放射性配体疗法在晚期恶性肿瘤中的应用现状及进展
作者简介:
邱大胜，男，博士，主任医师，主要从事肿瘤分子影像诊断及核素治疗，ORCID: 0000-0001-8200-6999
魏少忠: 湖北省肿瘤医院（华中科技大学同济医学院附属湖北肿瘤医院）院长、教授、博士生导师、主任医师；湖北省肿瘤医院结直肠癌、前列腺癌首席专家；湖北省癌症中心主任，湖北省肿瘤医学质控中心主任，湖北省结直肠癌临床医学研究中心主任。肿瘤外科专家。曾赴美国MD·Anderson癌症中心做访问学者，美国外科学院Fellowship，国家卫健委突出贡献中青年专家，湖北省医学领军人才。中华医学会肿瘤学分会常委；中国抗癌协会泌尿肿瘤专业委员会副主任委员、湖北省抗癌协会理事长。担任 《肿瘤防治研究》杂志主编及国内多家杂志编委。从事胃肠及泌尿男生殖系肿瘤临床和研究工作20余年。近年来，竭力推广肿瘤的多学科综合诊疗（MDT），为肿瘤的规范化诊疗做出了贡献。主持国家“863”研究项目、重大专项子课题、湖北省技术创新专项重大项目等其他各级科研项目共10余项；发表专业论文100余篇，SCI收录论文40余篇；主编专著10部；以第一完成人完成科技成果鉴定5项，其中2项达国际先进水平，并以第一完成人荣获湖北省科技进步二等奖、中国抗癌协会科技奖二等奖各1项
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通讯作者:
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摘要:
1946年，放射性碘131被报道首次用于治疗分化型甲状腺癌。然而，鉴于早期核药技术的限制以及缺乏特异性，核素治疗的疗效及不良反应限制了其在临床的广泛使用。近年来科学家和临床医生通过将放射性同位素与靶向部分（如肿瘤特异性小分子、肽或抗体）联系起来，努力开发更安全、更有效的核药。随着镭-223、Lutathera（镥-177）和Pluvicto（177Lu-PSMA-617）相继进入临床。放射性配体疗法逐渐在不同肿瘤中展现出较好疗效。本文聚焦治疗性放射性配体药物在晚期恶性肿瘤应用现状及最新的研究成果和治疗策略，助力实现更精准、个性化的治疗方式，从而提高疗效和减轻不良反应。
Abstract:In 1946, radioactive iodine 131 was first used for the treatment of differentiated thyroid cancer. However, the limitations of early nuclear medicine technology, the lack of specificity, the efficacy of nuclide therapy, and its adverse effects have limited its widespreadly clinical application. In recent years, scientists and clinicians have linked radioisotopes to targeted parts (tumor-specific small molecules, peptides, or antibodies) to develop safe and effective nuclear drugs. Ra-223, Lutathera (lutetium-177), and Pluvicto (177Lu-PSMA-617) have been successfully used in clinical treatment. Radioligand therapy has gradually shown good efficacy in different tumors. This paper focuses on the current situation of the application of therapeutic radioligand drugs in advanced malignant tumors and the latest research results and treatment strategies to achieve more accurate and personalized treatment methods, thereby to improve the curative effect, and reduce adverse reactions.
