一级预防又称初级预防，就是在问题尚未发生之前采取措施，减少问题的发生。从某种意义讲，一级预防是真正的预防，是最积极、最主动的预防。近年来，抗体缀合药物将若干小分子化疗药物缀合于大分子单克隆抗体，兼具化疗药物强大杀伤力和靶向药物高度针对性，已对乳腺癌显示出优异的疗效。不过，抗体缀合药物的疗效虽然令人鼓舞，但是仍然难以完全避免不良反应，造成减量甚至停药。因此，防患于未然、积极主动预防不良反应的发生，成为保证乳腺癌新药疗效的研究热点之一。
2025年6月18日，英国《柳叶刀》旗下《临床医学》在线发表西班牙医学科学创新研究中心牵头的PRIMED研究报告，初步探讨了HER2阴性晚期乳腺癌抗体缀合药物戈沙妥珠单抗相关中性粒细胞减少和腹泻的一级预防。
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NCT05520723: Preventive stRategy for IMMU132-relatED AEs in TNBC – PRIMED (PRIMED)
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Official Title: Multicenter, Open-label, Single Arm, Phase II Clinical Trial to Improve Sacituzumab Govitecan’s Tolerance in Patients With Metastatic Triple-Negative Breast Cancer.
该多中心单组二期临床研究于2023年2月至2023年9月从西班牙全国10家医院入组三阴性或者激素受体阳性HER2阴性晚期乳腺癌既往一至二线化疗失败（激素受体阳性晚期还用过CDK4/6抑制剂治疗）患者50例，给予戈沙妥珠单抗治疗直至疾病进展或者出现无法耐受的毒性。在前两个治疗周期第3、4、10、11天给予粒细胞集落刺激因子预防粒细胞减少，第2、3、4、9、10、11天给予洛哌丁胺预防腹泻，随后由医生酌情给予。主要终点为两个治疗周期后≥3级中性粒细胞减少发生率和≥2级腹泻发生率。次要终点包括疗效和长期安全性。
结果，截至2024年5月5日，中位随访9.0个月，范围0.2至13.5个月。在前两个治疗周期内，任何级别中性粒细胞减少和腹泻的发生率分别为28.0%和34.0%。≥3级中性粒细胞减少发生率仅16.0%，显著低于ASCENT和TROPiCS-02研究的50%（P=0.00023）。未出现中性粒细胞减少所致发热。≥2级腹泻发生率也是16.0%，低于ASCENT和TROPiCS-02研究的30%，虽然未达统计学显著性（P=0.084），但是发生风险降低47%具有临床意义。在前两个周期内，造成戈沙妥珠单抗减量的不良事件发生率为14.0%，也低于ASCENT和TROPiCS-02研究的20%至30%；造成暂时停药的不良事件发生率为30.0%，未造成永久停药。中位无进展生存6.24个月（三阴性6.37个月）优于ASCENT研究5.6个月（三阴性）以及TROPiCS-02研究5.5个月（激素受体阳性）。
因此，该研究结果表明，粒细胞集落刺激因子和洛哌丁胺一级预防给药，与历史数据相比，可以显著降低戈沙妥珠单抗相关中性粒细胞减少发生风险，有临床意义地降低腹泻发生风险和严重程度。毒性管理是抗体缀合药物发挥疗效的前提，一级预防策略可以将≥3级中性粒细胞减少发生风险降低60%，能够扫除抗体缀合药物临床应用的最大障碍。对于老年或多次化疗的患者，应该考虑粒细胞集落刺激因子一级预防；对于肠道功能基础较差经常腹泻的患者，应该考虑同步启用洛哌丁胺。此外，该研究脉冲式一级预防给药，而非首日或每日给药，可以精准对接抗体缀合药物毒性窗口期。保证剂量才能保证疗效，推动精准毒性防控，前两个治疗周期造成抗体缀合药物减量的不良事件发生率下降一半左右，更开创了抗体缀合药物毒性主动防控的新范式。根据复旦大学附属肿瘤医院邵志敏教授经常强调的药物毒性管理三部曲：预防→监测→干预，本研究初步探讨了关键的第一步，故有必要进一步开展大样本随机对照三期临床研究进行验证，并根据基因型与毒性关联探索个体化分层预防，以及肠道菌群调节增效的潜力，让更多患者对有效治疗药物持续获益。
EClinicalMedicine. 2025 Jun 18;85:103309. IF: 10.0
Prevention of sacituzumab govitecan-related neutropenia and diarrhea in patients with HER2-negative advanced breast cancer (PRIMED): an open-label, single-arm, phase 2 trial.
