Sunitinib Malate

整理：肿瘤资讯来源：肿瘤资讯乳腺癌的治疗在最近几十年历经了巨大的变革。从最初的化疗和激素治疗，到后来靶向治疗和免疫治疗的兴起，治疗手段不断丰富，但如何实现个体化精准治疗仍是临床面临的核心问题。随着众多临床试验的成功，美国食品药品监督管理局（FDA）和中国国家药品监督管理局（NMPA）批准了一系列创新药物用于乳腺癌的治疗。本文整理了近70年来乳腺癌领域的获批药物，以梳理乳腺癌治疗发展脉络和重要节点。本篇章概述了乳腺癌靶向治疗的获批药物，以期为临床医生了解行业进展和治疗用药提供参考。本文上接《乳腺癌领域获批药物盘点——化疗、内分泌治疗及免疫治疗篇》靶向治疗——个体化精准治疗新阶段过去，手术、放疗和化疗都无法精确定位并选择性杀伤肿瘤细胞，大量正常细胞也会受到损伤。针对这一局限，靶向药物应运而生。靶向药物又被称为“生物导弹”，它能够特异性地识别并结合肿瘤细胞上的靶点发挥作用，对肿瘤细胞实施精确打击。自1997年利妥昔单抗（Rituximab，抗CD20单克隆抗体）获FDA批准用于治疗非霍奇金淋巴瘤，这是首个获批用于治疗肿瘤的单克隆抗体，标志着靶向药物正式进入肿瘤治疗领域。随后在1998年，曲妥珠单抗（抗HER2单克隆抗体）也获得FDA批准，用于治疗转移性乳腺癌。近10年来，获批的靶向药物数量大幅增加，并逐渐成为抗肿瘤治疗的重要组成部分。肿瘤分子靶向治疗是针对肿瘤细胞的特异性分子靶点进行干预，影响细胞发生癌变的环节。主要通过抑制肿瘤细胞增殖、干扰细胞周期、诱导肿瘤细胞分化、抑制肿瘤细胞转移、诱发肿瘤细胞凋亡以及抑制肿瘤血管生成等途径发挥治疗作用。与传统治疗不同，靶向治疗能够精确作用在肿瘤细胞上，对正常细胞的毒副作用较小。肿瘤细胞表面的生长因子受体、信号转导分子、细胞周期调控蛋白、凋亡相关因子、蛋白酶类以及血管内皮生长因子等都可作为靶向治疗的分子靶点。图1 肿瘤领域获批小分子抑制剂的靶点1乳腺癌的靶向治疗目前乳腺癌靶向治疗所针对的靶点或通路主要包括HER2、VEGF、EGFR、PARP、PI3K/Akt/mTOR、CDK4/6等。根据分子靶向药物的作用部位可概括为：作用于细胞膜的药物：主要是靶向跨膜生长因子受体，包括作用于成纤维细胞生长因子受体（FGFR）的小分子酪氨酸激酶抑制剂（TKI），如在研的Dovitinib、lucitanib、仑伐替尼（lenvatinib）、infigratinib和erdafitinib等；作用于表皮生长因子受体（EGFR）及作用于HER2受体的单克隆抗体曲妥珠单抗等；作用于细胞质的药物：靶向于细胞内信号转导过程，如mTOR抑制剂依维莫司等；作用于细胞核的药物：靶向于DNA或RNA，例如细胞周期蛋白依赖性激酶4和6(CDK4/6)抑制剂、PARP抑制剂等；作用于肿瘤细胞外环境的药物：目前临床使用较为广泛的靶向于肿瘤相关血管的药物就属于此类，如血管内皮生长因子单克隆抗体贝伐珠单抗、重组人内皮抑素等。FDA批准的抗肿瘤药物时间轴如下，2000年以前，获批的抗肿瘤药物以化疗药物和激素类药物为主。2000年之后，获批的靶向治疗药物开始快速增加。图2 FDA批准的抗肿瘤药物时间轴18表1整理了FDA批准的乳腺癌领域的靶向治疗药物。下表所列药物中，除margetuximab已提交NMPA上市申请待审批外，其他药物均已获得我国药监部门批准上市。表1 FDA批准乳腺癌领域的靶向治疗药物01抗HER2治疗药物单克隆抗体（mAb）mAb通过与 HER2的胞外配体结合域结合，阻断细胞内HER2信号转导、抑制癌细胞周期；同时，可激活患者自身免疫系统的抗肿瘤活性，引发抗体依赖的细胞介导的细胞毒反应（ADCC）。如曲妥珠单抗（trastuzumab）、帕妥珠单抗（pertuzumab）和Margetuximab。曲妥珠单抗2022年10 月，据 NMPA 官网显示，罗氏旗下基因泰克研发的曲妥珠单抗注射液（皮下注射）在国内获批上市，联合化疗用于治疗早期和转移性 HER2 阳性乳腺癌患者。适应症：1）HER2阳性的转移性乳腺癌：作为单一药物治疗已接受过1个或多个化疗方案的转移性乳腺癌；与紫杉醇或者多西他赛联合，用于未接受化疗的转移性乳腺癌患者；2）HER2阳性早期乳腺癌：接受了手术、含蒽环类抗生素辅助化疗和放疗（如果适用）后的单药辅助治疗；多柔比星和环磷酰胺化疗后序贯本品与紫杉醇或多西他赛的联合辅助治疗；与多西他赛和卡铂联合的辅助治疗；与化疗联合新辅助治疗，继以辅助治疗，用于局部晚期（包括炎性）或者肿瘤直径>2cm的乳腺癌。2020年8月14日，国内首个曲妥珠单抗——HLX02获得NMPA批准用于HER2阳性早期乳腺癌、转移性乳腺癌和转移性胃癌。2020年7月29日，HLX02获得欧盟委员会批准，成为欧盟首个国产的单抗生物类似药。从此国人拥有了国际认证的国产曲妥珠单抗。帕妥珠单抗2018年12月，帕妥珠单抗在我国获批，现已批准多个适应症：1）早期乳腺癌：与曲妥珠单抗和化疗联合用于HER2阳性、局部晚期、炎性或早期乳腺癌患者（直径>2cm或淋巴结阳性）的新辅助治疗，作为早期乳腺癌整体治疗方案的一部分；用于具有高复发风险HER2阳性早期乳腺癌患者的辅助治疗；2）转移性乳腺癌：帕妥珠单抗与曲妥珠单抗和多西他赛联合，适用于HER2阳性、转移性或不可切除的局部复发性乳腺癌患者，患者既往未接受过针对转移性乳腺癌的抗HER2治疗或者化疗。2023年1月，据中国国家药监局药品审评中心（CDE）信息显示，齐鲁制药的帕妥珠单抗注射液的上市申请已获受理，用于治疗HER2阳性乳腺癌，这是国内首个申报上市的帕妥珠单抗生物类似药。另外，2023年5月24日，据CDE官网显示，正大天晴的帕妥珠单抗注射液生物类似药上市申请获得受理。Margetuximab2018年11月，再鼎医药从MacroGenics获得在大中华区开发和商业化margetuximab的权利。2020年12月，FDA批准margetuximab联合化疗，用于治疗既往接受过两种或两种以上抗HER2方案的转移性HER2阳性乳腺癌成人患者，其中至少一种方案是针对转移性疾病。2022年1月，再鼎医药宣布NMPA已受理margetuximab治疗经治转移性HER2阳性乳腺癌的新药上市申请。伊尼妥单抗（Inetetamab）三生制药旗下三生国健药业自主研发的注射用伊尼妥单抗，是我国自主研发的针对抗HER2治疗的一款“仿创结合”的抗HER2单抗。2020年获NMPA批准适用于HER2阳性，与长春瑞滨联合治疗已接受过1个或多个化疗方案的转移性乳腺癌患者。抗体偶联药物（ADC）ADC药物由抗体+连接子+细胞毒药物构成，即将有选择性的、只杀伤癌细胞的靶向药与泛性的细胞毒药物相结合。ADC具有双重抗肿瘤效应：一是特异性mAb与靶向的细胞表面抗原结合，被肿瘤细胞内化并由内溶酶体系统处理，有效载荷释放并杀灭肿瘤细胞；二是通过ADCC效应诱导肿瘤细胞死亡。代表药物为恩美曲妥珠单抗（trastuzumab emtansine，T-DM1）和德曲妥珠单抗（trastuzumab deruxtecan，T-DXd）等。恩美曲妥珠单抗2013年FDA获批T-DM1的乳腺癌适应症，2021年NMPA批准T-DM1用于：1）早期乳腺癌：T-DM1单药适用于接受了紫杉烷类联合曲妥珠单抗为基础的新辅助治疗后仍残存侵袭性病灶的HER2阳性早期乳腺癌患者的辅助治疗；2）晚期乳腺癌：T-DM1单药适用于接受了紫杉烷类和曲妥珠单抗治疗的HER2阳性、不可切除局部晚期或转移性乳腺癌患者。患者应具备以下任一情形：既往接受过针对局部晚期或转移性乳腺癌的治疗，或在辅助治疗期间或完成辅助治疗后6个月内出现疾病复发。德曲妥珠单抗2019年FDA批准T-DXd乳腺癌适应症，2023年，T-DXd获得NMPA正式批准，单药适用于治疗既往在转移性疾病阶段接受过至少一种系统治疗的，或在辅助化疗期间或完成辅助化疗之后6个月内复发的，不可切除或转移性HER2低表达（IHC 1+或IHC 2+/ISH-）成人乳腺癌患者。小分子TKIs小分子TKIs通过与 HER2 胞内酪氨酸激酶结合，以抑制酪氨酸激酶的磷酸化，从而抑制下游通路的活性。代表药物为拉帕替尼（lapatinib）、奈拉替尼（neratinib）、吡咯替尼（pyrotinib）。