Sacituzumab govitecan-hziy

抗体偶联药物（Antibody-Drug Conjugates，ADCs）将靶向抗体疗法与强效细胞毒性药物相结合，已成为肿瘤学领域的一项关键创新，其应用从血液肿瘤已经发展到实体瘤。以泌尿系统肿瘤为例，在尿路上皮癌中，世界范围内已经有3款ADCs获批上市。结合以下内容，我们一起对ADCs在泌尿系统恶性肿瘤中的临床研究进展进行了总结和展望。 无论是单药治疗还是联合治疗方案，ADCs都在晚期泌尿系统恶性肿瘤中发挥着关键作用。 1.尿路上皮癌：截至目前，世界范围内累计有3款ADCs获批治疗转移性尿路上皮癌，该疾病也是ADCs药物开展临床研究最多的泌尿系统恶性肿瘤。 2.前列腺癌：ADCs以靶向PSMA和STEAP1的居多，研发进展值得期待。 3.肾细胞癌：ADCs在该疾病领域的研发进行了初步探索，但突破尚面临不小的挑战。 4.睾丸癌：ADCs在该疾病领域的初步结果有矛盾之处，尚需进一步探索。 一、背景 泌尿生殖系统恶性肿瘤是一组具有各种组织学和生物学行为的异质性强的肿瘤，包括但不限于肾细胞癌、膀胱癌、前列腺癌和睾丸癌。 近些年泌尿生殖系统肿瘤的治疗格局发生了重大变化，其中免疫检查点抑制剂（抗PD-1，抗CTLA-4等）和ADCs最为亮眼。以ADCs为例，转移性尿路上皮癌既往的标准治疗是含铂化疗，2023年ESMO报道的EV-302研究，enfortumab vedotin （EV）联合帕博利珠单抗1线治疗晚期尿路上皮癌相较于含铂化疗的中位总生存期（OS）分别为 31.5个月和16.1个月，取得了生存期获益的显著阳性结果。 ADCs兼具传统小分子细胞毒药物的强大杀伤效应和抗体药物的肿瘤靶向性。从结构而言，ADCs主要由三个部分组成：负责选择性识别和靶向肿瘤的抗体（mAb），有效载荷（payload，目前常为小分子细胞毒药物），以及连接抗体与有效载荷的连接子（linker)。从作用机制而言，ADCs 药物依靠抗体对肿瘤细胞相关抗原的特异性，靶向性结合肿瘤细胞，并且通过内吞作用进入该细胞，连接子在细胞内受到低 pH 值或溶酶体酶促反应等作用下断裂，释放出有效载荷，引起细胞凋亡和抗体依赖性细胞毒性（ADCC）。除了这种直接影响外，还存在“旁观者效应”，即由于有效载荷扩散到肿瘤微环境中而发生细胞对邻近癌细胞的损伤。此外，Fab 部分还具有刺激免疫系统细胞的能力，从而激活免疫介导的反应，有可能对癌细胞造成进一步的伤害。 二、不同的泌尿系统恶性肿瘤中 ADCs的临床研究进展 1.肾细胞癌（Renal cell carcinoma, RCC） RCC约占全球癌症患者的3%，2020年全球范围内新发病例数约为 43万、死亡病例数约为18万。不同的临床分期生存率差异较大：Ⅰ-Ⅱ期和Ⅲ期RCC患者的5年生存率分别为 80%和60%，Ⅳ期或转移性RCC（mRCC）患者的5年生存率约为10%，中位OS为10-15个月。 目前转移性肾细胞癌（mRCC）的标准治疗是免疫联合治疗，中位OS可延长到 3年以上（以III期Checkmate-9ER研究的数据为例，纳武利尤单抗联合卡博替尼1线治疗mRCC患者的中位OS为 46.5个月）。晚期RCC的一线治疗发生了巨大的改变，而一线治疗失败后的标准治疗方案没有定论，如何延长患者的生存期、改善生活质量，就需要创新疗法，ADCs特别受到关注。 但与尿路上皮癌相比，ADCs在晚期RCC治疗领域的进展较慢。这可能与以下因素有关：肿瘤内异质性高、肿瘤摄取低、肾癌相关的肿瘤特异性抗原较少、ATP泵上调引起的药物外排，以及循环系统中的不同形式的靶蛋白等。 截至目前，晚期RCC中尚无ADCs的Ⅱ或Ⅲ期临床试验数据报道。 Ⅰ期临床试验如下（主要是靶向ENPP3和靶向TIM-1）。 2.尿路上皮癌（Urothelial cancer, UC） 尿路上皮癌可发生在膀胱、肾盂、输尿管和后尿道，但以膀胱癌最为多见。膀胱癌是世界范围内第10常见肿瘤，全球范围内2020年新发病例数和死亡病例数分别为57.3万和21.3万。其中90%的膀胱癌是尿路上皮癌。不同临床分期的膀胱癌预后不同，膀胱原位癌、局限期膀胱癌和转移性尿路上皮癌（mUC）的5年生存率分别为97%、71%和8%。 mUC的一线标准治疗是含铂化疗，中位OS约为14-15个月。随着3期研究Checkmate 901和EV-302数据的报道，一线治疗格局发生了重大变化：ICIs联合化疗，或联合EV证实了优于含铂化疗的显著获益。但是，一线化疗进展后二线治疗的应答率较低,，以帕博利珠单抗为例，二线治疗的ORR约为 21.1%。 ADCs显著改善了晚期尿路上皮癌的治疗格局，下面看一下ADCs在尿路上皮癌的临床研究进展。 1）Nectin-4 ADCs：Nectin-4在80%的膀胱癌和60%的上尿路尿路上皮癌过表达。以enfortumab vedotin （EV）为例，EV是靶向Nectin-4的ADC，payload是微管抑制剂 MMAE。2023年ESMO报道的EV-302研究，EV联合帕博利珠单抗1线治疗晚期尿路上皮癌相较于含铂化疗的中位总生存期（OS）分别为 31.5个月和16.1个月，取得了生存期获益的显著阳性结果，亚组分析数据提示，无论是否耐受顺铂、PD-L1表达和肝转移存在与否，EV+帕博利珠单抗较含铂化疗均显示了显著获益。Ⅰb/Ⅱ期 EV-103的K队列数据，与EV单药相比，EV+帕博利珠单抗的ORR更高（64.5% vs 45.2%）。但是，EV的应用同样存在一些挑战，例如ADCs相关的毒性、EV是否有必要持续使用直至疾病进展、由此产生的成本以及药物可及性等。 2）Trop-2 ADCs：TROP-2在95%的尿路上皮癌过表达。以 Sacituzumab govitecan（SG）为例，SG是靶向Trop-2的ADC，payload是SN-38（拓扑异构酶IB抑制剂）。根据TROPHY（IMMU-132-06）研究数据，在既往接受过含铂化疗和PD-1或PD-L1治疗过的晚期尿路上皮癌患者中，SG治疗组的确认的ORR为 27.7%，完全缓解率为 5.4%，部分缓解率为 22.3%，中位DOR为 7.2个月。SG+帕博利珠单抗1线治疗mUC的临床研究目前在进行中。 3）HER2 ADCs：HER2约在46%的尿路上皮癌过表达。以维迪西妥昔单抗为例，该药物是以HER2作为靶点，payload是MMAE。在2期RC48-C005研究中，既往常规治疗失败的HER2阳性表达的晚期尿路上皮癌患者的确认的ORR为51.2%，疾病控制率为 90.7%，中位无进展生存期为 6.9个月，中位总生存期为 13.9个月。 4）ADC联合ADC治疗：根据EV+SG联合治疗2线进展的mUC患者的Ⅰ期研究数据，ORR为 70%，≥3级TRAE发生率为 78%。