Zoldonrasib

KRAS作为癌症中最常见的突变基因之一，自四十多年前被发现以来，一直是药物研发的重点关注方向。随着Lumakras（sotorasib）和Krazati（adagrasib）两款KRAS靶向疗法的获批，KRAS抑制剂的研发热潮迅速兴起。尽管KRAS G12C抑制剂已率先实现临床突破，但在KRAS突变中占比最高之一的KRAS G12D目前仍缺乏获批的靶向药物。目前，产业界已有多项针对KRAS G12D的在研临床项目正加速推进。本文将梳理这些处于临床阶段、涵盖多种治疗模式的KRAS G12D靶向疗法及其新近临床进展。 图片来源：123RF RAS蛋白家族是一类重要的小分子GTP酶（约21 kDa），包括KRAS4A、KRAS4B、HRAS和NRAS四种亚型。在正常生理条件下，RAS蛋白通过在GDP结合的非活性状态与GTP结合的活性状态之间循环，调控细胞的增殖、分化和存活等关键信号通路。然而，在肿瘤细胞中，KRAS基因突变是最常见的驱动事件之一，其中多数发生在密码子12位点（如G12D、G12V和G12C）。这些突变显著改变了GTP水解或核苷酸交换的速率，使KRAS长期处于活化状态，从而持续驱动下游信号通路。值得注意的是，KRAS G12D突变在所有KRAS突变肿瘤中约占29%，在肺腺癌（4.9%）、结直肠癌（CRC，15.0%）、胰腺癌（39.5%）以及其他实体瘤中均有较高发生率，因此成为多种主要癌症类型的重要治疗靶点。随着KRAS G12C抑制剂的成功问世，针对KRAS G12D的药物研发也日益活跃，目前已有多款候选疗法进入临床阶段，展现出巨大的临床转化潜力。 药物名称：Zoldonrasib（RMC-9805） 临床阶段：临床2期 开发公司：Revolution Medicines Zoldonrasib是一款口服KRAS G12D（ON）选择性共价抑制剂，能够靶向KRAS G12D蛋白的活性态（ON，与GTP结合）。此前公布的临床结果显示，在90例实体瘤患者中，zoldonrasib在每日一次1200 mg剂量（2期推荐剂量）下具有良好耐受性，相关不良事件多为低等级。疗效方面，在18例可评估的KRAS G12D突变经治非小细胞肺癌（NSCLC）患者中，客观缓解率（ORR）达到61%，疾病控制率（DCR）高达89%。目前，该疗法已进入多项2期临床试验，正在评估其在胰腺导管腺癌（PDAC）和NSCLC患者中的治疗潜力。 药物名称：HRS-4642 临床阶段：临床2期 开发公司：江苏恒瑞医药（Jiangsu Hengrui Pharmaceuticals） HRS-4642是一款高亲和力、选择性、长时效、非共价的KRAS G12D抑制剂。去年7月，其1期临床研究结果刊登在《细胞》子刊《癌细胞》（Cancer Cell）上。HRS-4642展示出良好的抗肿瘤活性。2名接受过多线标准抗肿瘤治疗的晚期NSCLC患者，接受每周一次200 mg和300 mg HRS-4642治疗后，靶病灶分别缩小53%和31%，达部分缓解标准。目前HRS-4642正在临床2期试验中接受评估其用于治疗胰腺癌的疗效与安全性。 药物名称：QLC1101 临床阶段：临床1b/2期 开发公司：齐鲁制药（Qilu Pharmaceutical） QLC1101是一款可口服的小分子可逆性抑制剂，专门针对致癌性的KRAS G12D突变蛋白，具有潜在的抗肿瘤活性。口服给药后，QLC1101能够选择性结合并可逆性抑制KRAS G12D，从而阻断其介导的信号传导及下游生存通路的激活。目前，该药物正开展一项1b/2期临床研究，旨在评估QLC1101联合其他疗法在携带KRAS G12D突变的晚期实体瘤患者中的安全性、耐受性及疗效。该试验初步结果预计在2026年9月完成。 药物名称：VS-7375 临床阶段：临床1/2a期 开发公司：Verastem Oncology与劲方医药（GenFleet Therapeutics） VS-7375由Verastem Oncology与劲方医药合作开发，是一款口服、高活性、高选择性小分子抑制剂，能够同时作用于KRAS G12D蛋白的活性态（ON）和非活性态（OFF，与GDP结合）。该分子通过非共价形式结合KRAS G12D蛋白，抑制其与下游效应蛋白结合，高效抑制肿瘤细胞增殖。今年4月，VS-7375的IND申请获得美国FDA批准，公司目前已经启动一项1/2a期临床研究，并正在招募患者。公司并计划在晚期实体瘤（如胰腺癌、CRC和NSCLC）中开展多个扩展队列试验，包括作为联合疗法进行评估。 药物名称：AZD0022 临床阶段：临床1/2a期 开发公司：阿斯利康（AstraZeneca） AZD0022是一款高选择性、可逆性的KRAS G12D（ON/OFF）抑制剂，具备良好的口服生物利用度。在体外和体内研究中，该药物在CRC、PDAC及NSCLC等模型中展现出随浓度增加而增强的抑制效果，能够显著抑制KRAS G12D突变肿瘤细胞的增殖与存活。口服给药的药代动力学结果显示，AZD0022在小鼠、大鼠及犬体内均具有较高暴露水平和较长的半衰期。在多种动物模型中，该药物展现出广泛的抗肿瘤活性，并在与西妥昔单抗联合治疗时进一步增强疗效，实现持续的肿瘤缩小。目前，AZD0022已进入首次人体临床试验阶段，患者招募正在进行中。 药物名称：TSN1611 临床阶段：临床1/2期 开发公司：泰励生物（Tyligand Pharmaceuticals） TSN1611是一款创新型KRAS G12D（ON/OFF）小分子抑制剂。临床前研究显示，该药物在体外对KRAS G12D突变肿瘤细胞展现出高度效力与选择性，并在PDAC、CRC及NSCLC多种体内模型中有效抑制肿瘤生长。目前，TSN1611正开展一项开放标签、多中心的1/2期临床试验，纳入携带KRAS G12D突变的晚期实体瘤患者。截至2025年1月5日，共有18例实体瘤患者接受每日两次（BID）50至600 mg剂量治疗。结果显示，未观察到剂量限制性毒性，最大耐受剂量尚未达到。在可评估的13例患者中，4例（30.8%）达疾病稳定，其中3例（CRC、PDAC及NSCLC各1例）在200或400 mg BID剂量下出现肿瘤缩小且治疗仍在进行中。该试验剂量递增部分仍在推进中。 药物名称：INCB161734 临床阶段：临床1期 开发公司：Incyte INCB161734是一款高选择性靶向KRAS G12D突变的口服小分子药物，其可以皮摩尔级亲和力同时结合KRAS G12D的ON和OFF两种状态，相较于野生型KRAS展现出超过80倍的选择性。临床前研究显示，该药物具备优异的口服生物利用度。口服给药后，INCB161734能够实现持续的高水平靶点占有率，在KRAS G12D突变胰腺癌小鼠模型中几乎可维持整个给药间隔的接近最大程度的抑制效果。在胰腺癌及CRC等多种G12D突变肿瘤模型中，INCB161734均表现出显著的抗肿瘤活性，能够显著抑制肿瘤生长，甚至诱导肿瘤缩小。目前，一项针对携带KRAS G12D突变的晚期或转移性实体瘤患者的1期临床研究正在开展，以进一步评估其安全性与疗效。初步结果预计在2027年1月完成。 药物名称：LY3962673 临床阶段：临床1期 开发公司：礼来（Eli Lilly and Company） LY3962673是一款强效且具有口服活性的KRAS G12D抑制剂，对KRAS G12D展现出高度选择性，而对野生型KRAS及其他RAS突变或扩增几乎无显著作用。在临床前研究中，该药物无论单药使用，还是联合其他药物，在多种KRAS G12D患者来源异种移植模型（PDX）中均展现出显著的抗肿瘤活性。目前，LY3962673正进入首次人体临床试验——MOONRAY-01研究。这是一项全球多中心、开放标签的1期研究，设计分为两个阶段：1a期为剂量递增部分，评估LY3962673单药的安全性、耐受性及初步疗效；1b期则为剂量扩展与随机剂量优化部分，探索LY3962673单药及联合其他抗癌疗法的抗肿瘤活性。该研究的主要目标是验证LY3962673在携带KRAS G12D突变的晚期实体瘤患者中的安全性、耐受性和疗效。 药物名称：QTX3046 临床阶段：临床1期 开发公司：Quanta Therapeutics QTX3046是一款选择性靶向KRAS G12D的非共价口服变构抑制剂，具备高效力和良好口服生物利用度。在作用机制上，QTX3046通过浓度依赖性方式破坏KRAS G12D与RAF1的蛋白互作，且QTX3046对KRAS野生型及其他KRAS突变几乎无活性。进一步研究显示，QTX3046对KRAS G12D非活性态的结合亲和力达到皮摩尔级（0.01 nM），较KRAS野生型提升400倍以上。此外，在KRAS G12D驱动的异种移植瘤模型中，QTX3046口服给药可使全部肿瘤缩小且同时展现良好的耐受性。目前，1期临床试验正在开展，以评估QTX3046在携带KRAS G12D突变的晚期实体瘤患者中的安全性、耐受性、药代动力学及疗效，研究设计包括单药治疗及联合西妥昔单抗的探索。 药物名称：ASP3082 临床阶段：临床1期 开发公司：安斯泰来（Astellas Pharma） ASP3082是一款新型靶向KRAS G12D的蛋白降解剂。在去年9月欧洲肿瘤内科学会（ESMO）年会当中公布的1期临床数据显示，该药在既往接受过系统治疗的晚期实体瘤患者中展现出可接受的安全性与初步抗肿瘤活性。截至2024年4月1日，共纳入98例患者，包括胰腺癌（67例）、CRC（16例）、NSCLC（13例）及其他肿瘤（2例）。治疗相关不良事件发生率为69.4%，最大耐受剂量尚未达到。在疗效方面，140 mg组（9例）的ORR为11.1%，DCR为33.3%；200 mg组（9例）的ORR为0%，DCR为55.6%；而在300 mg组（12例）中，ORR提升至33.3%，DCR达75.0%，其中在胰腺癌和NSCLC患者中均观察到部分缓解。整体结果显示，ASP3082在较高剂量下展现出更为积极的抗肿瘤信号。目前该1期试验仍在进行中，初步结果预计于2026年10月完成。 药物名称：ASP4396 临床阶段：临床1期 开发公司：安斯泰来（Astellas Pharma） ASP4396是安斯泰来开发的另一款KRAS G12D靶向蛋白降解剂。目前，该药物的首次人体临床试验正在进行中。该试验为一开放标签、多中心的剂量递增与剂量扩展1期试验，入组对象为携带KRAS G12D突变、局部晚期（不可切除）或转移性实体瘤的成年患者。患者需具备至少一个可测量病灶，既往接受过KRAS G12D靶向治疗的患者则被排除。试验的主要终点包括安全性与耐受性以及推荐2期剂量和/或最大耐受剂量；次要终点则涵盖抗肿瘤活性（ORR、缓解持续时间、DCR、无进展生存期和总生存期）及药代动力学/药效学评价。目前该试验正在持续招募患者中，初步结果预计于2027年4月完成。 除已进入临床试验阶段的多款KRAS G12D靶向疗法外，产业界也在积极探索不同治疗模式的创新方向。今年8月，安进（Amgen）在《自然》子刊Nature Communications上发布了其开发的KRAS G12D靶向溶酶体膜靶向嵌合体（Lysosome Membrane Targeting Chimeras，LYMTAC）小分子技术平台。该平台通过双特异性小分子与半衰期极短的溶酶体膜蛋白结合，将目标蛋白牵引至溶酶体内实现降解；即使未被彻底降解，也能通过将其从细胞膜转移至溶酶体表面，有效阻断信号传导。在概念验证实验中，研究人员已成功利用LYMTAC实现了KRAS突变体的降解。 随着越来越多创新疗法的不断推进，无论是正在临床验证的候选药物，还是处于探索阶段的新兴技术，都为攻克KRAS G12D靶点带来了新的希望。让我们期待，在不远的将来，患者能够真正迎来首款获批的KRAS G12D靶向疗法，为多种难治性肿瘤的治疗开辟新的路径。 参考资料： [1] Yoshinari T, Nagashima T, Ishioka H, Inamura K, Nishizono Y, Tasaki M, Iguchi K, Suzuki A, Sato C, Nakayama A, Amano Y, Tateishi Y, Yamanaka Y, Osaki F, Yoshino M, Kuramoto K, Imaizumi T, Hayakawa M. Discovery of KRAS(G12D) selective degrader ASP3082. Commun Chem. 2025 Aug 23;8(1):254. doi: 10.1038/s42004-025-01662-4. PMID: 40849515; PMCID: PMC12375097. [2] Nalawansha DA, Mazis G, Husemoen G, Ashton KS, Deng W, Wurz RP, Tran AT, Lanman BA, Xie J, Guenette RG, Li S, Smith CE, Archunan S, Agnihotram MK, Sadhukhan A, Kapoor R, Wilde C, Koirala S, De Sousa E Melo F, Potts PR. LYMTACs:chimeric small molecules repurpose lysosomal membrane proteins for target protein relocalization and degradation. Nat Commun. 2025 Aug 21;16(1):7812. doi: 10.1038/s41467-025-63128-4. PMID: 40841368; PMCID: PMC12370906. [3] 608O Preliminary safety and clinical activity of ASP3082, a first-in-class, KRAS G12D selective protein degrader in adults with advanced pancreatic (PC), colorectal (CRC), and non-small cell lung cancer (NSCLC). Retrieved August 27, 2025 from https://www.annalsofoncology.org/article/S0923-7534(24)02194-X/fulltext [4] Trial in progress: Phase 1 study of the selective protein degrader ASP4396 in patients with locally advanced or metastatic solid tumors with KRAS G12D mutations. Retrieved August 27, 2025 from https://ascopubs-org.libproxy1.nus.edu.sg/doi/10.1200/JCO.2025.43.16_suppl.TPS3178 [5] A Study of ASP3082 in Adults With Advanced Solid Tumors. Retrieved August 27, 2025 from https://clinicaltrials.gov/study/NCT05382559 [6] INCB161734: A Novel, Potent, and Orally Bioavailable KRAS G12D Selective Inhibitor Demonstrates Antitumor Activity in KRAS G12D Mutant Tumors. Retrieved August 27, 2025 from https://www.incytemi.com/document/Poster/AACR%202024%20-%20KRASG12D%20mutant%20poster.pdf [7] A Study to Evaluate INCB161734 in Participants With Advanced or Metastatic Solid Tumors With KRAS G12D Mutation. Retrieved August 27, 2025 from https://clinicaltrials.gov/study/NCT06179160?intr=INCB161734&rank=2 [8] MOONRAY-01, A Study of LY3962673 in Participants With KRAS G12D-Mutant Solid Tumors (MOONRAY-01). Retrieved August 27, 2025 from https://clinicaltrials.gov/study/NCT06586515?intr=LY3962673&rank=1 [9] MOONRAY-01, a phase 1 study of LY3962673, a potent, orally bioavailable, and selective KRAS G12D inhibitor in KRAS G12D-mutant solid tumors. Retrieved August 28, 2025 from https://ascopubs-org.libproxy1.nus.edu.sg/doi/10.1200/JCO.2025.43.4_suppl.TPS845 [10] The first-in-human phase 1/2 study of TSN1611, a highly selective KRAS G12D inhibitor, in patients with advanced solid tumors. Retrieved August 28, 2025 from https://ascopubs-org.libproxy1.nus.edu.sg/doi/10.1200/JCO.2025.43.16_suppl.3083 [11] A Phase I Clinical Study of QLC1101 in Patients With Advanced Solid Tumors. Retrieved August 28, 2025 from https://ichgcp.net/clinical-trials-registry/NCT06403735 [12] KRAS G12D inhibitor QLC1101. Retrieved August 28, 2025 from https://www.cancer.gov/publications/dictionaries/cancer-drug/def/kras-g12d-inhibitor-qlc1101 [13] Abstract LB321: Discovery and characterization of QTX3046, a potent, selective, and orally bioavailable non-covalent KRASG12D inhibitor. Retrieved August 28, 2025 from https://aacrjournals-org.libproxy1.nus.edu.sg/cancerres/article/83/8_Supplement/LB321/725422/Abstract-LB321-Discovery-and-characterization-of [14] A Phase I/IIa Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Efficacy of AZD0022 as Monotherapy and in Combination With Anti-cancer Agents in Adult Participants With Tumours Harbouring a KRASG12D Mutation (ALAFOSS-01). Retrieved August 28, 2025 from https://clinicaltrials.gov/study/NCT06599502?intr=AZD0022&rank=1 免责声明：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。 版权说明：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「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新

MIAMI--(BUSINESS WIRE)--Summit Therapeutics Inc. (NASDAQ: SMMT) ("Summit," "we," or the "Company") today reports its financial results and provides an update on operational progress for the third quarter ended September 30, 2025. Planned BLA Submission for Ivonescimab in Q4 2025 Today, Summit announces that, based on the results of the HARMONi clinical trial, it plans to submit a Biologics License Application (BLA) in order to seek approval for ivonescimab plus chemotherapy for this proposed indication. We intend to submit the BLA in the fourth quarter of 2025. The positive results of the multiregional Phase III study are detailed further below. As previously noted, the FDA noted that a statistically significant overall survival benefit is necessary to support marketing authorization in this setting. After careful consideration of the safety and efficacy profile of the current FDA-approved options for patients in this setting, the positive results of the Phase III multiregional study, including regional consistency, as well as discussions with key opinion leaders and those physicians who have administered ivonescimab to patients in a clinical study setting, we believe that the safety and efficacy data generated in the HARMONi study demonstrates that patients suffering from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) in this setting can benefit from the ivonescimab regimen despite the lack of a statistically significant showing on overall survival. Further Expansion of the Phase III Ivonescimab Clinical Development Program In addition to the announcement HARMONi-GI3, a new global Phase III study in first-line unresectable metastatic colorectal cancer (CRC), Summit today announces its intention to expand its ivonescimab clinical development program with an additional set of Phase III clinical studies. We intend to provide additional color with respect to these Phase III studies in the first quarter of 2026. Other Operational & Corporate Updates Operational progress continues with ivonescimab (SMT112), an investigational, potentially first-in-class bispecific antibody combining the effects of immunotherapy via a blockade of PD-1 with the anti-angiogenesis effects associated with blocking VEGF into a single molecule: Since in-licensing ivonescimab (SMT112), from Akeso Inc. (Akeso, HKEX Code: 9926.HK) in January 2023, over 3,000 patients have been treated with ivonescimab in clinical studies globally, and over 40,000 patients when considering those treated in a commercial setting in China as noted by Akeso. Summit has rights to develop and commercialize ivonescimab in the United States, Canada, Europe, Japan, Latin America, including Mexico and all countries in Central America, South America, and the Caribbean, the Middle East, and Africa while Akeso retains development and commercialization rights for the rest of the world, including China. Summit is developing ivonescimab in NSCLC, specifically conducting Phase III clinical trials in the following proposed indications: HARMONi : Ivonescimab combined with chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who were previously treated with a third-generation EGFR tyrosine kinase inhibitor (TKI) HARMONi-3 : Ivonescimab combined with chemotherapy in patients with first-line metastatic NSCLC HARMONi-7: Ivonescimab monotherapy in patients with first-line metastatic NSCLC whose tumors have high PD-L1 expression HARMONi : Ivonescimab combined with chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who were previously treated with a third-generation EGFR tyrosine kinase inhibitor (TKI) HARMONi-3 : Ivonescimab combined with chemotherapy in patients with first-line metastatic NSCLC HARMONi-7: Ivonescimab monotherapy in patients with first-line metastatic NSCLC whose tumors have high PD-L1 expression In addition, Summit plans to start developing ivonescimab in CRC with an intention to begin a Phase III clinical study in the following proposed indication: HARMONi-GI3 : ivonescimab combined with chemotherapy in patients with first-line metastatic CRC HARMONi-GI3 : ivonescimab combined with chemotherapy in patients with first-line metastatic CRC In September 2025, we announced detailed results from our multiregional, double-blinded, placebo-controlled, Phase III study, HARMONi, including data from the study’s prespecified primary analysis as well as results from longer-term follow up in western patients. At the prespecified primary data analysis, ivonescimab in combination with chemotherapy demonstrated a statistically significant improvement in progression-free survival (PFS), the magnitude of which we believe to be clinically meaningful, with a hazard ratio (HR) of 0.52 (95% CI: 0.41 – 0.66; p<0.00001); median