Pelareorep

Company to leverage strong durability and survival data in second-line and later metastatic squamous cell anal carcinoma Pivotal study expected to focus on patients in a post-standard-of-care patient population with no FDA-approved therapies SAN DIEGO, April 27, 2026 (GLOBE NEWSWIRE) -- Oncolytics Biotech ® Inc. (Nasdaq: ONCY) (“Oncolytics” or the “Company”), a clinical-stage immunotherapy company developing pelareorep, an investigational, systemically delivered immunotherapy that has been shown to activate innate immune-sensing pathways, today announced that a Type C meeting with the U.S. Food and Drug Administration (“FDA”) has resulted in alignment on the design of a pivotal clinical study to support approval of pelareorep in patients with unresectable metastatic squamous cell carcinoma of the anal canal (“SCAC”). “We want to thank the FDA for its very clear guidance and helping us create an efficient pathway for pelareorep in a disease that is desperate for new treatments,” said Jared Kelly, Chief Executive Officer of Oncolytics. “While a single-arm study was possible in this setting, following a productive discussion with the FDA and in consideration of recent regulatory decisions regarding similar studies, we have aligned on a randomized controlled trial designed to potentially support both accelerated approval and full approval within the same study. This approach directly addresses relevant and rigorous evidentiary standards while allowing for approval based on multiple endpoint assessments.” SCAC is a rare gastrointestinal malignancy affecting more than 10,000 patients annually in the United States. Patients whose disease progresses following first-line chemotherapy/checkpoint inhibitor treatment have no FDA-approved therapeutic options and limited National Comprehensive Cancer Network recommended treatments. In a recent study combining pelareorep with a checkpoint inhibitor in second-line and later SCAC, the combination achieved a median duration of response of 15.5 months versus 9.5 months and 12-month survival of 82% versus 45.7%, each measured against the current standard of care. 1 “The post-first-line SCAC setting remains an area of significant unmet need,” said Dr. Van Morris, Associate Professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, TX. “Pelareorep provides a strong rationale for evaluation in this population, and the study design represents a thoughtful and appropriate approach to advancing new options