RET

精彩内容近日，翰森制药发布2023年业绩报告，实现营收约101.04亿元（+7.7%），归母净利润约32.78亿元（+26.9%），其中创新药与合作产品收入约68.65亿元（+37.1%），占总收入比例提升至67.9%。经过近30年发展，翰森制药已成为国内领先的创新驱动型Big Pharma，目前已有7款创新药获批上市，42款新药（40款1类新药）处于申请临床及以上阶段，叠加国际化进程不断提速，公司逐步开启跨越式发展新征程。营收破百亿！创新药收入占比达67.9%翰森制药成立于1995年，2002年开始专注创新研发，是国内最早布局创新药的企业之一。2019年6月，翰森制药在港交所挂牌上市（股票代码03692）。近年来，翰森制药创新药收入占比逐年提升，由2020年的18%提升至2023年的67.9%，这意味着，经过近30年的发展，翰森制药已成功蜕变为国内领先的创新驱动型Big Pharma。近年来翰森制药创新药收入情况（单位：亿元）来源：公司公告，米内网整理从分领域收入看，2023年翰森制药在抗肿瘤、抗感染、中枢神经、代谢及其它疾病领域分别录得收入约61.69亿元、12.69亿元、13.67亿元、12.99亿元，占收入比分别约为61%、12.6%、13.5%、12.9%。2023年翰森制药分治疗领域收入情况（单位：亿元）来源：公司公告在抗肿瘤领域，翰森制药目前已上市阿美乐（甲磺酸阿美替尼片）与豪森昕福（甲磺酸氟马替尼片）两款自研创新产品。2020年首次获批的阿美替尼市场爆发力惊人，2022年在中国三大终端六大市场（统计范围详见本文末）的销售额合计超过24亿元，同比增长约47%，2023年上半年继续以约16%的增速增长。在抗感染领域，翰森制药拥有恒沐（艾米替诺福韦片）和迈灵达（吗啉硝唑氯化钠注射液）两款上市自研创新药。2021年首次获批的艾米替诺福韦市场表现不俗，2023年上半年在中国三大终端六大市场的销售额超过3亿元，比上年同期增长约240%。在中枢神经系统领域，翰森制药引进的昕越（伊奈利珠单抗注射液）于2022年获批上市，为全球唯一获批用于抗AQP4抗体阳性的NMOSD成人患者的CD19单抗；在代谢及其它疾病领域，翰森制药的创新产品组合主要包括圣罗莱（培莫沙肽注射液）、孚来美（聚乙二醇洛塞那肽注射液）。翰森制药已获批上市的创新药（不含改良型新药）来源：米内网综合数据库研发开支突破20亿！40款1类新药在路上潜心创新研发是翰森制药快速实现转型的底蕴，而这离不开持续的研发投入及日益壮大的研发团队。2023年公司研发开支约为20.97亿元，同比增长约23.8%，占总收入比例增至20.8%。翰森制药的研发团队由位于美国马里兰州，中国上海、常州及连云港4个研发中心的1600余人组成。值得一提的是，3月29日，翰森制药集团全球研发总部在上海开工，将建成全球领先的创新药物研发基地，并承担全球研发管理职能，将成为翰森制药前沿科学创新的策源地和技术高地。近年来翰森制药研发开支情况（单位：亿元）来源：公司公告，米内网整理2023年至今，翰森制药在国内新药研发动态频发：创新药枸橼酸艾瑞芬净片（Ibrexafungerp）上市申请获受理；10个1类新药首次获批临床；HS-10241（c-MET-TKI）、HS-10365（RET-TKI）、HS-20089（B7-H4 ADC）、HS-20093（B7-H3 ADC）、HS-20094（GLP-1/GIP双受体激动剂）等多个重点在研管线，以及阿美替尼、艾米替诺福韦、氟马替尼等创新产品均取得关键研发进展。米内网数据显示，目前翰森制药有42款新药（不含已上市新药及拓展新适应症）处于申请临床及以上阶段，包括40款1类新药、1款进口5.1类新药等，涵盖抗肿瘤、抗感染、中枢神经系统、代谢系统、自身免疫等优势领域。公司预计，未来3年每年将有8-10个IND申请，2-3个NDA申请，至2025年将有15款以上的创新药（含新适应症）上市，创新药收入占比也将超过80%。抗肿瘤是翰森制药重点聚焦的领域，公司布局了CDK4/6、EGFR、PIK3、c-Met、RET、Bcr-Abl、HIF-2α等多个靶点，涵盖肺癌、乳腺癌、卵巢癌、白血病、肾细胞癌等细分病种。阿美替尼、氟马替尼已获批上市，目前均在开展不同适应症及联合用药的临床试验。HS-10241（c-Met抑制剂）、HS-20090（地舒单抗生物类似药）已步入III期临床，HS-10342（CDK4/6抑制剂）、HS-20089（B7-H4 ADC）、HS-20093（B7-H3 ADC）等均在开展II期临床。值得一提的是，在当下国内外药企扎堆的ADC赛道，翰森制药并未选择HER2、TROP2、EGFR等热门靶点，而是差异化布局了B7-H3（HS-20093，II期）、B7-H4（HS-20089，II期）等潜力靶点，不管是研发速度上还是适应症布局都极具竞争优势。可见翰森制药在新药研发上遵循以临床需求为导向，注重差异化研发的策略。在抗感染领域，吗啉硝唑、艾米替诺福韦已获批上市；引进的艾瑞芬净（全新三萜类结构的糖原合成酶抑制剂）已提交NDA，用于治疗外阴阴道念珠菌病(VVC)；聚乙二醇胸腺素α1是一款胸腺类免疫调节剂，HBeAg阳性慢性乙肝适应症已进行到III期临床。自研+BD双向发力，稳步推进国际化进程在深耕自主研发的同时，翰森制药也在加速推进全球合作，通过许可引进、合作开发等方式，快速融入国际医药生态圈，进一步提升公司的创新能力及创新产品管线布局，促进创新药产出和商业化。近年来，翰森制药开展了10余项BD交易，其中2个已处于商业化阶段，9个已在国内获批开展临床试验。通过BD交易，一方面引入了有竞争力的早期项目或成熟的创新产品，与公司自研产品形成组合疗法，极大地提升了研发效率，也进一步挖掘了自研产品的临床价值；另一方面，强化了公司与AI平台、GalNAc-asiRNA平台等新兴技术平台的合作。