*僅供醫學專業人士閱讀參考
撥雲見日，一文了解抗體藥物偶聯物（ADC）在肺癌腦轉移治療領域的研究進展。
肺癌腦轉移是導致患者死亡的重要原因，儘管近20年靶向治療或免疫療法的出現為肺癌腦轉移患者帶來了療效提升，但仍面臨耐藥後後續治療選擇有限的難題。近年來，ADC作為一種新型治療手段，憑藉其精準靶向和強大殺傷力，逐漸展現出治療優勢，有望改善肺癌腦轉移患者的預後。近期發表在Translational Lung Cancer Research雜誌上的一篇敘述性綜述彙總了ADC藥物在肺癌腦轉移治療領域的最新研究進展[1]，為ADC藥物在肺癌腦轉移臨床實踐中提供了重要醫學參考。現攫取重要內容如下，以饗讀者。
肺癌腦轉移的治療現狀——機遇與挑戰並存
肺癌是全球常見惡性之一 [2] ，約 20%的非小細胞肺癌（NSCLC）患者初診時伴有腦轉移 [3] ， 20%~65%患者在疾病過程中發生腦轉移 [4] 。小細胞肺癌 (SCLC)患者首次就診時腦轉移的發生率為10%，診療過程中為40%～50% [5-7] 。 EGFR基因突變是NSCLC最常見的驅動基因 突變型別 ，突變患者的 3年累積 腦轉移率為 29.4%~60.3% [8] ； HER2突變患者治療中腦轉移發生率更高，且治療選擇有限 [9] 。
肺癌腦轉移治療主要受限於血腦屏障(BBB)的阻礙。BBB可作為物理屏障調控大多數分子運輸，阻止有害物質進入中樞神經系統（CNS），大多數大分子化療藥和靶向藥物難以穿透。腦轉移患者中，BBB被破壞形成血腫瘤屏障（BTB），其通透性增加，使得某些大分子藥物能夠透過BTB[10]，如果該藥物不是內皮細胞上外排轉運蛋白底物，則有利於藥物在顱內的蓄積。
當前治療策略主要包括系統性治療與區域性治療。系統治療中，化療藥物對顱內轉移灶的療效受限[11]。靶向治療在EGFR、ALK等驅動基因陽性NSCLC腦轉移中取得進展，但患者仍面臨腦轉移復發風險。免疫檢查點抑制劑（ICIs）治療在驅動基因陰性NSCLC腦轉移患者中顯示出一定療效。抗血管生成藥物透過靶向VEGF或其受體，抑制血管生成，不依賴於透過BBB/BTB[12]，並與化療聯合使用可預防腦轉移的發生。區域性治療如放療和手術主要用於區域性控制和緩解顱內症狀，但受多種因素限制。因此，在以上治療手段“乏力”的情況下，大分子藥物ADC藥物可結合靶向治療的精準性和化療的強效性，在腦轉移治療中展現出潛力，為肺癌腦轉移治療提供了新方向。
一些ADC藥物發揮優異顱內療效與獨特的藥物結構有關
傳統大分子藥物因通透性差，難以穿透BBB/BTB發揮顱內抗腫瘤活性。但研究表明，HER2陽性乳腺癌患者腦轉移灶中放射性標記的抗HER2單克隆抗體（如曲妥珠單抗）的攝取增加 [13] ，這表明大分子可能透過受損的BBB獲得進入CNS的途徑。在HER2陽性乳腺癌PDX模型中，T-DXd為HER2陽性或低表達腦轉移患者提供了臨床前證據，並對T-DM1耐藥者仍有效 [14] 。研究還發現，TROP2 ADC藥物Dato-DXd能顯著提高腦腫瘤組織滲透深度，優於非靶向對照ADC，表明其能有效穿透BBB [15] 。ADC藥物由單克隆抗體、細胞毒性藥物和連線子組成，透過靶向、內化和藥物釋放實現精準治療 [16] ，T-DXd的藥物設計對其顱內抗腫瘤活性至關重要 [17] ，可能主要因為以下4點：
圖1. ADC藥物透過BTB，具有強效載藥且DAR值更高的的藥物對腦轉移灶療效更好[17]
圖2. 臨床前研究顯示，相較於非均一ADC，DAR均一的ADC更容易入腦，在腦部分佈更多，抗腫瘤作用也就更強，小鼠的總生存時間越長[18]
T-DXd引入強效拓撲異構酶I抑制劑DXd作為載藥，並透過可切割的四肽連線子釋放載藥，載藥能夠有效抑制腫瘤細胞。
最佳化的偶聯技術使其均一性良好，顯著提高了穿透BBB/BTB的能力，便於進入CNS。
T-DXd載藥不是細胞膜上ABC(ATP-binding cassette)轉運蛋白的有效底物[19]，利於載藥在腫瘤細胞內保持較高濃度，增強顱內抗腫瘤活性。
