Ceralasertib

点击蓝字 关注我们 编者按：驱动基因突变阴性的晚期非小细胞肺癌（NSCLC），免疫治疗耐药后始终缺乏高效、标准的后线治疗方案。当前标准的多西他赛单药获益极为有限，临床需求远未被满足。尽管学术界围绕耐药后的治疗策略开展了诸多探索，包括新型靶点联合免疫治疗等方向，但至今鲜有实质性突破。如何建立真正有效的标准化治疗路径、如何借助精准标志物筛选优势人群，仍是摆在研究者面前的严峻挑战。 LATIFY研究 今年欧洲肺癌大会，最为重磅的第一项突破性口头汇报（LBA1）公布了III期LATIFY研究的数据。这项肩负重要希望的研究旨在确认对于免疫检查点抑制剂及含铂双药化疗耐药的局部晚期或转移性NSCLC患者，Ceralasertib——一款ATR抑制剂联合度伐利尤单抗——一款针对PD-L1的免疫检查点抑制剂的组合，相较于多西他赛在这部分患者中的疗效及安全性。 这项前瞻性随机对照临床研究共纳入594例患者，以OS作为主要研究终点，这也是涉及免疫治疗中常用的主要研究终点，两组分别有25.1%和27.1%的患者接受过2种不同的治疗方案。遗憾的是，研究仍然以失败告终。两组中位OS分别为11.1和10.0个月，HR=0.90，P=0.287，在亚组分析中，几乎所有的亚组患者的HR点估计值均在0.85以上，意味着没有获益的亚组。 两组OS数据 另一个重要的疗效终点——PFS，同样没有优势，两组中位PFS均为4.1个月，HR=0.87，P=0.133，亚组分析同样未能发现获益人群。 两组PFS数据 从短期疗效客观缓解率（ORR）看，多西他赛组为17.3%，新组合仅有7.7%，只是在缓解持续时间长，新的组合展示了优势，长达16.9个月，远远优于多西他赛组的4.4个月。联合治疗展示了略优的安全性，联合治疗组和多西他赛单药组的3度以上全因不良反应发生率分别为46.8%和59.9%，其中，治疗相关的3度以上不良反应发生率为26.9%和43.8%。 其实，这项研究在启动之前，进行了充分的前期研究准备，不仅有充分的基础研究准备，同时还有临床前的研究数据，相关研究结果发表于Nature Medicine杂志。这项II期、标志物为指导的临床研究纳入了ATR抑制剂、PARP抑制剂、反义寡核苷酸药物以及针对CD73的单克隆抗体。在这项聚焦在免疫耐药人群的研究中，最终数据显示，只有联合ATR抑制剂这组患者取得显著获益。联合ATR抑制剂患者的中位PFS为5.8个月，显著优于联合其他组合的2.7个月的中位PFS；联合ATR抑制剂的中位OS为17.4个月，更是显著优于其他组合的9.4个月。但即便有充分的前期数据做支持，III期临床研究仍然以失败告终。显示了免疫耐药后患者的难治性。 前期研究数据 PRESERVE-003研究 另外一个传统靶点——CTLA-4，有可能为克服PD-1/PD-L1的耐药带来新的曙光。CTLA-4是既PD-1/PD-L1之后第2个成熟的免疫检查点，围绕这一靶点的药物并没有像PD-1/PD-L1这条通路一样成为现象级产品，在肺癌领域，围绕这一靶点目前并无任何一款药物单独成药，目前获批的适应症均为与PD-1/PD-L1联合应用或进一步与含铂双药化疗联合应用，另外，由于药物的安全性原因，导致其目前在临床的应用并不普及。而今年欧洲肺癌大会，一款新型的CTLA-4抑制剂——gotistobart，为免疫耐药的晚期肺癌患者带来新的曙光和希望。该药的酸环境依赖的作用机制，可避免在溶酶体中被降解，从而保护 CTLA-4 分子和抗体，早期药物研究中，该药后线治疗免疫耐药的NSCLC患者的ORR和DCR分别为29.6%和70.4%，支持其进一步研发，III期临床研究中，鳞癌患者的数据尤其亮眼，并于近期发表于Nature Medicine杂志。 基于前期的剂量探索，该药的标准给药剂量为6 mg/kg， Q3W，其中，前两周给予10 mg/kg  Q3W的负荷剂量，多西他赛作为标准对照。Gotistobart和多西他赛组分别入组45例和42例患者，二线治疗比例分别为31.1%和19.0%。主要研究终点OS明显延长。Gotistobart组和多西他赛组的中位OS分别为未达到和10.0个月，HR=0.46，P=0.0102，12个月OS率分别为63.1%和30.3%。但是，由于缺乏标志物的选择，由此出现了两个有意思的现象——由于缺乏标志物对超进展患者排除，同时叠加免疫起效慢的特点，研究早期Gotistobart组的生存曲线在多西他赛组下面；同样由于缺乏标志物的选择，无法有效富集可以长期获益的患者，由此生存曲线出现交叉，两组中位PFS非常接近，甚至Gotistobart组在数值上略差于多西他赛组（2.4个月vs. 2.6个月），但HR值显示了Gotistobart组的获益(HR=0.69)，同时展示了长期的生存获益，两组12个月的PFS率分别为25.2%和0%。两组ORR分别为20%和4.8%，该药也展示了免疫治疗特有的特点——一旦起效，会维持非常长的时间，两组中位DoR分别为11.0个月和3.8个月。 两组的OS数据 总结与思考 目前，驱动基因突变阴性的晚期肺癌患者的诊疗存在很多困局：首先，如何进一步提高疗效。对于PD-L1大于等于50%的患者而言，免疫单药是标准，除此以外，其他患者的标准治疗为免疫联合含铂双药化疗，中位OS基本在25个月左右，已经遇到了瓶颈，以PD-1/VEGF为代表的双抗有迭代当前标准治疗的趋势，但数据尚不丰富；而一旦免疫耐药后，如何建立标准化治疗流程，则是至今都未解决的问题。此外，缺乏高效的标志物以区分不同人群是至今都未解决的问题。虽然PD-L1在临床应用广泛，但是其区分效率远没有驱动基因那么高，PD-L1高表达只意味着有效率高，而低表达患者并非完全无效，这与驱动基因突变阳性和阴性患者有效率的差异天差地别，虽然TMB、肿瘤浸润淋巴细胞等在一段时间有望成为精准治疗的标志物，但始终未能在临床广泛应用。与突变阳性患者动辄超过5年的生存时间相比，突变阴性患者亟需新的治疗策略及更加精准的标志物。 参考文献：1.Kai He,et al. Anti-tumor activity of gotistobart compared to docetaxel in patients with metastatic squamous non-small cell lung cancer (sqNSCLC) progressing on PD-(L)1 inhibitors: Stage 1 PRESERVE-003 phase III trial2026 ELCC. Abstract 3O.2.Benjamin Besse, et al. Ceralasertib (C) + durvalumab (D) in patients (pts) with locally advanced (LA) or metastatic (m) NSCLC who progressed on or after anti-PD-(L)1 and platinum-based chemotherapy (CT): Results from LATIFY. 2026 ELCC. Abstract LBA1. （来源：《肿瘤瞭望》编辑部） 声 明 凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