近年来翰森制药license-in情况来源：公司公告，米内网整理此外，翰森制药储备了多个同类首创（FIC）或同类最优（BIC）的自研高潜能产品，通过与MNC的合作，稳健开拓国际市场。2023年10月及12月，翰森制药分别授予葛兰素史克开发及商业化HS-20089(B7-H4 ADC)、HS-20093(B7-H3 ADC)的海外独占许可，目前全球暂无靶向B7-H4、B7-H3的ADC药物获批。在HS-20089项目上，翰森制药将收取8500万美元的首付款，以及最多14.85亿美元的里程碑付款；在HS-20093项目上，公司将收取1.85亿美元的首付款，以及最多15.25亿美元的里程碑付款。结语经过多年的积累沉淀，翰森制药已然搭建起良好的全球化创新生态体系，在内卷的创新药环境中确立了适合自己的差异化发展路径。公司以现有产品及优势领域为基础，进行垂直深化布局，发挥产品间协同效应及已有的渠道优势，医药龙头效应有望进一步凸显。资料来源：米内网数据库、公司公告等注：米内网《中国三大终端六大市场药品竞争格局》，统计范围是：城市公立医院和县级公立医院、城市社区中心和乡镇卫生院、城市实体药店和网上药店，不含民营医院、私人诊所、村卫生室，不含县乡村药店；上述销售额以产品在终端的平均零售价计算。数据统计截至3月26日，如有疏漏，欢迎指正！本文为原创稿件，转载请注明来源和作者，否则将追究侵权责任。投稿及报料请发邮件到872470254@qq.com稿件要求详询米内微信首页菜单栏商务及内容合作可联系QQ：412539092【分享、点赞、在看】点一点不失联哦

作者｜小麦奥希替尼是目前全球临床上使用最广泛的EGFR靶向药，将中位无进展生存期延长至18.9个月，2023年创下57.99亿美元的销售额，然而奥希替尼也面临严峻的耐药问题。为了克服奥希替尼耐药性，一些新策略如EGFR的PROTACs、双抗以及ADC等纷纷涌现，给后奥希替尼时代带来了曙光。   01  EGFR抑制剂耐药性机制EGFR是一种受体酪氨酸激酶（RTK），由28个外显子和27个内含子组成，包括细胞外结构域，跨膜结构域和细胞内结构域三个组成部分。EGFR在人上皮细胞的信号转导途径中起关键作用，它的异常与很多疾病相关，如在非小细胞肺癌（NSCLC）中约35%的患者由EGFR基因突变引起。已经有很多EGFR靶向药获批上市，如1-3代EGFR小分子抑制剂和EGFR/Met双抗等。目前获批上市的EGFR小分子靶向药中奥希替尼是最畅销的药物，2023年全球销售额达到57.99亿美元，然而很多患者在使用奥希替尼之后会出现耐药问题，为了克服奥希替尼耐药问题，很多公司开发新的药物。奥希替尼继发耐药机制包括EGFR靶向和非EGFR脱靶性两种（图1）[1]。1)靶向耐药: 在仍依靠 EGFR通路的情况下，肿瘤细胞发生奥希替尼耐药，如T790M缺失、C797x突变、奥希替尼18号外显子L718Q/V位点突变和G724S突变等。2)非EGFR脱靶性耐药:肿瘤细胞通过其它途径绕过 EGFR通路，持续增殖，如CCNE1扩增、MET扩增、HER2扩增、AKT/PTEN/PIK3CA突变、致癌基因融合（FGFR3、RET、NTRK）等。 图1. EGFR抑制剂耐药机制  02  靶向EGFR的PROTACsPROTAC因其可以降解整个蛋白而不是仅仅抑制蛋白酶活性而备受关注，尤其是针对易突变蛋白，PROTAC有望克服其耐药问题。全球有多家企业布局EGFR PROTACs。● 海思科HSK40118：全球首款，进入临床海思科自主研发的口服EGFR-PROTAC HSK40118的临床试验申请于2023年3月15日获得NMPA批准，用于治疗不可手术的、携带EGFR突变的晚期NSCLC患者，成为全球首款进入临床的EGFR PROTAC药物。●  CFT8919：变构 BiDAC™ 降解剂，进入临床CFT8919是由C4 Therapeutics研发的具有口服生物利用度的变构 BiDAC™ 降解剂，对携带EGFR L858R 突变具有良好的活性和选择性，同时，CFT8919对像T790M或C797S突变的EGFR继发耐药突变有效。2023年5月30日，贝达与C4 Therapeutics达成合作协议，贝达向C4支付3500万美元，包括1000万美元的首付款和贝达投资(香港)有限公司将一次性认购C4T 2500万美元股权，取得在中国（包括香港、澳门和台湾地区）开发、制造和商业化CFT8919的权利，并可获得前述区域以外约定比例的销售提成[2]。2023年12月5日，CFT8919的临床试验申请已获得NMPA批准开展，拟用于携带EGFR突变的局晚期或晚期NSCLC患者。除此之外，临床前也有很多在研的EGFR PROTACs，如百济的EGFR CDAC，它对多种EGFR突变都有抑制活性，在奥希替尼敏感或耐药肿瘤中都有很好的抑瘤活性（图2）。 图2. 百济的EGFR CDAC活性  02  靶向EGFR的双特异性抗体除了C797S突变，还有其它因素导致奥希替尼耐药，如MET扩增等，因此EGFR/Met双抗有望解决奥希替尼耐药问题。● 强生埃万妥单抗:EGFR/c-Met，一线疗法获批埃万妥单抗是强生研发的首款获批上市的靶向EGFR ex20ins（EGFR 20号外显子突变）突变的EGFR/c-Met双抗药物，EGFR ex20ins是EGFR第三大突变类型，于2021年5月获FDA加速批准用于二线治疗EGFR ex20ins患者。强生对埃万妥单抗寄予厚望，一方面探索埃万妥单抗单药或联合治疗EGFR 突变NSCLC患者一线疗法，另一方面探索埃万妥单抗对奥希替尼耐药患者的疗效。2023年8月，强生向FDA递交了埃万妥单抗的补充生物制品许可申请(sBLA)，与化疗联用一线治疗携带EGFR外显子20插入突变的局部晚期或转移性NSCLC患者。2024年3月1日，强生宣布FDA已批准埃万妥单抗联合化疗一线治疗EGFR外显子20插入突变的局部晚期或转移性NSCLC患者。