T-DXd還可透過旁觀者效應在腫瘤細胞間擴散，對低表達或不表達靶抗原的細胞也具有療效[20]。
總之，透過高活性載藥、藥物的均一性，以及非ABC轉運蛋白底物以及強效的旁觀者效應，新一代ADC藥物在腦轉移治療中展現出治療潛力。
ADC藥物在腦轉移治療領域嶄露頭角，為患者帶來新的選擇
近年來，ADC藥物在腦轉移治療中取得顯著進展，T-DXd憑藉更高的DAR和旁觀者效應展現出強效抗腫瘤活性。 薈萃分析證實其在穩定性腦轉移患者中具有良好的顱內療效 [21] 。 DESTINY-Breast03研究結果顯示，T-DXd組相較於T-DM1穩定性腦轉移患者的中位PFS延長了12個月（15.0個月 vs 3.0個月），T-DXd組的ORR為67.4%，而T-DM1組的ORR僅為20.5% [22] ，這一結果進一步凸顯了T-DXd相比於T-DM1在顱內療效上的優勢。 除乳腺癌外，針對HER2、HER3、TROP2和細胞間充質上皮轉化因子（c-MET）等靶點的ADC藥物在肺癌腦轉移治療中也顯示出廣闊前景。
表1. ADC藥物在乳腺癌腦轉移患者中的研究進展[22-30]
（非頭對頭研究結果，資料請勿直接對比）
T-DXd打破肺癌腦轉移患者治療困境，成為新的治療選擇
II期DESTINY-Lung01研究納入33例無症狀腦轉移HER2突變NSCLC患者，T-DXd在腦轉移患者中的ORR為54.5%，與無腦轉移患者的ORR（55.2%）相當[31]，提供了T-DXd治療HER2突變NSCLC腦轉移的循證證據。DESTINY-Lung02研究顯示，T-DXd 5.4 mg/kg和6.4 mg/kg在HER2突變晚期NSCLC患者中均表現出良好療效，無論腦轉移情況或既往治療史如何[32,33]。
2023年歐洲腫瘤內科學會（ESMO）大會公佈的DESTINY-Lung01和DESTINY-Lung02研究的彙總分析顯示[34]，T-DXd對伴或不伴腦轉移的患者均有顯著療效，5.4 mg/kg組腦轉移患者的cORR為46.9%，DCR為90.6%；6.4 mg/kg組療效與5.4 mg/kg組相似。在顱內療效方面，5.4 mg/kg組的顱內cORR為50%，並有3例達完全緩解（CR）。
表2. DESTINY-Lung01和DESTINY-Lung02研究彙總分析中兩組的療效及安全性資料
T-DXd不僅在HER2突變晚期NSCLC患者有著良好的療效，而且逐漸把獲益人群擴充套件至HER2過表達NSCLC。DESTINY-Lung03研究表明，T-DXd對HER2過表達NSCLC患者展現出療效[35]，對HER2過表達NSCLC腦轉移患者可能也有療效，待進一步資料結果。
HER3-DXd展現出優異顱內療效，或可為EGFR突變NSCLC腦轉移患者帶來新選擇
U31402-A-U102研究納入52例鉑類化療經治患者，結果顯示，HER3-DXd在有腦轉移病史的患者（n=25）中的ORR達32%，而無腦轉移病史的患者（n=27）的ORR為41%[36,37]。HERTHENA-Lung01研究納入115例有腦轉移病史的EGFR突變NSCLC患者，HER3-DXd在腦轉移患者中的cORR為28.7%，DCR達70.4%，中位持續緩解時間（DoR）達5.5個月。在30名未接受過腦轉移治療的EGFR突變NSCLC患者中，HER3-DXd顱內cORR達33.3%，包括9例CR和1例PR，中位CNS-DoR為8.4個月[38,39]。這些結果進一步證明了HER3-DXd對EGFR突變NSCLC腦轉移的強效顱內抗腫瘤活性。此外，一項正在進行的臨床試驗（NCT05865990）正在探究HER3-DXd在治療乳腺癌或NSCLC腦膜轉移方面的潛力。
圖3. HERTHENA-Lung01研究中腦轉移亞組的療效結果
其他ADC藥物也為肺癌腦轉移患者帶來新的治療希望
