Combination therapy has become a cornerstone in cancer treatment to potentiate therapeutic effectiveness and overcome drug resistance and metastasis. In this work, we explore combination trials in breast cancer brain metastasis (BCBM), highlighting deficiencies in trial design and underlining promising combination strategies. On October 31, 2019, we examined ClinicalTrials.gov for interventional and therapeutic clinical trials involving combination therapy for BCBM, without limiting for date or location. Information on trial characteristics was collected. Combination therapies used in trials were analyzed and explored in line with evidence from the medical literature. Sixty‐five combination therapy trials were selected (n = 65), constituting less than 0.7% of all breast cancer trials. Most trials (62%) combined ≥2 chemotherapeutic agents. Chemotherapy with radiation was main‐stay in 23% of trials. Trastuzumab was mostly used in combination (31%), followed by lapatinib (20%) and capecitabine (15%). Common strategies involved combining tyrosine kinase inhibitors with thymidylate synthase inhibitors (6 trials), dual HER‐dimerization inhibitors (3 trials), microtubule inhibitors and tyrosine kinase inhibitors (3 trials), and HER‐dimerization inhibitors and tyrosine kinase inhibitors (3 trials). The combination of tucatinib and capecitabine yielded the highest objective response rate (83%) in early phase trials. The triple combination of trastuzumab, tucatinib and capecitabine lowered the risk of disease progression or death by 52% in patients with HER2‐positive BCBM. Combining therapeutic agents based on biological mechanisms is necessary to increase the effectiveness of available anti‐cancer regimens. Significant survival benefit has yet to be achieved in future combination therapy trials. Enhancing drug delivery through blood–brain barrier permeable agents may potentiate the overall therapeutic outcomes.

中文翻译：

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乳腺癌脑转移联合治疗试验的概况。

联合治疗已成为癌症治疗的基石，可增强治疗效果并克服耐药性和转移。在这项工作中，我们探索了乳腺癌脑转移（BCBM）的联合试验，强调了试验设计的缺陷并强调了有前途的联合策略。2019 年 10 月 31 日，我们检查了 ClinicalTrials.gov 上涉及 BCBM 联合治疗的介入和治疗性临床试验，不限制日期或地点。收集有关试验特征的信息。根据医学文献的证据对试验中使用的联合疗法进行了分析和探索。选择了 65 项联合治疗试验（n = 65），占所有乳腺癌试验的不到 0.7%。大多数试验 (62%) 联合使用 ≥2 种化疗药物。在 23% 的试验中，化疗加放疗是主要疗法。曲妥珠单抗主要联合使用（31%），其次是拉帕替尼（20%）和卡培他滨（15%）。常见策略包括联合使用酪氨酸激酶抑制剂与胸苷酸合酶抑制剂（6 项试验）、双 HER-二聚化抑制剂（3 项试验）、微管抑制剂和酪氨酸激酶抑制剂（3 项试验）以及 HER-二聚化抑制剂和酪氨酸激酶抑制剂（3 项试验） 。图卡替尼和卡培他滨的组合在早期试验中产生了最高的客观缓解率 (83%)。曲妥珠单抗、图卡替尼和卡培他滨的三联疗法将 HER2 阳性 BCBM 患者的疾病进展或死亡风险降低了 52%。为了提高现有抗癌方案的有效性，有必要结合基于生物机制的治疗药物。未来的联合治疗试验尚未实现显着的生存获益。通过血脑屏障渗透剂增强药物输送可能会增强整体治疗效果。