PALB2

关注并星标CPHI制药在线日前，恒瑞医药的「氟唑帕利胶囊」和「甲磺酸阿帕替尼片」被CDE拟纳入突破性治疗品种，适应症为：两者联合治疗gBRCA突变的HER2阴性乳腺癌。       氟唑帕利（艾瑞颐®）是恒瑞医药自主研发的一款PARP抑制剂，已在国内获批两项适应症：既往经二线及以上化疗的伴有胚系BRCA突变(gBRCAm)的铂敏感复发性卵巢癌、输卵管癌或原发性腹膜癌（2020.12）；铂敏感的复发性上皮性卵巢癌、输卵管癌或原发性腹膜癌成人患者在含铂化疗达到完全缓解或部分缓解后的维持治疗（2021.06）。此外，氟唑帕利单药或联合阿帕替尼用于晚期上皮性卵巢癌、输卵管癌或原发性腹膜癌患者在一线含铂化疗达到完全缓解或部分缓解后的维持治疗的上市申请正在国内接受审查（相关受理号为：CXHS2300070）。       甲磺酸阿帕替尼（艾坦®）是恒瑞自主研发的小分子抗血管生成靶向药（作用靶点为VEGFR-2），目前已在国内获批三项适应症：既往至少接受过2种系统化疗后进展或复发的晚期胃腺癌或胃-食管结合部腺癌（2014.10）；既往接受过至少一线系统性治疗后失败或不可耐受的晚期肝细胞癌（HCC）（2020.12）；联合PD-1抑制剂卡瑞利珠单抗一线治疗晚期肝细胞癌（2023.01）。       氟唑帕利联合阿帕替尼被开发用于治疗gBRCA突变、HER2-乳腺癌是有理论和临床研究支持的。研究发现，抗血管生成药物可以引起肿瘤微环境缺氧，导致遗传不稳定性和BRCA1/2的下调，从而增强对PARP抑制剂的敏感性。既往研究也表明PARP抑制剂来联合抗血管生成药物可改善患者PFS。       《BMC Medicine》上发表的氟唑帕利联合阿帕替尼治疗晚期卵巢癌和三阴性乳腺癌的1期研究结果显示：最高剂量下，即氟唑帕利100mg联合阿帕替尼500mg治疗组的客观缓解率（ORR）为50%，其中gBRCA突变的患者ORR和中位无进展生存期（PFS）均优于gBRCA野生型患者。而且，氟唑帕利联合阿帕替尼治疗晚期卵巢癌或三阴性乳腺癌患者安全性良好。期待氟唑帕利联合阿帕替尼可以早日攻克gBRCA突变、HER2-乳腺癌。       gBRCA突变、HER2-乳腺癌治疗现状       据WHO最新数据，乳腺癌已取代肺癌成为全球第一大恶性肿瘤，2020年全球新增病例达226万。BRCA1/2基因是目前已知最主要的乳腺癌易感基因，约5%-10%的乳腺癌患者携带BRCA基因突变。携带BRCA1/2基因突变的乳腺癌在临床上表现出更强的侵袭性，预后相对较差。       BRCA是人体内重要的抑癌基因，主要通过同源重组修复（HRR）途径参与DNA双链断裂修复，来“医治”细胞内因突变而造成的遗传物质的损伤，防治细胞癌变。BRCA突变包括胚系BRCA（gBRCA）突变和体细胞BRCA（sBRCA）突变，其中gBRCA突变来源于生殖细胞（卵子/精子），在三阴性乳腺癌（TNBC，ER-/PR-/HRE2-）和HR+/HER2-型乳腺癌患者中发生率较高。       PARP（多聚腺苷二磷酸核糖聚合酶）主要作用于DNA单链损伤修复，当双链断裂修复过程中的BRCA1、BRCA2和PALB2等蛋白所在的DNA同源重组修复（HRR）通路失效时，PARP就能接替HRR工作继续进行DNA修复。基于“合成致死”原理，理论上PARP抑制剂可用于治疗BRCA突变肿瘤。       目前，全球获批治疗gBRCA突变、HER2阴性乳腺癌的疗法有限。其中阿斯利康与默沙东合作开发的PARP抑制剂奥拉帕利（Lynparza）于2018年1月被FDA批准用于治疗携带gBRCA基因突变、HER2-转移性乳腺癌。此外，该药还于2022年3月被FDA批准单药或联合内分泌治疗用于既往接受过新辅助或辅助化疗的gBRCA1/2突变的HER2-早期高危乳腺癌成人患者的辅助治疗。辉瑞PARP抑制剂他拉唑帕利（Talzenna）于2018年10月被FDA批准用于治疗gBRCA突变、HER2-局部晚期或转移性乳腺癌。       遗憾的是，上述两款药物均未在国内获批治疗gBRCA突变、HER2-乳腺癌。不过奥拉帕利单药或联合内分泌疗法用于既往接受过新辅助或辅助化疗的gBRCA1/2突变、HER2-早期高危乳腺癌成人患者辅助治疗的上市申请正在国内接受优先审查。       此外，国内还有多款PARP抑制剂被开发用于治疗gBRCA突变、HER2-乳腺癌，如天士力的TSL-1502、百济神州的帕米帕利、上海药物研究所的希明哌瑞。       其中TSL-1502是天士力帝益药业开发的一款PARP抑制剂，对多种BRCA1/2突变的人肿瘤裸小鼠皮下移植模型有明显疗效，并且对BRCA野生型肿瘤明显增效其他细胞毒药物（卡铂、伊立替康）的抗肿瘤作用。而且，TSL-1502体内、体外活性总体上与奥拉帕利相当。目前，TSL-1502针对gBRCA突变、HER2-局部晚期或转移性乳腺癌的临床试验已进入2期。       帕米帕利是一种PARP1和PARP2的强效、选择性抑制剂，已于2021年5月在国内被批准用于治疗既往经过二线及以上化疗的伴gBRCA突变的复发性晚期卵巢癌、输卵管癌或原发性腹膜癌。已公布的帕米帕利治疗携带gBRCA突变晚期或转移性TNBC和HR+/HER2-乳腺癌的开放标签、单臂2期临床研究BGB-290-201数据显示：TNBC队列中，独立评审委员会(IRC)评估的客观反应率（ORR）为38.2%，中位缓解持续时间(mDoR)为7.0个月，中位无进展生存期(mPFS)为5.5个月，中位总生存期(mOS)为17.1个月；HR+/HER2-队列中，IRC评估的ORR为61.9%，mDoR为7.5个月，mPFS为9.2个月，mOS未达到。       而且，TNBC的ORR亚组分析显示，既往接受化疗线数较少的患者ORR更高：帕米帕利一线治疗患者的ORR达到66.7%；帕米帕利二线治疗患者ORR的为34.5%；帕米帕利三线治疗患者的ORR为9.1%。同时，与使用过铂类患者相比，未使用过铂类患者有更高的ORR：既往未接受铂治疗的患者ORR达到50.0%，既往接受铂治疗的患者ORR为24.0%。       