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Key words:
- Radioligand therapy /
- Malignancy /
- Advanced
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0 引言
近年来，肿瘤治疗方式随着科学技术的进步而快速发展，其中，放射性配体疗法（Radioligand therapy, RLT）是目前快速发展的治疗方法之一。随着中国国家药品监督管理局药品审评中心（Center for Drug Evaluation, NMPA, CDE）2024年9月24日公示，镥[177Lu]特昔维匹肽注射液拟纳入优先审评，适用于治疗前列腺特异性膜抗原（Prostate specific membrane antigen, PSMA）阳性转移性去势抵抗性前列腺癌（Metastatic castration-resistant prostate cancer, mCRPC）、已接受雄激素受体通路抑制和紫杉类化疗的成年患者[1]。RLT在我国即将进入一个新时代。为此，本文梳理并阐述了放射性配体疗法在肿瘤中的应用现状和进展，以期给临床医师带来帮助。
1 放射性配体疗法定义
放射性配体疗法是使用放射性靶向药物（称为放射性配体）治疗癌症的一种新方法。放射性配体由靶向结合细胞表面抗体的放射性原子（放射性核素）和与肿瘤细胞表面特定分子结合的小分子（配体）组成，例如，靶向PSMA的放射性配体疗法和PSMA受体[2]。
放射性配体疗法通过静脉注射特异性放射性配体药物，药物通过血液循环到达肿瘤处，与肿瘤靶细胞膜上的受体结合，在靶肿瘤部位聚集放射性配体药物分子，并释放细胞毒性辐射诱导DNA链断裂，从而导致肿瘤细胞凋亡或死亡[3]。
2 放射性配体疗法在前列腺癌中的应用现状及进展
2.1 应用现状
放射性配体疗法在实体瘤治疗领域取得了显著的进展，已经改写了多种肿瘤目前治疗现状，特别是在前列腺癌和神经内分泌肿瘤中的应用。PSMA是一种由750个氨基酸组成的Ⅱ型跨膜蛋白（110 kDa），锚定在前列腺癌（Prostate cancer, PC）上皮细胞的细胞膜上。PSMA在所有前列腺组织类型中均有表达，且在前列腺癌中表达增加。PSMA也会表达在某些肿瘤相关的新生血管和一些正常组织中，但通常表达水平低于PC细胞。与其他生物标志物即前列腺特异性抗原（Prostate specific antigen, PSA）、前列腺分泌蛋白、前列腺酸性磷酸酶不同，PSMA不会明显释放到血液循环中，这使其成为潜在的治疗靶点。使用Ga-68或F-18放射性核素标记的PSMA配体显像剂推动了靶向PSMA正电子发射计算机断层显像（Positron emission computed tomography, PET）诊断性成像的成功发展，能够使PC患者的PSMA阳性肿瘤组织（包括转移灶）可视化。在高风险PC男性患者中，靶向PSMA PET成像的准确性优于传统成像（CT联合骨扫描）。这使得PSMA成为PC中可操作的治疗靶点，无论病灶位置如何，均能够对靶病灶进行可视化诊断，并确定适合靶向治疗的患者[4]。
177Lu-PSMA-617在治疗晚期前列腺癌患者的Ⅲ期临床试验（VISION）中获积极结果，达到了两个主要终点[5]。177Lu-PSMA-617显著改善了PSMA阳性mCRPC患者的总生存期（Overall survival, OS）和放射学无进展生存期（Radiographic progression-free survival, rPFS）。结果显示，与标准治疗相比，联合177Lu-PSMA-617治疗的OS显著延长（15.3月vs. 11.3月，P<0.001），中位影像学无进展生存期（PFS）也显著延长（8.7月vs. 3.4月，P<0.001）。基于VISION研究结果，国内外权威指南也先后将177Lu-PSMA-617纳入到mCRPC的治疗推荐中，进一步明确了177Lu-PSMA-617在mCRPC中的治疗地位。近期，发表在Lancet杂志上的Ⅲ期针对相对前线的PSMAfore研究正在进行中，有望填补这一治疗领域的靶向放射配体疗法应用空白[6]。PSMAfore研究是一项随机对照Ⅲ期研究，在接受过雄激素受体通路抑制剂（Androgen receptor pathway inhibitors, ARPI）进展但未接受过化疗的mCRPC 患者中，评估177Lu-PSMA-617与换用雄激素受体通路抑制剂相比，是否改善患者的rPFS和OS[7]。该研究入组约450例患者，1∶1随机分配后分别接受177Lu-PSMA-617与另一种ARPI治疗。第三次数据截止的更新分析（自随机至第三次数据截止时间为24.11个月）：177Lu-PSMA-617组与换用ARPI组的中位rPFS分别为11.60与5.59个月（HR=0.49；95%CI: 0.39~0.61）。该研究表明，放射性配体疗法能够显著延长前列腺癌患者的无进展生存期，为核医学在肿瘤治疗中的应用提供了新的证据。