这也是一项有意义的探索。 ADCs在尿路上皮癌的已公布临床研究数据汇总表格如下： 3.前列腺癌（Prostate cancer, PC） 前列腺癌全球范围内年发病例数超过120万，年死亡例数超过35万。前列腺癌分为激素敏感性前列腺癌和去势抵抗性前列腺癌。转移性激素敏感性前列腺癌（ mHSPC)的5年生存率根据不同的危险因素而不同，约为 30%-70%。转移性去势抵抗性前列腺癌（ mCRPC）的中位OS约为 3.5年。 mHSPC的治疗方案涵盖了从单纯ADT治疗到多药联合治疗，例如双药联合：ADT+化疗/多西他赛，或ADT+新型雄激素受体抑制剂（ARPI），三药联合（ADT+化疗/多西他赛+ARPI）。mCRPC的治疗，除了ARPI和化疗外，还包括PARP抑制剂、放疗和免疫治疗等联合治疗策略。 ADT耐药的机制已经明确，耐药后的治疗策略是加强治疗和联合ARPIs。ARPIs耐药的机制仍不明确，耐药后如何治疗是未满足的临床需求。ADCs作为新的治疗方式，在前列腺癌领域也是进行了初步探索，靶向PSMA和STEAP1的ADCs在临床开发的进展值得关注。 ADCs药物在前列腺癌领域的临床在研药物汇总如下： ADCs药物在mCRPC的已公布临床研究数据汇总表格如下： 4.睾丸癌（Testicular cancer, TC） 睾丸干细胞癌（TGCTs）发病罕见，全球发病率约为 1.5/10万。TGCTs占男性恶性肿瘤的 1%，是15-35岁男性中最常见的肿瘤类型。 低危的转移性TGCTs治愈率高，含铂化疗的5年生存率＞90%。而中危和高危患者的治愈率分别为 80%和50-60%，呈现显著的铂类耐药。根治性治疗后的复发最常见于2年内，但有 1-4%的患者延迟复发且预后差。截至目前的研究数据提示，TGCTs患者对免疫治疗和靶向治疗均不敏感。ADCs药物作为新的治疗方式在睾丸癌患者的应用正在探索。 CD30在 95%的睾丸胚胎癌表达。Brentuximab vedotin（BV）是靶向CD30的ADCs，payload是MMAE。但是，BV仅有的2项临床试验结果存在相互矛盾之处，所以在睾丸癌领域需继续探索ADC药物发挥作用的可能性。 ADCs治疗睾丸癌的已公布临床研究数据汇总表格如下： 展望 在尿路上皮癌中，ADCs已经取得了非常良好的成绩。但在其他泌尿系统恶性肿瘤中，虽然已经有了早期研究数据，但还需要继续探索寻找更优秀的ADCs。 在前列腺癌中，靶向PSMA、STEAP1、Trop-2、B7-H3、CD46的ADCs的试验显示出不同程度的疗效和安全性，但由于mCRPC 的复杂性，疗效尚不突出。在肾细胞癌中，靶向ENPP3和靶向TIM-1的ADCs已经进行了 I 期试验，尽管存在治疗耐药性比例较高的挑战，但也显示出可作为替代治疗方案的潜力。在睾丸癌中，当常规治疗失败时，ADCs的探索特别有价值。 随着新药的问世，近些年恶性肿瘤的治疗发生了巨大的变化，尤其是随着一线治疗格局的改变，后线治疗如何选择存在巨大的未满足的需求，一线治疗也存在继续改善的空间。ADCs作为新的治疗方式，受到了广泛的关注，泌尿系统恶性肿瘤中已经在尿路上皮癌率先取得了突破，但是在克服耐药、优化ADCs组成、提高可及性、以及将ADC与现有治疗方案相结合以增强治疗效果方面，仍然需要进一步探索。下一步需继续探索新的靶点和联合治疗策略，以及做好安全性管理，这对于挖掘泌尿系统肿瘤中ADCs的充分潜力至关重要。 新靶点的开拓是最吸引各方关注的创新路径，比如LILRB4。LILRB4属于LILRB超家族的I型跨膜蛋白，是表达在髓系单核细胞包括树突状细胞等细胞表面的一种免疫抑制性蛋白。LILRB4通过MDSC等免疫抑制性细胞负调节肿瘤免疫。在多种泌尿系统肿瘤如肾细胞癌、前列腺癌等肿瘤微环境均发现LILRB4高表达和MDSC重要免疫抑制调节作用。开发靶向LILRB4的ADCs可通过高效杀伤免疫抑制性细胞而对肿瘤免疫起到调节作用，激活免疫系统治疗肿瘤，前景值得期待。 来源 | 医麦客

Progression free survival (PFS) extended to 9.1 months in ADC resistant patient - quadruple the PFS of patients in similar studies 1, 2, 3Significant reduction of “Eye-Bulging” metastatic breast cancer tumor was previously reportedHeavily pre-treated patient had failed 8 prior regimens including antibody-drug conjugate (ADC) therapy and continues to receive BriaCell treatment PHILADELPHIA and VANCOUVER, British Columbia, July 18, 2024 (GLOBE NEWSWIRE) -- BriaCell Therapeutics Corp. (Nasdaq: BCTX, BCTXW) (TSX: BCT) (“BriaCell” or the “Company”), a clinical-stage biotechnology company that develops novel immunotherapies to transform cancer care, is pleased to report significantly higher PFS for its top responder patient in the Phase 2 study of BriaCell’s Bria-IMT™ regimen in combination with an immune checkpoint inhibitor in metastatic breast cancer. The patient remains alive and she continues to receive BriaCell’s treatment regimen. “We are extremely pleased with the unprecedented survival benefit in this very-difficult-to-treat patient,” stated Dr. William V. Williams, BriaCell’s President and