拉帕替尼2013年拉帕替尼被NMPA批准与卡培他滨联合使用，适用于HER2过表达且既往接受过包括蒽环类、紫杉类和曲妥珠单抗治疗的晚期或转移性乳腺癌。奈拉替尼2020年，NMPA批准奈拉替尼用于HER2阳性的早期乳腺癌成年患者，在接受含曲妥珠单抗辅助治疗之后的强化辅助治疗。吡咯替尼吡咯替尼是恒瑞医药自主研发且具有知识产权的口服HER1/HER2/HER4酪氨酸激酶抑制剂。吡咯替尼联合卡培他滨，适用于HER2阳性、既往未接受或接受过曲妥珠单抗的复发或转移性乳腺癌患者。使用吡咯替尼前患者应接受过蒽环类或紫杉类化疗。02CDK4/6抑制剂细胞周期蛋白依赖性激酶4和6（CDK4/6）在癌细胞的增殖中起重要作用。CDK4/6活化通过磷酸化导致Rb活化。激活的Rb通过开启E2F转录使细胞周期进展成为可能。此外，CDK4和CDK6通过磷酸化支持FOXM1的稳定和活化，这反过来促进G1/S期基因的上调和避免细胞衰老。CDK4/6抑制剂，如哌柏西利（palbociclib）、瑞波西利（ribociclib）、阿贝西利（abemaciclib）或达尔西利（dalpiciclib），通过抑制CDK4/6下游信号传导事件来阻滞细胞周期。哌柏西利哌柏西利于2015年2月获得FDA批准上市，国内于2018年7月获批用于HR+/HER2-晚期或转移性乳腺癌成人患者：1）与芳香化酶抑制剂（AI）联合使用作为绝经后女性或男性患者的初始内分泌治疗；2）联合氟维司群（fulvestrant）用于接受内分泌疗法后病情进展的患者。瑞波西利瑞波西利于2017年3月获FDA批准上市；于2023年1月19日获得NMPA批准，与AI联合用药，作为HR+/HER2-局部晚期或转移性乳腺癌绝经前或围绝经期女性患者的初始内分泌治疗，使用内分泌疗法治疗时应联用黄体生成素释放激素（LHRH）激动剂。并且，2023年5月，瑞波西利获NMPA批准新增适应症（新增绝经后人群适应症）。自此，瑞波西利成为我国首个且目前唯一一款在晚期乳腺癌一线治疗领域覆盖绝经前/围绝经期、绝经后人群的CDK4/6抑制剂。阿贝西利阿贝西利于2017年9月获得FDA批准上市，并于2020年12月获得NMPA批准，用于HR+/HER2-的局部晚期或转移性乳腺癌：1) 与AI联合使用作为绝经后女性患者的初始内分泌治疗；2) 与氟维司群联合用于既往曾接受内分泌治疗后出现疾病进展的患者。2021年1月，阿贝西利获NMPA批准早期乳腺癌适应症：联合内分泌治疗（他莫昔芬或AI）适用于HR+/HER2-、淋巴结阳性，高复发风险且Ki-67≥20%早期乳腺癌成人患者的辅助治疗，成为国内首个且唯一被批准用于早期乳腺癌患者的CDK4/6抑制剂。达尔西利 2021年，恒瑞医药研发的首款国产CDK4/6抑制剂达尔西利获NMPA批准联合氟维司群，适用于既往接受内分泌治疗后出现疾病进展的HR阳性、HER2阴性的复发或转移性乳腺癌患者。03PARP抑制剂PARP抑制剂是一种靶向聚ADP核糖聚合酶（Poly ADP-ribose Polymerase，PAR）的抗癌疗法。PARP是一种DNA修复酶，在DNA修复通路中起关键作用，能够有效治疗带有BRCA突变蛋白之类缺乏DNA同源重组修复机制的肿瘤，抑制PARP可阻止DNA修复并导致DNA链断裂。代表药物有奥拉帕利（olaparib）和他拉唑帕利（talazoparib）等。奥拉帕利2018年1月，FDA批准奥拉帕利用于治疗携带BRCA突变的HER2阴性转移性乳腺癌。这是PARP抑制剂首次获批用于治疗乳腺癌。奥拉帕利在我国获批了上皮性卵巢癌、输卵管癌或原发性腹膜癌及前列腺癌适应症，暂未获批乳腺癌适应症。他拉唑帕利他拉唑帕利于2018年10月由FDA批准上市，用于治疗BRCA突变、HER2阴性晚期或转移乳腺癌的患者，成为第二个治疗该类型患者的PARP抑制剂。2023年4月1日，CDE官网公示，辉瑞（Pfizer）递交了甲苯磺酸他拉唑帕利胶囊的上市申请并获得受理。04靶向VEGF药物血管内皮生长因子（VEGF）是血管生成的关键因素，而血管新生是导致肿瘤发生、发展、转移的主要原因，因此，靶向血管新生的治疗也是乳腺癌治疗的重要策略之一。 目前，乳腺癌领域针对VEGF靶点的抗血管新生药物包括：靶向VEGF的贝伐珠单抗和靶向血管内皮细胞生长因子受体2（VEGFR2）的雷莫芦单抗，以及多靶点的舒尼替尼（sunitinib）、索拉非尼（sorafenib），这些药物均尚未获批乳腺癌的适应症。贝伐珠单抗贝伐珠单抗是一种抗VEGF单克隆抗体，基于E2100试验（NCT 00028990）的结果，FDA在2008年2月批准了贝伐珠单抗联合化疗（紫杉醇）用于治疗转移性乳腺癌。然而，由于贝伐珠单抗不能改善总生存期且药价昂贵，该方案的疗效和成本效益存在争议。这导致 FDA 于 2011 年撤销了该批准。相比之下，欧洲肿瘤内科学会 (ESMO) 和美国国家综合癌症网络 (NCCN)指南仍推荐该方案。05靶向PI3K/AKT/mTOR通路抑制剂磷脂酰肌醇3激酶/蛋白激酶B/哺乳类动物雷帕霉素靶蛋白（PI3K/Akt/mTOR）是细胞内存在的一个重要的信号通路，在乳腺癌的发生发展过程中，PI3K/AKT/mTOR通路发挥重要作用。它一方面处于HER2通路下游，PI3K/AKT/mTOR通路活化参与曲妥珠单抗治疗耐药；另一方面，它还与雌激素受体信号通路交互激活，参与内分泌治疗继发耐药的发病机制。mTOR抑制剂的代表药物为依维莫司（everolimus）。PI3K抑制剂代表药物为阿培利司（alpelisib）。依维莫司2013年8月NMPA批准依维莫司联合依西美坦用于治疗来曲唑或阿那曲唑治疗失败后的HR阳性、HER2阴性绝经后晚期女性乳腺癌患者。阿培利司阿培利司于2019年5月24日获美国FDA批准上市，与氟维司群联用治疗男性和绝经后女性的HR+/HER2-、携带PIK3CA突变的晚期转移性乳腺癌。同FDA还批准了一个筛选试剂盒，用以检测组织和/或液体活检中的PIK3CA突变。阿培利司是首个用于治疗该类乳腺癌的PI3K（具体是PI3Kα）抑制剂，目前已在我国香港获批上市。06Trop-2靶向ADC戈沙妥珠单抗戈沙妥珠单抗（sacituzumab govitecan）是一种由靶向滋养层细胞表面抗原-2（Trop-2）的抗体和拓扑异构酶抑制剂偶联组成的ADC。Trop-2是一种在许多类型肿瘤（包括超过 90% 的乳腺癌和膀胱癌）中均过度表达的细胞表面抗原。戈沙妥珠单抗有一个可与有效载荷拓扑异构酶Ⅰ抑制剂SN-38相连的可水解接头。这种独特的设计保证了在Trop-2 表达细胞和邻近微环境中的有效活性。2020年，FDA批准戈沙妥珠单抗的乳腺癌适应症。2022年，NMPA批准戈沙妥珠单抗用于既往至少接受过两种系统治疗（其中至少一种治疗针对转移性疾病），不可切除的局部晚期或转移性三阴性乳腺癌成人患者。07组蛋白去乙酰化酶抑制剂组蛋白是真核细胞染色质中的碱性蛋白质，与 DNA 共同组成核小体结构。组蛋白修饰（包括乙酰化、甲基化/去甲基化、泛素化/去泛素化等）可以改变染色质构型，导致转录激活或者基因沉默，从而调控基因表达。组蛋白去乙酰化酶（HDAC）抑制剂作为抗癌药的原理是通过抑制组蛋白去乙酰化酶的活性，提高组蛋白的乙酰化水平引发染色质重塑，改变肿瘤发生的多条信号通路的基因表达，促进肿瘤细胞生长停滞、分化及凋亡。西达本胺西达本胺是我国自主研发生产的新一代HDAC抑制剂，西达本胺通过选择性抑制相关 HDAC亚型，产生针对多条信号传递通路基因表达的改变（即表观遗传改变），进而抑制肿瘤细胞周期、诱导肿瘤细胞凋亡，同时对机体细胞免疫具有整体调节活性，诱导和增强自然杀伤细胞（NK）和抗原特异性细胞毒 T 细胞 （CTL介）导的肿瘤杀伤作用，与抗雌激素治疗药物具有抑制肿瘤生长的协同作用。2019年，NMPA批准西达本胺联合AI用于HR+/HER2-、绝经后、经内分泌治疗复发或进展的局部晚期或转移性乳腺癌患者。小结随着生物技术和医药研发的进步，肿瘤治疗已经从早期的化疗时代迈入了高度个体化的精准医疗时代。靶向治疗和免疫治疗的问世给肿瘤患者带来了更多希望，生存期和生活质量都得到明显改善。同时，我们也要注意合理使用药物，规范治疗方案，为每一位患者选择最合适的药物和治疗方式。