几乎所有前列腺癌患者经过18~24个月的标准内分泌治疗后，都进展为mCRPC，此时癌症恶性程度极高，患者生存率极低。目前靶向前列腺特异性膜抗原的放射性配体疗法方案主要有Lu-177联合PSMA-617等。多个医疗中心报告了225Ac-PSMA-RLT疗法治疗mCRPC患者的安全性和抗肿瘤活性，汇总了接受一个或多个周期静脉注射225Ac-PSMA-RLT治疗的mCRPC患者数据，治疗放射性剂量为每次8 MBq，间隔8周一次[8]。在此之前，mCRPC的治疗包括基于紫杉烷的化疗、雄激素受体信号轴抑制剂、177Lu-PSMA-RLT以及镭-223。研究的主要结局是总生存期和无进展生存期。2016年1月1日至2023年5月31日期间488名mCRPC的男性患者共接受1 174个周期的225Ac-PSMA-RLT治疗（中位数为2个周期）。患者平均年龄为68.1岁，中位前列腺特异性抗原为169.5 ng/mL。既往接收多西他赛治疗的患者324例（66%），卡巴他赛103例（21%），阿比特龙191例（39%），恩杂鲁胺188例（39%）， 177Lu-PSMA-RLT为154例（32%），镭-223为18例（4%）患者。中位随访时间为9.0个月，中位总生存期为15.5个月（95%CI: 13.4~18.3），中位无进展生存期为7.9个月（6.8~8.9个月）。该结果表示，225Ac-PSMA-RLT疗法在mCRPC患者中显示出有效的抗肿瘤作用。对于此前接受过mCRPC相关药物治疗的患者来说，225Ac-PSMA-RLT可作为一种治疗选择。在不良反应中，口干症最为常见，而严重的骨髓和肾脏毒性则较为少见。
有研究进行了安全性分析，共纳入了183例至少接受1剂177Lu-PSMA-617或卡巴他赛治疗的受试者。接受177Lu-PSMA-617治疗的患者（32/98，33%）与接受卡巴他赛治疗的患者（45/85，53%）发生了3级或4级不良事件。未发生因177Lu-PSMA-617治疗相关的死亡事件[9]。177Lu-PSMA-617治疗组3~4级血小板减少症的发生率比卡巴他赛治疗组更高（11% vs. 0）。177Lu-PSMA-617治疗组中3~4级中性粒细胞减少症发生率较低（4% vs. 13%），177Lu-PSMA-617治疗组未发生发热性中性粒细胞减少症事件（0 vs. 8%）。1例接受177Lu-PSMA-617治疗的男性患者和3例接受卡巴他赛治疗的男性患者因不良事件而中止研究药物治疗。12例接受177LuPSMA-617治疗的男性患者和21例接受卡巴他赛治疗的男性患者记录了药物剂量降低事件。从随机化开始至研究治疗末次给药后12周内，共发生19例死亡事件：其中177Lu-PSMA-617治疗组和卡巴他赛组分别有13例和6例死亡事件，未发生因研究药物相关的死亡事件[9]。见表1。
表 1 TheraP[9]试验组中>10%患者发生的所有不良事件Table 1 Adverse events occurring in >10% of patients in the Therap[9] trial groupAdverse events Cabazitaxel+Prednisolone+ADT(n=85) 177Lu-PSMA-617+ADT(n=98) Grades 1–2 Grades 3–4 Grades 1–2 Grades 3–4 Fatigue 61(72%) 3(4%) 69(70%) 5(5%) Pain* 52(61%) 4(5%) 60(61%) 11(11%) Xerostomia 18(21%) 0(0) 59(60%) 0(0) Diarrhea 44(52%) 4(5%) 18(18%) 1(1%) Nausea 29(34%) 0(0) 39(40%) 1(1%) Thrombopenia 4(5%) 0(0) 18(18%) 11(11%) Xerophthalmia 3(4%) 0(0) 29(30%) 0(0) Anemia 11(13%) 7(8%) 19(19%) 8(8%) Neuropathy† 22(26%) 1(1%) 10(10%) 0(0) Dysgeusia 23(27%) 0(0) 12(12%) 0(0) Hematuresis 12(14%) 5(6%) 3(3%) 1(1%) Neutropenia‡ 4(5%) 11(13%) 7(7%) 4(4%) Insomnia 12(14%) 1(1%) 9(9%) 0(0) Vomit 10(12%) 2(2%) 12(12%) 1(1%) Vertigo 1(1%) 0(0) 4(4%) 0(0) Leukopenia 5(6%) 1(1%) 10(10%) 1(1%) Other 34(40%) 45(53%) 53(54%) 32(33%) Notes: *: includes bone, hip, chest wall, side abdomen, neck, limbs, tumor pain or pelvic pain; †: movement or sensation; ‡: febrile neutropenia; ADT: androgen-deprivation therapy. 2.2 应用进展
177Lu-PSMA-617在mCRPC患者中的生存获益、安全性、生活质量已得到充分验证，进一步探索其在转移性激素敏感性前列腺癌（Metastatic hormone-sensitive prostate cancer, mHSPC）患者中的价值是研究的方向和趋势。PSMAddition（NCT04720157）研究是一项随机对照Ⅱ期研究，旨在评估177Lu-PSMA-617+标准治疗对比标准治疗用于mHSPC患者的有效性和安全性[10]。研究纳入1 126例初治或最小限度接受激素治疗的mHSPC患者，并按 1∶1 比例随机分配接受177Lu-PSMA-617+标准治疗或标准治疗。目前该研究入组已结束，期待能取得阳性结果，从而为更多mHSPC患者带来有价值的新型放射性配体疗法。目前正在进行或已经结束的关于177Lu-PSMA-617的临床研究见表2。
