Surufatinib

▲点击图片，了解详情  瞪羚社 /Kris. 素有“癌王”之称的胰腺癌，目前全球仍未获批很好的创新治疗手段。 直至Revolution Medicines的泛Kras抑制剂RMC-6236在早期临床对PDAC（胰腺导管癌）展现出优异疗效，泛Kras抑制剂的研发“肉眼可见”火热起来。在近期国内泛Kras开发走在前列的Biotech加科思也在业绩电话中提到：目前公司在谈的合作最受海外关注的仍然是pan-Kras，这一定程度折射出该领域的火热。 从pan-Kras抑制剂进度上可以看到，海外RMC-6236已经在二线治疗PDAC开启了三期临床，国内加科思JAB-23E73去年年底完成I/IIa期临床首例患者给药，而2025年辉瑞PF-07934040、百济神州BGB-53038也在国内进入临床阶段。 除了pan-Kras抑制剂之外，我们从国内外也看到了一些不同路径开发药物的早期积极数据。随着更多创新药物成熟临床数据，可以预见，胰腺癌治疗药物领域将出现重磅的BD交易。仅以Revolution公司RMC-6236在PDAC适应症的潜力，Jefferies预计将有约50亿美元的市场机会。 01 pan-Kras的开发方向 目前，pan-Kras抑制剂设计开发路线主要是以RMC-6236为首的分子胶路线，另外还有以辉瑞、礼来、加科思等同类的小分子抑制剂路线，两者的机制有着较为明确的区分。 RMC-6236是一种非共价RAS（ON）多选择性抑制剂，其能够与CypA（亲环蛋白A）结合形成二元复合物，最终与不同的RAS（ON）蛋白结合成三元复合物，阻断KRAS与其下游信号因子之间的相互作用，达到抑制肿瘤的目的。 RMC-6236特点在于“更广泛的抑制”，在临床前实验中显示出对多种RAS突变体（包括KRAS、HRAS和NRAS）的广谱抑制作用，但尚未有明确的临床数据表明其对KRAS突变外的其他突变肿瘤的疗效。 在RMC-6236未公布临床数据之前并不被看好，由于RMC-6236并对KARS、HRAS、NRAS不加选择性的通通抑制，有文章表明将3种RAS都抑制以后会产生更强的毒副作用。不过从RMC-6236公布的临床一期数据显示，接受治疗的患者≥3级的TRAEs发生率为22%，且没有患者因治疗相关不良事件而停止治疗。 小分子抑制剂的设计思路较为直接，通过提升对KARS突变体的选择性，使得分子不抑制HRAS、NRAS等其他变体来提升药物的安全性。 以辉瑞的PF-07934040为例，其设计思路与同类pan-Kras抑制剂有鲜明的的特征，主要在几个方面： 1）在机制上，PF-07934040能够结合两种状态，分别是OFF状态（GDP结合状态）、ON状态（GTP结合状态），前者是阻止其再次激活，后者则是阻断其与下游信号通路的相互作用； 2）PF-07934040对KRAS的选择性极高，其与KRAS的结合亲和力比HRAS和NRAS高出5000倍，极大降低了其抑制其他RAS家族成瘾带来的潜在安全性风险； 3）该药可抑制KRAS的野生型和多种主要突变亚型，包括常见的G12C、G12D、G12V等，拥有广谱治疗潜力； 目前，这条路径在研分子均未读出早期临床数据，后续临床数据值得期待。 02 其他胰腺癌的亮眼疗法 全球在探索胰腺癌治疗潜力的组合治疗并不在少数，包括和黄医药的索凡替尼、正大天晴的安罗替尼等均通过联用PD-1及化疗在开展临床后期，这里旨在展示新型的治疗手段。 全球范围内，亦有Biotech通过间接抑制RAS基因来实现对胰腺癌治疗药物的开发。Immuneering Corp是一个典型的例子，其核心管线是IMM-1-104，这是一款高选择性双MEK抑制剂，其作用机制基于MAPK（有丝分裂原激活蛋白激酶）信号通路的抑制。 MEK是RAS通路的关键节点，RAS蛋白的激活会导致MEK-ERK通路的持续激活，促进细胞的异常增殖和存活，MEK抑制剂可通过抑制MEK的活性来阻断RAS通路的信号传导，从而抑制肿瘤生长。 从Immuneering公司2025年公布的二期IMM-1-104联合化疗一线治疗胰腺癌临床数据显示，在7名可评估的患者中总体ORR为43%，DCR为86%；在应答者中，1例患者完全缓解（CR），3例患者部分缓解（PR），3例病情稳定（SD）。另外，安全性方面联合治疗在化疗基础上几乎未增加额外毒性，这给该药物赋予了很大的市场潜力（未来可与KRAS药物竞争又或联用）。 在胰腺癌取得突破的还有Novocure/再鼎医药的电场疗法——TTFields，去年12月Novocure公布TTFields一线治疗胰腺腺癌的三期研究PANOVA-3取得阳性结果：TTFields疗法联合化疗的mOS为16.2个月，化疗组mOS为14.16个月（HR=0.819）；另外，生存率获益随着时间的推移而增加，12个月时OS率提高了13%，24个月OS率提高了33%。尽管电场疗法价格昂贵（2.1万美金/月），但其做出了胰腺癌领域罕见的OS获益三期，取得的突破提振了研发界信心。 在ADC领域，也涌现出了几款早期数据亮眼的分子，国产含量极高。 信达生物的CLDN18.2 ADC产品IBI343便是其中之一，在最新ESMO Asia大会上IBI343更新了胰腺癌数据，43例二线及以上胰腺癌患者的ORR为32.6%，cORR为23.6%，cDCR为81.4%，mPFS为5.3个月，mPFS超出现有三线疗法的mPFS（约2个月），也超过现有二线疗法的mPFS（2-3.5个月）。 乐普生物的TF ADC产品MRG004A同样潜力不俗，在ASCO大会公布的I/II期临床数据显示，在12名中位治疗线数为3的胰腺癌患者中，有4例部分缓解（PR）和6例疾病稳定（SD），整体ORR为33.3%，DCR为83.3%。 03 国内大药企的开发路线 对于胰腺癌这类型的“难攻克性”强的瘤种，国内很少Biotech会将其设置为核心开发目标，一方面适应症不够大、难度系数高，另一方面可能即便做出优效但患者依然用药时长较短，出大药的性价比有限。不难看到，在这个领域布局占比较大的一般是一些实力较强的大药企。 信达生物是针对胰腺癌临床布局较多的药企，其围绕CLDN18.2这个靶点，开发出了前面提到的CLDN18.2 ADC管线IBI343和CLDN18.2/CD3双抗IBI389，IBI389一期临床数据显示：在27例接受治疗并至少接受一次基线后肿瘤评估的胰腺癌患者中，ORR为29.6%，确诊客观缓解率（cORR）为25.9%，DCR为70.4%，同样展现了不错的潜力。 百济神州则是跳过过去的热点Kras G12C和G12D，直接开发了一款pan-Kras抑制剂BGB-53038。无独有偶，BGB-53038的设计思路为高选择性地作用于KRAS，对NRAS和HRAS的影响较小，这样的好处是安全性带来的联用选择较多。 BGB-53038在初步的研究中，探索了与替雷利珠单抗联合用于非鳞状非小细胞肺癌、与西妥昔单抗联合用于结直肠癌（CRC）的疗效，展现出积极的结果，预计该药将在2025H2读出初步PoC数据。 