安全性方面，帕米帕利治疗乳腺癌最常见的≥3级治疗相关TEAE是血液学不良事件，包括贫血、白细胞计数水平下降和中性粒细胞计数水平下降等，发生率与其他PARP抑制剂相一致，整体安全可控。       BGB-290-201研究是首 个公布PARP抑制剂专门针对中国乳腺癌患者疗效和安全性数据的临床研究，已公布的数据也算积极，帕米帕利未来或成为我国携带gBRCA突变晚期或转移性TNBC和HR+/HER2-乳腺癌患者的新选择。不过笔者疑惑的是，自2021年该研究数据公布后，帕米帕利在该适应症上未再公布新进展。       总结       随着下一代测序技术（NGS）的发展，BRCA基因检测更加便捷和准确。乳腺癌NCCN指南2022.v4版推荐对所有复发或转移性乳腺癌患者行胚系BRCA1/2突变评估，以确定适合接受PARP抑制剂治疗的患者。目前，全球获批治疗携带gBRCA基因突变、HER2-乳腺癌的PARP抑制剂仅有奥拉帕利和他拉唑帕利。       目前，国内还未有PARP抑制剂获批治疗携带gBRCA突变、HER2-乳腺癌，该领域还存在很大未满足的市场需求。从目前相关药物进度来看，阿斯利康的奥拉帕利有望在国内率先获批。       恒瑞医药开发氟唑帕利联合阿帕替尼治疗携带gBRCA基因突变、HER2-乳腺癌有望给药企在该领域开发性药物组合带来新思路。目前全球已有多款CDK4/6抑制剂被开发用于治疗HR+/HER-乳腺癌、Trop-2靶向ADC、PD-1/L单抗被批准用于治疗TNBC，或许PARP抑制剂可以联合更多类型药物治疗携带gBRCA突变、HER2-乳腺癌。【智药研习社近期课程预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

前言胃癌是一个全球性的健康挑战。2020年胃癌新增病例1089103例，死亡768793例，是全球第五大常见癌症和第四大癌症死亡原因。胃癌的流行病学分布因性别和地理区域而异，男性的发病率是女性的两倍，东亚和东欧的发病率更高。胃癌通常可以根据两个解剖亚型分类，此外也包括不同的组织学和分子亚型。晚期胃癌和胃食管交接部癌（GOJC）患者的预后较差，5年相对生存率为6%。尽管化疗和手术方案有所改善，但这些患者的预后仍然很差。在晚期胃癌中，只有曲妥珠单抗和一些免疫检查点抑制剂，如nivolumab和pembrolizumab以及化疗，分别在HER2阳性和PD-L1阳性肿瘤患者中显示出一致和可靠的疗效。目前，针对胃癌和胃食管癌的内在特征，多种药物正在进行II期和III期临床试验，这些试验涉及靶向药物或免疫疗法，部分已经显示出良好的应用前景，有望改善胃癌患者的预后和生存。胃癌的分子特征约40%的胃癌在编码受体酪氨酸激酶蛋白（RTK）的基因中有扩增，如EGFR、ERBB2（HER2）、ERBB3、FGFR2、JAK2和MET、KRAS或NRAS、细胞周期介质和VEGFA。开发中的大多数胃癌II期和III期临床试验都是针对这些分子异常的治疗药物。2014年，癌症基因组图谱（TCGA）计划确定了四种胃癌亚型：EBV、微卫星不稳定型（MSI）、染色体不稳定型（CIN）和基因组稳定型。分子亚型与预后相关，MSI和EBV亚型切除胃癌肿瘤的患者术后进展似乎比其他肿瘤亚型患者好，基因组稳定的胃癌患者无复发生存率最差，CIN亚型患者从辅助化疗中获益最多。在转移性环境中， MSI-H的肿瘤患者对免疫检查点抑制剂（ICI）的治疗有最大反应。这些分子特征显示了患者间的异质性，这是一系列II期和III期临床试验失败的主要原因。此外，高达36%的胃癌表现出空间内异质性，原发性和转移性病变之间存在不一致。当比较靶向治疗前后同一患者的肿瘤样本时，还显示出时间异质性。通常与耐药机制有关。抗HER2治疗在一线治疗中，抗HER2抗体trastuzumab在2010年的III期TOGA试验中，在HER2阳性肿瘤患者中显示出益处。实验组患者的中位总生存率有所提高，尤其是免疫组化（IHC）评分为3+或FISH阳性且IHC评分为2+的患者。然而，随后在胃癌和HER2阳性肿瘤患者中进行的不同II期和III期试验的结果令人失望。JACOB试验将化疗加trastuzumab和化疗加trastuzumab以及pertuzumab进行了比较，最终分析未显示总生存率有显著改善（HR 0.84，95%CI  0.71–1.00；P = 0.057)。Lapatinib是EGFR和HER2的小分子酪氨酸激酶双抑制剂，在HER2扩增肿瘤患者的一线（LOGIC试验）和二线（TyTAN试验）治疗中均未显示出疗效。而T-DM1也在HER2扩增肿瘤患者的二线治疗中失败了（GATSBY试验）。 HER2靶向治疗也已在局部晚期可切除胃癌中得到评估。II期NEOHX试验是首次公开的研究，显示了HER2阻断剂的活性。该II期非随机试验在36例HER2阳性胃癌患者中测试了奥沙利铂和卡培他滨与trastuzumab的联合治疗。达到了主要终点，18个月无病生存率为71%（95%CI 53-83%）。此外，提前结束的随机二期PETRARCA试验评估了trastuzumab和pertuzumab联合标准FLOT联合化疗与单独化疗的疗效。双HER2阻断联合FLOT化疗显著提高了病理完全缓解率（12%对35%；P=0.02）和阴性淋巴结的百分比（39%对68%）。部分临床试验的失败，除了归咎于HER2评分的复杂性之外，还包括HER2靶向治疗的耐药机制。一些基因改变可以补偿HER2信号传导阻断，如PTEN的缺失、PIK3CA、FGFR2融合的激活突变以及CCNE1或EGFR的扩增。此外，抗HER2治疗后可产生获得性耐药，HER2表达的缺失是更常见的耐药机制之一；EGFR和MET扩增可以激活PI3K信号，克服路径上游的HER2抑制。为了克服这些挑战，正在开发新型ADC和更有效抗体的新策略。Trastuzumab–deruxtecan是一种新型的ADC，由Trastuzumab、可裂解的四肽连接子和拓扑异构酶I抑制剂有效载荷组成。