PFS was 6.8 months for those patients receiving ivonescimab plus chemotherapy compared to 4.4 months for those receiving chemotherapy. In a longer-term follow-up of PFS, which included all western patients, ivonescimab plus chemotherapy demonstrated a consistent improvement in PFS with an observed HR of 0.57 (95% CI: 0.46 – 0.71). We believe the PFS HR that was observed in both Asian and western sub-populations to be clinically meaningful. In both the primary analysis as well as longer-term follow-up analysis, consistency of the magnitude of PFS benefit was demonstrated between patients randomized in Asia and ex-Asia. PFS was assessed by blinded independent central radiology review committee (BICR) compared to placebo in combination with chemotherapy. The longer-term follow-up analysis of PFS was performed at the time of the primary overall survival (OS) analysis. In the prespecified primary analysis, a positive trend in OS was observed without achieving a statistically significant benefit with an HR of 0.79 (95% CI: 0.62 – 1.01; p=0.057). Median OS was 16.8 months for those patients administered ivonescimab plus chemotherapy vs. 14.0 months for those receiving placebo plus chemotherapy. Analysis from longer-term follow-up in western patients, resulted in an OS HR consistent with the primary analysis with an improved nominal p-value (HR=0.78; 95% CI: 0.62 – 0.98; nominal p=0.0332). Median OS in the longer-term follow-up analysis remained the same in both arms from the primary analysis, 17.0 months in western patients receiving ivonescimab compared to 14.0 months for those receiving placebo (HR=0.84). Median OS in North American patients, specifically, had not yet been reached in the ivonescimab arm compared to 14.0 months in the placebo arm (HR=0.70). The HRs for western patients in totality, as well as patients from the North American and European regions individually, improved from the primary OS analysis to the analysis with longer-term follow-up of western patients. Consistent benefit was observed across pre-defined subgroups, with both Asian and North American patients demonstrating a positive trend in OS. These trends provide further support for ivonescimab’s use in 2L+ EGFRm NSCLC, a setting where high unmet need continues to exist with limited approved options in the United States and other western territories. Currently there are no FDA-approved regimens that have demonstrated a statistically significant OS benefit in this patient setting. The results of the primary and longer-term follow up analysis in this multiregional study were consistent with that of the single-region HARMONi-A study, which demonstrated an OS HR of 0.80 at 52% data maturity in a similar patient population. The dual primary endpoints were allocated separate alpha levels and tested individually. The alpha was recycled from the PFS to the OS analysis upon the successful achievement of the PFS endpoint. Observed overall response rates (ORR) were 45% in the ivonescimab arm vs. 34% in the placebo arm; median duration of response (DoR) was longer in those patients administered ivonescimab plus chemotherapy (7.6 months) compared to those receiving placebo and chemotherapy (4.2 months). The safety profile of ivonescimab in combination with chemotherapy was acceptable and manageable in the context of the observed clinical benefit, with comparable rates of discontinuation and death between both arms. There were 16 patients (7.3%) who discontinued ivonescimab due to treatment-related adverse events (TRAEs) compared to 11 patients (5.0%) who discontinued placebo due to TRAEs. There were four patients (1.8%) in the ivonescimab plus chemotherapy arm and five patients (2.3%) in the chemotherapy alone arm who died as a result of TRAEs. In the ivonescimab plus chemotherapy arm, 50.0% of patients experienced Grade 3 or higher TRAEs compared to 42.2% in the chemotherapy arm. Of note, 0.9% of patients in the ivonescimab plus chemotherapy arm experienced Grade 3 or higher hemorrhage (bleeding) events. At the prespecified primary data analysis, ivonescimab in combination with chemotherapy demonstrated a statistically significant improvement in progression-free survival (PFS), the magnitude of which we believe to be clinically meaningful, with a hazard ratio (HR) of 0.52 (95% CI: 0.41 – 0.66; p<0.00001); median PFS was 6.8 months for those patients receiving ivonescimab plus chemotherapy compared to 4.4 months for those receiving chemotherapy. In a longer-term follow-up of PFS, which included all western patients, ivonescimab plus chemotherapy demonstrated a consistent improvement in PFS with an observed HR of 0.57 (95% CI: 0.46 – 0.71). We believe the PFS HR that was observed in both Asian and western sub-populations to be clinically meaningful. In both the primary analysis as well as longer-term follow-up analysis, consistency of the magnitude of PFS benefit was demonstrated between patients randomized in Asia and ex-Asia. PFS was assessed by blinded independent central radiology review committee (BICR) compared to placebo in combination with chemotherapy. The longer-term follow-up analysis of PFS was performed at the time of the primary overall survival (OS) analysis. In the prespecified primary analysis, a positive trend in OS was observed without achieving a statistically significant benefit with an HR of 0.79 (95% CI: 0.62 – 1.01; p=0.057). Median OS was 16.8 months for those patients administered ivonescimab plus chemotherapy vs. 14.0 months for those receiving placebo plus chemotherapy. Analysis from longer-term follow-up in western patients, resulted in an OS HR consistent with the primary analysis with an improved nominal p-value (HR=0.78; 95% CI: 0.62 – 0.98; nominal p=0.0332). Median OS in the longer-term follow-up analysis remained the same in both arms from the primary analysis, 17.0 months in western patients receiving ivonescimab compared to 14.0 months for those receiving placebo (HR=0.84). Median OS in North American patients, specifically, had not yet been reached in the ivonescimab arm compared to 14.0 months in the placebo arm (HR=0.70). The HRs for western patients in totality, as well as patients from the North American and European regions individually, improved from the primary OS analysis to the analysis with longer-term follow-up of western patients. Consistent benefit was observed across pre-defined subgroups, with both Asian and North American patients demonstrating a positive trend in OS. These trends provide further support for ivonescimab’s use in 2L+ EGFRm NSCLC, a setting where high unmet need continues to exist with limited approved options in the United States and other western territories. Currently there are no FDA-approved regimens that have demonstrated a statistically significant OS