表 2 177Lu-PSMA-617临床研究概述Table 2 Overview of clinical research on 177Lu-PSMA-617Localized disease mHNPC/mHSPC mCRPC 1L mCRPC 2L mCRPC 3L LuTectomy stage Ⅰ/Ⅱ: monotherapy (IIT) UpFrontPSMA 1L mHSPC stage Ⅱ: combination therapy (±docetaxel) (IIT) ENZA-p stage Ⅱ: combination therapy (±enzalutamide) (IIT) RESIST-PC stage Ⅱ: monotherapy (completed) VISION stage Ⅲ: combination therapy (±SoC) (completed) NCT03828838 stage Ⅰ/Ⅱ: monotherapy (IIT) NCT03805594 stage Ⅰb: combination therapy (+ pembrolizumab) (IIT) TheraP stage Ⅱ: monotherapy vs. cabazitaxel (IIT) PSMAddition stage Ⅲ: combination therapy (+SoC) (ongoing) PRINCE stage Ⅰb/Ⅱ: combination therapy (+pembrolizumab) (IIT) Fractionated 177Lu-PSMA-617 stage Ⅰ/Ⅱ: monotherapy; 3+3; 68Ga-PSMA-11 disease assessment (IIT) Bullseye stage Ⅱ: monotherapy (IIT) PR21/PLUDO stage Ⅱ: monotherapy vs.
docetaxel (IIT)Lu-PSMA stage Ⅱ: monotherapy (IIT) PSMAfore stage Ⅲ: monotherapy vs. ARPI therapy (completed) LuPin stage Ⅰ/Ⅱ: combination therapy (+idronoxil) (IIT) LuPARP stage Ⅱ: combination therapy
(+Olaparib) (IIT)Notes: 1L: the first line; 2L: the second line; 3L: the third line; ARPI: androgen receptor pathway inhibitors; SoC: standard of care; mCRPC: metastatic castration-resistant prostate cancer; mHNPC: metastatic hormone-naive prostate cancer; mHSPC: metastatic hormone-sensitive prostate cancer; PC: prostate cancer; PSMA: prostate-specific membrane antigen. 目前，225Ac-PSMA-617用于177Lu-PSMA-617难治性mCRPC患者中的临床经验有限。如部分前瞻性和回顾性研究的初步分析所示，即使在患者初始暴露于177Lu-PSMA-617后疾病发生进展，225Ac标记的PSMA再治疗仍可能有效[11]。在一项前瞻性队列研究中[12]，纳入28例接受225Ac-PSMA-617治疗的mCRPC患者，其中15例（54%）患者既往接受过177Lu-PSMA-617治疗，13例（46%）既往未接受过177Lu-PSMA-617治疗。两个亚组的分析结果显示，13例既往未暴露于177Lu-PSMA-617治疗的患者中有7例（53.8%）显示PSA显著降低，而既往接受过177Lu-PSMA-617治疗的15例患者中仅有4例（26.7%）。两组的PSA进展趋势相似。在同一组的长期随访研究中，177Lu-PSMA-617难治性患者随后接受225Ac-PSMA-617作为下一线治疗。这些患者在缓解率、改善总生存期和安全性方面显示出较好的疗效，且治疗相关不良反应较小。在一项回顾性研究中[13]，225Ac-PSMA-617作为177Lu-PSMA-617治疗进展后的mCRPC患者的挽救治疗。225Ac-PSMA-617显示出了抗肿瘤作用，65%的患者PSA下降≥50%，而3/4级血液学不良事件和永久性口干比既往研究报告的更常见[14]。
PSMA已经成为放射性核素治疗的第二个成功案例：基于Ⅲ期VISION试验的结果， 177Lu-PSMA-617已被批准用于PSMA阳性转移性去势抵抗性前列腺癌。因此，临床现在有兴趣将PSMA作为其他PSMA表达癌症的靶点。在一项病例研究中[15-16]，利用177Lu-PSMA-617进行PSMA靶向的概念得到了验证，但未报告结果。另一名复发性胶质母细胞瘤患者接受了177Lu-PSMA-617治疗，并且对该治疗产生了反应。总的来说，PSMA在胶质母细胞瘤中仍是一个主要的血管靶点。
针对目前开发的多项涉及PSMA-靶向治疗的临床试验见表3。VISION、PSMAfore是目前已有Ⅲ期的PSMA RLT试验（批准日期根据文件）。
表 3 PSMA靶向的RLTs和目前正在开发的其他治疗汇总Table 3 Summary of RLTs targeted by PSMA and other ongoing therapiesRadioligand Clinical trial number Research topic Phase Main objective 177Lu-PSMA-I&T NCT04188587 177Lu-PSMA-I&T in mCRPC Ⅱ To clarify the safety and efficacy of 177Lu-PSMA-I&T in the treatment of mCRPC NCT04647526 177 Lu-PSMA-I&T in mCRPC after second-line hormonal therapy (SPLASH) Ⅲ To evaluate the efficacy and safety of 177Lu-PNT2002 for mCRPC patients with progression after ARPI treatment 177Lu-PSMA-1403