José Manuel Pérez-García, María Gion, Manuel Ruiz-Borrego, Isabel Blancas, Elena López-Miranda, Salvador Blanch, Sabela Recalde, Cristina Reboredo Rendo, Xavier González, Nerea Ancizar, Serafin Morales, Patricia Cortez, Zuzanna Piwowarska, Eileen Shimizu, José Antonio Guerrero, Miguel Sampayo-Cordero, Alejandro Martínez-Bueno, Javier Cortés, Antonio Llombart-Cussac.
Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain; International Breast Cancer Center (IBCC), Pangaea Group, Quiron Group, Barcelona, Spain; Hospital Universitario Ramón y Cajal, Madrid, Spain; IOB Madrid, Hospital Beata María Ana, Madrid, Spain; Hospital Universitario Virgen del Rocío, Sevilla, Spain; Hospital Universitario Clínico San Cecilio, Granada, Spain; Medicine Department, Granada University, Granada, Spain; Instituto de Investigación Biosanitaria de Granada, Granada, Spain; Instituto Valenciano de Oncología, Valencia, Spain; Institut Català d’Oncologia Hospitalet- Hospital Moises Broggi. Barcelona, Spain; Complejo Hospitalario Universitario A Coruna, Coruna, Spain; Institut Oncològic Dr. Rosell, Hospital General de Catalunya, Sant Cugat del Vallès, Spain; Hospital Universitario de Donostia, San Sebastián, Spain; Hospital Universitario de Arnau de Villanova de Lleida, Lleida, Spain; IOB Institute of Oncology, Hospital Ruber Internacional, Quiron Group, Madrid, Spain; Instituto Oncológico Dr. Rosell, Hospital Quiron Dexeus, Barcelona, Spain; Universidad Europea de Madrid, Madrid, Spain; Hospital Universitario Torrejón, Ribera Group, Madrid, Spain; Arnau de Vilanova, Valencia, Spain; Universidad Cardenal Herrera-CEU, Alfara del Patriarca, Spain; Medica Scientia Innovation Research (MEDSIR), Ridgewood, NJ, USA.
BACKGROUND: Neutropenia and diarrhea are common sacituzumab govitecan-related adverse events, frequently leading to treatment modifications. PRIMED evaluated primary prophylactic granulocyte colony-stimulating factor (G-CSF) and loperamide to improve sacituzumab govitecan tolerability.
METHODS: PRIMED (NCT05520723) was an open-label, single-arm, phase II study that enrolled HER2-negative advanced breast cancer patients previously treated with 1-2 chemotherapy regimens for metastatic disease. Patients with hormone receptor positive tumors previously received CDK4/6 inhibitor in the advanced setting. Sacituzumab govitecan was administered until disease progression or unacceptable toxicity. G-CSF (5 MU/kg/day) and loperamide (2 mg/twice a day or 4 mg/day) were given during the first two cycles and at physician’s discretion thereafter. Primary endpoints were (i) incidence of grade ≥3 neutropenia and (ii) incidence of grade ≥2 diarrhea, both assessed after two treatment cycles. Secondary endpoints included efficacy and extended safety.
FINDINGS: Between February 2023 and September 2023, 50 patients were enrolled. At data cut-off, median follow-up was 9.0 months (range, 0.2-13.5). Disease progression was the main reason for treatment discontinuation (33 patients, 66.0%). During the first two cycles, incidence of any grade neutropenia and diarrhea were 28.0% and 34.0%, respectively. Eight patients (16.0%) had ≥ grade 3 neutropenia, meeting this primary endpoint (p = 0.00023). No patients developed febrile neutropenia. Eight patients (16.0%) had ≥ grade 2 diarrhea (4.0% grade 3) (p = 0.084). The rate of adverse events associated with dose reductions and temporary treatment interruptions during the first two cycles was 14.0% and 30.0%, respectively.
INTERPRETATION: Primary prophylactic administration of G-CSF and loperamide resulted in a clinically relevant reduction of the incidence and severity of sacituzumab govitecan-related neutropenia and diarrhea.
FUNDING: Gilead Sciences, S.L.U.
KEYWORDS: Sacituzumab govitecan, Triple-negative, Hormone receptor-positive/HER2-negative, Neutropenia, Diarrhea, Advanced breast cancer
DOI: 10.1016/j.eclinm.2025.103309
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