benefit in this patient setting. The results of the primary and longer-term follow up analysis in this multiregional study were consistent with that of the single-region HARMONi-A study, which demonstrated an OS HR of 0.80 at 52% data maturity in a similar patient population. The dual primary endpoints were allocated separate alpha levels and tested individually. The alpha was recycled from the PFS to the OS analysis upon the successful achievement of the PFS endpoint. Observed overall response rates (ORR) were 45% in the ivonescimab arm vs. 34% in the placebo arm; median duration of response (DoR) was longer in those patients administered ivonescimab plus chemotherapy (7.6 months) compared to those receiving placebo and chemotherapy (4.2 months). The safety profile of ivonescimab in combination with chemotherapy was acceptable and manageable in the context of the observed clinical benefit, with comparable rates of discontinuation and death between both arms. There were 16 patients (7.3%) who discontinued ivonescimab due to treatment-related adverse events (TRAEs) compared to 11 patients (5.0%) who discontinued placebo due to TRAEs. There were four patients (1.8%) in the ivonescimab plus chemotherapy arm and five patients (2.3%) in the chemotherapy alone arm who died as a result of TRAEs. In the ivonescimab plus chemotherapy arm, 50.0% of patients experienced Grade 3 or higher TRAEs compared to 42.2% in the chemotherapy arm. Of note, 0.9% of patients in the ivonescimab plus chemotherapy arm experienced Grade 3 or higher hemorrhage (bleeding) events. Last week, we announced the expansion of our Phase III clinical development program into CRC with the planned initiation of the global Phase III HARMONi-GI3 trial. The trial will evaluate ivonescimab plus chemotherapy compared to bevacizumab plus chemotherapy as first line therapy in patients with unresectable metastatic CRC. Clinical trial sites for HARMONi-GI3 are planned to begin activating in the United States prior to the end of the year. The study intends to enroll 600 patients in this multiregional study. The primary endpoint for this study is PFS. Each year, approximately 48,000 patients are estimated to be diagnosed with or have unresectable recurrent metastatic microsatellite stable (MSS) CRC (also known as mismatch repair-proficient colorectal cancer, or pMMR CRC). There have been limited options approved in the United States in the last 20 years for those first-line patients whose tumors are not positive for certain biomarkers or other activating mutations. MSS CRC is a setting where monoclonal PD-1 inhibitors such as pembrolizumab and nivolumab have failed to show a clinically meaningful benefit. Anti-VEGF therapy (e.g., bevacizumab) plus chemotherapy is the standard of care for many patients with first-line metastatic MSS CRC. Each year, approximately 48,000 patients are estimated to be diagnosed with or have unresectable recurrent metastatic microsatellite stable (MSS) CRC (also known as mismatch repair-proficient colorectal cancer, or pMMR CRC). There have been limited options approved in the United States in the last 20 years for those first-line patients whose tumors are not positive for certain biomarkers or other activating mutations. MSS CRC is a setting where monoclonal PD-1 inhibitors such as pembrolizumab and nivolumab have failed to show a clinically meaningful benefit. Anti-VEGF therapy (e.g., bevacizumab) plus chemotherapy is the standard of care for many patients with first-line metastatic MSS CRC. In April 2025, Akeso announced that HARMONi-6, which evaluated ivonescimab combined with platinum-based chemotherapy vs. tislelizumab, a PD-1 inhibitor, with the same chemotherapy in patients with locally advanced or metastatic squamous NSCLC, regardless of PD-L1 expression, met its primary endpoint of PFS. Yesterday, additional HARMONi-6 data were presented as part of the Presidential Symposium at the European Society for Medical Oncology 2025 Congress (ESMO 2025) and featured in a manuscript published in The Lancet simultaneously. The presentation and publication are based on the results of HARMONi-6, a single region, multi-center, Phase III study conducted in China sponsored by Akeso, Inc., with data generated and analyzed by Akeso. In the HARMONi-6 planned interim analysis of progression-free survival (PFS), ivonescimab in combination with chemotherapy demonstrated a statistically significant improvement in the primary endpoint, PFS, by Independent Radiologic Review Committee (IRRC), when compared to tislelizumab in combination with chemotherapy, achieving a hazard ratio (HR) of 0.60 (95% CI: 0.46, 0.78; p<0.0001). A clinically meaningful benefit was demonstrated across clinical subgroups, including those with either PD-L1 negative or positive expression. Both the overall response rate (ORR) measured according to RECIST v1.1 criteria, as well as the duration of response (DoR) were higher in patients treated with ivonescimab plus chemotherapy compared to those treated with tislelizumab plus chemotherapy. Ivonescimab demonstrated an acceptable and manageable safety profile in the HARMONi-6 study, which was consistent with previous Phase III studies conducted studying ivonescimab. In squamous NSCLC, VEGF-A monoclonal antibodies have not been approved by health authorities including the FDA and have had limited clinical development based on historical early phase clinical trials, primarily due to significant risks of toxicity, including hemorrhage and other life-threatening, bleeding-related complications. The results of this study further validate the unique mechanism of action of ivonescimab, including key differences as compared to separately administering an anti-PD-1 monoclonal antibody and an anti-VEGF monoclonal antibody. In this Phase III study, there were nine patients (3.4%) who discontinued ivonescimab plus chemotherapy due to treatment-related adverse events (TRAEs) compared to 11 patients (4.2%) who discontinued tislelizumab plus chemotherapy due to TRAEs. There were eight patients (3.0%) in the ivonescimab plus chemotherapy arm and 10 patients (3.8%) in the tislelizumab plus chemotherapy arm who died as a result of TRAEs in this Phase III study. The most frequent TRAEs for ivonescimab treatment in combination with chemotherapy were common chemotherapy-related AEs, including alopecia, anemia, and various laboratory abnormalities, including neutrophil, white blood cell, and platelet count decreases. Grade 3 or higher immune-related adverse events occurred in 9.0% of patients receiving ivonescimab in combination with chemotherapy and 10.2% of patients receiving tislelizumab in combination with chemotherapy. Grade 3 or higher adverse events that were possibly VEGF-related in the ivonescimab plus chemotherapy arm were 