CTT-1403NCT03822871 A trial of CTT1403 for metastatic castration-resistant prostate cancer Ⅰ To explore the highest dose level and safety of 177Lu-PSMA-CTT-1403 for mCRPC patients 177Lu-J591 NCT00859781 177Lu radiolabeled monoclonal antibody HuJ591(177Lu-J591) and ketoconazole in patients with prostate cancer Ⅱ To determine the effectiveness of 177Lu-J591 combined with ketoconazole and hydrocortisone in the treatment of PC 225Ac-J591 NCT03276572 Phase Ⅰ trial of 225Ac-J591 in patients with mCRPC Ⅰ To study dose escalation of DLT and MTD in a single administration regimen of 225Ac-J591 131I-MIP-1095 NCT03939689 Radiotherapy in combination with enzalutamide in patients with metastatic castration- resistant prostate cancer who are chemotherapy naive and have progressed on abiraterone (ARROW) Ⅱ To evaluate the efficacy and safety of 131I-MIP-1095 combined with enzalutamide in the treatment of PSMA-positive mCRPC patients NCT04085991 Two tracer positron emission tomography combination for efficacy estimation of prostate specific membrane antigen radioligand therapy in patients
with metastatic prostate cancer (CROSSBOW)Ⅱ To evaluate the safety and efficacy of 131I-MIP-1095 combined with enzalutamide in the treatment of PSMA-positive metastatic PC patients 227Th-PSMA-TTC NCT03724747 Study to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of a thorium-227 labeled antibody-chelator conjugate, in patients with
mCRPCⅠ To clarify the safety and tolerability characteristics as well as MTD of BAY2315497 AMG 160
(HLE BiTE
immunotherapy)NCT03792841 A phase 1 study evaluating the safety, tolerability, pharmacokinetics, and efficacy of prostate specific membrane antigen half-life extended bispecific T-cell engager AMG 160 in subjects with metastatic castration-resistant prostate cancer Ⅰ To evaluate the safety and tolerability of half-life extension (HLE) bispecific T cell linkage system (BiTE®) antibody AMG 160 AMG 160/AMG 404
(HLE BiTE immunotherapy/PD1 inhibitor)NCT04631601 A master protocol evaluating the safety and efficacy of therapies for metastatic castration-resistant prostate cancer (mCRPC) Ⅰ To evaluate the safety, tolerability, MTD or RP2D, and efficacy of AMG 160 in combination with enzalutamide, abiraterone, or PD-1 inhibitor AMG 404 and AMG 404 monotherapy in mCRPC subjects AMG 509