通过积极开展基础研究，不断优化临床设计，我们有理由相信，随着科技的进一步发展，肿瘤治疗将会更加准确和高效。相关阅读1. 乳腺癌｜新型抗肿瘤药物临床应用指导原则（2022年版）2. 靶向HER2阳性乳腺癌：研究进展和未来方向（上）3. 靶向HER2阳性乳腺癌：研究进展和未来方向（下）4. PHARMACOL REV｜靶向雄激素受体治疗三阴性乳腺癌5. 乳腺癌靶向治疗和免疫治疗的临床进展——靶向治疗篇参考文献[1] edard PL, Hyman DM, Davids MS, Siu LL. Small molecules, big impact: 20 years of targeted therapy in oncology. Lancet. 2020 Mar 28;395(10229):1078-1088. doi: 10.1016/S0140-6736(20)30164-1.[2] FDA (1998). These highlights do not include all the information needed to use Herceptin safely and effectively. See full prescribing information for Herceptin. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/103792s5250lbl.pdf.[3] FDA (2018). These highlights do not include all the information needed to use TYKERB safely and effectively. See full prescribing information for TYKERB. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022059s007lbl.pdf.[4] FDA (2010). Drugs at FDA. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022334s6lbl.pdf.[5] FDA (2012). Drugs at FDA. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/125409orig1s000ltr.pdf.[6] FDA (2019). FDA approves ado-trastuzumab emtansine for early breast cancer. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ado-trastuzumab-emtansine-early-breast-cancer[7] FDA (2015). These highlights do not include all the information needed to use IBRANCE safely and effectively. See full prescribing information for IBRANCE. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/207103s008lbl.pdf.[8] FDA (2022). Drugs at FDA. Available at: https://investor.lilly.com/news-releases/news-release-details/us-fda-broadens-indication-verzenior-abemaciclib-hr-her2-node.[9] FDA (2018). FDA approves first cancer drug through new oncology review pilot that enables greater development efficiency. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-cancer-drug-through-new-oncology-review-pilot-enables-greater-development[10] FDA (2017). Assessed date drugsatfda. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208051s000lbl.pdf.[11] FDA (2022). FDA approves olaparib for adjuvant treatment of high-risk early breast cancer. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-adjuvant-treatment-high-risk-early-breast-cancer[12] FDA (2018). FDA approves talazoparib for gBRCAm HER2-negative locally advanced or metastatic breast cancer. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-gbrcam-her2-negative-locally-advanced-or-metastatic-breast-cancer#:~:text=On%20October%2016%2C%202018%2C%20the%20Food%20and%20Drug,%28gBRCAm%29%2C%20HER2%E2%80%91negative%20locally%20advanced%20or%20metastatic%20breast%20cancer[13] FDA (2019). FDA approves alpelisib for metastatic breast cancer. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-alpelisib-metastatic-breast-cancer[14] FDA (2022). FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-her2-low-breast-cancer[15] FDA (2020). FDA approves margetuximab for metastatic HER2-positive breast cancer. Available at:https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-margetuximab-metastatic-her2-positive-breast-cancer.[16] FDA (2023). Drugs at FDA. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/213411s004lbl.pdf.[17] Wahby S, Fashoyin-Aje L, Osgood CL, et al. FDA Approval Summary: Accelerated Approval of Sacituzumab Govitecan-hziy for Third-line Treatment of Metastatic Triple-negative Breast Cancer. Clin Cancer Res. 2021 Apr 1;27(7):1850-1854. doi: 10.1158/1078-0432.CCR-20-3119.[18] Mohini Chaurasia, Romi Singh, Srija Sur,et al. A review of FDA approved drugs and their formulations for the treatment of breast cancer. Frontiers in Pharmacology. Volume 14 - 2023 | https://doi.org/10.3389/fphar.2023.1184472.责任编辑：肿瘤资讯-Paine排版编辑：肿瘤资讯-Paine               版权声明本文专供医学专业人士参考，未经著作人许可，不可出版发行。同时，欢迎个人转发分享，其他任何媒体、网站如需转载或引用本网版权所有内容，须获得授权，且在醒目位置处注明“转自：良医汇-肿瘤医生APP”。

