen Research and Development, Spring House (B.Z., A.S.-W., A.O., A.A.) - both in Pennsylvania; Weill Cornell Medical College, New York (S.T.T.); University of Iowa Hospitals and Clinics, Holden Comprehensive Cancer Center, Iowa City (Y.Z.); Janssen Research and Development, Beerse, Belgium (K.S., P.D.P.); and the University of Texas M.D. Anderson Cancer Center, Houston (A.O.S.-R.).
N Engl J Med. 2019 Jul 25;381(4):338-348. doi: 10.1056/NEJMoa1817323.
Alterations in the gene encoding fibroblast growth factor receptor () are common in urothelial carcinoma and may be associated with lower sensitivity to immune interventions. Erdafitinib, a tyrosine kinase inhibitor of FGFR1-4, has shown antitumor activity in preclinical models and in a phase 1 study involving patients with alterations.
In this open-label, phase 2 study, we enrolled patients who had locally advanced and unresectable or metastatic urothelial carcinoma with prespecified alterations. All the patients had a history of disease progression during or after at least one course of chemotherapy or within 12 months after neoadjuvant or adjuvant chemotherapy. Prior immunotherapy was allowed. We initially randomly assigned the patients to receive erdafitinib in either an intermittent or a continuous regimen in the dose-selection phase of the study. On the basis of an interim analysis, the starting dose was set at 8 mg per day in a continuous regimen (selected-regimen group), with provision for a pharmacodynamically guided dose escalation to 9 mg. The primary end point was the objective response rate. Key secondary end points included progression-free survival, duration of response, and overall survival.
A total of 99 patients in the selected-regimen group received a median of five cycles of erdafitinib. Of these patients, 43% had received at least two previous courses of treatment, 79% had visceral metastases, and 53% had a creatinine clearance of less than 60 ml per minute. The rate of confirmed response to erdafitinib therapy was 40% (3% with a complete response and 37% with a partial response). Among the 22 patients who had undergone previous immunotherapy, the confirmed response rate was 59%. The median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months. Treatment-related adverse events of grade 3 or higher, which were managed mainly by dose adjustments, were reported in 46% of the patients; 13% of the patients discontinued treatment because of adverse events. There were no treatment-related deaths.
The use of erdafitinib was associated with an objective tumor response in 40% of previously treated patients who had locally advanced and unresectable or metastatic urothelial carcinoma with alterations. Treatment-related grade 3 or higher adverse events were reported in nearly half the patients. (Funded by Janssen Research and Development; BLC2001 ClinicalTrials.gov number, NCT02365597.).
成纤维细胞生长因子受体（FGFR）基因编码的改变在尿路上皮癌中很常见，并且可能与对免疫干预的敏感性降低有关。FGFR1-4 的酪氨酸激酶抑制剂厄达替尼在临床前模型和涉及 FGFR 改变的患者的 1 期研究中显示出抗肿瘤活性。
在这项开放标签、2 期研究中，我们招募了患有局部晚期、不可切除或转移性尿路上皮癌且具有预设 FGFR 改变的患者。所有患者在至少一次化疗期间或之后或新辅助或辅助化疗后 12 个月内疾病进展。允许进行先前的免疫治疗。我们最初在研究的剂量选择阶段将患者随机分配至连续或间断接受厄达替尼治疗。基于中期分析，起始剂量设定为每日 8mg 连续给药（选择方案组），并提供根据药代动力学指导进行剂量递增至 9mg。主要终点是客观缓解率。关键次要终点包括无进展生存期、缓解持续时间和总生存期。
选择方案组中共有 99 例患者接受了中位数为 5 个周期的厄达替尼治疗。其中，43%的患者至少接受了两次先前的治疗，79%的患者有内脏转移，53%的患者肌酐清除率低于 60ml/min。厄达替尼治疗的确认缓解率为 40%（3%完全缓解，37%部分缓解）。在 22 例接受过先前免疫治疗的患者中，确认缓解率为 59%。无进展生存期的中位数为 5.5 个月，总生存期的中位数为 13.8 个月。主要通过剂量调整进行管理的 3 级或以上治疗相关不良事件在 46%的患者中发生；由于不良事件，13%的患者停止治疗。无治疗相关死亡。
在先前接受治疗的局部晚期、不可切除或转移性尿路上皮癌且具有 FGFR 改变的患者中，厄达替尼的使用与客观肿瘤缓解相关，缓解率为 40%。近一半的患者出现 3 级或以上的治疗相关不良事件。（由 Janssen Research and Development 资助；BLC2001 ClinicalTrials.gov 编号，NCT02365597.）。