for these patients.” The Company plans to incorporate FDA feedback into the final protocol, which is expected to be a single, randomized controlled trial for which accelerated approval and full approval could be applied at different points in time. About Oncolytics Biotech Inc. Oncolytics is a clinical-stage biotechnology company developing pelareorep, an investigational intravenously delivered double-stranded RNA immunotherapeutic agent. Pelareorep has demonstrated encouraging results in multiple first-line pancreatic cancer studies, two randomized Phase 2 studies in metastatic breast cancer, and early-phase studies in anal and colorectal cancer. It is designed to induce anti-cancer immune responses by converting immunologically “cold” tumors “hot” through the activation of innate and adaptive immune responses. The Company is advancing pelareorep in combination with chemotherapy and/or checkpoint inhibitors in metastatic gastrointestinal cancers, where pelareorep has received Fast Track designation from the FDA for colorectal and pancreatic cancer. Oncolytics is actively pursuing strategic partnerships to accelerate development and maximize commercial impact. For more about Oncolytics, please visit: or follow the Company on social media on LinkedIn and on X @ oncolytics . Reference Rao S, et al. A phase II study of retifanlimab (INCMGA00012) in patients with squamous carcinoma of the anal canal who have progressed following platinum-based chemotherapy (POD1UM-202). ESMO Open. 2022 Aug;7(4):100529 Forward-looking statements This press release contains forward-looking statements, within the meaning of Section 21E of the U.S. Securities Exchange Act of 1934, as amended, and forward-looking information under applicable Canadian securities laws (such forward-looking statements and forward-looking information are collectively referred to herein as “forward-looking statements”). Forward-looking statements contained in this press release include statements regarding beliefs as to the potential, registration, mechanism of action and benefits of pelareorep as a cancer therapeutic; the Company’s goals, strategies, and objectives; expectations around the design, milestones, anticipated timelines and expected outcomes for current and future studies, and projected outcomes of the Company’s planned clinical study of pelareorep, including the potential for accelerated regulatory approval; its belief in the clinical promise of pelareorep in anal, colorectal, pancreatic