TROPION-Lung系列研究及其他臨床試驗分別證實了靶向TROP2的ADC藥物Dato-DXd與靶向EGFR和HER3的雙特異性ADC藥物BL-B01D1在NSCLC腦轉移患者中的治療潛力[40-45]，值得進一步探索，或可為NSCLC腦轉移患者提供新的治療選擇。
總結與展望
總之，肺癌腦轉移是導致患者死亡的重要原因，靶向和免疫等為肺癌腦轉移患者帶來了療效提升，但仍面臨耐藥後續治療選擇有限的難題。近年來，ADC藥物憑藉其精準靶向和強大殺傷力，展現出治療優勢，為突破腦轉移困境提供了新可能。展望未來，放療是腦轉移區域性治療的有效方式，ADC藥物與放療的聯合將是值得探索的方向，與放療聯合的安全性和時機都值得深入研究；隨著技術的不斷進步和研究的深入，相信ADC藥物不斷最佳化，在肺癌腦轉移治療中的應用將更加廣泛和深入；以及尋找可靠的生物標誌物來預測治療反應，也將是未來研究的重點。這些研究方向有望進一步拓展ADC藥物在肺癌腦轉移治療中的應用，為患者帶來更長的生存期和更高的生活質量。
精彩資訊等你來
參考文獻：
[1]Zhou H, Zeng Y, Hida T, et al. The current landscape and prospects of antibody-drug conjugates for lung cancer brain metastases: a narrative review. Transl Lung Cancer Res 2024;13(12):3778-3794.
[2]Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 Apr 4.
[3]Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Curr Oncol Rep. 2012 Feb;14(1):48-54.
[4]Vogelbaum MA, Brown PD, Messersmith H, et al. Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline. J Clin Oncol 2022;40:492-516.
[5]Goncalves PH, Peterson SL, Vigneau FD, et al. Risk of brain metastases in patients with nonmetastatic lung cancer: Analysis of the Metropolitan Detroit Surveillance, Epidemiology, and End Results (SEER) data. Cancer 2016;122:1921-7.
[6]Murray N, Sheehan F. Limited stage small cell lung cancer. Curr Treat Options Oncol 2001;2:63-70.
[7]中國醫師協會腫瘤醫師分會, 中國醫療保健國際交流促進會腫瘤內科分會. 肺癌腦轉移中國治療指南(2021年版)[J]. 中華腫瘤雜誌, 2021, 43(3):269-281.
[8]Zhao W, Zhou W, Rong L, et al. Epidermal grow th factor receptor mutations and brain metastases in non-small cell lung cancer. Front Oncol, 2022, 12: 912505.
[9]Offin M, Feldman D, Ni A, et al. Frequency and outcomes of brain metastases in patients with HER2-mutant lung cancers. Cancer. 2019 Dec 15;125(24):4380-4387.