恒瑞医药目前在Kras靶点布局了Kras G12D管线HRS-4642，目前HRS-4642亦有初步的临床数据披露，在多线治疗的KRAS G12D突变实体瘤（其中含1例胰腺癌）中观察到初步疗效：1例患者出现PR，所有肿瘤总体DCR为77.8%，其中NSCLC的DCR为90%。另外，亦有药物数据库报道指出，恒瑞医药也在开发pan-KRAS，处于药物发现阶段。 结语：从现有全球各个研发阶段的胰腺癌药物来看，未来迫近的BD或者M&A事件大概率将集中在KRAS和CLDN18.2这两个主要的靶点当中，当然KRAS更下游的MEK也有机会。或许待到RMC-6236释放更多成熟数据，又或是加科思和百济神州读出pan-KRAS抑制剂的早期数据之后，相关的交易可能将井喷。 毕竟我们不只是仅仅在说癌王的机会，而是一个广谱重磅药物的诞生。 往 期 推 荐 1 百济神州也“NewCo” 2 百济神州，正在走安进曾经的路 _ 3 头对头击败奥希替尼，这款大药将起飞？ _ *声明：本稿件为转载，仅用于分享，不代表本公众号立场，如涉及版权等问题，请尽快联系我们，我们将第一时间更正或删除，谢谢！ 投稿请添加小助手：bioclub666

— SAVANNAH Phase II trial demonstrated high and durable response rates with savolitinib plus TAGRISSO® in MET-high lung cancer, representing a promising chemo-free oral treatment strategy to address mechanisms of resistance in the advanced setting — — Long-term survival benefit and safety observed in savolitinib Phase IIIb study in METex14 NSCLC — HONG KONG and SHANGHAI and FLORHAM PARK, N.J., March 20, 2025 (GLOBE NEWSWIRE) -- HUTCHMED (China) Limited (“HUTCHMED”) (Nasdaq/AIM:HCM; HKEX:13) today announces that new and updated data from several studies of compounds discovered by HUTCHMED, savolitinib and surufatinib, will be presented at the European Lung Cancer Congress (ELCC) 2025, taking place on March 26-29, 2025 in Paris, France. Title:SAVANNAH: Savolitinib (savo) + osimertinib (osi) in patients (pts) with EGFRm advanced NSCLC and MET overexpression (OverExp) and/or amplification (Amp) following progressive disease (PD) on osiLead Author:Myung-Ju Ahn, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of KoreaSession:Proffered Paper session 1Abstract Number: #2ODate & Time:Wednesday, March 26, 2025,16:45 Central European TimeLocation:South Paris Room Results from the SAVANNAH Phase II trial (NCT03778229) showed savolitinib (300mg BID1) plus TAGRISSO® demonstrated a clinically meaningful and durable objective response rate (“ORR”) in patients with epidermal growth factor receptor mutated (“EGFRm”) non-small cell lung cancer (“NSCLC”) with high levels of MET overexpression and/or amplification whose disease progressed on treatment with first line TAGRISSO®. Savolitinib plus TAGRISSO® demonstrated confirmed ORR of 56% (95% CI2: 45%–67%) and 55% (95% CI: 43%–66%), median duration of response (“DoR”) of 7.1 (95% CI: 5.6–9.6) and 9.9 (95% CI: 6.0–13.7) months, and median progression-free survival (“PFS”) of 7.4 (95% CI: 5.5–7.6) and 7.5 (95% CI: 6.4–11.3) months by investigator and blinded independent central review (BICR) assessment, respectively. Safety results and discontinuation rates due to adverse events were consistent with the established profiles of each medicine and no new safety concerns were reported. In all patients treated with savolitinib (300mg BID) plus TAGRISSO®, Grade 3 or higher adverse events (AEs) occurred in 57% and Grade 3 or higher treatment related adverse events (TRAEs) occurred in 32% of the patients. Savolitinib is an oral, potent and highly selective MET tyrosine kinase inhibitor (“TKI”) being jointly developed and commercialized by AstraZeneca