and other gastrointestinal cancers; and the Company’s goals and expectations for its potential registrational development path for pelareorep in multiple gastrointestinal cancers. In any forward-looking statement in which Oncolytics expresses an expectation or belief as to future results, such expectations or beliefs are expressed in good faith and are believed to have a reasonable basis, but there can be no assurance that the statement or expectation or belief will be achieved. These statements involve known and unknown risks and uncertainties that may cause actual results to differ materially from those anticipated. These risks include, but are not limited to, regulatory outcomes, trial execution, financial resources, access to capital markets, and market dynamics. Please refer to Oncolytics’ public filings with securities regulators in the United States and Canada for more information. The Company assumes no obligation to update forward-looking statements, except as required by law. Company Contact Jon Patton Director of IR & Communication jpatton@oncolytics.ca

整理：肿瘤资讯来源：肿瘤资讯在结直肠癌（Colorectal Cancer, CRC）的分子进化史上，KRAS基因突变始终被视为驱动肿瘤发生、发展及产生治疗耐药的轴心因素。作为RAS/MAPK信号通路的枢纽，KRAS蛋白通过在激活的GTP结合状态与失活的GDP结合状态之间进行分子转换，严密调控着细胞的增殖、分化与凋亡 [1]。在结直肠癌患者中，KRAS突变的发生率高达40%至50%，且展现出显著的异质性，这种异质性不仅体现在突变频率上，更深刻地影响了患者的预后及对现有治疗方案的敏感性 [1]。长期以来，KRAS被生物医药界公认为“不可成药”的靶点，这主要归结于其蛋白质表面缺乏可供小分子药物高效结合的疏水口袋，以及其对GTP极高的亲和力。直到共价抑制技术在第12位半胱氨酸（G12C）位点取得突破，这一僵局才被打破 1。然而，在结直肠癌中，KRAS突变的分布与非小细胞肺癌（NSCLC）截然不同。在CRC中，G12D（约占30%~36%）、G12V（约占20%-22%）和G13D（约占15%~18%）占据了主导地位，而G12C突变仅占约3%至4% 7。这意味着，针对结直肠癌的药物研发必须跨越G12C的局限，向更广泛的突变谱系进军。从临床应用角度看，KRAS突变状态是筛选结直肠癌抗EGFR单克隆抗体（如西妥昔单抗和帕尼单抗）适用人群的法定生物标志物。携带KRAS任何形式激活突变的患者，其下游信号通路处于持续激活状态，导致抗EGFR疗法无法通过阻断上游受体来抑制肿瘤，从而产生内在耐药 1。这种强烈的临床需求驱动了从特定等位基因抑制剂到泛KRAS抑制剂，乃至蛋白质降解剂、癌症疫苗和T细胞疗法的全面技术迭代 7。结直肠癌中KRAS突变亚型的分布与临床属性突变亚型发生频率 (约占KRAS突变CRC)优势癌种分布特征临床预后影响G12D30% ~ 36%CRC与胰腺癌中最常见亚型关联高度侵袭性，目前是研发的首要难点 7G12V20% ~ 22%频率位居第二，常见于黏液性腺癌易发生腹膜转移，对传统化疗敏感度较低 7G13D15% ~ 18%特异性分布于结肠右半侧肿瘤预后极差，传统观点认为其对抗EGFR疗效存在轻微争议但总体耐药 1G12C3% ~ 4%比例虽低但药物开发最为成熟首个靶向药物获批位点，与吸烟史存在微弱关联 7其他 (Q61H/L, G12R等)5% ~ 10%较为罕见，常作为二线治疗后的获得性耐药机制出现涉及不同密码子的复杂生物学效应 1KRAS G12C 抑制剂的结直肠癌征途：从单药折戟到联合制胜KRAS G12C抑制剂的研发利用了突变产生的半胱氨酸残基的亲核性，通过共价结合锁定蛋白质于非活性的GDP结合状态（OFF状态）。虽然索托拉西布（Sotorasib）和阿达格拉西布（Adagrasib）在肺癌中展现了单药缓解的奇迹，但在结直肠癌中，单药ORR通常徘徊在10%左右 8。深度机制研究揭示，结直肠癌细胞具有极高的内源性EGFR活性，当KRAS G12C被阻断后，细胞会迅速通过EGFR反馈回路重新激活MAPK通路，这种“旁路激活”是CRC对单药抑制剂产生内在耐药的核心原因 10。索托拉西布 (Sotorasib, Lumakras) - 安进 (Amgen)索托拉西布作为全球首款上市的KRAS G12C抑制剂，在结直肠癌领域的应用已通过联合用药方案实现了跨越式发展。