Pemigatinib 是一种口服、有效、选择性成纤维细胞生长因子受体 (FGFR) 1-3 抑制剂。 FIGHT-101 是一项三部分、开放标签、首次人体 I/II 期研究 (NCT02393248)，评估了 pemigatinib 对晚期实体瘤患者的疗效。在第 1 部分和第 2 部分中，pemigatinib 单药疗法在 FGFR 改变的肿瘤中具有可控的安全性和抗肿瘤活性。第 3 部分（pemigatinib 联合疗法）结果在此介绍。患者接受 9、13.5 或 20 mg 口服每日一次的 pemigatinib，连续或间歇性服用吉西他滨和顺铂 (pemi/gem/cis)、多西紫杉醇 (pemi/doc)、曲妥珠单抗 (pemi/tras)、派姆单抗 (pemi/pembro) 或瑞替凡利单抗 (pemi/reti)，无论肿瘤是否被确认为 FGFR 改变。主要终点是安全性和药效学。次要终点是研究者评估的肿瘤客观缓解率 (ORR) 和药代动力学 (PK)。 65 名入组患者（pemi/gem/cis，n = 8；pemi/doc，n = 7；pemi/tras，n = 6；pemi/gem/cis，n = 8；pemi/doc，n = 7；pemi/tras，n = 6） pemi/pembro，n = 26；pemi/reti，n = 18），全部停产。治疗引起的不良事件 (TEAE) 通常与个别药物的 AE 一致。治疗组中严重和≥3级 TEAE 的发生率分别为 0%-85.7% 和 33.3%-100.0%。所有培米加替尼组合均表现出与单一疗法相当的稳态 PK。除 pemi/gem/cis 外，所有 pemigatinib 组合的药效学效果均与单一疗法一致。这种组合对 FGFR2α 磷酸化的抑制较小。 ORR（95% 置信区间）分别为 37.5% [8.5% 至 75.5% (pemi/gem/cis)]、14.3% [0.4% 至 57.9% (pemi/doc)]、0% (pemi/tras)、26.9% [11.6% 至 47.8% (pemi/pembro)] 和 11.1% [1.4% 至 34.7% (pemi/reti)]。所有组均出现肿瘤缩小的情况。可评估的 FGFR 重排和突变患者的 ORR 分别为 50% 和 33%。Pemigatinib 联合治疗未显示出意外的毒性。 PK 和药效学与培米加替尼单药治疗基本一致。 Pemi/gem/cis (37.5%) 和 pemi/pembro (26.9%) 的 ORR 最高；大多数响应者都有 FGFR 改变。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

Pemigatinib is an oral, potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor. FIGHT-101, a three-part, open-label, first-in-human, phase I/II study (NCT02393248), evaluated pemigatinib in patients with advanced solid tumors. In parts 1 and 2, pemigatinib monotherapy had a manageable safety profile and antitumor activity in FGFR-altered tumors. Part 3 (pemigatinib combination therapies) results are presented here.Patients received 9, 13.5, or 20 mg oral once-daily pemigatinib on continuous or intermittent schedules with gemcitabine and cisplatin (pemi/gem/cis), docetaxel (pemi/doc), trastuzumab (pemi/tras), pembrolizumab (pemi/pembro), or retifanlimab (pemi/reti) irrespective of whether the tumor was confirmed as FGFR altered. Primary endpoints were safety and pharmacodynamics. Secondary endpoints were investigator-assessed tumor objective response rates (ORRs) and pharmacokinetics (PK).Of 65 enrolled patients (pemi/gem/cis, n = 8; pemi/doc, n = 7; pemi/tras, n = 6; pemi/pembro, n = 26; pemi/reti, n = 18), all discontinued. Treatment-emergent adverse events (TEAEs) were generally consistent with individual drug AEs. Serious and grade ≥3 TEAEs occurred in 0%-85.7% and 33.3%-100.0% of patients across treatment groups, respectively. All pemigatinib combinations demonstrated steady-state PK comparable to monotherapy. Pharmacodynamic effects in all pemigatinib combinations, except pemi/gem/cis, were consistent with monotherapy. Less inhibition of FGFR2α phosphorylation was observed with this combination. ORRs (95% confidence interval) were 37.5% [8.5% to 75.5% (pemi/gem/cis)], 14.3% [0.4% to 57.9% (pemi/doc)], 0% (pemi/tras), 26.9% [11.6% to 47.8% (pemi/pembro)], and 11.1% [1.4% to 34.7% (pemi/reti)]. All groups had instances of tumor shrinkage. ORRs in assessable patients with FGFR rearrangements and mutations were 50% and 33%, respectively.Pemigatinib combination therapy showed no unexpected toxicities. PK and pharmacodynamics were mostly consistent with pemigatinib monotherapy. Pemi/gem/cis (37.5%) and pemi/pembro (26.9%) had the highest ORR; most responders had FGFR alterations.Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.