Vancouver, British Columbia, April 30, 2026 – Rakovina Therapeutics Inc. (“Rakovina” or the “Company”) (TSX-V: RKV) (FSE: 7J0), a biopharmaceutical company advancing next-generation cancer therapies through artificial intelligence (AI)-powered drug discovery, today announced its financial results for the fourth quarter and fiscal year ended December 31, 2025, and provided a corporate update. As Rakovina enters 2026, the Company is advancing its three primary drug discovery programs toward key value-creating milestones. For kt-5000, lead optimization continues with Variational AI, with lead candidate selection and IND-enabling studies targeted for the second half of 2026. For kt-3283, in vivo ADME and efficacy testing of the LNP formulation is underway with NanoPalm. For kt-2000, a second round of AI output and in vitro testing is advancing. Across all programs, the Company intends to progress pharmaceutical partnership discussions as preclinical data matures. “Completing the first phase of our restructuring marks an important inflection point for Rakovina,” said Kim Oishi, CEO of Rakovina. “Through the recent debenture restructuring, new financing, and the strengthening of our board and executive team, we are well on our way to repositioning the Company for success. As we continue to put our financial house in order, we are sharpening our focus on execution — advancing our DDR inhibitor pipeline, expanding our strategic partnerships, and unlocking the full potential of our world-class AI-driven drug discovery engine to deliver value for our shareholders.” 2025 Highlights and Recent Developments Leadership and Board On January 27, 2026, Rakovina appointed Kim Oishi as Chief Executive Officer. Mr. Oishi brings over 25 years of capital markets experience, including as founder of Grand Rock Capital Inc. and partner at First Growth Equity Partners Inc. On January 27, 2026, Rakovina welcomed Frank Holler to its Board of Directors. Mr. Holler has been directly involved in the founding and development of a number of Canada’s leading biopharma companies, including ID Biomedical Corp., Angiotech Pharmaceuticals Inc. and Xenon Pharmaceuticals Inc. On May 5, 2025, Rakovina appointed Dr. David Kideckel, PhD, MBA as Chief Financial Officer. Dr. Kideckel brings over 20 years of life sciences and capital markets experience, with prior senior operational and finance positions at both public and private companies, including at Johnson & Johnson, Alexion Pharmaceuticals (acquired by AstraZeneca), and ATB Cormark Capital Markets. On April 29, 2025, Rakovina appointed Yevgeniy Meshcherekov and Dr. David Kideckel to the Board, with Mr. Meshcherekov assuming Chair of the Audit Committee. Financing and Capital Structure On March 5, 2026, Rakovina closed a non-brokered private placement of convertible debenture units for gross proceeds of $1,000,000 and concurrently restructured $1,587,131 in existing debentures through a combination of share settlements (3,265,585 shares at $0.12) and replacement debentures, significantly strengthening the Company’s balance sheet. On July 15, 2025, Rakovina common shares became eligible for electronic clearing and settlement through the Depository Trust Company (DTC), broadening access for U.S. investors. On June 24, 2025, Rakovina completed a 10-to-1 share consolidation of its issued and outstanding common shares. On June 6, 2025, Rakovina closed a non-brokered private placement of equity units for gross proceeds of $3,555,150, concurrent with a $1,350,000 convertible debenture financing. On January 30, 2025, Rakovina listed its common shares on the Frankfurt Stock Exchange (FSE) under the ticker symbol “7J0”, broadening access to European investors. AI Platform Partnerships On January 8, 2026, Rakovina expanded its collaboration with Variational AI and its Enki™ generative AI platform for continued lead optimization of the kt-5000 dual ATR-mTOR inhibitor program. On August 12, 2025, Rakovina and