这种药物具有旁观者效应，能够破坏周围的细胞，考虑到肿瘤的异质性，这种效应是一个很有趣的机制。DESTINY-Gastric01试验是一项针对两种或多种治疗方案的随机II期试验，总体有效率（ORR）的主要目标已实现，两组之间存在显著差异：接受Trastuzumab–deruxtecan治疗的为51%，而对照组（紫杉醇或伊立替康）为14%（P<0.001)。其他HER2靶向ADC目前正在进行临床试验，用于HER2阳性胃癌患者。Margetuximab是一种具有高亲和力的抗HER2抗体，在一期试验中作为单一药物显示出良好的活性，总体控制率为62%，50%的患者病情稳定，12%的患者有部分缓解。Tucatinib是一种小分子药物，可逆地结合HER2受体内部结构域的ATP结合袋，目前正在进行的一项II–III期试验。最后，zanidatamab，一种阻断HER2胞外结构域2和4的双特异性抗体，目前正在研究中。免疫治疗免疫疗法，尤其是ICI，改变了癌症治疗的方向，胃癌也不例外。胃癌包括具有中高肿瘤突变负荷（TMB）的肿瘤，一些亚型如MSI-H肿瘤或EBV相关癌症，对免疫治疗特别敏感。一些抗PD-1药物已在一线环境中与标准化疗联合使用。在包括1581名患者的III期CheckMate-649试验中，Nivolumab联合化疗（奥沙利铂和氟嘧啶）优于单独化疗。实验组的中位总生存期为13.1个月，对照组为11.1个月（P<0.0001）。在KEYNOTE-062试验中，免疫化疗联合治疗的结果没有重复，这是一项采用相同方法进行的pembrolizumab的III期试验，在化疗中加入pembrolizumab与化疗相比没有任何益处。尽管存在争议，但在PD-L1 CPS≥10的人群中，pembrolizumab单药治疗优于化疗。KEYNOTE-590 III期试验主要集中于食管癌，但12%的患者肿瘤位于GOJ。这项研究表明，在所有患者中，在化疗中加入pembrolizumab对总生存率有益处，中位总生存期12.4个月vs 9.8个月（P<0.0001）。总之，关于免疫疗法，每个试验中选择的化疗类型可能会影响结果的差异。ICI的治疗线也有所不同，关于ICI治疗的最佳治疗线仍不确定。考虑到相关试验的令人鼓舞的结果以及胃癌患者的脆弱性，一线治疗可能会带来更好的结果。此外，最近的数据显示HER2和PD-L1阳性之间存在实质性重叠（85%），这支持抗HER2和抗PD-L1双重治疗。目前正在进行ICI和多重激酶抑制剂的联合检测，包括regorafenib和nivolumab或lenvatinib和pembrolizumab的组合。这些组合的基本原理仍然存在疑问，但可以基于ICI和靶向治疗之间可能的协同作用来解释。在局部晚期的围手术期治疗中，免疫治疗也已取得初步结果。已经测试了不同的组合，包括camrelizumab（抗PD-1）加奥沙利铂和5-氟尿嘧啶-亚叶酸（FOLFOX6），toripalimab（抗PD-1）加FLOT，或avelumab（抗PD-L1）加多西紫杉醇-顺铂-5-氟尿酸的改良方案。在新辅助放化疗后的局部晚期疾病中，CheckMate-577研究是首次在GOJC患者中显示nivolumab辅助治疗阳性结果的III期试验。该研究包括食管癌患者（60%；鳞状细胞癌和腺癌）和GOJC患者（40%）。nivolumab组的无病生存率更好（22.4个月 vs 11.0个月；P<0.001)。抗血管生成治疗血管生成是癌症的特征之一，胃癌通常表达高水平的血管内皮生长因子（VEGF）并分泌促血管生成细胞因子。然而，抗血管生成治疗在胃癌的临床实践中的结果一直存在差异。抗VEGFR2抗体Ramucirumab在二线治疗中，与安慰剂相比，显示出有限的单一治疗效果（REGARD试验）；与单独化疗相比，Ramucirumab与紫杉醇的联合略微提高了总生存率（RAINBOW试验）。因此，Ramucirumab和紫杉醇的联合治疗成为新的治疗标准。目前，一项测试Ramucirumab和tusamitamab–ravtansine组合的研究将进一步评估这种有希望的疗效（NCT05071053）。Apatinib是一种VEGFR2的小分子酪氨酸激酶抑制剂，在267名中国患者的临床试验中，与安慰剂相比，它提高了难治性人群的总体生存率。不幸的是，这些结果没有在国际试验中重现。尽管如此，Apatinib作为二线治疗的使用正在评估中。尽管在二线及以上的治疗中有活性，但在一线治疗中靶向血管生成似乎与疗效无关。在未经选择的胃癌患者中，将Ramucirumab（RAINFALL试验）和抗VEGFA单克隆抗体bevacizumab（AVAGAST试验）加入一线化疗时，均未显示出足够的活性。靶向治疗在最初的靶向治疗中，一些靶点未能证明更好的疗效。例如EGFR，在5–10%的胃癌中检测到EGFR扩增或EGFR过表达，但使用单克隆抗体或TKIs在未选定人群中进行的大型III期试验失败。然而，在后期生物标志物分析或小型临床研究中，治疗EGFR扩增肿瘤的患者的结果要好得多，有效率为58%，PFS为10个月，表明在选定人群中有益处。MET受体是肝细胞生长因子的酪氨酸激酶受体，两种针对此靶点的单克隆抗体，分别为onatuzumab和rilotumumab，在一线治疗中进行的两项大型随机III期试验（METGasteric试验和RILOMET-1试验）的结果显示，总体存活率没有改善。MET靶向策略仍然具有挑战性，必须仔细评估肿瘤异质性以及原发和获得性耐药。同源重组修复缺陷使肿瘤对DNA损伤化疗和聚ADP核糖聚合酶抑制剂（PARPi）敏感。在全球7-12%的胃癌中发现了同源重组修复缺陷相关特征，高达3%的患者在同源重组修复相关基因如BRCA1、PALB2和RAD51C中出现了种系突变。然而，一项紫杉醇与olaparib的III期GOLD试验中，显示无明显益处。目前，正在评估其他PARPi和抗血管生成剂以及免疫治疗的组合。已观察到胃癌患者中哺乳动物雷帕霉素（mTOR）靶点的失调，早期试验中报告了口服mTOR抑制剂everolimus的一些活性。