Efficacy and safety of TAS-102 plus Surufatinib in third and later line metastatic pancreatic cancer: a prospective, single center and biomarker exploratory, phase II study

IF 33.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yunxin Lu, Qingguang Lin, Yongxin Mo, Furong Liu, Mengwei Zhang, Runjie Huang, Yun Wang, Yinnan Wang, Zhiqiang Wang, Huiyan Luo, Guifang Guo, Jianwen Chen, Yu Liu, Mingming He, Fenghua Wang, Feng Wang, Dongsheng Zhang
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引用次数: 0

Abstract

Metastatic pancreatic cancer (mPC) has a dismal prognosis, with first line systemic therapy relying primarily on FOLFIRINOX (5FU/irinotecan/oxaliplatin) or AG (Gemcitabine/Nab-Paclitaxel). Therapeutic options for mPC refractory to these regimens remain poorly defined, and data on later-line options are scarce. This prospective, single-arm study evaluated the safety and preliminary efficacy of combining the anti-angiogenic agent surufatinib with the cytotoxic drug TAS-102 (Trifluridine/Tipiracil) in mPC patients who had progressed on ≥ 2 prior lines of therapy. mPC patients who were refractory to at least 2 previous regimens were enrolled and received TAS-102 (35 mg/m2, po, bid, D1-D5, D8-D12) plus surufatinib (250 mg, po, qd) in a 4-week cycle. The tumor response was assessed by the researcher every 8 weeks and treatment continued until disease progression, unacceptable toxicity, investigator discretion, or patient withdrawal of informed consent. Primary and secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Between January 2023 and June 2024, 22 patients were enrolled into this study. Among 20 patients analyzed for efficacy, median PFS was 2.35 months (95% CI: 1.91–3.94) and median OS was 6.34 months (95% CI: 3.81–10.09). The ORR and DCR were 20% (4/20; all partial response) and 30% (6/20), respectively. All patients experienced treatment emergent adverse events (TEAEs), with anemia (59.1%), neutropenia (54.6%), leukocytopenia (50.0%), and lymphocytopenia (45.5%) as the most common any-grade events. Grade ≥ 3 TEAEs including neutropenia (31.8%), lymphocytopenia (13.6%), and anemia (9.1%), were observed in 50.0% (11/22) of patients. Subgroup analysis identified metastases involving > 2 organs or hepatic sites as potential predicative biomarkers for inferior efficacy. Proteomic screening revealed that overexpressed OCIAD2 correlated with poor prognosis, a finding validated in two publicly available external cohorts (CPTAC database and RuiJin cohort). Combination of TAS-102 and surufatinib demonstrates clinically meaningful efficacy and manageable toxicity as therapeutic option for later-line mPC. The biomarkers identified in this study may hold the potential to guide patient stratification and warrant further investigation to optimize precision application of this regimen. This study was prospectively registered at clinicaltrials.gov with the number NCT05481463 on August 1st 2022.
TAS-102联合舒法替尼治疗三线及晚期转移性胰腺癌的疗效和安全性:一项前瞻性、单中心和生物标志物探索性II期研究
转移性胰腺癌(mPC)预后不佳,一线全身治疗主要依赖于FOLFIRINOX (5FU/伊立替康/奥沙利铂)或AG(吉西他滨/ nab -紫杉醇)。对这些方案难治的mPC的治疗选择仍然不明确,关于后期治疗方案的数据很少。这项前瞻性单组研究评估了抗血管生成药物舒法替尼与细胞毒性药物TAS-102 (Trifluridine/Tipiracil)联合治疗既往≥2条治疗线进展的mPC患者的安全性和初步疗效。对至少2个先前方案难治性的mPC患者入组,在4周的周期内接受TAS-102 (35 mg/m2, po, bid, D1-D5, D8-D12)加舒法替尼(250 mg, po, qd)。研究人员每8周评估一次肿瘤反应,并持续治疗,直到疾病进展、不可接受的毒性、研究者的判断或患者撤回知情同意。主要和次要终点包括无进展生存期(PFS)、总生存期(OS)、客观缓解率(ORR)、疾病控制率(DCR)和安全性。在2023年1月至2024年6月期间,22名患者入组该研究。在20例疗效分析中,中位PFS为2.35个月(95% CI: 1.91-3.94),中位OS为6.34个月(95% CI: 3.81-10.09)。ORR和DCR分别为20%(4/20,全部部分缓解)和30%(6/20)。所有患者均出现治疗紧急不良事件(teae),其中贫血(59.1%)、中性粒细胞减少(54.6%)、白细胞减少(50.0%)和淋巴细胞减少(45.5%)是最常见的不良事件。50.0%(11/22)患者出现≥3级teae,包括中性粒细胞减少症(31.8%)、淋巴细胞减少症(13.6%)和贫血(9.1%)。亚组分析发现,转移灶涉及>2器官或肝脏部位是疗效较差的潜在预测生物标志物。蛋白质组学筛查显示,OCIAD2过表达与预后不良相关,这一发现在两个公开的外部队列(CPTAC数据库和瑞金队列)中得到了验证。TAS-102联合舒法替尼作为晚期mPC的治疗选择,具有临床意义的疗效和可控的毒性。本研究中发现的生物标志物可能具有指导患者分层的潜力,并值得进一步研究以优化该方案的精确应用。本研究已于2022年8月1日在clinicaltrials.gov前瞻性注册,注册号为NCT05481463。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
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