and HUTCHMED. In 2023, savolitinib and TAGRISSO® received Fast Track Designation from the US Food and Drug Administration (FDA) in this setting. Title:Final Overall Survival and Long-term Safety Outcomes of Savolitinib in Patients with Locally Advanced or Metastatic NSCLC Harboring MET Exon 14 (METex14) Mutation: An Update from a Phase 3b Study Lead Author:Yongfeng Yu, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaSession:Poster Display sessionAbstract Number: #80PDate & Time:Friday March 28, 2025,13:00 Central European TimeLocation:Poster area Updated results from the savolitinib Phase IIIb study in China demonstrated survival benefits and long-term safety in MET exon 14 skipping alteration NSCLC, particularly in treatment-naïve patients (NCT04923945). Among the 166 patients who received savolitinib treatment, the median follow-ups for 87 treatment-naïve patients and 79 previously treated patients were 34.5 and 25.1 months, respectively. In 87 treatment-naïve patients, median overall survival (“OS”) was 28.3 months (95% CI: 17.5–not evaluable), and the 36-month OS rate was 44.7%. In 79 previously treated patients, median OS was 25.3 months (95% CI: 20.5–30.5), and the 24-month OS rate was 51.7%. Post-hoc OS subgroup analysis suggested that patients with baseline brain metastasis also gain survival benefit with median OS of 15.3 months and 25.3 months in treatment-naïve patients (10/87 patients) and previously treated (21/79 patients) with brain metastasis, respectively. No new safety signal was observed. Savolitinib is approved in China under the brand name ORPATHYS® for this patient population. Title:Final overall survival (OS) of surufatinib plus PD-1/PD-L1 antibodies as maintenance therapy following first line (1L) platinum-based chemotherapy (Chemo) plus PD-1/PD-L1 antibodies in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC)Lead Author:Yi Hu, Chinese PLA General Hospital, Beijing, ChinaSession:Poster Display sessionAbstract Number: #310PDate & Time:Friday March 28, 2025,13:00 Central European TimeLocation:Poster area Results from the exploratory study suggests surufatinib plus immunotherapy as maintenance therapy following first line chemo-immunotherapy demonstrated durable survival benefit for patients with extensive-stage small cell lung cancer (“SCLC”) patients (NCT05509699). At data cut-off on July 31, 2024, a total of 21 patients were enrolled in this single arm Phase IIa part of the study and received at least one dose of surufatinib plus PD-1/PD-L1 antibodies treatment. The median follow-up duration was 17.1 months for maintenance and 22.5 months for first line (induction + maintenance) therapy. The 12-month and 18-month OS rates were both 57.1% for maintenance therapy; and 85.7% and 57.1% for first line therapy. About NSCLC and SAVANNAH Lung cancer is the leading cause of cancer death among men and women, accounting for about one-fifth of all cancer deaths. Lung cancer is broadly split into SCLC or NSCLC, the latter