III期GRANITE-1试验在656名未选择的胃癌患者中进行。然而，与安慰剂相比，everolimus并没有改善这些患者的总体生存率。虽然，这些最初探索的靶向治疗未能取得很好的疗效，但目前出现一些新的，有前途的靶点，显示出良好的应用前景。FGFR2在全球高达15%的胃癌患者中扩增，并与更糟糕的预后相关，一些药物已经针对该受体进行了测试。例如bemarituzumab在随机II期FIGHT试验中进行了测试，该试验将标准化疗（FOLFOX6）与联合bemarituzumab进行了比较。该组合改善了FGFR2b过表达胃癌的PFS和总生存率。Derazantinib是一种口服的FGFR1、FGFR2和FGFR3 TKI，正在进行一项临床试验测试Derazantinib作为单一疗法或与紫杉醇、ramucirumab或atezolizumab联合治疗携带FGFR2基因畸变的HER2阴性胃癌患者的疗效。Claudins（CLDNs）是维持细胞间紧密连接粘附的蛋白质，CLDN18.2存在于胃粘膜的分化上皮细胞中，在胃癌患者中高表达。zolbetuximab是一种靶向CLDN18.2的嵌合IgG1抗体，在随机II期FAST试验中，与一线化疗相比，在化疗中加入zolbetuximab提高了PFS和总生存率。此外，一些新的抗CLDN18.2药物正在评估中。例如，针对CLDN18.2特异性的CAR-T细胞正在进行的I期临床试验中报告了阳性结果，28例CLDN18.2阳性胃癌患者的有效率为57.1%。目前，其他临床试验正在进行中。小结胃癌是世界上第五大最常见的癌症，也是第四大癌症死亡原因，其明显的流行病学、组织学和分子差异加剧了这种复杂疾病的治疗难度。目前，HER2和PD-L1 CPS阳性胃癌肿瘤具有已建立的靶向治疗，其他新的组合方法也正在研究中。治疗策略侧重于不同RTK途径中存在干扰的肿瘤，如FGFR2扩增或CLDN18.2阳性胃癌。此外，更具包容性的大规模测序计划正在扩大胃癌患者肿瘤个性化治疗的前景。考虑到胃癌患者分子特性、空间和时间肿瘤异质性，整合每个胃癌患者的临床和分子数据，必将有助于制定最佳的个体化治疗策略，最终提高患者的总体生存率和生活质量。参考文献：1.Current developments in gastric cancer: from molecular profiling to treatment strategy. Nat Rev Gastroenterol Hepatol.2022 Nov 7.封面图来源：123rf版权声明/免责声明本文为授权转载文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢!药时代官方网站:www.drugtimes.cn联系方式:电话:13651980212微信:27674131邮箱:contact@drugtimes.cnFerring首席科学家杨翼博士：肥胖症疫苗离我们还有多远？礼来D药推迟上市，FDA的B面下一代GLP-1类药物早期临床数据读出，直接推动诺和诺德成为6000亿美元市值药企！点击这里，欣赏更多精彩内容！

– Antigen-specific T cell responses were observed at all dose levels – – IFNγ and IL-17, immune-mediated biomarkers of T cell activation, increased over time from baseline – – Vaccine was safe and well tolerated – – Conference call to commence today at 6:30 p.m. ET – SAN JOSE, Calif., Dec. 6, 2023 /PRNewswire/ -- Anixa Biosciences, Inc. ("Anixa" or the "Company") (NASDAQ: ANIX), a biotechnology company focused on the treatment and prevention of cancer, today announced new and updated positive results from the Phase 1 clinical trial of its breast cancer vaccine. The trial is being conducted in collaboration with Cleveland Clinic with funding by a grant from the U.S. Department of Defense. The data were presented at the 2023 San Antonio Breast Cancer Symposium by G. Thomas Budd, M.D., staff physician at Cleveland Clinic Cancer Institute and principal investigator of the study, in a poster entitled "Phase I Trial of alpha-lactalbumin vaccine in high-risk operable triple negative breast cancer (TNBC) and patients at high genetic risk for TNBC." Patients who had been curatively treated for TNBC received three vaccinations given once every two weeks. IFNγ and IL-17, which are T cell immune response indicators (cellular immunity), and antibody production (B cell humoral immunity) were measured to evaluate the vaccination effect. Data from the 16 patients treated to date showed that: The majority of patients developed ELISpot (T-cell) responses that met the rigorous protocol-specified definition of an immune response, with a measurable but lesser magnitude of response noted in the remaining patients. 