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Real-world data demonstrate non-classical mutations are present in 20-30% of all patients with EGFRm NSCLC Emerging data show non-classical EGFR mutations can be co-expressed with the classical L858R mutation, a setting characterized by shorter duration of response to osimertinib BDTX-1535 profile differentiated as the most advanced fourth-generation oral TKI in clinical development addressing the full spectrum of classical, non-classical, and C797S resistance EGFR mutations CAMBRIDGE, Mass., April 07, 2024 (GLOBE NEWSWIRE) -- Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a clinical-stage oncology company developing MasterKey therapies that target families of oncogenic mutations in patients with cancer, presented real-world evidence of the evolving epidermal growth factor receptor (EGFR) mutation landscape in non-small cell lung cancer (NSCLC), and the potential of BDTX-1535 to address a broader range of mutations compared to existing therapies. The results were disclosed in an oral presentation on April 7, 2024, at the 2024 American Association of Cancer Research (AACR) Annual Meeting held in San Diego, California. The oral presentation, titled “BDTX-1535 – A MasterKey EGFR Inhibitor Targeting Classical, Non-Classical and the C797S Resistance Mutation to Address the Evolved Landscape of EGFR Mutant NSCLC,” evaluated more than 235,000 sequenced cases of NSCLC sourced from Guardant Health (GuardantINFORM™) and Foundation Medicine (FoundationInsights™). The analyses reveal a broad spectrum of non-classical mutations, as well as an increased prevalence of the acquired resistance mutation, C797S. Over 100 unique non-classical EGFR oncogenic driver mutations were identified in newly diagnosed patients with NSCLC, and these non-classical EGFR mutations were present in 20-30% of patients across all lines of treatment. “The landscape of EGFR mutations in NSCLC continues to evolve, revealing classical and non-classical driver mutations,” said John Heymach, M.D., Ph.D., Chair of Thoracic/Head and Neck Medical Oncology at MD Anderson Cancer Center. “Non-classical mutations fall into categories including kinase domain PACC mutations and ectodomain mutations; therefore, next generation EGFR targeted therapies must effectively cover multiple subgroups of mutations.” “Novel targeted therapies are still needed to continue to improve clinical outcomes for patients with EGFR-mutant lung cancers,” added Xiuning Le, M.D., Ph.D., Associate