结合奥希替尼耐药机制，埃万妥单抗联合三代EGFR抑制剂拉泽替尼方案获得广泛关注。2023年9月，埃万妥单抗联合拉泽替尼和化疗治疗奥希替尼耐药的一项3期MARIPOSA-2试验取得积极结果：与化疗相比，埃万妥单抗加化疗以及埃万妥单抗加拉泽替尼加化疗的无进展生存期（PFS）显著延长，疾病进展或死亡的风险比（HR）分别为0.48和0.44，中位PFS分别为6.3个月和8.3个月，化疗组为4.2个月（图3）[3]。通过研究者评估得到一致的 PFS 结果，埃万妥单抗加化疗以及埃万妥单抗加拉泽替尼加化疗的疾病进展或死亡的HR分别为0.41和0.38，中位PFS分别为8.2个月和8.3个月，化疗组为4.2个月。 图3. MARIPOSA-2试验结果2023年10月26日，埃万妥单抗在国内的上市申请获药监局受理。● 百利天恒SI-B001：EGFR/HER3，Ⅲ期临床除了埃万妥单抗之外，临床上还有很多在研的靶向EGFR的双抗药物，如百利天恒的Izalontamab（SI-B001）等。SI-B001是由百利天恒基于自主建立的SEBA平台独立研发的靶向 EGFR/HER3 的双抗药物，已在多个 II 期临床试验中表现了具备突破性疗效的有效性和良好的耐受性。HER3属于受体酪氨酸激酶EGFR家族。据估计，在EGFR TKI治疗后，约 83% 的原发性NSCLC和 90% 的晚期EGFR突变肿瘤会表达HER3。靶向EGFR/HER3 的双抗有望解决解决奥希替尼耐药问题。2023年6月，百利天恒在药物临床试验登记与信息公示平台登记了SI-B001的第一项3期临床试验，旨在评估SI-B001联合多西他赛对比多西他赛二线治疗局部晚期或转移性无驱动基因变异的非小细胞肺腺癌和肺鳞癌患者的有效性和安全性。SI-B001在结肠癌SW48异种移植、头颈部鳞状细胞癌FaDu异种移植和食管癌KYSE-150异种移植中显示明显的抗肿瘤功效（图4）[4]。 图4. SI-B001的抗肿瘤功效SI-B001在EGFR/ALK野生型非小细胞肺癌的肺鳞癌后线（中位四线）的初步临床试验显示积极的疗效：疾病控制率（DCR）为 87.50%（7/8），其中部分缓解（PR）为12.50%（1/8）；非小细胞肺癌二线化疗药物多西他赛的历史数据，DCR为48.54%（50/103），其中PR为5.82%（6/103）[5]。  03  第一三共：HER3-Dxd已申报上市在NSCLC中，HER3表达与晚期疾病、转移时间缩短和生存率降低有关。HER3的高表达也与EGFR TKIs耐药有关，所以人们寄希望于HER3靶向药能解决奥希替尼耐药问题。目前尚无靶向HER3疗法被获批上市，HER3-DXd（Patritumab deruxtecan）是由第一三共原研的一款靶向HER3的ADC药物，是目前研发进展最快的HER3 ADC药物，通过半胱氨酸定点偶联连接方式将马来酰亚胺-GGFG接头连接HER3单抗patritumab和拓扑异构酶I抑制剂deruxtecan而得。HER3-DXd（Patritumab deruxtecan）于 2021 年 12 月获FDA授予突破性疗法认定（BTD），用于治疗在第三代EGFR TKI和含铂化疗期间或之后疾病进展的EGFR突变局部晚期或转移性NSCLC患者。此前，Patritumab Deruxtecan在一项旨在评估其在使用EGFR TKI治疗和含铂化疗疾病进展后的EGFR突变局部晚期或转移性NSCLC患者中安全性和有效性的全球、多中心、开放标签、双臂2期HETHENA-Lung01（NCT04619004）试验取得积极结果。研究结果显示：截至 2023 年 5 月 18 日，中位研究持续时间为 18.9 个月（范围为 14.9-27.5 个月）。BICR确认的ORR为29.8%（95%CI，23.9至36.2）;中位缓解持续时间为 6.4个月；中位无进展生存期为5.5个月；中位总生存期为 11.9 个月。既往接受过奥希替尼和铂类化疗（PBC）患者亚组具有相似的结果（图5）[6]。 图5. HETHENA-Lung01试验抗肿瘤活性对30 名来自疗效人群的脑部转移患者颅内反应分析（通过 CNS BICR），这些患者既往未接受过脑部放疗。在这些患者中，有7例发现了目标病灶；其余只有非靶病灶。CNS ORR（根据 CNS BICR）为 33.3%，有9个中枢神经系统 CR（其中8 例为仅具有非目标病灶的患者）和1例PR。这些反应基于单独的CT成像（5个 CR和1个PR）、单独的 MRI（2个CR）或CT成像和MRI确认（2个CR）。疾病稳定（包括非CR/非进展性疾病）的最佳CNS反应[PD]）PD的发生率为43.3%（13/30）和13.3%（4/30）（图6）。 图6 . Patritumab Deruxtecan对脑转移NSCLC患者疗效Patritumab Deruxtecan在已知和未知的EGFR TKI耐药机制谱中都产生了抗肿瘤活性（图7）[7]。57例中有23例（不包括T790M）已知EGFR相关耐药机制患者，这些患者确诊的ORR为35%（CR/PR，8；SD，7；PD，5；NE，3）。57 例中有13例具有EGFR非依赖性耐药机制的患者，确认的ORR为46%（CR/PR，6；SD，4；PD，2；NE，1）。57例中有21例具有其他/未知耐药机制的患者，确诊的 ORR为 38%（CR/PR，8 例；SD，8；PD，2；NE，3）。 图7. Patritumab Deruxtecan对EGFR TKI耐药患者疗效2023年10月20日，默沙东与第一三共就包括Patritumab deruxtecan在内的三款ADC药物达成了高达220亿美元的合作协议。基于2期HERTHENA-Lung01积极结果，2023年12月22日，第一三共和默沙东共同宣布patritumab deruxtecan的BLA获FDA受理并予以优先审评，用于治疗既往至少接受过两种系统治疗的EGFRm局部晚期或转移性NSCLC， PDUFA日期为2024年6月26日, patritumab deruxtecan成为首款申报上市的HER3 ADC。  