Tremelimumab

引言肝细胞癌（Hepatocellular Carcinoma，HCC），长期以来，尽管研究人员不断努力，晚期肝细胞癌的一线治疗选择带来的生存改善依然有限，患者急需更有效、能带来长期希望的疗法。5月8日在《The Lancet》上刚刚发表的CheckMate 9DW研究“Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): an open-label, randomised, phase 3 trial”，这是一项旨在改写晚期肝细胞癌一线治疗格局的关键性临床试验。这项研究将一种全新的双免疫联合疗法——纳武利尤单抗（nivolumab）联合伊匹木单抗（ipilimumab），与目前广泛使用的标准疗法乐伐替尼（lenvatinib）或索拉非尼（sorafenib）进行了直接PK。结果震撼人心！这项研究取得了显著的成功，双免疫联合疗法让患者的中位总生存期突破了23个月，达到了23.7个月，相比对照组的20.6个月，生存获益是实实在在的。更令人振奋的是，在更长期的随访中，这种生存优势持续扩大，双免疫组在24个月和36个月的生存率分别高达49%和38%，远超对照组的39%和24%。尽管初期治疗曲线有所交叉，但长期的随访数据清晰地展示了双免疫疗法带来的更持久的生存希望。此外，这项疗法还带来了更高的客观缓解率（36% vs 13%）和更长的缓解持续时间（中位尚未达到 vs 12.9个月），且安全性可控。CheckMate 9DW的研究发现，不仅为晚期肝细胞癌患者提供了一个疗效显著、长期生存潜力更强的全新一线选择，也再次印证了免疫联合疗法在肿瘤治疗中的巨大力量。一线治疗的困境与求索长期以来，晚期不可切除肝细胞癌的一线系统治疗主要依赖多激酶抑制剂（multikinase inhibitors），比如索拉非尼（sorafenib）和乐伐替尼（lenvatinib）。这些药物的出现，为患者带来了希望的曙光，但它们带来的中位总生存期（Overall Survival，OS）改善相对有限，大约在12个月到14个月之间，而且不良反应（adverse events）的发生率也比较高，患者的耐受性（tolerability）仍有待提高。近五年来，随着免疫治疗（immunotherapy）的飞速发展，特别是PD-1/PD-L1抑制剂（PD-1/PD-L1 inhibitors）的问世及其与抗血管生成药物（anti-angiogenic therapy）或其他免疫检查点抑制剂（immune checkpoint inhibitors）的联合应用，晚期肝细胞癌的一线治疗格局发生了显著变化。例如，阿替利珠单抗（atezolizumab）联合贝伐珠单抗（bevacizumab）以及度伐利尤单抗（durvalumab）联合替西木单抗（tremelimumab）等免疫联合方案，在一线治疗中显示出优于索拉非尼的总生存期获益，中位总生存期达到了16个月到19个月，客观缓解率（Objective Response Rate，ORR）也有所提高，为患者提供了新的治疗选择。然而，尽管取得了这些进步，晚期肝细胞癌患者的长期预后仍然不理想，临床上仍然需要能够带来更长久生存希望的创新疗法。纳武利尤单抗（nivolumab）是一种PD-1抑制剂，而伊匹木单抗（ipilimumab）是一种CTLA-4抑制剂。这两种免疫检查点抑制剂的联合治疗，已经在多种肿瘤类型中展示出了良好的疗效和可控的安全性。在既往的CheckMate 040 II期研究中，纳武利尤单抗联合伊匹木单抗在既往接受过索拉非尼治疗的晚期肝细胞癌患者中显示出了长期的疗效和可控的安全性，并据此在美国获得了加速批准。这一成功为在更早期、即一线治疗中使用这种双免疫联合方案奠定了基础。然而，此前纳武利尤单抗单药在一线治疗中的表现（CheckMate 459研究）并未显示出优于索拉非尼的总生存期优势。CheckMate 9DW 启航：挑战标准疗法正是在这样的背景下，CheckMate 9DW研究应运而生。这是一项开放标签（open-label）、随机（randomised）、III期临床试验，旨在评估纳武利尤单抗联合伊匹木单抗作为晚期不可切除肝细胞癌一线治疗的疗效（efficacy）和安全性（safety），并将其与当前的标准治疗药物——乐伐替尼或索拉非尼进行比较。