*仅供医学专业人士阅读参考
拨云见日，一文了解抗体药物偶联物（ADC）在肺癌脑转移治疗领域的研究进展。
肺癌脑转移是导致患者死亡的重要原因，尽管近20年靶向治疗或免疫疗法的出现为肺癌脑转移患者带来了疗效提升，但仍面临耐药后后续治疗选择有限的难题。近年来，ADC作为一种新型治疗手段，凭借其精准靶向和强大杀伤力，逐渐展现出治疗优势，有望改善肺癌脑转移患者的预后。近期发表在Translational Lung Cancer Research杂志上的一篇叙述性综述汇总了ADC药物在肺癌脑转移治疗领域的最新研究进展[1]，为ADC药物在肺癌脑转移临床实践中提供了重要医学参考。现攫取重要内容如下，以飨读者。
肺癌脑转移的治疗现状——机遇与挑战并存
肺癌是全球常见恶性肿瘤之一 [2] ，约 20%的非小细胞肺癌（NSCLC）患者初诊时伴有脑转移 [3] ， 20%~65%患者在疾病过程中发生脑转移 [4] 。小细胞肺癌 (SCLC)患者首次就诊时脑转移的发生率为10%，诊疗过程中为40%～50% [5-7] 。 EGFR基因突变是NSCLC最常见的驱动基因 突变类型 ，突变患者的 3年累积 脑转移率为 29.4%~60.3% [8] ； HER2突变患者治疗中脑转移发生率更高，且治疗选择有限 [9] 。
肺癌脑转移治疗主要受限于血脑屏障(BBB)的阻碍。BBB可作为物理屏障调控大多数分子运输，阻止有害物质进入中枢神经系统（CNS），大多数大分子化疗药和靶向药物难以穿透。脑转移患者中，BBB被破坏形成血肿瘤屏障（BTB），其通透性增加，使得某些大分子药物能够透过BTB[10]，如果该药物不是内皮细胞上外排转运蛋白底物，则有利于药物在颅内的蓄积。
当前治疗策略主要包括系统性治疗与局部治疗。系统治疗中，化疗药物对颅内转移灶的疗效受限[11]。靶向治疗在EGFR、ALK等驱动基因阳性NSCLC脑转移中取得进展，但患者仍面临脑转移复发风险。免疫检查点抑制剂（ICIs）治疗在驱动基因阴性NSCLC脑转移患者中显示出一定疗效。抗血管生成药物通过靶向VEGF或其受体，抑制血管生成，不依赖于透过BBB/BTB[12]，并与化疗联合使用可预防脑转移的发生。局部治疗如放疗和手术主要用于局部控制和缓解颅内症状，但受多种因素限制。因此，在以上治疗手段“乏力”的情况下，大分子药物ADC药物可结合靶向治疗的精准性和化疗的强效性，在脑转移治疗中展现出潜力，为肺癌脑转移治疗提供了新方向。
一些ADC药物发挥优异颅内疗效与独特的药物结构有关
传统大分子药物因通透性差，难以穿透BBB/BTB发挥颅内抗肿瘤活性。但研究表明，HER2阳性乳腺癌患者脑转移灶中放射性标记的抗HER2单克隆抗体（如曲妥珠单抗）的摄取增加 [13] ，这表明大分子可能通过受损的BBB获得进入CNS的途径。在HER2阳性乳腺癌PDX模型中，T-DXd为HER2阳性或低表达脑转移患者提供了临床前证据，并对T-DM1耐药者仍有效 [14] 。研究还发现，TROP2 ADC药物Dato-DXd能显著提高脑肿瘤组织渗透深度，优于非靶向对照ADC，表明其能有效穿透BBB [15] 。ADC药物由单克隆抗体、细胞毒性药物和连接子组成，通过靶向、内化和药物释放实现精准治疗 [16] ，T-DXd的药物设计对其颅内抗肿瘤活性至关重要 [17] ，可能主要因为以下4点：
图1. ADC药物透过BTB，具有强效载药且DAR值更高的的药物对脑转移灶疗效更好[17]
图2. 临床前研究显示，相较于非均一ADC，DAR均一的ADC更容易入脑，在脑部分布更多，抗肿瘤作用也就更强，小鼠的总生存时间越长[18]
T-DXd引入强效拓扑异构酶I抑制剂DXd作为载药，并通过可切割的四肽连接子释放载药，载药能够有效抑制肿瘤细胞。
优化的偶联技术使其均一性良好，显著提高了穿透BBB/BTB的能力，便于进入CNS。
T-DXd载药不是细胞膜上ABC(ATP-binding cassette)转运蛋白的有效底物[19]，利于载药在肿瘤细胞内保持较高浓度，增强颅内抗肿瘤活性。
T-DXd还可通过旁观者效应在肿瘤细胞间扩散，对低表达或不表达靶抗原的细胞也具有疗效[20]。
总之，通过高活性载药、药物的均一性，以及非ABC转运蛋白底物以及强效的旁观者效应，新一代ADC药物在脑转移治疗中展现出治疗潜力。
ADC药物在脑转移治疗领域崭露头角，为患者带来新的选择