Professor, Thoracic/Head and Neck Medical Oncology at MD Anderson Cancer Center. “To extend survival for our patients, newer drugs need to have good mutational coverage, good tolerability, and good brain penetrance.” Preclinical data demonstrated that BDTX-1535 potently inhibits more than 50 clinically relevant, non-classical EGFR mutations (as well as the classical L858R and exon19-del mutations) while sparing wild-type EGFR. The compound also potently inhibits the drug resistance C797S mutation, which emerges following treatment with third-generation EGFR inhibitors, including osimertinib. Real-world data indicate non-classical EGFR mutations can be co-expressed with classical mutation L858R, a setting that has been characterized by shorter duration of response to osimertinib first-line therapy. Preclinical data show that BDTX-1535 potently inhibits these co-expressed non-classical mutations. “BDTX-1535 was designed to address a broad spectrum of more than 50 non-classical oncogenic EGFR mutations, as well as the C797S resistance mutation,” said Elizabeth Buck, Ph.D., Chief Scientific Officer and co-founder of Black Diamond Therapeutics. “We believe that the potency of BDTX-1535 against the full spectrum of classical, non-classical, and C797S mutations positions the compound as the first and best-in-class fourth-generation EGFR inhibitor potentially offering NSCLC patients a well-tolerated, brain-penetrant, oral therapy across various lines of treatment.” Phase 1 proof-of-concept data demonstrating durable responses in recurrent NSCLC patients with both non-classical and acquired resistance C797S mutations were presented in October 2023. Black Diamond is currently advancing BDTX-1535 in a Phase 2 trial for patients with EGFRm NSCLC across multiple lines of therapy. Patients are being enrolled both in a first-line (1L) setting (for those expressing EGFR non-classical mutations) and in second- and third-line (2L/3L) settings following prior treatment with an EGFR inhibitor. Initial results from 2L/3L patients are anticipated in the third quarter of 2024. About BDTX-1535BDTX-1535 is an oral, brain-penetrant MasterKey inhibitor of oncogenic epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC), including classical driver mutations, non-classical driver mutations, and the acquired resistance C797S mutation. BDTX-1535 is a fourth-generation tyrosine kinase inhibitor (TKI) that potently inhibits, based on preclinical data, more than 50 oncogenic EGFR mutations expressed across