7.5% vs. 2.3% for tislelizumab plus chemotherapy. Most of the possibly VEGF-related adverse events occurring in the ivonescimab plus chemotherapy arm were classified as Grade 1 or 2. Of note, Grade 3 or higher hemorrhage events were observed in five patients in the ivonescimab plus chemotherapy arm compared to two patients in the tislelizumab plus chemotherapy arm in this study. This marks the first known Phase III trial in NSCLC to show significant improvement over PD-(L)1 inhibitor therapy combined with chemotherapy in a head-to-head setting. Following the success of Akeso’s HARMONi-2 study in China, this is the second instance where ivonescimab-based regimens have demonstrated a statistically significant benefit compared to standard-of-care PD-(L)1 inhibitor-based regimens in a Phase III trial. In the HARMONi-6 planned interim analysis of progression-free survival (PFS), ivonescimab in combination with chemotherapy demonstrated a statistically significant improvement in the primary endpoint, PFS, by Independent Radiologic Review Committee (IRRC), when compared to tislelizumab in combination with chemotherapy, achieving a hazard ratio (HR) of 0.60 (95% CI: 0.46, 0.78; p<0.0001). A clinically meaningful benefit was demonstrated across clinical subgroups, including those with either PD-L1 negative or positive expression. Both the overall response rate (ORR) measured according to RECIST v1.1 criteria, as well as the duration of response (DoR) were higher in patients treated with ivonescimab plus chemotherapy compared to those treated with tislelizumab plus chemotherapy. Ivonescimab demonstrated an acceptable and manageable safety profile in the HARMONi-6 study, which was consistent with previous Phase III studies conducted studying ivonescimab. In squamous NSCLC, VEGF-A monoclonal antibodies have not been approved by health authorities including the FDA and have had limited clinical development based on historical early phase clinical trials, primarily due to significant risks of toxicity, including hemorrhage and other life-threatening, bleeding-related complications. The results of this study further validate the unique mechanism of action of ivonescimab, including key differences as compared to separately administering an anti-PD-1 monoclonal antibody and an anti-VEGF monoclonal antibody. In this Phase III study, there were nine patients (3.4%) who discontinued ivonescimab plus chemotherapy due to treatment-related adverse events (TRAEs) compared to 11 patients (4.2%) who discontinued tislelizumab plus chemotherapy due to TRAEs. There were eight patients (3.0%) in the ivonescimab plus chemotherapy arm and 10 patients (3.8%) in the tislelizumab plus chemotherapy arm who died as a result of TRAEs in this Phase III study. The most frequent TRAEs for ivonescimab treatment in combination with chemotherapy were common chemotherapy-related AEs, including alopecia, anemia, and various laboratory abnormalities, including neutrophil, white blood cell, and platelet count decreases. Grade 3 or higher immune-related adverse events occurred in 9.0% of patients receiving ivonescimab in combination with chemotherapy and 10.2% of patients receiving tislelizumab in combination with chemotherapy. Grade 3 or higher adverse events that were possibly VEGF-related in the ivonescimab plus chemotherapy arm were 7.5% vs. 2.3% for tislelizumab plus chemotherapy. Most of the possibly VEGF-related adverse events occurring in the ivonescimab plus chemotherapy arm were classified as Grade 1 or 2. Of note, Grade 3 or higher hemorrhage events were observed in five patients in the ivonescimab plus chemotherapy arm compared to two patients in the tislelizumab plus chemotherapy arm in this study. This marks the first known Phase III trial in NSCLC to show significant improvement over PD-(L)1 inhibitor therapy combined with chemotherapy in a head-to-head setting. Following the success of Akeso’s HARMONi-2 study in China, this is the second instance where ivonescimab-based regimens have demonstrated a statistically significant benefit compared to standard-of-care PD-(L)1 inhibitor-based regimens in a Phase III trial. Yesterday, we announced an update to our HARMONi-3 Phase III clinical trial evaluating ivonescimab combined with chemotherapy compared to pembrolizumab, a PD-1 inhibitor, combined with chemotherapy in patients with first-line metastatic, squamous and non-squamous NSCLC. The primary endpoints for this study are PFS and OS. Summit has amended the protocol for the HARMONi-3 study in order to separate the statistical analysis (i.e., the outcome) of the primary endpoints by histology. Therefore, there will be separate analyses conducted to evaluate ivonescimab plus chemotherapy compared to pembrolizumab plus chemotherapy in patients with squamous NSCLC and in patients with non-squamous NSCLC. As a result of having two separate intention-to-treat analyses within the HARMONi-3 study, the analyses for squamous tumors and non-squamous tumors may be conducted at separate times, as each analysis will be conducted upon the prespecified numbers of events being reached in the separate cohorts. Summit currently expects to complete enrollment in the squamous cohort of HARMONi-3 in the first half of 2026 and expects to reach the prespecified number of events for the PFS primary endpoint analysis for this cohort in the second half of 2026. An interim analysis for overall survival may be conducted at a similar time. At present time, Summit expects to complete enrollment in the non-squamous cohort of HARMONi-3 in the second half of 2026 and expects to reach the prespecified number of events for the PFS primary endpoint analysis for this cohort in the first half of 2027. An interim analysis for overall survival is planned to be conducted based upon reaching a prespecified number of events. In order to sufficiently power each of the dual primary endpoints in both cohorts of this study, Summit plans to enroll 600 patients with squamous NSCLC and 1,000 patients with non-squamous NSCLC. Summit has amended the protocol for the HARMONi-3 study in order to separate the statistical analysis (i.e., the outcome) of the primary endpoints by histology. Therefore, there will be separate analyses conducted to evaluate ivonescimab plus chemotherapy compared to pembrolizumab plus chemotherapy in patients with squamous NSCLC and in patients with non-squamous NSCLC. As a result of having two separate intention-to-treat analyses within the HARMONi-3 study, the analyses for squamous tumors and non-squamous tumors may be conducted at separate times, as each analysis will be conducted upon the prespecified numbers of events being reached in the separate cohorts. Summit currently expects to complete enrollment in the squamous cohort of HARMONi-3 in the first half of 