这项研究在全球25个国家的163家医院和癌症中心招募了符合条件的患者。入组标准非常严格：年龄18岁及以上，组织学确诊的晚期肝细胞癌，不可切除或既往局部治疗后进展，未接受过晚期肝细胞癌的系统性治疗（systemic therapy），至少有一个可测量病灶（measurable lesion），Child-Pugh评分为5或6（A级或B级），以及ECOG体能状态（performance status）评分为0或1。研究排除了已知是纤维板层型、肉瘤样或混合性肝细胞癌、既往肝移植、近期（12个月内）发生过≥2级肝性脑病（hepatic encephalopathy）、有临床意义的腹水（ascites）等情况的患者。研究还排除了合并活动性乙肝（HBV）和丙肝（HCV）共感染，或乙肝和丁肝（HDV）共感染的患者。符合条件的患者按照1:1的比例，通过交互式响应技术系统（interactive response technology system）被随机分配到两个治疗组：纳武利尤单抗联合伊匹木单抗组：患者接受纳武利尤单抗 1 mg/kg 和伊匹木单抗 3 mg/kg 静脉输注，每3周一次，最多进行4次。之后，患者继续接受纳武利尤单抗 480 mg 静脉输注，每4周一次。乐伐替尼或索拉非尼组：由研究者根据患者情况选择口服乐伐替尼（根据体重每日8 mg或12 mg）或口服索拉非尼（每日两次，每次400 mg）。随机化时根据病因（乙肝病毒 vs 丙肝病毒 vs 非感染）、大血管侵犯（macrovascular invasion）和/或肝外扩散（extrahepatic spread）（存在 vs 不存在）、以及基线甲胎蛋白（alpha-fetoprotein，AFP）浓度（<400 ng/mL vs ≥400 ng/mL）进行分层。主要研究终点是总生存期（Overall Survival，OS），评估对象是所有随机分组的患者。安全性作为探索性终点（exploratory endpoint），评估对象是所有接受了至少一剂研究药物的患者。肿瘤评估会定期进行，以评估治疗响应。这项研究共随机分配了668例患者，其中335例进入纳武利尤单抗联合伊匹木单抗组，333例进入乐伐替尼或索拉非尼组。实际接受治疗的患者有657例（纳武利尤单抗联合伊匹木单抗组332例，乐伐替尼或索拉非尼组325例）。在乐伐替尼或索拉非尼组中，有275例（85%）患者接受了乐伐替尼，50例（15%）接受了索拉非尼。里程碑式的生存数据：扭转战局的关键CheckMate 9DW研究达到了其主要终点，纳武利尤单抗联合伊匹木单抗在一线治疗晚期不可切除肝细胞癌患者中，与乐伐替尼或索拉非尼相比，显示出显著的总生存期获益。在中位随访时间为35.2个月时，纳武利尤单抗联合伊匹木单抗组的中位总生存期达到了23.7个月（95% CI 18.8-29.4），而乐伐替尼或索拉非尼组的中位总生存期为20.6个月（95% CI 17.5-22.5）。两组的总生存期差异具有统计学意义（分层对数秩检验 p=0.018），风险比（Hazard Ratio，HR）为0.79（95% CI 0.65-0.96）。这意味着纳武利尤单抗联合伊匹木单抗治疗的患者死亡风险降低了21%。值得注意的是，研究观察到了Kaplan-Meier生存曲线的早期交叉现象。在随机分组后的前6个月内，纳武利尤单抗联合伊匹木单抗组的死亡人数相对较多（风险比 1.65 [95% CI 1.12-2.43]），但这之后曲线出现了持续分离，并且分离趋势有利于纳武利尤单抗联合伊匹木单抗组（风险比 0.61 [95% CI 0.48-0.77]）。这种早期交叉可能是多种因素造成的，比如部分免疫相关不良事件（immune-mediated adverse events）在治疗初期发生，或是免疫治疗起效需要一定时间，而乐伐替尼/索拉非尼作为靶向药物，其抗肿瘤作用相对更快，但不足以实现长期的控制。然而，一旦免疫治疗起效，其疗效往往更为持久。更令人振奋的是长期生存率数据：纳武利尤单抗联合伊匹木单抗组的24个月总生存率为49%（95% CI 44–55），而乐伐替尼或索拉非尼组为39%（95% CI 34-45）。