[10]Steeg PS. The blood-tumour barrier in cancer biology and therapy. Nat Rev Clin Oncol 2021;18:696-714.
[11]Arvanitis CD, Ferraro GB, Jain RK. The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. Nat Rev Cancer 2020;20:26-41.
[12]Buttigliero C, Bertaglia V, Novello S. Anti-angiogenetic therapies for central nervous system metastases from non-small cell lung cancer. Transl Lung Cancer Res 2016;5:610-27.
[13]St-Amour I, Paré I, Alata W, et al. Brain bioavailability of human intravenous immunoglobulin and its transport through the murine blood-brain barrier. J Cereb Blood Flow Metab 2013;33:1983-92.
[14]Kabraji S, Ni J, Sammons S, et al. Preclinical and Clinical Efficacy of Trastuzumab Deruxtecan in Breast Cancer Brain Metastases. Clin Cancer Res 2023;29:174-82.
[15]Jones KJ, Suksomboon M. Abstract 1911: Dato-DXd mediates anti-tumor activity in preclinical TROP2-expressing intracranial tumor model. Cancer Res 2024;84:1911.
[16]Hoffmann RM, Coumbe BGT, Josephs DH, et al. Antibody structure and engineering considerations for the design and function of Antibody Drug Conjugates (ADCs). Oncoimmunology 2018;7:e1395127.
[17]Mair MJ, Bartsch R, Le Rhun E, et al. Understanding the activity of antibody-drug conjugates in primary and secondary brain tumours. Nat Rev Clin Oncol 2023;20:372-89.
[18]Anami Y, Otani Y, Xiong W, et al. Homogeneity of antibody-drug conjugates critically impacts the therapeutic efficacy in brain tumors. Cell Rep. 2022 May 24;39(8):110839.
[19]Ogitani Y, Aida T, Hagihara K, et al. DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1. Clin Cancer Res 2016;22:5097-108.
[20]Tarantino P, Carmagnani Pestana R, Corti C, et al. Antibody-drug conjugates: Smart chemotherapy delivery across tumor histologies. CA Cancer J Clin 2022;72:165-82.
[21]Jerusalem G, Park YH, Yamashita T, et al. Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases: A DESTINY-Breast01 Subgroup Analysis. Cancer Discov 2022;12:2754-62.
[22]Hurvitz SA, Kim SB, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial. ESMO Open. 2024;9(5):102924.
[23]Bartsch R, Berghoff AS, Furtner J, et al. Final outcome analysis from the phase II TUXEDO-1 trial of trastuzumab-deruxtecan in HER2-positive breast cancer patients with active brain metastases. Neuro Oncol. 2024;26(12):2305-2315.
[24]Montemurro F, Delaloge S, Barrios CH, et al. Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial☆. Ann Oncol. 2020;31(10):1350-1358.
[25]Modi S, Saura C, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2020;382(7):610-621.
[26]André F, Cortés J, Curigliano G, et al. A pooled analysis of trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer with brain metastases. Ann Oncol. 2024;35(12):1169-1180.
[27]Effects of trastuzumab deruxtecan on health-related quality of life & neurological function in patients HER2+ advanced/metastatic breast cancer with or without brain metastases: DESTINY-Breast12 results. 2024 SABCS. PS14-10.
[28]Bartsch R, Berghoff AS, Furtner J, et al. FINAL outcome ANALYSIS FROM THE PHASE II TUXEDO-1 TRIAL OF TRASTUZUMAB-DERUXTECAN IN HER2-positive breast cancer PATIENTS WITH active brain metastases. Neuro Oncol. Published online July 4, 2024.
[29]Pérez-García JM, Batista MV, Cortez P, et al. Trastuzumab Deruxtecan in Patients with Central Nervous System Involvement from HER2-Positive Breast Cancer: The DEBBRAH Trial. Neuro Oncol. 2022 May 26:noac144.