a diverse group of patients with NSCLC in multiple lines of therapy. Based on preclinical data, BDTX-1535 also inhibits EGFR extracellular domain mutations and alterations commonly expressed in glioblastoma (GBM) and avoids paradoxical activation observed with earlier generation reversible TKIs. A “window of opportunity” trial of BDTX-1535 in patients with GBM is ongoing (NCT06072586) and a Phase 2 trial is ongoing in patients with NSCLC (NCT05256290). About Black Diamond TherapeuticsBlack Diamond Therapeutics is a clinical-stage oncology company focused on the development of MasterKey therapies that address families of oncogenic mutations in clinically validated targets. The Company’s MasterKey therapies are designed to address broad genetically defined patient populations, overcome resistance, minimize wild-type mediated toxicities, and be brain penetrant to treat CNS disease. The Company is advancing two clinical-stage programs: BDTX-1535, a brain-penetrant fourth-generation EGFR MasterKey inhibitor targeting EGFR mutant NSCLC and GBM, and BDTX-4933, a brain-penetrant RAF MasterKey inhibitor targeting KRAS, NRAS and BRAF alterations in solid tumors. For more information, please visit www.blackdiamondtherapeutics.com. Forward-Looking StatementsStatements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements regarding: the potential of BDTX-1535 to address a broader range of mutations compared to existing therapies, the position of BDTX-1535 as compared to other fourth-generation EGFR inhibitors, the timing of clinical updates for BDTX-1535 in patients with NSCLC and in patients with recurrent GBM, and the potential of BDTX-1535 to benefit patients with NSCLC. Any forward-looking statements in this statement are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include those risks and uncertainties set forth in its Annual Report on Form 10-K for the year ended December 31, 2023, filed with the United States Securities and Exchange Commission and in its subsequent filings filed with the United States Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. The Company undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. ContactsFor Investors:Mario Corso, Head of Investor Relations, Black Diamond Therapeuticsmcorso@bdtx.com For Media:media@bdtx.com