写在最后  EGFR是一个易突变的蛋白，奥希替尼是目前全球最畅销的EGFR抑制剂，但长期使用容易产生耐药问题，后奥希替尼时代已悄然来临。针对奥希替尼耐药问题，各大药企各显神通，第四代EGFR抑制剂、EGFR的PROTACs、双抗、ADC等纷纷上桌，多项试验传来了好消息，相信不久的将来奥希替尼耐药问题必将被克服。参考文献1.Yufeng Li et.al, Toward the next generation EGFR inhibitors: an overview of osimertinib resistance mediated by EGFR mutations in non‑small cell lung cancer, Cell Communication and Signaling (2023) 21:712.强强联手｜贝达药业与美国C4 Therapeutics达成合作引进CFT8919项目3.Amivantamab plus chemotherapy with and without lazertinib in EGFRmutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study4.Anti-tumor efficacy of SI-B001, a novel EGFR×HER3 bispecific antibody, against EGFR-driven epithelial tumors alone or in combination with paclitaxel and carboplatin5.医药魔方：全球首款！百利天恒HER3/EGFR双抗启动III期临床6.Helena A. Yu, MD 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 41:5363-53757.Pasi A. Jänne et.al, Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor– Resistant, EGFR-Mutated Non–Small Cell Lung Cancer, Cancer Discov 2022;12:74–89共建Biomedical创新生态圈！如何加入BiG会员？

— Oral presentation at the European Lung Cancer Congress 2024 of Phase IIIb data demonstrating median PFS of 13.7 months and median OS not reached in treatment-naïve patients — — If approved, would confirm 2021 conditional approval and expand indication to more patients — HONG KONG and SHANGHAI, China and FLORHAM PARK, N.J., March 27, 2024 (GLOBE NEWSWIRE) -- HUTCHMED (China) Limited (“HUTCHMED”) (Nasdaq/AIM:​HCM; HKEX:​13) today announces that the supplemental New Drug Application (“sNDA”) for savolitinib, in adult patients with locally advanced or metastatic non-small cell lung cancer (“NSCLC”) with mesenchymal epithelial transition factor (“MET”) exon 14 skipping alteration, has been accepted for review by the China National Medical Products Administration (NMPA). If approved, the new label indication for savolitinib will be expanded to include treatment-naïve patients in China. Savolitinib was previously granted conditional approval in China for the treatment of patients with NSCLC with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy. Savolitinib was launched and is marketed under the brand name ORPATHYS® by our partner, AstraZeneca for this patient population, representing the first selective MET inhibitor approved in China. More than a third of the world’s lung cancer patients are in China and, among those with NSCLC globally, approximately 2-3% have tumors with MET exon 14 