Department of Medical Oncology, University Hospital Geneva, Switzerland.
Department of Medical Oncology, University Hospital Basel, Switzerland; SAKK Coordinating Centre, Bern, Switzerland.
Lung Cancer. 2022 Oct;172:154-159. doi: 10.1016/j.lungcan.2022.08.016. Epub 2022 Aug 28.
Patients with advanced squamous-cell lung cancer (SQCLC) frequently (46%) exhibit tumor overexpression of fibroblast growth factor receptor (FGFR) messenger ribonucleic acid (mRNA). Rogaratinib is a novel oral pan-FGFR inhibitor with a good safety profile and anti-tumor activity in early clinical trials as a single agent in FGFR pathway-addicted tumors. SAKK 19/18 determined clinical activity of rogaratinib in patients with advanced SQCLC overexpressing FGFR1-3 mRNA.
Patients with advanced SQCLC failing standard systemic treatment and with FGFR1-3 mRNA tumor overexpression as defined in the protocol received rogaratinib 600 mg BID until disease progression or intolerable toxicity. A 6-months progression-free survival rate (6mPFS) ≤15 % was considered uninteresting (H0), whereas a 6mPFS ≥38 % was considered promising (H1). According to a Simon 2-stage design, 2 out of 10 patients of the first stage were required to be progression-free at 6 months. Comprehensive Genomic Profiling was performedusing the Oncomine Comprehensive Assay Plus (Thermo Fisher Scientific).
Between July 2019 and November 2020, 49 patients were screened and 20 were classified FGFR-positive. Among a total of 15 patients, 6mPFS was reached in 1 patient (6.7 %), resulting in trial closure for futility after the first stage. There were 7 (46.7 %) patients with stable disease and 5 (33.3 %) patients with progressive disease. Median PFS was 1.6 (95 % CI 0.9-3.5) months and median overall survival (OS) 3.5 (95 % CI 1.0-5.9) months. Most frequent treatment-related adverse events (TRAEs) included hyperphosphatemia in 8 (53 %), diarrhea in 5 (33 %), stomatitis in 3 (20 %) and nail changes in 3 (20 %) patients. Grade ≥3 TRAEs occurred in 6 (40 %) patients. No associations between mutational profile and treatment outcome were observed.
Despite preliminary signals of activity, rogaratinib failed to improve PFS in patients with advanced SQCLC overexpressing FGFR mRNA. FGFR inhibitors in SQCLC remain a challenging field, and more in-depth understanding of pathway crosstalks may lead to the development of drug combinations with FGFR inhibitors resulting in improved outcomes.
晚期鳞状细胞肺癌（SQCLC）患者常（46%）表现出成纤维细胞生长因子受体（FGFR）信使核糖核酸（mRNA）的肿瘤过表达。罗加替尼是一种新型口服泛 FGFR 抑制剂，在早期临床试验中作为 FGFR 通路依赖性肿瘤的单一药物，具有良好的安全性和抗肿瘤活性。SAKK 19/18 确定了罗加替尼在 FGFR1-3 mRNA 过度表达的晚期 SQCLC 患者中的临床活性。
标准系统治疗失败且符合方案中定义的 FGFR1-3 mRNA 肿瘤过表达的晚期 SQCLC 患者接受罗加替尼 600mg 每日两次（BID）治疗，直至疾病进展或无法耐受毒性。6 个月无进展生存率（6mPFS）≤15%被认为不感兴趣（H0），而 6mPFS≥38%被认为有前景（H1）。根据西蒙两阶段设计，第一阶段需要有 2 例患者在 6 个月时无进展。使用 Oncomine Comprehensive Assay Plus（Thermo Fisher Scientific）进行综合基因组分析。
2019 年 7 月至 2020 年 11 月，共筛选了 49 例患者，其中 20 例被分类为 FGFR 阳性。在总共 15 例患者中，1 例患者（6.7%）达到 6mPFS，因此在第一阶段后因无效而关闭试验。7 例（46.7%）患者疾病稳定，5 例（33.3%）患者疾病进展。中位无进展生存期（PFS）为 1.6 个月（95%CI 0.9-3.5），中位总生存期（OS）为 3.5 个月（95%CI 1.0-5.9）。最常见的治疗相关不良事件（TRAEs）包括 8 例（53%）患者的高磷血症、5 例（33%）患者的腹泻、3 例（20%）患者的口腔炎和 3 例（20%）患者的指甲改变。6 例（40%）患者出现≥3 级 TRAEs。未观察到突变谱与治疗结果之间的相关性。
尽管有初步的活性信号，但罗加替尼未能改善 FGFR mRNA 过度表达的晚期 SQCLC 患者的 PFS。FGFR 抑制剂在 SQCLC 中仍然是一个具有挑战性的领域，更深入地了解途径串扰可能会导致与 FGFR 抑制剂联合用药，从而改善治疗结果。