2026 and expects to reach the prespecified number of events for the PFS primary endpoint analysis for this cohort in the second half of 2026. An interim analysis for overall survival may be conducted at a similar time. At present time, Summit expects to complete enrollment in the non-squamous cohort of HARMONi-3 in the second half of 2026 and expects to reach the prespecified number of events for the PFS primary endpoint analysis for this cohort in the first half of 2027. An interim analysis for overall survival is planned to be conducted based upon reaching a prespecified number of events. In order to sufficiently power each of the dual primary endpoints in both cohorts of this study, Summit plans to enroll 600 patients with squamous NSCLC and 1,000 patients with non-squamous NSCLC. Clinical trial collaborations and investigator sponsored trials with leading organizations, including MD Anderson, the Memorial Sloan Kettering Cancer Center, and the Dana Farber Cancer Institute, among others, continue to progress and expand evaluating ivonescimab in solid tumor settings outside of metastatic NSCLC. In June 2025, we announced a clinical collaboration with Revolution Medicines to evaluate ivonescimab in combination with three RAS(ON) inhibitors, including the multi-selective inhibitor daraxonrasib (RMC-6236), G12D-selective inhibitor zoldonrasib (RMC-9805), and G12C-selective inhibitor elironrasib (RMC-6291), in solid tumor settings with RAS mutations. We expect that clinical trials associated with this collaboration will begin in early 2026. Enrollment continues in Summit's global Phase III trials, HARMONi-3 and HARMONi-7. In addition to the enrollment in multiregional studies conducted and sponsored by Summit, our partners at Akeso are also enrolling several single-region Phase III studies exclusively in China in multiple indications, including biliary-tract cancer, triple-negative breast cancer, head and neck squamous cell carcinoma, colorectal cancer, and pancreatic cancer. Financial Highlights Cash and Cash Equivalents and Short-term Investments Aggregate cash and cash equivalents and short-term investments were $238.6 million and $412.3 million at September 30, 2025 and December 31, 2024, respectively. GAAP and Non-GAAP Operating Expenses GAAP operating expenses were $234.2 million for the third quarter of 2025, compared to $58.4 million for the same period of the prior year. The increase in GAAP operating expenses was due to the increase in stock-based compensation expense of $111.4 million primarily related to modification to our performance-based stock option awards which occurred earlier during the current fiscal year. Non-GAAP operating expenses were $103.4 million for the third quarter of 2025, compared to $39.0 million for the same period of the prior year. The increase in Non-GAAP operating expenses due to expansion of clinical studies and development costs related to ivonescimab. GAAP and Non-GAAP Research and Development (R&D) Expenses GAAP R&D expenses were $131.1 million for the third quarter of 2025, compared to $37.7 million for the same period of the prior year. The increase was due to the increase in stock-based compensation expense of $34.8 million primarily related to modification to our performance-based stock option awards which occurred earlier during the current fiscal year. Non-GAAP R&D expenses were $90.5 million for the third quarter of 2025, compared to $31.9 million for the same period of the prior year. The increase is primarily related due to expansion of clinical studies and development costs related to ivonescimab. GAAP and Non-GAAP General and Administrative (G&A) Expenses GAAP G&A expenses were $103.1 million for the third quarter of 2025, compared to $20.7 million for the same period of the prior year. The increase was due to the increase in stock-based compensation expense of $76.6 million primarily related to modification to our performance-based stock option awards which occurred earlier during the current fiscal year. Non-GAAP G&A expenses were $12.9 million for the third quarter of 2025, compared to $7.1 million for the same period of the prior year. The increase is related to building our infrastructure to support the development of ivonescimab. GAAP and Non-GAAP Net Loss GAAP net loss in the third quarter of 2025 and 2024 was $231.8 million or $(0.31) per basic and diluted share, and $56.3 million or $(0.08) per basic and diluted share, respectively. Non-GAAP net loss in the third quarter of 2025 and 2024 was $101.0 million or $(0.13) per basic and diluted share, and $36.9 million or $(0.05) per basic and diluted share, respectively. Use of Non-GAAP Financial Measures This release includes measures that are not in accordance with U.S. generally accepted accounting principles (“Non-GAAP measures”). These Non-GAAP measures should be viewed in addition to, and not as a substitute for, Summit's reported GAAP results, and may be different from Non-GAAP measures used by other companies. In addition, these Non-GAAP measures are not based on any comprehensive set of accounting rules or principles. Summit management uses these Non-GAAP measures for internal budgeting and forecasting purposes and to evaluate Summit’s financial performance. Summit management believes the presentation of these Non-GAAP measures is useful to investors for comparing prior periods and analyzing ongoing business trends and operating results. For further information regarding these Non-GAAP measures, please refer to the tables presenting reconciliations of our Non-GAAP results to our U.S. GAAP results and the “Notes on our Non-GAAP Financial Information” that accompany this press release. About Ivonescimab Ivonescimab, known as SMT112 in Summit’s license territories, North America, South America, Europe, the Middle East, Africa, and Japan, and as AK112 in China and Australia, is a novel, potential first-in-class investigational bispecific antibody combining the effects of immunotherapy via a blockade of PD-1 with the anti-angiogenesis effects associated with blocking VEGF into a single molecule. Ivonescimab displays unique cooperative binding to each of its intended targets with multifold higher affinity to PD-1 when in the presence of VEGF. This could differentiate ivonescimab as there is potentially higher expression (presence) of both PD-1 and VEGF in tumor tissue and the tumor microenvironment (TME) as compared to normal tissue in the body. Ivonescimab’s specifically engineered tetravalent structure (four binding sites) enables higher avidity (accumulated strength of multiple binding interactions) in the TME (Zhong, et al., SITC, 2023). This tetravalent structure, the intentional novel design of the molecule, and bringing these two targets into a single bispecific antibody with