skipping alterations. Preliminary efficacy and safety data from the first-line cohort of the confirmatory Phase IIIb clinical trial (NCT04923945) were presented during the IASLC World Conference on Lung Cancer (WCLC) in September 2023. Final data from the confirmatory Phase IIIb trial were presented at the European Lung Cancer Congress on March 20, 2024. The data from this study provide confirmatory evidence for savolitinib as a targeted treatment option for treatment-naïve or previously treated patients with MET exon 14 skipping alteration NSCLC. In treatment-naïve patients, objective response rate (“ORR”) was 62.1% (95% CI: 51.0% to 72.3%), disease control rate (“DCR”) was 92.0% (95% CI: 84.1% to 96.7%) and median duration of response (“DoR”) was 12.5 months (95% CI: 8.3 months to 15.2 months), as assessed by an independent review committee. Median progression free survival (“PFS”) was 13.7 months (95% CI: 8.5 months to 16.6 months) and median overall survival (“OS”) was not reached with median follow-up of 20.8 months. In previously treated patients, ORR was 39.2% (95% CI: 28.4% to 50.9%), DCR was 92.4% (95% CI: 84.2% to 97.2%) and median DoR was 11.1 months (95% CI: 6.6 months to not reached), as assessed by an independent review committee. Median PFS was 11.0 months (95% CI: 8.3 months to 16.6 months) and median OS was not mature with median follow-up of 12.5 months. Responses occurred early (time to response 1.4-1.6 months) in both treatment-naïve and previously treated patients. The safety profile was tolerable and no new safety signals were observed. The most common drug-related treatment-emergent adverse events of Grade 3 or above (5% or more of patients) were abnormal hepatic function (16.9%), increased alanine aminotransferase (14.5%), increased aspartate aminotransferase (12.0%), peripheral oedema (6.0%) and increased gamma-glutamyltransferase (6.0%). About NSCLC and MET aberrations Lung cancer is the leading cause of cancer death among men and women, accounting for about one-fifth of all cancer deaths.1 Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.2 The majority of NSCLC patients (approximately 75%) are diagnosed with advanced disease, and approximately 10-15% of NSCLC patients in the U.S. and Europe and 30-40% of patients in Asia have EGFRm NSCLC. 