到了36个月，纳武利尤单抗联合伊匹木单抗组的生存率进一步维持在38%（95% CI 32–43），而乐伐替尼或索拉非尼组则降至24%（95% CI 19-30）。CheckMate 9DW研究报告的24个月和36个月生存率是目前已获批的一线系统疗法中最高之一，这突显了双免疫联合治疗为晚期肝细胞癌患者带来的长期生存希望。由于存在比例风险假定（proportional hazards assumption）的违反，研究还进行了额外的支持性分析，包括限制性平均生存时间（restricted mean survival time）和分段风险比（piecewise HRs）分析，这些分析结果与主要分析一致，均支持纳武利尤单抗联合伊匹木单抗带来的整体生存获益。亚组分析也显示，总生存获益在各个临床相关亚组中基本一致，包括不同病因（如乙肝、丙肝、非感染）。为何效果更持久？深入了解响应机制除了延长生存期，纳武利尤单抗联合伊匹木单抗治疗在肿瘤缓解方面也展现出显著优势。通过盲法独立中心评估（Blinded Independent Central Review，BICR），纳武利尤单抗联合伊匹木单抗组的客观缓解率（ORR）高达36%（121/335），而乐伐替尼或索拉非尼组仅为13%（44/333）。这一差异具有高度统计学意义（p<0.0001）。其中，纳武利尤单抗联合伊匹木单抗组有23例（7%）患者达到完全缓解（Complete Response，CR），而对照组只有6例（2%）。更高的缓解率意味着更多的患者能从治疗中看到肿瘤缩小或消失。更重要的是，纳武利尤单抗联合伊匹木单抗带来的肿瘤缓解更为持久。两组达到缓解的患者中，中位缓解持续时间（Duration of Response，DoR）在纳武利尤单抗联合伊匹木单抗组尚未达到（>30.4个月，95% CI 21.2-未达到），而乐伐替尼或索拉非尼组为12.9个月（95% CI 10.2-31.2）。这意味着一旦患者对双免疫治疗产生响应，这种响应持续的时间要比靶向药物长得多。研究发现，在纳武利尤单抗联合伊匹木单抗组中，许多达到缓解的患者在停止治疗后依然保持着响应，在36个月时仍有高达47%的响应者维持持续缓解，这充分体现了免疫治疗可能带来的长期控制潜力。在疾病进展方面，尽管基于BICR的无进展生存期（Progression-Free Survival，PFS）中位数两组相似（纳武利尤单抗联合伊匹木单抗组9.1个月 [95% CI 6.6–10.5] vs 乐伐替尼或索拉非尼组9.2个月 [95% CI 7.9-11.1]，HR 0.87），但纳武利尤单抗联合伊匹木单抗组在18个月和24个月的无进展生存率更高（18个月：34% vs 18%；24个月：28% vs 12%），这与总生存期和缓解持续时间的数据趋势是一致的。这些数据共同勾勒出纳武利尤单抗联合伊匹木单抗治疗的特点：并非所有患者都会迅速响应，但一旦响应，其深度和持久性可能带来显著的长期生存优势。安全性：可控的挑战任何有效的治疗方法都伴随着不良反应的风险。研究显示，两组治疗方案的3-4级治疗相关不良事件（treatment-related adverse events，TRAEs）发生率相似：纳武利尤单抗联合伊匹木单抗组为41%（332例患者中的137例），乐伐替尼或索拉非尼组为42%（325例患者中的138例）。这表明双免疫联合方案的严重不良事件发生率并未显著高于目前的标准靶向治疗。因TRAEs导致停药的比例在纳武利尤单抗联合伊匹木单抗组为18%（59/332），乐伐替尼或索拉非尼组为10%（34/325）。因3-4级TRAEs停药的比例分别为13%（44/332）和6%（21/325）。这些不良事件，特别是免疫治疗可能引起的免疫相关不良事件，虽然可能影响治疗的连续性，但在CheckMate 9DW研究中，大多数免疫相关不良事件都能够通过既定的管理算法进行处理，并且有29%的患者需要使用高剂量皮质类固醇进行管理，但多数事件并未导致永久停药。治疗相关的死亡事件在纳武利尤单抗联合伊匹木单抗组发生了12例，在乐伐替尼或索拉非尼组发生了3例。