cooperative binding qualities have the potential to direct ivonescimab to the tumor tissue versus healthy tissue. The intent of this design, together with a half-life of 6 to 7 days after the first dose (Zhong, et al., SITC, 2023) increasing to approximately 10 days at steady state dosing, is to improve upon previously established efficacy thresholds, in addition to side effects and safety profiles associated with these targets. Ivonescimab was engineered by Akeso Inc. (HKEX Code: 9926.HK) and is currently engaged in multiple Phase III clinical trials. Over 3,000 patients have been treated with ivonescimab in clinical studies globally, and over 40,000 treated in a commercial setting in China as noted by Akeso. Summit began its clinical development of ivonescimab in NSCLC, commencing enrollment in 2023 in two multiregional Phase III clinical trials, HARMONi and HARMONi-3. In early 2025, the Company began enrolling patients in the United States for HARMONi-7. Summit intends to open clinical trial sites in the United States for the Phase III study in CRC by the end of 2025. HARMONi is a Phase III clinical trial which intends to evaluate ivonescimab combined with chemotherapy compared to placebo plus chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who were previously treated with a 3rd generation EGFR TKI (e.g., osimertinib). Enrollment in HARMONi was completed in the second half of 2024, and top-line results were announced in May of 2025, with detailed results provided in September 2025. HARMONi-3 is a Phase III clinical trial which is intended to evaluate ivonescimab combined with chemotherapy compared to pembrolizumab combined with chemotherapy in patients with first-line metastatic, squamous or non-squamous NSCLC, irrespective of PD-L1 expression. HARMONi-7 is a Phase III clinical trial which is intended to evaluate ivonescimab monotherapy compared to pembrolizumab monotherapy in patients with first-line metastatic NSCLC whose tumors have high PD-L1 expression. HARMONi-GI3 is a planned Phase III clinical trial evaluating ivonescimab in combination with chemotherapy compared with bevacizumab plus chemotherapy in patients with first-line unresectable metastatic CRC. In addition, Akeso has recently had positive read-outs in three single-region (China), randomized Phase III clinical trials for ivonescimab in NSCLC: HARMONi-A, HARMONi-2, and HARMONi-6. HARMONi-A was a Phase III clinical trial which evaluated ivonescimab combined with chemotherapy compared to placebo plus chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who have progressed after treatment with an EGFR TKI. HARMONi-2 is a Phase III clinical trial evaluating monotherapy ivonescimab against monotherapy pembrolizumab in patients with locally advanced or metastatic NSCLC whose tumors have positive PD-L1 expression. HARMONi-6 is a Phase III clinical trial evaluating ivonescimab in combination with platinum-based chemotherapy compared with tislelizumab, an anti-PD-1 antibody, in combination with platinum-based chemotherapy in patients with locally advanced or metastatic squamous NSCLC, irrespective of PD-L1 expression. Akeso is actively conducting multiple Phase III clinical studies in settings outside of NSCLC, including biliary tract cancer, colorectal cancer, breast cancer, pancreatic cancer, small cell lung cancer, and head and neck cancer. Ivonescimab is an investigational therapy that is not approved by any regulatory authority in Summit’s license territories, including the United States and Europe. Ivonescimab was initially approved for marketing authorization in China in May 2024. Ivonescimab was granted Fast Track designation by the US Food & Drug Administration (FDA) for the HARMONi clinical trial setting. About Summit Therapeutics Summit Therapeutics Inc. is a biopharmaceutical oncology company focused on the discovery, development, and commercialization of patient-, physician-, caregiver- and societal-friendly medicinal therapies intended to improve quality of life, increase potential duration of life, and resolve serious unmet medical needs. Summit was founded in 2003 and our shares are listed on the Nasdaq Global Market (symbol "SMMT"). We are headquartered in Miami, Florida, and we have additional offices in Menlo Park, California, and Oxford, UK. For more information, please visit https://www.smmttx.com and follow us on X @SMMT_TX. Summit Forward-looking Statements Any statements in this press release about the Company’s future expectations, plans and prospects, including but not limited to, statements about the clinical and preclinical development of the Company’s product candidates, entry into and actions related to the Company’s partnership with Akeso Inc., the Company's anticipated spending and cash runway, the therapeutic potential of the Company’s product candidates, the potential commercialization of the Company’s product candidates, the timing of initiation, completion and availability of data from clinical trials, the potential submission of applications for marketing approvals, the expected timing of BLA submissions, potential acquisitions, statements about the previously disclosed At-The-Market equity offering program (“ATM Program”), the expected proceeds and uses thereof, the Company’s estimates regarding stock-based compensation, and other statements containing the words "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "plan," "potential," "predict," "project," "should," "target," "would," and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including the Company’s ability to sell shares of our common stock under the ATM Program, the conditions affecting the capital markets, general economic, industry, or political conditions, including the effects of geopolitical developments, domestic and foreign trade policies, and monetary policies, the results of our evaluation of the underlying data in connection with the development and commercialization activities for ivonescimab, the outcome of discussions with regulatory authorities, including the Food and Drug Administration, the uncertainties inherent in the initiation of future clinical trials, availability and timing of data from ongoing and future clinical trials, the results of such trials, and their success, global public health crises, that may affect timing and status of our clinical trials and operations, whether preliminary results from a clinical trial will be predictive of the final results of that trial or whether results of early clinical trials or preclinical studies will be indicative of the results of later clinical trials, whether business development opportunities to expand the Company’s pipeline of drug candidates, including without limitation, through potential acquisitions of, and/or collaborations with, other entities