2025年1月，美国FDA正式批准了索托拉西布联合帕尼单抗（Panitumumab）用于治疗既往接受过含氟嘧啶、奥沙利铂和伊立替康化疗的KRAS G12C突变转移性结直肠癌 15。这一批准标志着首个专门针对KRAS突变CRC的靶向疗法落地，通过双重阻断KRAS和其上游EGFR节点，有效克服了反馈激活 20。CodeBreaK 300研究（NCT05198934）是支持该疗法的关键III期试验。试验将患者随机分为索托拉西布960mg组、240mg组以及研究者选择的标准治疗组（TAS-102或瑞戈非尼） 19。评估参数960mg 索托拉西2布 + 帕尼单抗240mg 索托拉西布 + 帕尼单抗标准治疗 (SOC)中位无进展生存期 (mPFS)5.6 ~ 5.7 个月3.9 ~ 4.0 个月2.0 ~ 2.2 个月风险比 (Hazard Ratio)0.49 (p=0.006)0.58 (p=0.03)参照客观缓解率 (ORR)26.4% ~ 30.2%5.7% ~ 7.5%0% ~ 1.9%疾病控制率 (DCR)92.5%未详细披露-中位总生存期 (mOS)15.2 个月 (趋势向好但未达统计学显著性)-统计分析不具备效力 8安进的策略是将该方案向一线治疗推进，目前正在开展CodeBreaK-301试验，比较索托拉西布联合帕尼单抗与标准含铂化疗在未经治疗的mCRC患者中的疗效 12。此外，CodeBreaK 101研究的分支H探讨了“索托拉西布+帕尼单抗+FOLFIRI”的三联方案，ORR高达58%，DCR达94%，这暗示了靶向联合化疗可能成为未来更强力的干预手段 8。阿达格拉西布 (Adagrasib, Krazati) - 百时美施贵宝 (BMS/Mirati)百时美施贵宝在收购Mirati后，正式接手了阿达格拉西布的全球开发。阿达格拉西布的设计初衷是具有优化的药代动力学性能，包括更长的半衰期和跨越血脑屏障的能力 5。在结直肠癌领域，KRYSTAL-1研究（NCT03785249）评估了阿达格拉西布单药及联合西妥昔单抗（Cetuximab）的疗效 9。阿达格拉西布联合西妥昔单抗在既往治疗过的mCRC中表现出了强劲的数据。根据最新更新，该方案的ORR达到34%至46%，中位PFS为6.9个月，中位OS达到15.9个月 8。研究发现，相比于单药，联合方案能更彻底地清除血浆中的KRAS G12C突变等位基因频率（MAF），这从分子水平解释了联合用药的优越性 8。2024 年 6 月 21 日，美国食品药品监督管理局 (FDA) 加速批准 adagrasib联合西妥昔单抗用于此前接受过氟尿嘧啶、奥沙利铂和伊立替康治疗的 KRAS G12C 突变的局部晚期或转移性CRC 成年患者，是首个获批用于治疗CRC的 KRAS 靶向药物25。结直肠癌KRAS G12C后续竞争管线除两大巨头外，多家药企正在开发具有差异化优势的G12C抑制剂，力求在效价、安全性或耐药逆转方面取得突破。药物名称研发企业作用机制/特点结直肠癌相关数据/状态Divarasib (GDC-6036)罗氏 (Genentech)极高效价、高选择性共价结合联合西妥昔单抗在CRC中ORR达62.5%，mPFS达8.1个月，疗效极其突出 8Olomorasib (LY3537982)礼来 (Eli Lilly)旨在减少胃肠道毒性，高靶向覆盖正在开展联合化疗或抗EGFR的III期研究 5Glecirasib (JAB-21822)加科思 (Jacobio)中国自主研发，优化溶解度联合西妥昔单抗在CRC中已进入注册性临床阶段 29Garsorasib (D-1553)益方生物良好的PK稳定性与肿瘤组织渗透正在评估单药及联合方案在CRC中的潜力 12Calderasib (MK-1084)默沙东 (Merck)重点在于与免疫联合的能力与帕博利珠单抗联合方案在早期试验中显示出安全性 5FMC-376Frontier Med同时抑制ON/OFF状态，旨在克服耐药处于早期临床探索阶段，关注NSCLC、CRC及胰腺癌 26攻坚主流突变：KRAS G12D 与 G12V 的研发突破由于KRAS G12D和G12V在结直肠癌中占据超过半数的比例，针对这些突变的开发不仅是医学上的挑战，更是商业上的“高价值白区” 7。与G12C不同，G12D和G12V缺乏可利用的亲核残基，因此研发路径主要分为非共价抑制、活性状态（ON状态）阻断以及定向蛋白质降解（PROTAC） 1。KRAS G12D 抑制剂与降解剂的爆发G12D突变利用其天冬氨酸电荷特性，研究人员开发了电荷互补的结合策略。MRTX1133 - 百时美施贵宝 (BMS/Mirati)MRTX1133是该领域的先驱，它是一种高度选择性的非共价KRAS G12D抑制剂，能够结合GDP态和GTP态。在结直肠癌的临床前模型中，MRTX1133不仅能诱导肿瘤消退，还显示出与氟尿嘧啶化疗以及免疫检查点抑制剂的协同潜力7。目前的临床试验（NCT05737706）正在评估其作为单药或联合方案在G12D突变CRC患者中的活性 7。Zoldonrasib (RMC-9805) - 革命医药 (Revolution Medicines)RMC-9805采用了一种创新的“三复合物”技术，通过结合亲环素A（Cyclophilin A）形成三复合物，从而直接抑制处于活性状态的RAS(ON)蛋白。这种机制理论上比传统的“OFF”状态抑制剂具有更直接的通路切断能力 32。FDA已授予Zoldonrasib突破性疗法认定，其在CRC中的研究正在加速推进（NCT06040541）27。Setidegrasib (ASP3082) - 安斯泰来 (Astellas)安斯泰来的ASP3082是一款针对KRAS G12D的靶向蛋白质降解剂。它通过将G12D突变蛋白标记为泛素化降解对象，实现对该致癌驱动子的清除。