Achieved efficacy threshold to advance Epstein-Barr virus-positive (EBV+) peripheral T-cell lymphoma into Stage 2 becoming the leading indication in pivotal NAVAL-1 study of Nana-val Prioritized EBV+ diffuse large B-cell lymphoma and EBV+ post-transplant lymphoproliferative disease as key follow-on indications in NAVAL-1 trial Published Phase 1b/2 clinical trial data reporting promising durable signal of efficacy for Nana-val in patients with relapsed or refractory EBV+ lymphoma in Blood Advances, a Journal of the American Society of Hematology Completed enrollment into the fifth dose escalation level of the Phase 1b/2 study of Nana-val in advanced EBV+ solid tumors without any dose-limiting toxicities Strengthened leadership with the appointment of Darrel P. Cohen, M.D., Ph.D. as Chief Medical Officer SAN DIEGO, Aug. 14, 2023 (GLOBE NEWSWIRE) -- Viracta Therapeutics, Inc. (Nasdaq: VIRX), a clinical-stage precision oncology company focused on the treatment and prevention of virus-associated cancers that impact patients worldwide, today provided a business update and reported financial results for the second quarter of 2023. “In the second quarter of 2023, we achieved key milestones in the pivotal NAVAL-1 study of Nana-val by enabling the advancement of this global clinical trial into Stage 2 and establishing EBV-positive PTCL as Nana-val’s leading indication. This milestone was based on a strong signal of efficacy with a favorable safety profile, consistent with our promising Phase 1b/2 clinical trial data,” said Mark Rothera, President and Chief Executive Officer of Viracta. “Given the high unmet medical need in patients with EBV-positive PTCL and our positioning of Nana-val as a potential important treatment option for these patients, our goal is to move forward rapidly towards registration in the U.S. We intend to complete Stage 2 enrollment and meet with the U.S. Food and Drug Administration in 2024 to discuss additional requirements for regulatory approval.” Darrel P. Cohen, M.D., Ph.D., Chief Medical Officer of Viracta commented, “We are thrilled to have our Phase 1b/2 study results published in a high-quality peer-reviewed journal, such as Blood Advances, which underscores the potential of Nana-val to treat patients with EBV-positive lymphoma and elevates the importance of the NAVAL-1 trial. Following the advancement of the PTCL cohort and to optimize our resources behind this trial, we have strategically prioritized key subtypes of EBV-positive lymphoma where we can address high unmet medical needs, increase the probability of success, and focus on the largest EBV-positive lymphoma patient populations.” Clinical Trial Updates and Anticipated Milestones Pivotal NAVAL-1 study of Nana-val in patients with relapsed or refractory (R/R) EBV+ lymphoma The EBV+ peripheral T-cell lymphoma (PTCL) cohort of the pivotal NAVAL-1 clinical trial met the efficacy threshold for expansion into Stage 2 of the study, which was based upon a pre-specified minimum number of objective responses achieved; initial data are consistent with results from the Phase 1b/2 study and establish EBV+ PTCL as Nana-val’s leading indication. Strategically