(bispecific antibody)NCT04221542 Study of AMG 509 in subjects with metastatic castration-resistant prostate cancer Ⅰ To evaluate the safety, tolerability, and MTD of AMG 509 in adult subjects Notes: RLT: radioligand therapy; DLT: dose-limiting toxicity; MTD: maximum tolerated dose. 3 放射性配体疗法在神经内分泌肿瘤中的应用现状及进展
3.1 应用现状
神经内分泌肿瘤（Neuroendocrine tumors, NET）是一种起源于全身神经内分泌细胞的肿瘤，可以发生于全身各个部位。根据肿瘤的生物学行为可以分为良性、交界性和恶性。而恶性神经内分泌肿瘤即神经内分泌癌进展迅速，预后不良。尽管NET在临床上并不多见，但其发病率在过去30年中增长了500%以上，因此迫切需要为新确诊的无法手术或晚期患者提供更多的治疗方案[17-18]。
177Lu-dotatate（Lutathera）是属于新兴的肽受体放射性核素疗法，是一种177Lu标记的生长抑素类似物，也就是一种放射性同位素标记的奥曲肽。Lutathera注射到患者体内后，借助受体-配体的靶向识别作用，捕捉到肿瘤细胞，继而将放射性核素导入肿瘤组织，177Lu释放高能量的β射线，最终杀灭肿瘤细胞，也可以称之为“靶向内照射治疗”。2018年1月，美国食品及药物管理局批准了该疗法用于治疗生长抑素受体（Somatostatin receptor, SSTR）阳性胃肠胰神经内分泌肿瘤患者[19-21]。
3.2 应用进展
NETTER-2（NCT03972488）是一项开放标签、多中心、随机对照的Ⅲ期试验，入选患者组织学证实为SSTR阳性、转移性或局部晚期、无法手术、分化良好的2级或3级胃肠胰神经内分泌瘤（Gastroenteropancreatic neuroendocrine tumors, GEP-NETs），且在入组前6个月内确诊。Lutathera联合奥曲肽显著延长新诊断的2级和3级晚期GEP-NETs患者的中位PFS至22.8个月，而高剂量奥曲肽单药组的中位PFS为8.5个月。研究未观察到新的或意外的安全性发现，数据与Lutathera已经确立的安全性特征一致。Lutathera组的大多数患者（88%）接受了所有4个周期的Lutathera治疗。Lutathera组与对照组比较，最常见的所有级别AE（≥20%）为恶心（27.2% vs. 17.8%）、腹泻（25.9% vs. 34.2%）和腹痛（17.7% vs. 27.4%），最常见的≥3级AE为淋巴细胞计数下降（5.4% vs. 0）[22-23]。该数据也已在2024年美国临床肿瘤学会（ASCO）胃肠道（GI）肿瘤研讨会上公布。NETTER-2是Lutathera的第二项Ⅲ期试验，为患者带来了具有临床意义的结果。
靶向放射性核素治疗可以被视为一种精准医学的方法，其基于对特定分子靶标的识别，进而对肿瘤疾病进行治疗。免疫组织化学方法两年前检测出SSTR2蛋白在胶质瘤中的存在，主要位于肿瘤细胞上。部分学者认为SSTR2作为胶质母细胞瘤靶点存在一定争议。在90Y-DOTATOC治疗的三名复发性胶质母细胞瘤患者中，有一名获得完全缓解，两名获得部分缓解，后续研究探讨了177Lu-DOTATATE在8名新诊断或复发胶质瘤患者中的疗效，基于RANO MRI标准，报告了2例完全缓解和3例部分缓解[24]。目前正在进行一项剂量探索研究，评估177Lu-DOTATATE与标准治疗联合应用于新诊断胶质母细胞瘤中的效果，以及其在复发胶质母细胞瘤中作为单一药物的疗效（NCT05109728）[25]。212Pb-DOTAMTATE也是目前全球热点核素药物之一，适用于患有不可切除的转移性生长抑素受体阳性神经内分泌肿瘤的受试者。其由Pb-212标记的靶向SSTR的肽复合物组成，该复合物可作为α粒子的体内发生器。Pb-212同位素因其半衰期、高能量、衰变路径长度短和双链DNA的不可逆损伤而特别适用于SSTR治疗。该疗法于2018年获得FDA的孤儿药指定。今年2月，FDA还授予了该药品突破性疗法认定，用于治疗不可切除或转移性、表达生长抑素受体的成人胃肠胰神经内分泌肿瘤，这些患者可接受肽受体放射性核素治疗。其突破性疗法认定是基于Ⅰ期和正在进行的Ⅱ期临床试验的结果，这些试验评估了AlphaMedix的安全性和疗效。在Ⅰ期研究中，AlphaMedix耐受性良好，可显著减轻肿瘤负担，持久反应率（根据 RECIST 1.1）ORR为 62.5%[26]。
4 放射性配体疗法在其他晚期恶性肿瘤治疗进展
胃泌素释放肽受体（Gastrin-releasing peptide receptor, GRPR）是G蛋白偶联受体家族的一员，报道显示其在胶质瘤中高度表达，但抗体特异性的问题导致数据不一致。GRPR作为靶点正在用于靶向放射性核素治疗，NeoB（NeoBOMB1）是一种高亲和力GRPR拮抗剂，标记为68Ga用于诊断，标记为177Lu用于治疗，目前正在进行Ⅰ期临床试验（NCT03872778）[27]。
基于喹啉的成纤维细胞活化蛋白抑制剂（Fibroblast activation protein inhibitors, FAPIs）已成为全球核医学领域研究的热点，其在肿瘤诊疗及各种非肿瘤性疾病诊断中的应用前景十分广阔。大量研究结果表明，68Ga或18F标记的FAPI在检测各种消化系统肿瘤（包括食管癌、胃癌、十二指肠癌、结直肠癌、肝癌、胆管癌和胰腺癌）的原发灶和转移病灶方面优于18F-FDG PET/CT[28-31]。一项研究纳入34名胃印戒细胞癌患者，研究结果表明68Ga-FAPI-04 PET比18F-FDG PET在检测原发灶/复发肿瘤和转移病灶方面具有更高的放射性示踪剂摄取、更好的肿瘤本底比值和诊断效能[32]。除PET/CT外，使用68Ga-FAPI-04 PET/MRI进行多序列成像也能有效识别胰腺癌病灶，并能精准检测阻塞性炎性反应和微小肝转移病灶[33]。Qin等对20名胃癌患者进行了研究，结果显示多序列MRI在检测肝脏、子宫、直肠、骨骼和卵巢的转移病灶中具有显著优势[34]。因此，多序列MRI与FAPI PET协同可增强对软组织病变的评估。在FAP中低度表达的肿瘤中，177Lu标记的FAPI四聚体比其二聚体和单体具有更好的肿瘤摄取和抗肿瘤疗效。因此，对于FAP中低度表达的肿瘤，使用FAPI四聚体进行放射性配体治疗可能比FAPI二聚体更合适。然而，在中国已研究的一系列多聚化FAPI衍生物中，只有68Ga-DOTA-2P（FAPI）2已经应用于临床[35]。