3,4,5,6 MET is a tyrosine kinase receptor that has an essential role in normal cell development.7 MET overexpression and/or amplification can lead to tumor growth and the metastatic progression of cancer cells, and is one of the mechanisms of acquired resistance to EGFR TKIs for metastatic EGFR-mutated NSCLC.7,8 Approximately 2-3% of NSCLC patients have tumors with MET exon 14 skipping alterations, a targetable mutation in the MET gene.9 Among patients who experience disease progression post-osimertinib treatment, approximately 15-50% present with MET aberration.10,11,12,13,14 The prevalence of MET depends on the sample type, detection method and assay cut-off used.15 About Savolitinib (ORPATHYS® in China) Savolitinib is an oral, potent and highly selective MET tyrosine kinase inhibitor that has demonstrated clinical activity in advanced solid tumors. It blocks atypical activation of the MET receptor tyrosine kinase pathway that occurs because of mutations (such as exon 14 skipping alterations or other point mutations), gene amplification or protein overexpression. Savolitinib is marketed in China under the brand name ORPATHYS® for the treatment of patients with non-small cell lung cancer with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy. It is currently under clinical development for multiple tumor types, including lung, kidney and gastric cancers, as a single treatment and in combination with other medicines. Starting on March 1, 2023, ORPATHYS® was included in the National Reimbursement Drug List (NRDL) for the treatment of locally advanced or metastatic NSCLC adult patients with MET exon 14-skipping alterations who have progressed after or unable to tolerate platinum-based chemotherapy. In 2011, AstraZeneca and HUTCHMED entered a global licensing and collaboration agreement to jointly develop and commercialize savolitinib. Joint development of savolitinib in China is led by HUTCHMED, while AstraZeneca leads development outside of China. HUTCHMED is responsible for the marketing authorization, manufacturing and supply of savolitinib in China. AstraZeneca is responsible for the commercialization of savolitinib in China and worldwide. Sales of savolitinib are recognized by AstraZeneca. About HUTCHMED HUTCHMED (Nasdaq/AIM:​HCM; HKEX:​13) is an innovative, commercial-stage, biopharmaceutical company. It is committed to the discovery, global development and commercialization of targeted therapies and immunotherapies for the treatment of cancer and immunological diseases. It has approximately 5,000 personnel across all its companies, at the center of which is a team of about 1,800 in oncology/immunology. Since inception, HUTCHMED has focused on bringing cancer drug candidates from in-house discovery to patients around the world, with its first three medicines marketed in China, the first of which is also marketed in the U.S. For more information, please visit: www.hutch-med.com or follow us on LinkedIn. