PO.CT01.05 · 临床试验
经6周AG诱导治疗后，索凡替尼联合吉西他滨和白蛋白结合型紫杉醇（AG）序贯治疗或单用AG作为局部晚期或转移性胰腺导管腺癌（mPDAC）一线治疗：一项双队列、探索性II期研究
Sequential treatment with surufatinib combined with gemcitabine and nab-paclitaxel (AG) or AG alone as first-line therapy for locally advanced or metastatic pancreatic ductal adenocarcinoma (mPDAC) after 6 weeks of AG induction therapy: A two-cohort, exploratory phase II study
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：PDAC是一种极具侵袭性的恶性肿瘤，治疗选择有限。尽管有AG等现有一线治疗，5年生存率仍低于5%。索凡替尼（S）是一种新型酪氨酸激酶抑制剂，选择性靶向VEGFR1-3、FGFR1和CSF-1R。本研究旨在评估S联合AG或单用AG作为mPDAC患者一线治疗的疗效和安全性。
方法：这项探索性II期试验（NCT05969171）入组了两个队列。符合条件的患者（pts）年龄18-75岁、经组织学确诊为mPDAC、在6周AG诱导治疗后无疾病进展（SD增大的患者也被排除），被分配至队列1（S 250 mg qd，口服，q3w联合AG：白蛋白结合型紫杉醇1000 mg/m²，静脉注射，d1、d8；吉西他滨1000 mg/m²，静脉注射，d1、d8，q3w）或队列2（单用AG，q3w）。主要终点为PFS。次要终点包括ORR、DCR、OS和安全性。
结果：截至2025年12月31日，队列1入组26例患者（中位年龄61.0岁；57.7%为男性；50%有≥1个转移器官；中位CA19-9为206.0 U/mL），队列2入组26例患者（中位年龄60.0岁；65.4%为男性；38.4%有>1个转移器官；中位CA19-9为438.5 U/mL）。在队列1中，6例患者（23.1%）在6周AG治疗后达到PR，另有14例患者在S联合AG治疗期间达到PR，ORR为76.9%。中位PFS（从AG治疗开始到PD或死亡的时间）为13.96个月（95% CI：5.6-22.3）。亚组分析显示，无转移器官的患者较有≥1个转移器官的患者具有更长的mPFS（未达到对8.64个月，p=0.081），CA19-9下降≥90%的患者较下降<90%的患者mPFS更长（未达到对9.26个月，p=0.046）。在队列2中，8例患者（30.8%）在AG治疗期间达到PR，另有10例患者在持续AG治疗中达到PR，ORR为69.2%。中位PFS为10.68个月（95% CI：9.3-12.1）。与队列1一致，亚组分析显示≤1个转移器官的患者较>1个转移器官的患者PFS延长（12.52对6.64个月，p=0.0083），CA19-9下降≥70%的患者较下降<70%的患者PFS更长（11.6对8.34个月，p=0.072）。两个队列的中位OS均未达到。队列1中常见的≥3级TEAEs为脱发（80.8%）、中性粒细胞减少（42.3%）和白细胞减少（30.8%）；队列2中为脱发（76.9%）、白细胞减少（34.6%）和中性粒细胞减少（26.9%）。
结论：6周AG诱导治疗后序贯索凡替尼联合AG，作为mPDAC的一线治疗显示出良好的疗效和可控的安全性特征。该治疗策略可能对无转移器官的患者或在治疗期间CA19-9下降≥90%的患者尤为有益。
查看英文原文 English abstract
Background: PDAC is an extremely aggressive malignancy with limited therapeutic options. Despite current first-line therapies like AG, the 5-year survival rate remains below 5%. Surufatinib (S) is a novel tyrosine kinase inhibitor that selectively targets VEGFR1-3, FGFR1, and CSF-1R. This study aimed to evaluate the efficacy and safety of S plus AG or AG alone as first-line treatment for patients with mPDAC.
Methods: This exploratory, phase II trial (NCT05969171) enrolled two cohorts. Eligible patients (pts) with 18-75 years, histologically confirmed mPDAC, with no disease progression after 6 weeks of AG induction therapy (pts with increased SD were also excluded) were assigned to cohort 1 (S 250 mg qd, po, q3w plus AG: nab-paclitaxel 1000mg/m 2 , iv, d1, d8; gemcitabine 1000mg/m 2 , iv, d1, d8, q3w) or cohort 2 (AG alone, q3w). The Primary endpoint was PFS. Secondary endpoints included ORR, DCR, OS, and safety.
Results: As of December 31, 2025, 26 pts were enrolled in cohort 1 (median age 61.0 years; 57.7% male; 50% had ≥1 metastatic organ; median CA19-9 206.0 U/mL) and 26 pts in cohort 2 (median age 60.0 years; 65.4% male; 38.4% had >1 metastatic organs; median CA19-9 438.5 U/mL). In cohort 1, 6 pts (23.1%) achieved PR following 6 weeks of AG therapy, and an additional 14 pts achieved PR during S plus AG treatment, resulting in an ORR of 76.9%. The median PFS (time from initiation of AG treatment to PD or death) was 13.96 months (95% CI: 5.6-22.3). Subgroup analysis revealed longer mPFS in pts without metastatic organ compared to those with ≥1 metastatic organ (not reached vs. 8.64 months, p=0.081) and in pts with a ≥90% reduction in CA19-9 versus those with a <90% reduction (not reached vs. 9.26 months, p=0.046). In cohort 2, 8 pts (30.8%) achieved PR during AG therapy, and 10 additional pts achieved PR with continued AG treatment, yielding an ORR of 69.2%. The median PFS was 10.68 months (95% CI: 9.3-12.1). Consistent with cohort 1, subgroup analysis showed prolonged PFS in pts with ≤1 metastatic organ versus those with >1 metastatic organs (12.52 vs. 6.64 months, p=0.0083) and in pts with a ≥70% reduction in CA19-9 versus those with a <70% reduction (11.6 vs. 8.34 months, p=0.072). Median OS was not reached in either cohort. Common TEAEs of grade ≥3 in cohort 1 were alopecia (80.8%), neutropenia (42.3%), and leukopenia (30.8%); in cohort 2, these were alopecia (76.9%), leukopenia (34.6%), and neutropenia (26.9%).
Conclusions: Induction therapy with 6 weeks of AG followed by sequential surufatinib plus AG demonstrated promising efficacy with a manageable safety profile as first-line treatment for mPDAC. This therapeutic strategy may be particularly beneficial for patients without metastatic organs or those who achieve a ≥90% reduction in CA19-9 during treatment.
利益披露 Disclosure
J. Li, None..
M. Wei, None..
N. Du, None..
S. Shi, None..
J. Xu, None..
X. Yu, None.