Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL.
High Impact Cancer Research Program, Harvard Medical School, Boston, MA.
Int J Cancer. 2020 Oct 1;147(7):1939-1952. doi: 10.1002/ijc.32937. Epub 2020 Mar 9.
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.
联合治疗已成为癌症治疗的基石，以增强治疗效果并克服耐药性和转移。在这项工作中，我们探讨了乳腺癌脑转移（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，我们在 ClinicalTrials.gov 上检查了涉及 BCBM 联合治疗的干预和治疗性临床试验，没有限制日期或地点。收集了有关试验特征的信息。分析了试验中使用的联合疗法，并根据医学文献中的证据进行了探讨。选择了 65 项联合治疗试验（n=65），占所有乳腺癌试验的比例不足 0.7%。大多数试验（62%）联合使用≥2 种化疗药物。23%的试验以化疗加放疗为主。曲妥珠单抗是最常用的联合药物（31%），其次是拉帕替尼（20%）和卡培他滨（15%）。常见的策略包括将酪氨酸激酶抑制剂与胸苷酸合成酶抑制剂联合使用（6 项试验）、双重 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联合使用（3 项试验），以及 HER 二聚化抑制剂和酪氨酸激酶抑制剂联合使用（3 项试验）。早期试验中，tucatinib 和卡培他滨联合治疗的客观缓解率最高（83%）。曲妥珠单抗、tucatinib 和卡培他滨三联治疗可使 HER2 阳性 BCBM 患者疾病进展或死亡的风险降低 52%。基于生物学机制联合治疗药物对于提高现有抗癌方案的有效性是必要的。未来的联合治疗试验尚未取得显著的生存获益。通过血脑屏障通透性药物增强药物输送可能会增强整体治疗效果。