prioritized three lymphoma subtypes: (1) EBV+ PTCL, a T-cell lymphoma with high unmet medical need; (2) EBV+ diffuse large B-cell lymphoma (DLBCL), an aggressive and distinct B-cell lymphoma subtype characterized by adverse clinical outcomes, and (3) EBV+ PTLD, a potentially fatal complication after transplantation, which is highly associated with EBV. Prioritization also enables the allocation of resources to those indications with the greatest probability of success and market opportunity in key geographies. Enrollment into HIV-lymphoma and Hodgkin lymphoma cohorts will be discontinued. Patients with extranodal NK/T-cell lymphoma (ENKTL) and other ultra-rare subtypes of EBV+ lymphoma will continue to be enrolled. Completion of enrollment into Stage 2 of the R/R EBV+ PTCL cohort and engagement with FDA on additional requirements for regulatory approval is anticipated in 2024. Phase 1b/2 clinical trial of Nana-val in patients with R/R EBV+ lymphoma In August 2023, Viracta announced the publication in Blood Advances featuring results from an open-label, multicenter, Phase 1b/2 study of Nana-val in patients with R/R EBV+ lymphoma titled, “Targeted therapy with nanatinostat and valganciclovir in recurrent Epstein-Barr virus-positive lymphoid malignancies: a Phase 1b/2 study.” The publication included a more recent data cut reflecting multiple patients with an ongoing durable response exceeding 30 months across multiple EBV+ lymphoma subtypes, including EBV+ PTCL and EBV+ DLBCL, and two patients with an ongoing response of approximately 36 months. Nana-val was generally well tolerated with reversible low-grade toxicities. The most commonly observed treatment emergent adverse events were reversible cytopenias, low-grade creatinine elevations, and gastrointestinal symptoms. Phase 1b/2 study of Nana-val in patients with recurrent or metastatic (R/M) EBV+ nasopharyngeal carcinoma (NPC) and other advanced EBV+ solid tumors Enrollment completed through the fifth dose level of the Phase 1b dose escalation portion of the trial without any dose-limiting toxicities reported. The Company remains on track to report complete Phase 1b dose escalation data and select a Recommended Phase 2 Dose (RP2D) of Nana-val in the second half of 2023. Initiation of the trial’s randomized Phase 2 expansion cohort designed to evaluate Nana-val at the RP2D with or without pembrolizumab in patients with R/M EBV+ NPC is expected in the second half of 2023. Initiation of the trial’s exploratory Phase 1b expansion cohort designed to evaluate Nana-val at the RP2D in patients with other advanced EBV+ solid tumors, including gastric carcinoma, leiomyosarcoma, and lymphoepithelioma, is expected in the second half of 2023. Business Updates Strengthened the leadership team with the appointment of Darrel P. Cohen, M.D., Ph.D. as Chief Medical Officer (CMO) In August 2023, Dr. Cohen was appointed as CMO to oversee the clinical development and regulatory advancement of Viracta’s pipeline. Dr. Cohen is a highly accomplished physician and biopharmaceutical executive with more than 25 years of oncology clinical research and drug development experience in both solid tumors and hematologic malignancies. Dr. Cohen was involved in multiple successful regulatory submissions of new targeted cancer drugs such as SUTENT® (sunitinib), XALKORI® (crizotinib), and IBRANCE® (palbociclib) while at Pfizer Oncology. Strengthened intellectual property estate In July 2023, Viracta received a Notice