背景:Pemigatinib是一种口服,强力,选择性成纤维细胞生长因子受体(FGFR)1-3抑制剂。FIGHT-101,由三部分组成,开放标签,人类第一,I/II期研究(NCT02393248),评价了培米加替尼在晚期实体瘤患者中的疗效。在第1部分和第2部分中,培米替尼单药治疗在FGFR改变的肿瘤中具有可控的安全性和抗肿瘤活性。第三部分(培米加替尼联合治疗)结果在此呈现。
方法:患者连续或间歇服用吉西他滨和顺铂(pemi/gem/cis),每天一次口服9、13.5或20mg培米替尼,多西他赛(pemi/doc),曲妥珠单抗(pemi/tras),pembrolizumab(pemmi/pembro),或retifanlimab(pemi/reti),无论肿瘤是否被证实为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反应率(ORR)和药代动力学(PK)。
结果:在65名登记患者中(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)通常与单个药物AE一致。严重和≥3级TEAE发生在0%-85.7%和33.3%-100.0%的患者中。分别。所有培米加替尼组合显示与单一疗法相当的稳态PK。所有培米加替尼组合的药效学效应,除了pemi/gem/cis,与单一疗法一致。用这种组合观察到较少的FGFR2α磷酸化抑制。ORR(95%置信区间)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)]。所有组均有肿瘤缩小的情况。FGFR重排和突变的可评估患者的ORR分别为50%和33%,分别。
结论:Pemigatinib联合治疗无意外毒性。PK和药效学与培米替尼单药治疗基本一致。Pemi/gem/cis(37.5%)和pemmi/pembro(26.9%)的ORR最高;大多数响应者都有FGFR改变。
BACKGROUND: 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.
METHODS: 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).
RESULTS: 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.
CONCLUSIONS: 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.