虽然初步数据多见于胰腺癌（响应率约24%），但其在CRC中由于能绕过部分结构约束而受到广泛关注 13。KRAS G12V 及其他突变的针对性开发G12V突变（缬氨酸替代）在CRC中常预示着更差的生存期和对常规治疗的耐受 7。针对这一亚型，研究重点已转向选择性抑制和免疫干预。RMC-5127 (Revolution Medicines): 这是一款专门针对RAS(ON) G12V的抑制剂，目前已进入首位患者给药阶段（NCT07349537）。其设计思路同样基于三复合物平台，旨在为G12V驱动的CRC、胰腺癌和NSCLC提供精准打击 32。JAB-23000 (加科思): 作为中国药企在非C12位点抑制剂上的代表作，JAB-23000是等位基因特异性KRAS G12V抑制剂，正处于IND申请后的早期临床准备中 7。NW-301V (纽安津生物): 在2025年ESMO大会上公布的I期结果显示，这款针对G12V突变的自体TCR-T细胞疗法在包括结直肠癌在内的实体瘤中显示出50%的ORR和良好的安全性，开启了KRAS突变CRC的细胞治疗新赛道 38。泛KRAS (Pan-KRAS) 抑制剂：跨越等位基因的全局策略随着单一等位基因抑制剂暴露出“逃逸突变”和覆盖不足的问题，研发社区开始转向能同时覆盖G12D、G12V、G12R等多种突变体以及野生型KRAS过度激活的“泛KRAS”策略。这类药物被认为具有更广的适应症潜力，但也面临着对正常组织野生型RAS抑制产生的毒性挑战 5。Daraxonrasib (RMC-6236) - 革命医药 (Revolution Medicines)RMC-6236是目前进度最快、影响力最大的泛RAS(ON)抑制剂。它作为非共价的三复合物抑制剂，能够高效识别并阻断处于激活状态的所有主要KRAS、HRAS和NRAS突变体 9。在RMC-6236-001试验中，针对经治的KRAS G12X突变CRC患者，ORR达到29%，中位PFS为5.6个月 8。革命医药在2026年的布局显示，RMC-6236已不仅局限于末线治疗，多项III期试验（RASolute系列）正在全球铺开。其中，针对胰腺癌的RASolute 302试验已宣布达到PFS和OS的主要终点，这极大提振了其在结直肠癌领域成功的信心 9。全球泛KRAS管线格局比较药企名称候选药物靶向范围与技术特征结直肠癌研发状态革命医药RMC-6236泛RAS(ON) 三复合物I/II期临床，显示初步CRC获益 8和誉医药ABSK211泛KRAS 抑制剂临床前数据覆盖G12/13/Q61，启动IND 44BridgeBioBBO-11818泛KRAS 抑制剂进入KONQUER-101临床，获FDA快速通道 46勃林格殷格翰BI-2865非共价泛KRAS临床前研究证明能抑制多种亚型并克服G12C耐药 7安进 (Amgen)AMG 410泛KRAS处于临床早期，作为Lumakras的后继补充 5礼来 (Lilly)LY4066434泛KRASI期研究中，探索CRC与实体瘤 27辉瑞 (Pfizer)PF-07934040泛KRAS正在进行联合用药研究 27克服耐药的纵向联合与交叉策略：上游、下游与免疫的合围结直肠癌的复杂信号网络决定了任何单一节点的抑制都极易被代偿途径中和。为了提高缓解深度和持续时间，研究人员正在通过纵向（抑制通路上游或下游）和横向（结合免疫或化疗）的策略进行合围 12。SHP2 与 SOS1：切断上游激活源SHP2和SOS1是受体酪氨酸激酶（RTK）向KRAS传递信号的关键节点。抑制这些节点可以减少KRAS蛋白从GDP态向GTP态的转换速率，从而增强KRAS抑制剂的效力 39。 诺华 (Novartis): 正在临床评估SHP2抑制剂TNO155（Batoprotafib）联合阿达格拉西布（Krazati）或奥普努拉西布（Opnurasib/JDQ443）在CRC中的应用 27。加科思 (Jacobio): 其SHP2抑制剂JAB-3312（Sitneprotafib）与Glecirasib的联用已展现出强力的协同作用，并在临床试验中探讨如何克服EGFR反馈激活 18。勃林格殷格翰 (BI): 正在测试SOS1抑制剂BI 1701963联合阿达格拉西布。SOS1抑制被认为具有比SHP2更广的变异覆盖潜力 7。癌症疫苗与免疫微环境重塑结直肠癌中约95%的患者属于微卫星稳定（MSS）型，传统免疫治疗收效甚微。针对KRAS突变的新抗原疫苗和免疫增强剂旨在将这些“冷肿瘤”转变为“热肿瘤” 52。ELI-002 癌症疫苗 - Elicio TherapeuticsELI-002采用了AMP（Amphiphile）平台技术，将KRAS突变多肽直接递送至淋巴结。在AMPLIFY-201研究中，这种方案在术后具有微小残留病灶（MRD）的CRC患者中诱导了强大的T细胞反应。最新的2026年长期随访数据显示，在强免疫应答组中，中位无复发生存期（RFS）尚未达到，而弱应答组仅为3.02个月 53。目前，针对七种突变的ELI-002 7P正在进行II期研究 56。Pelareorep - Oncolytics BiotechPelareorep是一款静脉给药的溶瘤病毒疗法，通过诱导全身性免疫激活来辅助化疗和靶向药。FDA授予其快速通道认定，用于治疗KRAS突变、MSS型mCRC患者。在II期数据中，其联合贝伐珠单抗方案的ORR达到33%，显著高于历史对照，中位OS更是达到了惊人的27个月 52。