of Allowance from the US Patent and Trademark Office on Viracta’s patent claims directed to a next-generation formulation of nanatinostat. This Notice of Allowance supports Viracta’s life-cycle management strategy, and upon issuance, the claims will expire in October 2041. Second Quarter 2023 Financial Results Cash position – Cash, cash equivalents, and short-term investments totaled approximately $72.9 million as of June 30, 2023, which Viracta expects will be sufficient to fund its operations into late 2024 excluding any additional borrowing under a $50.0 million credit facility, of which $25.0 million remains available, at the Company’s request and subject to the discretion of the lenders. Research and development expenses – Research and development (R&D) expenses were approximately $8.2 million and $15.8 million for the three and six months ended June 30, 2023, respectively, compared to approximately $6.3 million and $12.4 million for the same periods in 2022. This increase in R&D expenses was primarily driven by increases in costs incurred to support the advancement and expansion of our clinical development programs, including incremental costs to support NAVAL-1, our pivotal study of Nana-val in patients with R/R EBV+ lymphoma, and the initiation of our Phase 1b/2 study of Nana-val for the treatment of patients with EBV+ solid tumors, as well as an increase in personnel-related costs. General and administrative expenses – General and administrative (G&A) expenses were approximately $4.3 million and $8.9 million for the three and six months ended June 30, 2023, respectively, compared to $4.2 million and $8.5 million for the same periods in 2022. The increase in G&A expenses can be primarily attributed to an increase in personnel-related costs. Net loss – Net loss was approximately $12.5 million, or $0.32 per share, (basic and diluted) for the quarter ended June 30, 2023, compared to a net loss of $10.6 million, or $0.28 per share, (basic and diluted) for the same period in 2022. Net loss was approximately $24.7 million, or $0.64 per share, (basic and diluted) for the six months ended June 30, 2023, compared to a net loss of $21.1 million, or $0.56 per share, (basic and diluted) for the same period in 2022. About NAVAL-1 NAVAL-1 (NCT05011058) is a global, multicenter, clinical trial of Nana-val in patients with relapsed or refractory (R/R) Epstein-Barr virus-positive (EBV+) lymphoma. This trial employs a Simon two-stage design where, in Stage 1, participants are enrolled into one of six indication cohorts based on EBV+ lymphoma subtype. If a pre-specified antitumor activity threshold is reached within a lymphoma subtype in Stage 1 (n=10), then additional patients will be enrolled in Stage 2 for a total of 21 patients. EBV+ lymphoma subtypes demonstrating promising antitumor activity in Stage 2 may be further expanded following discussion with regulators to potentially support registration. About the Phase 1b/2 Study of Nana-val in R/M EBV+ NPC and Other EBV+ Solid Tumors This Phase 1b/2 trial (NCT05166577) is an open-label, multinational clinical trial evaluating Nana-val alone and in combination with pembrolizumab. The Phase 1b dose escalation part is designed to evaluate safety and to determine the Recommended Phase 2 Dose (RP2D) of Nana-val in patients with recurrent or metastatic (R/M) Epstein-Barr virus-positive (EBV+) nasopharyngeal carcinoma (NPC). In Phase 2, up to 60 patients with R/M EBV+ NPC will be randomized