occur, expectations for regulatory approvals, laws and regulations affecting government contracts and funding awards, availability of funding sufficient for the Company’s foreseeable and unforeseeable operating expenses and capital expenditure requirements and other factors discussed in the "Risk Factors" and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” sections of filings that the Company makes with the Securities and Exchange Commission. Any change to our ongoing trials could cause delays, affect our future expenses, and add uncertainty to our commercialization efforts, as well as to affect the likelihood of the successful completion of clinical development of ivonescimab. Accordingly, readers should not place undue reliance on forward-looking statements or information. In addition, any forward-looking statements included in this press release represent the Company’s views only as of the date of this release and should not be relied upon as representing the Company’s views as of any subsequent date. The Company specifically disclaims any obligation to update any forward-looking statements included in this press release. Summit Therapeutics and the Summit Therapeutics logo are trademarks of Summit Therapeutics Inc. Copyright 2025, Summit Therapeutics Inc. All Rights Reserved Summit Therapeutics Inc. GAAP Condensed Consolidated Statements of Operations (Unaudited) (in millions, except per share data) Three Months Ended September 30, Nine Months Ended September 30, 2025 2024 2025 2024 Operating expenses: Research and development $ 131.1 $ 37.7 $ 390.4 $ 99.4 Acquired in-process research and development — — — 15.0 General and administrative 103.1 20.7 479.1 46.0 Total operating expenses 234.2 58.4 869.5 160.4 Other income, net 2.4 4.6 9.1 9.0 Interest expense — (2.5 ) — (8.7 ) Net loss $ (231.8 ) $ (56.3 ) $ (860.4 ) $ (160.1 ) Net loss per share attributable to common shareholders per share, basic and diluted $ (0.31 ) $ (0.08 ) $ (1.16 ) $ (0.22 ) Summit Therapeutics Inc. GAAP Condensed Consolidated Balance Sheet Information (in millions) Unaudited September 30, 2025 December 31, 2024 Cash and cash equivalents and short-term investments $ 238.6 $ 412.3 Total assets $ 261.7 $ 435.6 Total liabilities $ 69.5 $ 46.8 Total stockholders' equity $ 192.3 $ 388.7 Summit Therapeutics Inc. GAAP Condensed Consolidated Statement of Cash Flows Information (in millions) Unaudited Nine Months Ended September 30, 2025 2024 Net cash used in operating activities $ (221.0 ) $ (93.4 ) Net cash provided by (used in) investing activities 310.8 (288.8 ) Net cash provided by financing activities 43.7 404.8 Effect of exchange rate changes on cash 0.1 0.1 Increase in cash, cash equivalents and restricted cash $ 133.6 $ 22.7 Summit Therapeutics Inc. Schedule Reconciling Selected Non-GAAP Financial Measures (Unaudited) (in millions, except per share data) Three Months Ended September 30, Nine Months Ended September 30, 2025 2024 2025 2024 Reconciliation of GAAP to Non-GAAP Research and Development Expense GAAP Research and Development $ 131.1 $ 37.7 $ 390.4 $ 99.4 Stock-based compensation (Note 1) (40.6 ) (5.8 ) (173.2 ) (11.7 ) Non-GAAP Research and development $ 90.5 $ 31.9 $ 217.2 $ 87.7 Reconciliation of GAAP to Non-GAAP General and Administrative Expenses GAAP General and Administrative $ 103.1 $ 20.7 $ 479.1 $ 46.0 Stock-based compensation (Note 1) (90.2 ) (13.6 ) (447.4 ) (28.2 ) Non-GAAP General and administrative $ 12.9 $ 7.1 $ 31.7 $ 17.8 Reconciliation of GAAP to Non-GAAP Operating Expenses GAAP Operating Expenses $ 234.2 $ 58.4 $ 869.5 $ 160.4 Stock-based compensation (Note 1) (130.8 ) (19.4 ) (620.6 ) (39.9 ) Non-GAAP Operating expense $ 103.4 $ 39.0 $ 248.9 $ 120.5 Reconciliation of GAAP Net Loss to Non-GAAP Net Loss GAAP Net Loss $ (231.8 ) $ (56.3 ) $ (860.4 ) $ (160.1 ) Stock-based compensation (Note 1) 130.8 19.4 620.6 39.9 Non-GAAP Net Loss $ (101.0 ) $ (36.9 ) $ (239.8 ) $ (120.2 ) Reconciliation of GAAP Net Loss to Non-GAAP Net Loss Per Common Share GAAP Net Loss Per Basic and Diluted Common Share $ (0.31 ) $ (0.08 ) $ (1.16 ) $ (0.22 ) Stock-based compensation (Note 1) 0.18 0.03 0.83 0.06 Non-GAAP Net loss Per Basic and Diluted Common Share $ (0.13 ) $ (0.05 ) $ (0.33 ) $ (0.16 ) Basic and Diluted Common Shares 743.4 726.7 741.4 712.2 Summit Therapeutics Inc. Schedule Reconciling Selected Non-GAAP Financial Measures (in millions) Unaudited Three Months Ended September 30, 2025 June 30, 2025 March 31, 2025 December 31, 2024 September 30, 2024 Reconciliation of GAAP to Non-GAAP Operating Expenses GAAP Operating Expenses $ 234.2 $ 568.4 $ 66.8 $ 65.6 $ 58.4 Stock-based compensation (Note 1) (130.8 ) (478.8 ) (11.1 ) (11.0 ) (19.4 ) Non-GAAP Operating Expense (Note 2) $ 103.4 $ 89.6 $ 55.7 $ 54.6 $ 39.0 Reconciliation of GAAP Net Loss to Non-GAAP Net Loss GAAP Net Loss $ (231.8 ) $ (565.7 ) $ (62.9 ) $ (61.2 ) $ (56.3 ) Stock-based compensation (Note 1) 130.8 478.8 11.1 11.0 19.4 Non-GAAP Net Loss (Note 2) $ (101.0 ) $ (86.9 ) $ (51.8 ) $ (50.2 ) $ (36.9 ) Summit Therapeutics Inc. Notes on our Non-GAAP Financial Information Non-GAAP financial measures adjust GAAP financial measures for the items listed below. These Non-GAAP measures should be viewed in addition to, and not as a substitute for Summit's reported GAAP results, and may be different from Non-GAAP measures used by other companies. In addition, these Non-GAAP measures are not based on any comprehensive set of accounting rules or principles. Summit management uses these Non-GAAP measures for internal budgeting and forecasting purposes and to evaluate Summit’s financial performance. Summit management believes the presentation of these Non-GAAP measures is useful to investors for comparing prior periods and analyzing ongoing business trends and operating results. Each of Non-GAAP Research and Development Expense, Non-GAAP General and Administrative Expenses, Non-GAAP Operating Expenses, Non-GAAP Net Loss and Non-GAAP EPS differ from GAAP in that such measures exclude the non-cash charges and costs associated with stock-based compensation. Note 1: Stock-based compensation is a non-cash charge and costs calculated for this expense can vary year-over-year depending on the stock price of awards on the date of grant as well as the timing of compensation award arrangements. Note 2: Beginning in the fourth quarter of 2024, the Company’s Non-GAAP financial measures will no longer exclude acquired in-process research and development expenses (“IPR&D”). Non-GAAP financial measures for the three months ended June 30, 2024 previously excluded $15.0 million of IPR&D which represented an upfront payment made to Akeso under an amendment to the Collaboration and License Agreement. Prior period amounts have been revised to conform to the current period presentation.