5 结语
放射性配体疗法目前已经改变部分肿瘤临床实践，且已有较多临床研究在多种肿瘤中开展，其在肿瘤治疗领域展现出巨大的潜力和前景。更多具有不同的射程和能量的同位素的研发在临床试验阶段取得了积极进展，为肿瘤诊疗提供了多样化的选择。在联合治疗方面，放射性配体疗法可以与其他疗法（如化疗、免疫疗法和靶向药物）联合使用，提供更全面有效的治疗策略。
Competing interests: The authors declare that they have no competing interests.利益冲突声明：所有作者均声明不存在利益冲突。作者贡献：邱大胜、崔殿生：论文撰写及修改James Nagarajah：资料整理及分析魏少忠：论文审核 -
表 1 TheraP[9]试验组中>10%患者发生的所有不良事件
Table 1 Adverse events occurring in >10% of patients in the Therap[9] trial group
Adverse events Cabazitaxel+Prednisolone+ADT(n=85) 177Lu-PSMA-617+ADT(n=98) Grades 1–2 Grades 3–4 Grades 1–2 Grades 3–4 Fatigue 61(72%) 3(4%) 69(70%) 5(5%) Pain* 52(61%) 4(5%) 60(61%) 11(11%) Xerostomia 18(21%) 0(0) 59(60%) 0(0) Diarrhea 44(52%) 4(5%) 18(18%) 1(1%) Nausea 29(34%) 0(0) 39(40%) 1(1%) Thrombopenia 4(5%) 0(0) 18(18%) 11(11%) Xerophthalmia 3(4%) 0(0) 29(30%) 0(0) Anemia 11(13%) 7(8%) 19(19%) 8(8%) Neuropathy† 22(26%) 1(1%) 10(10%) 0(0) Dysgeusia 23(27%) 0(0) 12(12%) 0(0) Hematuresis 12(14%) 5(6%) 3(3%) 1(1%) Neutropenia‡ 4(5%) 11(13%) 7(7%) 4(4%) Insomnia 12(14%) 1(1%) 9(9%) 0(0) Vomit 10(12%) 2(2%) 12(12%) 1(1%) Vertigo 1(1%) 0(0) 4(4%) 0(0) Leukopenia 5(6%) 1(1%) 10(10%) 1(1%) Other 34(40%) 45(53%) 53(54%) 32(33%) Notes: *: includes bone, hip, chest wall, side abdomen, neck, limbs, tumor pain or pelvic pain; †: movement or sensation; ‡: febrile neutropenia; ADT: androgen-deprivation therapy. 
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表 2 177Lu-PSMA-617临床研究概述
Table 2 Overview of clinical research on 177Lu-PSMA-617
Localized disease mHNPC/mHSPC mCRPC 1L mCRPC 2L mCRPC 3L LuTectomy stage Ⅰ/Ⅱ: monotherapy (IIT) UpFrontPSMA 1L mHSPC stage Ⅱ: combination therapy (±docetaxel) (IIT) ENZA-p stage Ⅱ: combination therapy (±enzalutamide) (IIT) RESIST-PC stage Ⅱ: monotherapy (completed) VISION stage Ⅲ: combination therapy (±SoC) (completed) NCT03828838 stage Ⅰ/Ⅱ: monotherapy (IIT) NCT03805594 stage Ⅰb: combination therapy (+ pembrolizumab) (IIT) TheraP stage Ⅱ: monotherapy vs. cabazitaxel (IIT) PSMAddition stage Ⅲ: combination therapy (+SoC) (ongoing) PRINCE stage Ⅰb/Ⅱ: combination therapy (+pembrolizumab) (IIT) Fractionated 177Lu-PSMA-617 stage Ⅰ/Ⅱ: monotherapy; 3+3; 68Ga-PSMA-11 disease assessment (IIT) Bullseye stage Ⅱ: monotherapy (IIT) PR21/PLUDO stage Ⅱ: monotherapy vs.