12 (75%) of the women had antigen-specific IFNγ and/or IL-17 ELISpot responses that were observed at all dose levels, while ELISA antibody responses were observed at Dose Level 2 and higher. A statistically significant (P = 0.03) increase in IFNγ over baseline (Day 0) was observed by Day 56; while a significant (P = 0.0001) increase in IL-17 over baseline was observed by Day 14. Among the doses studied, Dose Level 1 (10 mcg α-lactalbumin/10 mcg zymosan) was determined to be a usable immunologic dose as well as the maximum tolerated dose (MTD). No significant side effects were observed, at the MTD, besides irritation at the sites of injection. No myalgias, flu-like symptoms, or aberrant laboratory values were noted. Anixa and Cleveland Clinic plan to investigate additional intermediate dose levels and continue studying the vaccine's safety and immunologic effects in two additional patient cohorts. The first cohort, which opened for enrollment in August 2023, is evaluating the combination of the Company's breast cancer vaccine with Keytruda® (pembrolizumab) in post-operative patients found to have residual disease following neoadjuvant chemo-immunotherapy. The second cohort will investigate the safety and immunologic effects of the vaccine in patients who are BRCA1, BRCA2, or PALB2 mutation positive and are planning prophylactic risk-reducing mastectomies. "The data from our Phase 1 trial to date has exceeded our expectations, and we are pleased with our progress. This vaccine is designed to direct the immune system to destroy TNBC cancer cells through a mechanism that has never previously been utilized for cancer vaccine development," stated Dr. Amit Kumar, Chairman and CEO of Anixa Biosciences. "We look forward to reviewing additional data as the trial continues to completion, and we are in the planning stages of the Phase 2/3 studies of this vaccine. Our goal is to initially evaluate the vaccine's ability to prevent recurrence of cancer in survivors, and continue with extension studies to eventually determine its effectiveness in preventing the initial onset of TNBC." "There is a large unmet need for preventing TNBC, an aggressive form of breast cancer with few