结直肠癌靶向KRAS药物管线综合分析表 (2025-2026)研发企业作用机制临床进展/备注安进 (Amgen)共价抑制 (OFF)FDA批准联合帕尼单抗 15百时美施贵宝 (BMS)共价抑制 (OFF)联合西妥昔单抗报批中 25BMS/Mirati非共价抑制I/II期，CRC高潜力亚型 7革命医药活性状态抑制 (ON)FDA突破性认定，临床扩增中 35安斯泰来 (Astellas)蛋白质降解 (PROTAC)I/II期，关注胰腺癌与CRC 36革命医药活性状态抑制 (ON)2026年启动临床招募 32加科思 (Jacobio)等位基因特异性抑制临床申报阶段 30Elicio Therapeutics多肽癌症疫苗II期，涵盖G13D等多突变 53革命医药广谱活性状态抑制III期 registrational 试验进行中 42和誉医药非共价全覆盖IND获批，临床前显示广谱活性 45BridgeBio泛KRAS 抑制剂I期 (KONQUER-101研究) 46结直肠癌KRAS治疗范式的演进与产业格局深度洞察从“不可成药”的神话破灭，到如今多个细分领域抑制剂竞相角逐，结直肠癌的治疗正经历着一场前所未有的范式重构。首先，联合用药已成为结直肠癌KRAS治疗的“金标准”。由于CRC细胞复杂的反馈循环，单一节点的抑制已不再被视为最优解。索托拉西布与帕尼单抗的获批不仅是一个药理学的胜利，更是对联合阻断战略的商业验证 10。这一趋势正在从单纯的靶向联用向“靶向+化疗+免疫”的多维组合演进 8。其次，产业重心正在从G12C迅速向G12D、G12V以及Pan-RAS转移。结直肠癌的市场容量巨大，且由于肺癌G12C市场已趋于饱和，差异化竞争和更大患者群体的覆盖已成为企业估值的核心指标 5。以革命医药为代表的新兴力量通过RAS(ON)技术平台展现了对传统巨头（如安进）的强力挑战 9。最后，中国本土药企的深度参与已不可忽视。加科思、和誉医药、益方生物、齐鲁制药等企业在KRAS G12C及后续管线（G12D, SHP2等）中已占据重要位置，不仅通过License-out协议获得了国际认可，更在注册性临床研究中展现了与全球领先者并驾齐驱的研发速度 13。展望2026年及以后，随着Pan-RAS抑制剂数据在结直肠癌一线治疗中的成熟，以及新一代ADC、癌症疫苗对MRD（微小残留病灶）监测下患者复发的精准预防，KRAS突变结直肠癌有望从一种“预后恶劣”的代名词，转变为通过序贯靶向管理可长期生存的慢性化疾病 7。精准医学的下半场，正聚焦于如何利用这些新型武器，在更早的治疗窗口期彻底摧毁肿瘤的驱动中枢。参考文献1.KRAS-targeted therapies in colorectal cancer: a systematic analysis of mutations, inhibitors, and clinical trials - 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Elicio Therapeutics, 访问时间为 四月 23, 2026， https://elicio.com/pipeline/eli-002/54.Off-the-shelf cancer vaccine elicits strong immune response in patients with pancreatic and colorectal cancer | UCLA Health, 访问时间为 四月 23, 2026， https://www.uclahealth.org/news/release/shelf-cancer-vaccine-elicits-strong-immune-response-patients55.Final trial data from ELI-002 cancer immunotherapy vaccine reinforce promising results, 访问时间为 四月 23, 2026， https://www.mdanderson.org/newsroom/research-newsroom/final-trial-data-from-eli-002-cancer-immunotherapy-vaccine-reinforce-promising-results.h00-159778812.html56.Elicio Therapeutics Reports ELI-002 7P Achieved Robust mKRAS-Specific T Cell Responses in 99% of Evaluable Patients in Ongoing Phase 2 AMPLIFY-7P Trial, 访问时间为 四月 23, 2026， https://elicio.com/press_releases/elicio-therapeutics-reports-eli-002-7p-achieved-robust-mkras-specific-t-cell-responses-in-99-of-evaluable-patients-in-ongoing-phase-2-amplify-7p-trial/57.Top 10 Colorectal Cancer Updates – February 2026 - Oncodaily, 访问时间为 四月 23, 2026， https://oncodaily.com/oncolibrary/colorectal-cancer-updates-february-202658.Oncology Drugs Fast-Tracked by the FDA in February 2026, 访问时间为 四月 23, 2026， https://www.oncologynewscentral.com/drugs/info/oncology-drugs-fast-tracked-by-the-fda-in-february-2026责任编辑：肿瘤资讯-Linda 排版编辑：肿瘤资讯-as 版权声明 版权归肿瘤资讯所有。欢迎个人转发分享，其他任何媒体、网站如需转载或引用本网版权所有内容，须获得授权，且在醒目位置处注明“转自：良医汇-肿瘤医生APP”。