docetaxel (IIT)Lu-PSMA stage Ⅱ: monotherapy (IIT) PSMAfore stage Ⅲ: monotherapy vs. ARPI therapy (completed) LuPin stage Ⅰ/Ⅱ: combination therapy (+idronoxil) (IIT) LuPARP stage Ⅱ: combination therapy
(+Olaparib) (IIT)Notes: 1L: the first line; 2L: the second line; 3L: the third line; ARPI: androgen receptor pathway inhibitors; SoC: standard of care; mCRPC: metastatic castration-resistant prostate cancer; mHNPC: metastatic hormone-naive prostate cancer; mHSPC: metastatic hormone-sensitive prostate cancer; PC: prostate cancer; PSMA: prostate-specific membrane antigen.
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表 3 PSMA靶向的RLTs和目前正在开发的其他治疗汇总
Table 3 Summary of RLTs targeted by PSMA and other ongoing therapies
Radioligand Clinical trial number Research topic Phase Main objective 177Lu-PSMA-I&T NCT04188587 177Lu-PSMA-I&T in mCRPC Ⅱ To clarify the safety and efficacy of 177Lu-PSMA-I&T in the treatment of mCRPC NCT04647526 177 Lu-PSMA-I&T in mCRPC after second-line hormonal therapy (SPLASH) Ⅲ To evaluate the efficacy and safety of 177Lu-PNT2002 for mCRPC patients with progression after ARPI treatment 177Lu-PSMA-1403
CTT-1403NCT03822871 A trial of CTT1403 for metastatic castration-resistant prostate cancer Ⅰ To explore the highest dose level and safety of 177Lu-PSMA-CTT-1403 for mCRPC patients 177Lu-J591 NCT00859781 177Lu radiolabeled monoclonal antibody HuJ591(177Lu-J591) and ketoconazole in patients with prostate cancer Ⅱ To determine the effectiveness of 177Lu-J591 combined with ketoconazole and hydrocortisone in the treatment of PC 225Ac-J591 NCT03276572 Phase Ⅰ trial of 225Ac-J591 in patients with mCRPC Ⅰ To study dose escalation of DLT and MTD in a single administration regimen of 225Ac-J591 131I-MIP-1095 NCT03939689 Radiotherapy in combination with enzalutamide in patients with metastatic castration- resistant prostate cancer who are chemotherapy naive and have progressed on abiraterone (ARROW) Ⅱ To evaluate the efficacy and safety of 131I-MIP-1095 combined with enzalutamide in the treatment of PSMA-positive mCRPC patients NCT04085991 Two tracer positron emission tomography combination for efficacy estimation of prostate specific membrane antigen radioligand therapy in patients
with metastatic prostate cancer (CROSSBOW)Ⅱ To evaluate the safety and efficacy of 131I-MIP-1095 combined with enzalutamide in the treatment of PSMA-positive metastatic PC patients 227Th-PSMA-TTC NCT03724747 Study to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of a thorium-227 labeled antibody-chelator conjugate, in patients with
mCRPCⅠ To clarify the safety and tolerability characteristics as well as MTD of BAY2315497 AMG 160
(HLE BiTE
immunotherapy)NCT03792841 A phase 1 study evaluating the safety, tolerability, pharmacokinetics, and efficacy of prostate specific membrane antigen half-life extended bispecific T-cell engager AMG 160 in subjects with metastatic castration-resistant prostate cancer Ⅰ To evaluate the safety and tolerability of half-life extension (HLE) bispecific T cell linkage system (BiTE®) antibody AMG 160 AMG 160/AMG 404
(HLE BiTE immunotherapy/PD1 inhibitor)NCT04631601 A master protocol evaluating the safety and efficacy of therapies for metastatic castration-resistant prostate cancer (mCRPC) Ⅰ To evaluate the safety, tolerability, MTD or RP2D, and efficacy of AMG 160 in combination with enzalutamide, abiraterone, or PD-1 inhibitor AMG 404 and AMG 404 monotherapy in mCRPC subjects AMG 509
(bispecific antibody)NCT04221542 Study of AMG 509 in subjects with metastatic castration-resistant prostate cancer Ⅰ To evaluate the safety, tolerability, and MTD of AMG 509 in adult subjects Notes: RLT: radioligand therapy; DLT: dose-limiting toxicity; MTD: maximum tolerated dose.
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