targeted treatment options available," said Dr. Budd, Cleveland Clinic. "We are encouraged by the data gathered to date and look forward to determining the optimal vaccine dose in additional patient cohorts. Our hope is that future studies will demonstrate that the antigen-specific T cell responses we observed translate to the prevention of breast cancer recurrence." Anixa is the exclusive worldwide licensee to the novel breast cancer vaccine technology invented at Cleveland Clinic, the site of the Phase 1 trial. The grant from the U.S. Department of Defense was made directly to Cleveland Clinic. Conference Call Information Anixa is pleased to invite all interested parties to participate in a conference call, during which this new data will be discussed. About Triple-Negative Breast Cancer One in eight women in the U.S. will be diagnosed with an invasive breast cancer at some point in their lives. Approximately 10-15% of those diagnoses are TNBC, however TNBC accounts for a disproportionately higher percentage of breast cancer deaths and has a higher rate of recurrence. This form of breast cancer is twice as likely to occur in African-American women, and approximately 70% to 80% of the breast tumors that occur in women with mutations in the BRCA1 genes are triple-negative breast cancer. About Anixa Bioscience's Breast Cancer Vaccine Anixa's breast cancer vaccine takes advantage of endogenously produced proteins that have a function at certain times in life, but then become "retired" and disappear from the body. One such protein is a breast-specific lactation protein, α-lactalbumin, which is no longer found post-lactation in normal, aging tissues, but is present in the majority of triple-negative breast cancers. Activating the immune system against this "retired" protein provides preemptive immune protection against emerging breast tumors that express α-lactalbumin. The vaccine also contains an adjuvant that activates an innate immune response, which allows the immune system to mount a response against emerging tumors to prevent them from growing. This vaccine technology was invented by the late Dr. Vincent Tuohy, who was the Mort and Iris November Distinguished Chair in Innovative Breast Cancer Research in the Department of Inflammation and Immunity at Cleveland Clinic's Lerner Research Institute. Dr. Tuohy was inventor of the technology, which Cleveland Clinic exclusively licensed to Anixa Biosciences. He was entitled to a portion of the commercialization revenues received by Cleveland Clinic and also held equity in Anixa. About Anixa