NanoPalm Ltd. (Riyadh, Saudi Arabia) announced a non-binding Letter of Intent to form a joint venture to co-develop AI-discovered oncology therapies, beginning with kt-3283 delivered via NanoPalm’s patterned lipid nanoparticle (pLNP) system designed using its EnsaliX™ AI platform. Scientific and Clinical Milestones In April 2026, Rakovina presented two posters at the 2026 AACR Annual Meeting in San Diego. For kt-5000, a prototype lead candidate demonstrated in vivo tumour growth inhibition comparable to ceralasertib in an LNCaP prostate model, with significantly improved tolerability and no signs of hematological toxicity. For kt-3283 LNP, successful characterization of the EnsaliX-designed formulation confirmed uniform particle size, stable colloidal behavior, and surface features predicted to enhance cellular uptake. On November 24, 2025, Rakovina presented two posters at the Society for Neuro-Oncology (SNO) Annual Meeting, reporting CNS penetrance, metabolic stability, and in vivo tolerability for lead candidates in both the kt-5000 and kt-2000 programs. On November 18, 2025, Rakovina announced that President & CSO Prof. Mads Daugaard was invited to present and participate as a panelist at the 9th Annual DNA Damage Response (DDR) Inhibitors Summit in January 2026. On October 27, 2025, Rakovina presented pre-clinical data at the AACR-NCI-EORTC International Conference confirming potent ATR inhibition and CNS penetration for the kt-5000 series – a milestone differentiator in the DDR inhibitor space. On August 26, 2025, Rakovina announced that President & CSO Prof. Mads Daugaard was invited to speak at the 13th Tuscany Retreat on Cancer Research & Apoptosis (August 23-30), highlighting Rakovina’s DDR-targeted drug discovery and development accomplishments. On April 28-29, 2025, Rakovina presented pre-clinical data on the kt-2000 and kt-5000 programs at the 2025 American Association for Cancer Research (AACR) Annual Meeting. The Company’s preclinical kt-3283 program continues to demonstrate superior cytotoxicity versus FDA-approved olaparib and vorinostat across multiple tumor types, as reported in a peer-reviewed publication in Clinical Cancer Research. Pipeline Progress On July 23, 2025, Rakovina announced that its kt-5000 program had identified potent ATR inhibitor hits during early-stage screening. On March 12, 2025, Rakovina received the first synthesized batch of AI-generated ATR inhibitor compounds from its Variational AI collaboration. On January 13, 2025, Rakovina achieved a shortlist of AI-generated CNS-penetrant ATR-targeting molecules, completing the initial AI-driven candidate generation phase for kt-5000. On January 6, 2025, Rakovina received initial synthesized AI-generated PARP inhibitor compounds for in vitro and in vivo validation in the kt-2000 program. Summary Financial Results for the Fourth Quarter and Year Ended December 31, 2025 All dollar amounts reflected in Canadian dollars unless otherwise stated. At December 31, 2025, the Company had a working capital deficit of approximately $2,149,223 and cash and cash equivalents of $298,758. For the three- and twelve-months ended December 31, 2025, the Company reported a net loss of $1,893,159 and $8,680,576, respectively. Research and development expenses were $828,931 and $4,603,002; general and administrative expenses were $972,872 and $3,684,750 for the three- and twelve-months ended December 31, 2025, respectively. Total operating expenses for the three- and twelve-months ended December 31, 2025 were $1,801,803 and $8,287,752, respectively. Subsequent to year-end, the Company strengthened its balance sheet through approximately $1.0 million in new convertible debenture financing and the restructuring of $1,587,131 in existing debentures, as further described in the Company’s audited financial statements and MD&A for the year ended December 31, 2025, filed on SEDAR+. Rakovina Therapeutics’ financial statements as filed with SEDAR+ can be accessed from the Company’s website at: https://www.rakovinatherapeutics.com/corporate-profile/ About Rakovina Therapeutics Inc. Rakovina Therapeutics is a biopharmaceutical research company focused on the development of innovative cancer treatments. Our work is based on unique technologies for targeting the DNA-damage response powered by Artificial Intelligence (AI) using validated, proprietary platforms. By using AI, we can review and optimize drug candidates at a much greater pace than ever before. The Company has established a pipeline of distinctive DNA-damage response inhibitors with the goal of advancing one or more drug candidates into human clinical trials in collaboration with pharmaceutical partners. Further information may be found at http://www.rakovinatherapeutics.com. Neither TSX Venture Exchange nor its Regulation Services Provider (as that term is defined in policies of the TSXV) accepts responsibility for the adequacy or accuracy of this release. Notice Regarding Rakovina Therapeutics Forward-Looking Statements: This release includes forward-looking statements regarding the company and its respective business, which may include, but is not limited to, statements with respect to the proposed business plan of the company and other statements. Often, but not always, forward-looking statements can be identified by the use of words such as “plans,” “is expected,” “expects,” “scheduled,” “intends,” “contemplates,” “anticipates,” “believes,” “proposes” or variations (including negative variations) of such words and phrases, or state that certain actions, events, or results “may,” “could,” “would,” “might,” or “will” be taken, occur, or be achieved. Such statements are based on the current expectations of the management of the company. The forward-looking events and circumstances discussed in this release may not occur by certain specified dates or at all and could differ materially as a result of known and unknown risk factors and uncertainties affecting the company, including risks regarding the biopharmaceutical industry, economic factors, regulatory factors, the equity markets generally, and risks associated with growth and competition. Although the company has attempted to identify important factors that could cause actual actions, events, or results to differ materially from those described in forward-looking statements, there may be other factors that cause actions, events, or results to differ from those anticipated, estimated, or intended. No forward-looking statement can be guaranteed. Except as required by applicable securities laws, forward-looking statements speak only as of the date on which they are made, and the company undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, or otherwise. The reader is referred to the company’s most recent filings on SEDAR+ for a more complete discussion of all applicable risk factors and their potential effects, copies of which may be accessed through the company’s profile page at www.sedar.com. For Further Information Contact: Investor Relations Rakovina Therapeutics Inc. IR@rakovinatherapeutics.com