本文为转化医学网原创，转载请注明出处 作者：Rainbow 导读： 乳酸传统上被视为糖酵解的副产物，现在被认为是与肿瘤进展和各种其他疾病有关的重要信号分子。 4月4日，复旦大学张晓彪、谢涛和中国科学院黄薇共同通讯在期刊《Journal of Experimental & Clinical Cancer Research》上在线发表题为“GPR65 sensing tumor-derived lactate induces HMGB1 release from TAM via the cAMP/PKA/CREB pathway to promote glioma progression”的研究论文， 研究发现揭示了乳酸和HMGB1介导的TAMs与肿瘤细胞之间错综复杂的相互作用，从而推动了神经胶质瘤的肿瘤进展。GPR65在神经胶质瘤的TAMs上选择性高表达，通过cAMP/PKA/CREB信号通路感知乳酸刺激并促进HMGB1分泌。阻断这种反馈回路是治疗GBM的一种有希望的治疗策略。 https://jeccr-biomedcentral-com.libproxy1.nus.edu.sg/articles/10.1186/s13046-024-03025-8 研究背景 01 胶质瘤是最常见且侵袭性最强的原发性颅内肿瘤，占原发性颅内肿瘤的40%以上。根据世界卫生组织（WHO）的分类系统，胶质母细胞瘤（GBM）被归类为Ⅳ级胶质瘤，代表着最高恶性程度。尽管对于GBM患者有手术切除、化疗和放疗等治疗手段，但中位生存率仍低于15个月，通常在手术后一年内迅速复发和进展。 因此，探索肿瘤进展的潜在致病机制对于开发新的治疗策略以及最终改善胶质瘤，甚至GBM患者的预后具有重要意义。 乳酸已成为肿瘤微环境（包括神经胶质瘤）中的关键调节因子。然而，乳酸如何影响肿瘤细胞与肿瘤相关巨噬细胞（TAMs）（神经胶质瘤中最丰富的免疫细胞）之间通讯的确切机制仍知之甚少。 本研究旨在阐明肿瘤来源的乳酸对TAMs的影响，并研究控制TAMs介导的神经胶质瘤肿瘤促进的调控途径。 研究发现 02 在这项研究中，研究人员发现乳酸代谢在胶质瘤中上调，并且在肿瘤微环境中的高水平刺激了TAMs向促进肿瘤的M2亚型发展。此外，质子感应G蛋白偶联受体（GPRs）GPR65是在TAMs上感知乳酸信号的主要受体，在胶质瘤中介导了TAMs的促肿瘤效应。机制上，乳酸信号激活了TAMs上的GPR65，通过cAMP/PKA/CREB信号通路触发HMGB1的分泌，最终促进胶质瘤的发展。 总之，研究发现强调了乳酸和HMGB1介导的TAMs与肿瘤细胞之间的动态串扰，在促进胶质瘤进展中起着关键作用。通过靶向GPR65或HMGB1阻断这种反馈回路代表了治疗胶质瘤的一种有吸引力的选择。 研究结论 03 综上所述， 研究发现揭示了乳酸和HMGB1介导的TAMs与肿瘤细胞之间错综复杂的相互作用，从而推动了神经胶质瘤的肿瘤进展。GPR65在神经胶质瘤的TAMs上选择性高表达，通过cAMP/PKA/CREB信号通路感知乳酸刺激并促进HMGB1分泌。阻断这种反馈回路是治疗GBM的一种有希望的治疗策略。 参考资料： https://jeccr-biomedcentral-com.libproxy1.nus.edu.sg/articles/10.1186/s13046-024-03025-8 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。 热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！ 点击对应文字 查看详情

▎药明康德内容团队编辑近期，创新药新锐公司先博生物迎来诸多进展：今年3月，该公司宣布完成2亿元人民币A+轮融资；今年2月，先博生物首个通用型CAR-NK疗法用于系统性红斑狼疮的临床试验申请在中国获批；今年1月，该公司自主研发的靶向多个肿瘤抗原、同时分泌表达三抗分子的双靶CAR-T细胞疗法SNC109注射液获得美国FDA授予的孤儿药资格，用于治疗恶性胶质瘤，而该药用于治疗胶质母细胞瘤的临床申请也于去年12月刚获得中国NMPA批准。这一系列进展也引起了业界对这家细胞疗法领域新锐公司的关注。先博生物成立于2019年，专注于细胞治疗领域，其目前的研发领域涵盖CAR-NK细胞疗法、多靶向CAR-T细胞疗法，以及通过合作布局基于环状mRNA以及定向递送平台的下一代通用型体内细胞治疗产品。细胞疗法无疑是当下最受关注的新药研发形式之一。那么，先博生物的研发管线有何特点和优势？有望解决当下疾病治疗的哪些挑战？该公司又如何看待细胞疗法未来的潜力和机会？带着这些问题，药明康德内容团队采访了先博生物首席执行官（CEO）曹卓晓博士。曹卓晓博士曾负责和参与近40个不同类型药物形式的开发，拥有丰富的创新药研发经验。图片来源：先博生物提供，药明康德内容团队制作药明康德内容团队：在先博生物聚焦的肿瘤领域，当前治疗方式或临床解决方案还面临哪些关键挑战？ 曹卓晓博士：肿瘤大体可分成血液瘤、实体瘤两类。其中，血液瘤领域近年来的进展颇多，尤其是在细胞和基因疗法（CGT）领域，临床治疗手段已经较为丰富。这类患者面临的一个主要挑战是复发风险，尤其是末线治疗的患者通常需要新的方式延长生存期。相比于血液瘤领域，实体瘤领域面临的挑战在于近些年的突破仍然较少，除了抗体偶联药物（ADC）领域进展较快以外，其它新药研发类型仍然只限定在某些特定的适应症上，还有很多适应症面临无有效药物的窘境，存在巨大的临床未被满足需求。药明康德内容团队：先博生物的技术和产品管线有何优势？它们有望解决目前疾病治疗中的哪些难题？ 曹卓晓博士：先博生物研究的一个方向是通用型细胞治疗药物。自体CAR-T细胞疗法的出现无疑给患者带来了新的希望，但极高的成本也限制了其大范围临床应用。我认为研发通用型细胞治疗药物一定是未来的趋势，也是使细胞疗法造福更多患者的必经之路。在通用型细胞疗法的开发上，先博生物选择了CAR-NK疗法，这类疗法不仅有望即时可用，还叠加了NK细胞突出的安全性优势。先博生物的首个CAR-NK产品管线SNC103已经在中国获得多个IND批件，分别针对大B细胞淋巴瘤、B细胞急性淋巴细胞白血病和系统性红斑狼疮。不同于肿瘤患者，自免疾病患者的治疗选择更多，所以他们对于一款创新疗法的成本、安全性要求会更高。相较于自体CAR-T产品，通用型安全性更高的CAR-NK产品会更受到自免疾病患者的青睐，也会打开更广泛的市场。