Biosciences, Inc. Anixa is a clinical-stage biotechnology company focused on the treatment and prevention of cancer. Anixa's therapeutic portfolio consists of an ovarian cancer immunotherapy program being developed in collaboration with Moffitt Cancer Center, which uses a novel type of CAR- T, known as chimeric endocrine receptor T-cell (CER-T) technology. The Company's vaccine portfolio includes a novel vaccine being developed in collaboration with Cleveland Clinic to prevent breast cancer – specifically triple negative breast cancer (TNBC), the most lethal form of the disease – as well as a vaccine to prevent ovarian cancer. These vaccine technologies focus on immunizing against "retired" proteins that have been found to be expressed in certain forms of cancer. Anixa's unique business model of partnering with world-renowned research institutions on clinical development allows the Company to continually examine emerging technologies in complementary fields for further development and commercialization. To learn more, visit or follow Anixa on Twitter, LinkedIn, Facebook and YouTube. Forward-Looking Statements: Statements that are not historical fact may be considered forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are not statements of historical facts, but rather reflect Anixa's current expectations concerning future events and results. We generally use the words "believes," "expects," "intends," "plans," "anticipates," "likely," "will" and similar expressions to identify forward-looking statements. Such forward-looking statements, including those concerning our expectations, involve risks, uncertainties and other factors, some of which are beyond our control, which may cause our actual results, performance or achievements, or industry results, to be materially different from any future results, performance, or achievements expressed or implied by such forward-looking statements. These risks, uncertainties and factors include, but are not limited to, those factors set forth in "Item 1A - Risk Factors" and other sections of our most recent Annual Report on Form 10-K as well as in our Quarterly Reports on Form 10- Q and Current Reports on Form 8-K. We undertake no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. You are cautioned not to unduly rely on such forward- looking statements when evaluating the information presented in this press release. Contacts: Stephen Kilmer Investor Relations [email protected] 646-274-3580 Mike Catelani President, COO & CFO [email protected] 408-708-9808 SOURCE Anixa Biosciences, Inc.