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the “safe harbor” provisions of the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements reflect HUTCHMED’s current expectations regarding future events, including its expectations regarding the therapeutic potential of savolitinib, the further clinical development for savolitinib, its expectations as to whether any studies on savolitinib would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies. Forward-looking statements involve risks and uncertainties. Such risks and uncertainties include, among other things, assumptions regarding enrollment rates and the timing and availability of subjects meeting a study’s inclusion and exclusion criteria; changes to clinical protocols or regulatory requirements; unexpected adverse events or safety issues; the ability of savolitinib, including as a combination therapy, to meet the primary or secondary endpoint of a study, to obtain regulatory approval in different jurisdictions and to gain commercial acceptance after obtaining regulatory approval; the potential market of savolitinib for a targeted indication; and the sufficiency of funding. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. For further discussion of these and other risks, see HUTCHMED’s filings with the U.S. Securities and Exchange Commission, The Stock Exchange of Hong Kong Limited and on AIM. HUTCHMED undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise. Medical Information This press release contains information about products that may not be available in all countries, or may be available under different trademarks, for different indications, in different dosages, or in different strengths. Nothing contained herein should be considered a solicitation, promotion or advertisement for any prescription drugs including the ones under development. CONTACTS Investor Enquiries+852 2121 8200 / ir@hutch-med.com Media Enquiries Ben Atwell / Alex Shaw, FTI Consulting+44 20 3727 1030 / +44 7771 913 902 (Mobile) / +44 7779 545 055 (Mobile) / HUTCHMED@fticonsulting.comZhou Yi, Brunswick+852 9783 6894 (Mobile) / HUTCHMED@brunswickgroup.com Nominated Advisor Atholl Tweedie / Freddy Crossley / Daphne Zhang, Panmure Gordon+44 (20) 7886 