此外，针对更有挑战性的实体瘤领域，我们也在积极探索CAR-NK疗法联用靶向疗法等方案，希望未来在实体瘤适应症上也取得突破。我们的另一个研究方向是自体细胞疗法在实体瘤领域的应用。早前FDA已经批准了首款肿瘤浸润淋巴细胞（TIL）疗法用于治疗黑色素瘤，但细胞疗法还远远未在实体瘤领域取得大范围的突破。在这方面，我们选择的是临床需求较大、研发难度也较大的适应症，比如脑胶质瘤，该领域在过去二十年都很少有新药获批，目前的临床治疗手段依然很有限。在产品管线拓展上，先博生物的标准是从产品设计端就明确产品差异化，希望差异化产品最终体现在临床疗效的提升方面。比如我们正在研发的多靶向CAR-T细胞疗法SNC109注射液，这款CAR-T细胞表面携带两个CAR分子，分别靶向在胶质母细胞瘤中表达的IL13Rα2和HER2，同时该疗法还可以分泌靶向EGFR和EGFRvIII的双特异性抗体（BiTE），能够同时激活CAR阳性和CAR阴性T细胞来发挥杀伤肿瘤细胞作用。也就是说，我们针对胶质母细胞瘤这一瘤种的特点进行独特的4靶向设计，使得该产品拥有差异化优势。自主开发的同时，先博生物也在通过合作布局下一代通用型体内细胞治疗产品。2023年1月，先博生物已经和Orna Therapeutics（简称Orna公司）达成合作，旨在利用突破性环状mRNA技术（oRNA）开发的体内细胞治疗产品。环状RNA具有比线状mRNA更佳的稳定性优势，通过在免疫细胞中引入可表达CAR的环状RNA，可以在人体内直接生成CAR免疫细胞，从而实现识别和杀伤肿瘤细胞的效果。这样的创新技术可以避免从患者或者健康供者体内分离细胞、在体外进行工程化改造的繁琐过程，提高CAR-T细胞疗法对患者的可及性和进一步降低成本，很有希望成为下一代通用型细胞治疗的新药物形式。 药明康德内容团队：要实现先博生物在研产品的全部潜力，还有哪些关键挑战？以及有哪些潜在的解决方案？ 曹卓晓博士：先博生物瞄准的是国际范围内前沿创新的项目，这类项目往往缺少前序经验的参照，每一步都需要摸索和尝试，从研发到工艺开发，生产每前进一步都充满挑战。我们目前两款产品已经推进至1期临床研究阶段，当下亟需思考并解决的挑战就是在临床阶段最终确定最佳的临床给药方案。每个产品都有自身的特点，在临床端也不能照搬同类药物的临床方案设计，需要基于自身产品的设计特点和临床表现去摸索，并逐渐明确临床使用策略以及响应更佳的患者群体等等。药明康德内容团队：未来几年，预期先博生物在研发管线方面有望迎来哪些里程碑进展？曹卓晓博士：短期来看有几点：首先是先博生物CAR-NK产品管线SNC103、双CAR-T细胞疗法SNC109的多个1期临床研究项目完成，进入关键临床研究阶段；其次是我们与Orna公司合作的原位嵌合抗原受体（isCAR）T细胞技术项目ORN-101进入研究者发起的临床研究（IIT）或1期临床研究阶段。药明康德内容团队：您如何看待当前生物医药行业的创新趋势？创新机会在哪里？您对未来几年的预判是怎样的？曹卓晓博士：作为创新药研发领域的一员，我的直观感受是近年来的技术迭代越来越快，各种新的药物类型不断涌现，创新的周期越来越短。这对我们新药研发工作者来说无疑令人振奋。新的技术和产品均或多或少解决了已有产品的瓶颈和问题，使我们能从新技术中找到下一个能够突破的方向，而最终受益的是患者群体。在这样“百花齐放”的背景下，我认为创新的趋势和机会在于一家公司的技术积累是否足够强，是否有能力解决现有疗法的挑战，并最终在临床治疗中转化成患者的获益。另外我也看好新技术、新产品与临床已有产品的联用或组合。此外，定向递送技术在创新药领域非常重要，目前有很多不同的技术形式最终都是希望最大程度实现定向递送，更好地提升药物药效，同时降低安全性风险。具体到细胞治疗领域，我还是比较看好我们与合作伙伴Orna公司正在开发的PanCAR技术。这种技术能够在人体内直接生成有治疗效果的CAR免疫细胞，完全不需要任何体外制备的过程。而现有的细胞疗法无论是自体还是通用，都需要进行体外的一个制备，然后再回输给患者，而且该类药物不需要清淋的预处理，可以很好地避免清淋的预处理带来的临床风险。因此我预计该技术一旦在临床中取得验证，将会对传统的细胞治疗领域产生较强的冲击。 药明康德内容团队：您如何看待合作在新药研发中的作用？具体到先博生物所在的细胞和基因疗法领域，您认为需要怎样的合作，以加速创新疗法问世？ 曹卓晓博士：新药研发领域必然涉及各个层面、各种形式的合作。对于Biotech公司来说，我认为合作的活跃度可以一定程度上代表该公司产品、技术或临床开发方面存在的优势和价值，通过合作可以发挥合作方的各自优势，使得真正有价值的创新药尽快推进开发过程，最终更早惠及患者。具体到细胞疗法，这类疗法又有一定的特殊性。这类疗法的临床开发难度、CMC风险相较于大分子药物、小分子药物都更高，因此除了需要非常紧密的内部合作，比如临床需要与CMC高效、默契配合，还需要有效的外部合作，比如国际层面的临床开发，以及产品的商业化开发等。此外，我对合作的含义有更延展性的理解，比如与外部合作方进行创新药物的临床前研究的探索、与临床专家沟通讨论创新药的差异化临床研究方案设计、甚至与监管层面进行更多沟通交流促进对各类型创新药的理解认识的加深，这些广义的合作都有可能加速有价值的创新药的开发过程。药明康德内容团队：如果我们在10年后再次相聚于此，您认为细胞和基因疗法领域会有哪些变化？能否为我们描绘一幅10年后的相关场景？ 曹卓晓博士：我认为10年后，细胞疗法应该已经在通用化、突破实体瘤适应症这两方面都已经成为现实，在肿瘤以外的适应症，比如自身免疫性疾病、慢性病甚至大健康领域也有可能获得更大范围的应用。届时，我相信细胞疗法已经不再是“小众”的药物形式，而是像如今的小分子、大分子药物一样成为重要的临床用药分支。对于先博生物而言，我期待届时公司多款创新型细胞治疗药物获批上市，真正造福患者。本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。