[30]Nakayama T, Niikura N, Yamanaka T, et al. Trastuzumab deruxtecan for the treatment of patients with HER2-positive breast cancer with brain and/or leptomeningeal metastases: an updated overall survival analysis using data from a multicenter retrospective study (ROSET-BM). Breast Cancer. 2024 Nov;31(6):1184.
[31]Li BT, Smit EF, Goto Y, et al. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer. N Engl J Med. 2022 Jan 20;386(3):241-251.
[32]Goto K, Goto Y, Kubo T, et al. Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non-Small-Cell Lung Cancer: Primary Results From the Randomized, Phase II DESTINY-Lung02 Trial. J Clin Oncol. 2023 Nov 1;41(31):4852-4863.
[33]Pasi J, Yasushi G, Toshio K, et al. Trastuzumab deruxtecan (T-DXd) in patients with HER2-mutant metastatic non–small cell lung cancer (mNSCLC): Final analysis results of DESTINY-Lung02. 2024 ASCO. Abstract 8543.
[34]Li BT, Planchard D, Goto K, et al. Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2 (ERBB2)-mutant (HER2m) metastatic nonesmall cell lung cancer (NSCLC) with and without brain metastases (BMs): Pooled analyses from DESTINY-Lung01 and DESTINY-Lung02. 2023 ESMO 1321MO.
[35]Planchard D, Kim HR, Suksombooncharoen T, et al. Trastuzumab Deruxtecan Monotherapy in Pretreated HER2-overexpressing Nonsquamous Non-Small Cell Lung Cancer: DESTINY-Lung03 Part 1.2024 WCLC. OA16.05.
[36]Hidetoshi Hayashi, Helena A. Yu, Christina Baik, et al. First Report of Cohort 3 and Mature Survival Data From the U31402-A-U102 Study of HER3‑DXd in EGFR-Mutated NSCLC. 2023 JSMO. Abs PS1-2.
[37]Yu HA, Baik C, Kim DW, et al. Translational insights and overall survival in the U31402-A-U102 study of patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC. Ann Oncol. 2024 May;35(5):437-447.
[38]Yu HA,Goto Y, Hayashi H, et al. Patritumab Deruxtecan (HER3-DXd) in EGFR-Mutated NSCLC Following EGFRTKI and Platinum-Based Chemotherapy: HERTHENA-Lung01. 2023 WCLC. OA05.03.
[39]Yu HA, Goto Y, Hayashi H, et al. HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy. J Clin Oncol. 2023 Dec 10;41(35):5363-5375.
[40]Girard N, Okamoto I, Lisberg A, et al. Datopotamab Deruxtecan (Dato-DXd) in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer (NSCLC) - Nonsquamous (NSQ) Histology in the Phase 3 TROPION-Lung01 Trial. 2024 ELCC. 59P.
[41]Ahn MJ, Lisberg A, Paz-Ares L, et al. Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): Results of the randomized phase 3 study TROPION-Lung01. 2023 ESMO Asia. 509MO.
[42]Ahn MJ, Tanaka K, Paz-Ares L, et al. Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study. J Clin Oncol. 2024 Sep 9:JCO2401544.
[43]Sands J, Lisberg A, Okamoto I. et al. Datopotamab Deruxtecan Vs Docetaxel in Patients with Non-Small Cell Lung Cancer: Final Overall Survival from TROPION-Lung01. 2024 WCLC. OA08.03.
[44]Lisberg A, Ahn M, Kitazono S, et al. Intracranial efficacy of datopotamab deruxtecan (Dato-DXd) in patients (pts) with previously treated advanced/metastatic non-small cell lung cancer (a/m NSCLC) with actionable genomic alterations (AGA): Results from TROPION-Lung05. 2024 ASCO. Poster 457.
[45]Zhang L, Ma Y, Zhao Y, et al. BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic solid tumor: Results from a first-in-human phase 1 study. J Clin Oncol 2023;41:3001.
*此文僅用於向醫療衛生專業人士提供科學資訊，不代表平臺立場。