accounting for about 80% of cases. Approximately 10 to 15% of patients with NSCLC in the US and Europe and 30 to 40% of patients in Asia have an epidermal growth factor receptor (“EGFR”) mutation. While EGFR TKIs have significantly improved outcomes in the first line setting, treatment resistance and disease progression are extremely common, and a significant unmet need exists in later-line settings for effective and well-tolerated treatment options. SAVANNAH is an ongoing randomized, global Phase II trial studying the efficacy of savolitinib added to TAGRISSO® in patients with EGFRm, locally advanced or metastatic NSCLC with MET overexpression and/or amplification who progressed following treatment with TAGRISSO®. Based on the original single-arm trial design, patients were treated with savolitinib 300 or 600mg QD3 or 300mg BID, in combination with oral TAGRISSO® 80mg QD. In 2022, a comparison of savolitinib 300 mg BID and TAGRISSO® 80 mg QD to savolitinib 300mg BID and placebo was added to the trial to evaluate contribution of components. The trial enrolled over 360 patients in more than 80 centers globally, including in North America, Europe, South America and Asia. The primary endpoint is ORR and key secondary endpoints include PFS and DoR. In August 2022, positive interim results from the SAVANNAH trial were presented at the International Association for the Study of Lung Cancer 2022 World Conference on Lung Cancer (WCLC). The global SAFFRON Phase III trial is currently ongoing to further assess the savolitinib plus TAGRISSO® combination versus platinum-based doublet chemotherapy in patients with EGFRm, MET-overexpressed and/or amplified, locally advanced or metastatic NSCLC following TAGRISSO®. Patients are being prospectively selected using the high MET level cut-off identified in SAVANNAH. About Savolitinib Savolitinib is an oral, potent, and highly selective MET TKI that has demonstrated clinical activity in advanced solid tumors. MET is a tyrosine kinase receptor that has an essential role in normal cell development. Savolitinib 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. MET overexpression and/or amplification can lead to tumor growth and the metastatic progression of cancer cells, and is a known mechanism of acquired resistance to EGFR TKIs. The prevalence of MET depends on the sample type, detection method and assay cut-off used. Savolitinib is approved in China and is marketed under the brand name ORPATHYS® by our partner, AstraZeneca, for the treatment of adult patients with locally advanced or metastatic NSCLC with MET exon 14 skipping alteration, representing the first selective MET inhibitor approved in China. It has been included in the National Reimbursement Drug List of China (“NRDL”) since March 2023. 