CEO. “This data represents a step forward in our efforts to build on our knowledge and successes to transform cancer care for patients. We expect to replicate this positive data in our ongoing Phase 3 study and bring relief to cancer patients whose medical needs remain unmet.” “Despite recent advances in cancer therapy, metastatic breast cancer remains an unmet medical need, as current treatments are limited by poor survival and harsh side effects,” commented Dr. Giuseppe Del Priore, BriaCell’s Chief Medical Officer. “The Bria-IMT™ regimen produced a much longer than expected survival benefit in addition to its favorable safety and tolerability in this patient suggesting its potential as a therapeutic option for these cancer patients.” The patient had a large right orbital lesion (behind the right eye) and a right temporal lobe lesion (in the right side of the brain). The temporal lobe lesion is no longer detectable, while the orbital lesion has continued to shrink markedly (see figure showing resolution of proptosis post treatment (small arrows) with reduction in tumor indicated by the large arrows). In addition, her tumor markers (blood tests that correlate with the amount of tumor in the body) have markedly decreased from her pre-treatment levels. Figure 1: Responder Images - Bria-IMT™ Regimen Table 1: Bria-IMT™ and historical clinical data in MBC patients who failed multiple prior treatments StudyPFS (months)Top Responder Patient9.1+Bardia, A. et. al. 11.7Tripathy D. et. al. 21.9O’Shaughnessy J. et. al. non-TNBC 32.3O’Shaughnessy J. et. al. TNBC 31.6 1,2,3 Data is shown for the intent to treat population for the control group treated with treatment of physician’s choice, which is the comparator in the BriaCell’s ongoing pivotal Phase 3 study.2 This paper describes patients with brain metastases, which were also present in the patient described.+ Indicates the patient is ongoing in the study. References Bardia A, et al. Final Results From the Randomized Phase III ASCENT Clinical Trial in Metastatic Triple-Negative Breast Cancer and Association of Outcomes by Human Epidermal Growth Factor Receptor 2 and Trophoblast Cell Surface Antigen 2 Expression. J Clin Oncol. 2024 May 20;42(15):1738-1744. doi: 10.1200/JCO.23.01409. Epub 2024 Feb 29. PMID: 38422473.Tripathy D, et al. Treatment with etirinotecan pegol for patients with metastatic breast cancer and brain metastases: final results from the phase 3 ATTAIN randomized clinical trial. JAMA Oncol. 2022;8(7):1047-1052. doi:10.1001/jamaoncol.2022.0514.O’Shaughnessy J et al. Analysis of patients without and with an initial triple-negative breast cancer diagnosis in the phase 3 randomized ASCENT study of sacituzumab govitecan in metastatic triple-negative breast cancer. Breast Cancer Res Treat. 