近年来，ADC药物在脑转移治疗中取得显著进展，T-DXd凭借更高的DAR和旁观者效应展现出强效抗肿瘤活性。 荟萃分析证实其在稳定性脑转移患者中具有良好的颅内疗效 [21] 。 DESTINY-Breast03研究结果显示，T-DXd组相较于T-DM1稳定性脑转移患者的中位PFS延长了12个月（15.0个月 vs 3.0个月），T-DXd组的ORR为67.4%，而T-DM1组的ORR仅为20.5% [22] ，这一结果进一步凸显了T-DXd相比于T-DM1在颅内疗效上的优势。 除乳腺癌外，针对HER2、HER3、TROP2和细胞间充质上皮转化因子（c-MET）等靶点的ADC药物在肺癌脑转移治疗中也显示出广阔前景。
表1. ADC药物在乳腺癌脑转移患者中的研究进展[22-30]
（非头对头研究结果，数据请勿直接对比）
T-DXd打破肺癌脑转移患者治疗困境，成为新的治疗选择
II期DESTINY-Lung01研究纳入33例无症状脑转移HER2突变NSCLC患者，T-DXd在脑转移患者中的ORR为54.5%，与无脑转移患者的ORR（55.2%）相当[31]，提供了T-DXd治疗HER2突变NSCLC脑转移的循证证据。DESTINY-Lung02研究显示，T-DXd 5.4 mg/kg和6.4 mg/kg在HER2突变晚期NSCLC患者中均表现出良好疗效，无论脑转移情况或既往治疗史如何[32,33]。
2023年欧洲肿瘤内科学会（ESMO）大会公布的DESTINY-Lung01和DESTINY-Lung02研究的汇总分析显示[34]，T-DXd对伴或不伴脑转移的患者均有显著疗效，5.4 mg/kg组脑转移患者的cORR为46.9%，DCR为90.6%；6.4 mg/kg组疗效与5.4 mg/kg组相似。在颅内疗效方面，5.4 mg/kg组的颅内cORR为50%，并有3例达完全缓解（CR）。
表2. DESTINY-Lung01和DESTINY-Lung02研究汇总分析中两组的疗效及安全性数据
T-DXd不仅在HER2突变晚期NSCLC患者有着良好的疗效，而且逐渐把获益人群扩展至HER2过表达NSCLC。DESTINY-Lung03研究表明，T-DXd对HER2过表达NSCLC患者展现出疗效[35]，对HER2过表达NSCLC脑转移患者可能也有疗效，待进一步数据结果。
HER3-DXd展现出优异颅内疗效，或可为EGFR突变NSCLC脑转移患者带来新选择
U31402-A-U102研究纳入52例铂类化疗经治患者，结果显示，HER3-DXd在有脑转移病史的患者（n=25）中的ORR达32%，而无脑转移病史的患者（n=27）的ORR为41%[36,37]。HERTHENA-Lung01研究纳入115例有脑转移病史的EGFR突变NSCLC患者，HER3-DXd在脑转移患者中的cORR为28.7%，DCR达70.4%，中位持续缓解时间（DoR）达5.5个月。在30名未接受过脑转移治疗的EGFR突变NSCLC患者中，HER3-DXd颅内cORR达33.3%，包括9例CR和1例PR，中位CNS-DoR为8.4个月[38,39]。这些结果进一步证明了HER3-DXd对EGFR突变NSCLC脑转移的强效颅内抗肿瘤活性。此外，一项正在进行的临床试验（NCT05865990）正在探究HER3-DXd在治疗乳腺癌或NSCLC脑膜转移方面的潜力。
图3. HERTHENA-Lung01研究中脑转移亚组的疗效结果
其他ADC药物也为肺癌脑转移患者带来新的治疗希望
TROPION-Lung系列研究及其他临床试验分别证实了靶向TROP2的ADC药物Dato-DXd与靶向EGFR和HER3的双特异性ADC药物BL-B01D1在NSCLC脑转移患者中的治疗潜力[40-45]，值得进一步探索，或可为NSCLC脑转移患者提供新的治疗选择。
总结与展望
总之，肺癌脑转移是导致患者死亡的重要原因，靶向和免疫等为肺癌脑转移患者带来了疗效提升，但仍面临耐药后续治疗选择有限的难题。近年来，ADC药物凭借其精准靶向和强大杀伤力，展现出治疗优势，为突破脑转移困境提供了新可能。展望未来，放疗是脑转移局部治疗的有效方式，ADC药物与放疗的联合将是值得探索的方向，与放疗联合的安全性和时机都值得深入研究；随着技术的不断进步和研究的深入，相信ADC药物不断优化，在肺癌脑转移治疗中的应用将更加广泛和深入；以及寻找可靠的生物标志物来预测治疗反应，也将是未来研究的重点。这些研究方向有望进一步拓展ADC药物在肺癌脑转移治疗中的应用，为患者带来更长的生存期和更高的生活质量。
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*此文仅用于向医疗卫生专业人士提供科学信息，不代表平台立场。
