Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA.
Department of Medical Oncology, National Cancer Center Hospital East, Chiba, Japan.
Ann Oncol. 2024 Jan;35(1):107-117. doi: 10.1016/j.annonc.2023.10.003. Epub 2023 Oct 21.
Erdafitinib is an oral pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved to treat locally advanced/metastatic urothelial carcinoma (mUC) in patients with susceptible FGFR3/2 alterations (FGFRalt) who progressed after platinum-containing chemotherapy. FGFR-altered tumours are enriched in luminal 1 subtype and may have limited clinical benefit from anti-programmed death-(ligand) 1 [PD-(L)1] treatment. This cohort in the randomized, open-label phase III THOR study assessed erdafitinib versus pembrolizumab in anti-PD-(L)1-naive patients with mUC.
Patients ≥18 years with unresectable advanced/mUC, with select FGFRalt, disease progression on one prior treatment, and who were anti-PD-(L)1-naive were randomized 1 : 1 to receive erdafitinib 8 mg once daily with pharmacodynamically guided uptitration to 9 mg or pembrolizumab 200 mg every 3 weeks. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety.
The intent-to-treat population (median follow-up 33 months) comprised 175 and 176 patients in the erdafitinib and pembrolizumab arms, respectively. There was no statistically significant difference in OS between erdafitinib and pembrolizumab [median 10.9 versus 11.1 months, respectively; hazard ratio (HR) 1.18; 95% confidence interval (CI) 0.92-1.51; P = 0.18]. Median PFS for erdafitinib and pembrolizumab was 4.4 and 2.7 months, respectively (HR 0.88; 95% CI 0.70-1.10). ORR was 40.0% and 21.6% (relative risk 1.85; 95% CI 1.32-2.59) and median duration of response was 4.3 and 14.4 months for erdafitinib and pembrolizumab, respectively. 64.7% and 50.9% of patients in the erdafitinib and pembrolizumab arms had ≥1 grade 3-4 adverse events (AEs); 5 (2.9%) and 12 (6.9%) patients, respectively, had AEs that led to death.
Erdafitinib and pembrolizumab had similar median OS in this anti-PD-(L)1-naive, FGFR-altered mUC population. Outcomes with pembrolizumab were better than assumed and aligned with previous reports in non- FGFR-altered populations. Safety results were consistent with the known profiles for erdafitinib and pembrolizumab in this patient population.
厄达替尼是一种口服泛成纤维细胞生长因子受体（FGFR）酪氨酸激酶抑制剂，获批用于治疗局部晚期/转移性尿路上皮癌（mUC）患者，这些患者存在敏感 FGFR3/2 改变（FGFRalt），且在铂类化疗后进展。FGFR 改变的肿瘤在腔型 1 亚型中丰富，可能对抗程序性死亡配体-1（PD-（L）1）治疗的临床获益有限。这项在随机、开放标签 III 期 THOR 研究中的队列评估了厄达替尼与 pembrolizumab 在抗 PD-（L）1 初治患者中的疗效。
≥18 岁、不可切除的晚期/mUC 患者，有选择性 FGFRalt，在一线治疗后疾病进展，且为抗 PD-（L）1 初治，按 1:1 比例随机分配接受厄达替尼 8 mg 每日一次，与药效学指导的剂量递增至 9 mg 或 pembrolizumab 200 mg 每 3 周一次。主要终点是总生存期（OS）。次要终点包括无进展生存期（PFS）、客观缓解率（ORR）和安全性。
在意向治疗人群（中位随访 33 个月）中，厄达替尼和 pembrolizumab 组分别有 175 例和 176 例患者。厄达替尼和 pembrolizumab 组之间 OS 无统计学显著差异[中位 OS 分别为 10.9 个月和 11.1 个月，风险比（HR）为 1.18；95%置信区间（CI）为 0.92-1.51；P=0.18]。厄达替尼和 pembrolizumab 组的中位 PFS 分别为 4.4 个月和 2.7 个月（HR 0.88；95% CI 0.70-1.10）。ORR 分别为 40.0%和 21.6%（相对风险 1.85；95% CI 1.32-2.59），厄达替尼和 pembrolizumab 组的中位缓解持续时间分别为 4.3 个月和 14.4 个月。厄达替尼和 pembrolizumab 组分别有 64.7%和 50.9%的患者发生≥1 级 3-4 级不良事件（AE）；分别有 5（2.9%）和 12（6.9%）例患者因 AE 导致死亡。
在抗 PD-（L）1 初治、FGFR 改变的 mUC 人群中，厄达替尼和 pembrolizumab 的中位 OS 相似。pembrolizumab 的疗效优于预期，与非 FGFR 改变人群的既往报告一致。安全性结果与该患者人群中厄达替尼和 pembrolizumab 的已知特征一致。
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