2022 Sep;195(2):127-139. doi: 10.1007/s10549-022-06602-7. Epub 2022 May 11. PMID: 35545724; PMCID: PMC9374646. About BriaCell Therapeutics Corp. BriaCell is a clinical-stage biotechnology company that develops novel immunotherapies to transform cancer care. More information is available at https://briacell.com/. Safe Harbor This press release contains “forward-looking statements” that are subject to substantial risks and uncertainties. All statements, other than statements of historical fact, contained in this press release are forward-looking statements. Forward-looking statements contained in this press release may be identified by the use of words such as “anticipate,” “believe,” “contemplate,” “could,” “estimate,” “expect,” “intend,” “seek,” “may,” “might,” “plan,” “potential,” “predict,” “project,” “target,” “aim,” “should,” “will,” “would,” or the negative of these words or other similar expressions, although not all forward-looking statements contain these words. Forward-looking statements, including those about BriaCell replicating positive data in its ongoing Phase 3 study; BriaCell’s Bria-IMT™ regimen bringing relief to cancer patients whose medical needs remain unmet; and the Bria-IMT™ regimen becoming a therapeutic option for metastatic breast cancer patients, are based on BriaCell’s current expectations and are subject to inherent uncertainties, risks, and assumptions that are difficult to predict. Further, certain forward-looking statements are based on assumptions as to future events that may not prove to be accurate. These and other risks and uncertainties are described more fully under the heading “Risks and Uncertainties” in the Company’s most recent Management’s Discussion and Analysis, under the heading “Risk Factors” in the Company’s most recent Annual Information Form, and under “Risks and Uncertainties” in the Company’s other filings with the Canadian securities regulatory authorities and the U.S. Securities and Exchange Commission, all of which are available under the Company’s profiles on SEDAR+ at www.sedarplus.ca and on EDGAR at www.sec.gov. Forward-looking statements contained in this announcement are made as of this date, and BriaCell Therapeutics Corp. undertakes no duty to update such information except as required under applicable law. Neither the Toronto Stock Exchange nor its Regulation Services Provider (as that term is defined in the policies of the Toronto Stock Exchange) accepts responsibility for the adequacy or accuracy of this release. Contact Information Company Contact:William V. Williams, MDPresident & CEO1-888-485-6340info@briacell.com Media Relations:Jules AbrahamCORE IRjulesa@coreir.com Investor Relations Contact:CORE IRinvestors@briacell.com A photo accompanying this announcement is available at:https://www.globenewswire.com/NewsRoom/AttachmentNg/cef51e5b-ff25-4c3e-929d-22ad6df22927