2500 ____________________REFERENCES1World Health Organization. International Agency for Research on Cancer. All cancers fact sheet. Available at: https://gco.iarc.fr/today/­data/factsheets/cancers/39-All-cancers-fact-sheet.pdf. Accessed November 2022.2American Cancer Society. What is Lung Cancer? Available at: https://www.cancer.org/cancer/lung-cancer/about/what-is.html. Accessed November 2022.3Knight SB, et al. Progress and prospects of early detection in lung cancer. Open Biol. 2017;7(9): 170070.4Keedy VL, et al. American Society of Clinical Oncology Provisional Clinical Opinion: Epidermal Growth Factor Receptor (EGFR) Mutation Testing for Patients with Advanced Non-Small-Cell Lung Cancer Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. J Clin Oncol. 2011:29;2121-27.5Zhang Y, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016;7(48).6Szumera-Ciećkiewicz A, et al. EGFR Mutation Testing on Cytological and Histological Samples in 11. Non-Small Cell Lung Cancer: a Polish, Single Institution Study and Systematic Review of European Incidence. Int J Clin Exp Pathol. 2013:6;2800-12.7Uchikawa E, et al. Structural basis of the activation of c-MET receptor. Nat Commun. 2021;12(4074).8Wang Q, et al. MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer. Journal of Hematology & Oncology. 2019;63.9Vuong HG, et al. Clinicopathological implications of MET exon 14 mutations in non-small cell lung cancer – A systematic review and meta-analysis. Lung Cancer 2018; 123: 76-82.10Soria JC, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(2):113-125.11Mok TS, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017;376(7):629-640.12Hartmaier R, et al. Tumor genomics in patients (pts) with advanced epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer (NSCLC) whose disease has progressed on first-line (1L) osimertinib therapy in the Phase II ORCHARD study. Cancer Res 15 June 2022; 82 (12_Supplement): LB078.13Piotrowska, et al. MET amplification (amp) as a resistance mechanism to osimertinib. Journal of Clinical Oncology 2017 35:15_suppl, 9020-9020. 14Hartmaier, et al. Detection of MET-mediated EGFR tyrosine kinase inhibitor (TKI) resistance in advanced non-small cell lung cancer (NSCLC): biomarker analysis of the TATTON study. Cancer Res (2019) 79 (13_Supplement): 4897.15Coleman N, et al. Beyond epidermal growth factor receptor: MET amplification as a general resistance driver to targeted therapy in oncogene-driven non-small-cell lung cancer. ESMO Open. 2019;6(6).