to receive Nana-val at the RP2D with or without pembrolizumab to further evaluate antitumor activity, safety and tolerability, pharmacokinetics, and potential pharmacodynamic biomarkers. Additionally, patients with other advanced EBV+ solid tumors will be enrolled to receive Nana-val at the RP2D in a Phase 1b dose expansion cohort. About Nana-val (Nanatinostat and Valganciclovir) Nanatinostat is an orally available histone deacetylase (HDAC) inhibitor being developed by Viracta. Nanatinostat is selective for specific isoforms of Class I HDACs, which are key to inducing viral genes that are epigenetically silenced in Epstein-Barr virus (EBV)-associated malignancies. Nanatinostat is currently being investigated in combination with the antiviral agent valganciclovir as an all-oral combination therapy, Nana-val, in various subtypes of EBV-associated malignancies. Ongoing trials include a pivotal, global, multicenter, open-label Phase 2 basket trial in multiple subtypes of relapsed or refractory (R/R) EBV+ lymphoma (NAVAL-1) as well as a multinational Phase 1b/2 clinical trial in patients with recurrent or metastatic (R/M) EBV+ NPC and other EBV+ solid tumors. About EBV-Associated Cancers Approximately 90% of the world's adult population is infected with EBV. Infections are commonly asymptomatic or associated with mononucleosis. Following infection, the virus remains latent in a small subset of cells for the duration of the patient's life. Cells containing latent virus are increasingly susceptible to malignant transformation. Patients who are immunocompromised are at an increased risk of developing EBV-positive (EBV+) lymphomas. EBV is estimated to be associated with approximately 2% of the global cancer burden including lymphoma, nasopharyngeal carcinoma (NPC), and gastric cancer. About Viracta Therapeutics, Inc. Viracta is a clinical-stage precision oncology company focused on the treatment and prevention of virus-associated cancers that impact patients worldwide. Viracta’s lead product candidate is an all-oral combination therapy of its proprietary investigational drug, nanatinostat, and the antiviral agent valganciclovir (collectively referred to as Nana-val). Nana-val is currently being evaluated in multiple ongoing clinical trials, including a pivotal, global, multicenter, open-label Phase 2 basket trial for the treatment of multiple subtypes of relapsed or refractory (R/R) Epstein-Barr virus-positive (EBV+) lymphoma (NAVAL-1), as well as a multinational, open-label Phase 1b/2 clinical trial for the treatment of patients with recurrent or metastatic (R/M) EBV+ nasopharyngeal carcinoma (NPC) and other advanced EBV+ solid tumors. Viracta is also pursuing the application of its “Kick and Kill” approach in other virus-related cancers. For additional information, please visit . Forward-Looking Statements This communication contains "forward-looking" statements within the meaning of the Private Securities Litigation Reform Act of 1995, including, without limitation, statements regarding: the details, timeline and expected progress for Viracta's ongoing and anticipated clinical trials and updates regarding the same, the Company’s expectations related to the FDA submission process and timelines, expectations regarding our target patient populations, and expectations regarding our cash runway. Risks and uncertainties related to Viracta that may cause actual results to differ materially from those expressed or implied in any