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. About Surufatinib Surufatinib is a novel, oral angio-immuno kinase inhibitor that selectively inhibits the tyrosine kinase activity associated with vascular endothelial growth factor receptors (VEGFRs) and fibroblast growth factor receptor (FGFR), which both inhibit angiogenesis, and colony stimulating factor-1 receptor (CSF-1R), which regulates tumor-associated macrophages, promoting the body’s immune response against tumor cells. Its unique dual mechanism of action may be very suitable for possible combinations with other immunotherapies, where there may be synergistic anti-tumor effects. Surufatinib is marketed in China by HUTCHMED under the brand name SULANDA®, and was first included in the NRDL in January 2022 for the treatment of non-pancreatic and pancreatic neuroendocrine tumors (NETs). 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. Since inception, it has focused on bringing drug candidates from in-house discovery to patients around the world, with its first three medicines marketed in China, and the first of which is also approved around the world including in the US, Europe and Japan. 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 the savolitinib or surufatinib for the treatment of patients with lung cancer and the further clinical development of the savolitinib or surufatinib in this and other indications. Forward-looking statements involve risks and uncertainties. Such risks and uncertainties include, among other things, assumptions regarding the timing and outcome of clinical studies and the sufficiency of clinical data to support New Drug Application approval of the savolitinib or surufatinib in lung cancer or other indications in the US, China or other jurisdictions, its potential to gain approvals from regulatory authorities on an expedited basis or at all, the safety profile of savolitinib or surufatinib, HUTCHMED’s ability to fund, implement and complete its further clinical development and commercialization plans for savolitinib or surufatinib and the timing of these events. In addition, as certain studies rely on the use of other drug products such as osimertinib as combination therapeutics with savolitinib and PD-1/PD-L1 antibodies as combination therapeutics with surufatinib, such risks and uncertainties include assumptions regarding the safety, efficacy, supply and continued regulatory approval of these therapeutics. 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, on AIM and on The Stock Exchange of Hong Kong Limited. 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 FTI Consulting –+44 20 3727 1030 / HUTCHMED@fticonsulting.comBen Atwell / Alex Shaw+44 7771 913 902 (Mobile) / +44 7779 545 055 (Mobile)Brunswick – Zhou Yi+852 9783 6894 (Mobile) / HUTCHMED@brunswickgroup.com Panmure LiberumNominated Advisor and Joint BrokerAtholl Tweedie / Freddy Crossley / Rupert Dearden+44 20 7886 2500 HSBCJoint BrokerSimon Alexander / Alina Vaskina / Arnav Kapoor+44 20 7991 8888 CavendishJoint BrokerGeoff Nash / Nigel Birks+44 20 7220 0500______________________________ References and Abbreviations 1 BID = Twice per day. 2 CI = Confidence interval. 3 QD = Once per day.