forward-looking statement include, but are not limited to: Viracta's ability to successfully enroll patients in and complete its ongoing and planned clinical trials; Viracta's plans to develop and commercialize its product candidates, including all oral combinations of nanatinostat and valganciclovir; the timing of initiation of Viracta's planned clinical trials; the timing of the availability of data from Viracta's clinical trials; previous preclinical and clinical results may not be predictive of future clinical results; the timing of any planned investigational new drug application or new drug application; Viracta's plans to research, develop, and commercialize its current and future product candidates; the clinical utility, potential benefits, and market acceptance of Viracta's product candidates; Viracta's ability to manufacture or supply nanatinostat, valganciclovir, and pembrolizumab for clinical testing; Viracta's ability to identify additional products or product candidates with significant commercial potential; developments and projections relating to Viracta's competitors and its industry; the impact of government laws and regulations; Viracta's ability to protect its intellectual property position; and Viracta's estimates regarding future expenses, capital requirements, and need for additional financing in the future. If any of these risks materialize or underlying assumptions prove incorrect, actual results could differ materially from the results implied by these forward-looking statements. Additional risks and uncertainties that could cause actual outcomes and results to differ materially from those contemplated by the forward-looking statements are included under the caption "Risk Factors" and elsewhere in Viracta's reports and other documents that Viracta has or will file, with the SEC from time to time and available at . The forward-looking statements included in this communication are made only as of the date hereof. Viracta assumes no obligation and does not intend to update these forward-looking statements, except as required by law or applicable regulation. Investor Relations Contact: Ashleigh Barreto Head of Investor Relations & Corporate Communications Viracta Therapeutics, Inc. abarreto@viracta.com SOURCE Viracta Therapeutics, Inc. -- Financial tables attached – Viracta Therapeutics, Inc. Selected Balance Sheet Highlights (in thousands) June 30, December 31, 2023 2022 (Unaudited) Cash, cash equivalents and short-term investments $ 72,867 $ 91,043 Total assets $ 76,859 $ 95,991 Total liabilities $ 36,077 $ 34,888 Stockholders' equity $ 40,782 $ 61,103 Viracta Therapeutics, Inc. Condensed Consolidated Statement of Operations and Comprehensive Loss (in thousands except share and per share data) (Unaudited) Three Months Ended June 30, Six Months Ended June 30, 2023 2022 2023 2022 Operating expenses: Research and development $ 8,197 $ 6,324 $ 15,804 $ 12,420 General and administrative 4,253 4,181 8,853 8,517 Total operating expenses 12,450 10,505 24,657 20,937 Loss from operations (12,450 ) (10,505 ) (24,657 ) (20,937 ) Total other expense (34 ) (77 ) (36 ) (191 ) Net loss (12,484 ) (10,582 ) (24,693 ) (21,128 ) Unrealized (loss) gain on short-term investments (28 ) — 63 — Comprehensive loss (12,512 ) (10,582 ) (24,630 ) (21,128 ) Net loss per share, basic and diluted $ (0.32 ) $ (0.28 ) $ (0.64 ) $ (0.56 ) Weighted-average common shares outstanding, basic and diluted 38,560,376 37,599,244 38,509,887 37,567,734