在纳武利尤单抗联合伊匹木单抗组中，一些治疗相关的死亡是免疫介导的肝炎（immune-mediated hepatitis）或肝功能衰竭（hepatic failure），这些事件在晚期肝病背景下的患者中尤其需要警惕。肝功能衰竭是肝癌本身的常见且危及生命的并发症。研究者评估的12例治疗相关死亡中，有11例发生在随机分组后的前6个月内，其中9例与致命性肝脏事件相关，多见于伴有晚期肝病的患者。这也部分解释了Kaplan-Meier曲线的早期交叉。竞争风险分析（competing risk analysis）提示，除了治疗相关的死亡，一些与研究治疗无关的不良事件导致的早期死亡也对曲线的早期分离有显著贡献。尽管存在这些风险，但总体而言，纳武利尤单抗联合伊匹木单抗的安全性特征与先前在肝细胞癌二线治疗及其他肿瘤适应症中的报告一致，没有发现新的安全性问题，其安全性是可管理的。研究还观察到，与乐伐替尼或索拉非尼组相比，纳武利尤单抗联合伊匹木单抗组患者报告的健康相关生活质量（health-related quality of life）有改善趋势或恶化风险显著降低，这支持了该方案在患者中的可耐受性。对比现有疗法：优势何在？将CheckMate 9DW的研究结果置于当前晚期不可切除肝细胞癌一线治疗的整体格局中，其意义尤为突出。如前所述，既往的标准治疗多激酶抑制剂索拉非尼和乐伐替尼带来了中位总生存期约12-14个月的获益。新出现的PD-L1抑制剂联合方案（如阿替利珠单抗联合贝伐珠单抗）将中位总生存期提高到了19个月左右，客观缓解率也提高至30%左右，缓解持续时间约18-22个月。度伐利尤单抗联合替西木单抗的双免疫联合方案（HIMALAYA研究）也在总生存期上显示了获益（中位OS 16.4个月 vs 索拉非尼 16.4个月，但关键在于其死亡风险有显著降低，HR 0.78），带来了20%的客观缓解率和22.3个月的中位缓解持续时间。CheckMate 9DW研究中，纳武利尤单抗联合伊匹木单抗组报告的23.7个月的中位总生存期，以及36%的客观缓解率和长达30.4个月的中位缓解持续时间，尤其是在24个月和36个月展示出的优异生存率（49%和38%），显著高于既往报告的数据。更重要的是，本次研究的对照组中，绝大多数患者（85%）接受的是目前广泛使用的乐伐替尼，而此前大多数免疫治疗研究的对照组是索拉非尼。CheckMate 9DW在包含乐伐替尼作为主要对照药物的情况下依然取得了显著的总生存获益，这一点尤其具有说服力。尽管CheckMate 9DW是开放标签试验（可能对不良事件和生活质量评估带来潜在偏倚），但主要终点总生存期以及由BICR评估的客观缓解率和无进展生存期受此影响较小。CheckMate 9DW 的意义：为患者开启新篇章总而言之，CheckMate 9DW这项具有里程碑意义的III期研究证实，对于既往未接受过系统性治疗的不可切除肝细胞癌患者，纳武利尤单抗联合伊匹木单抗作为一线治疗方案，与乐伐替尼或索拉非尼相比，能带来显著的总生存期获益。尽管治疗初期存在生存曲线交叉的现象，但长期随访显示出了持续且优异的生存优势，尤其体现在更长的中位总生存期（23.7个月）和更高的长期生存率上。同时，双免疫联合方案的安全性与既往研究一致，是可管理的，且未发现新的安全性问题。更高的客观缓解率和更持久的缓解持续时间，进一步支持了该联合方案在控制肿瘤、延长患者生存方面的优越性。CheckMate 9DW研究的结果，为晚期不可切除肝细胞癌的一线治疗提供了一个强有力的新选择，特别是对于追求长期疾病控制和生存获益的患者。这项研究支持将纳武利尤单抗联合伊匹木单抗方案作为这类患者的新标准一线治疗选择，为全球众多肝细胞癌患者开启了新的希望篇章。未来的研究可能会进一步探索如何优化患者的选择，以及如何将这一方案与其他治疗手段结合，以期为患者带来更大的福音。参考文献https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00403-9/fulltext声明：本文仅用于分享，不代表平台立场，如涉及版权等问题，请尽快联系我们，我们第一时间更正，谢谢！往期热文：Nature | 脑海里的“寒风”真的会冷！新研究揭示：大脑如何通过情境记忆调控全身代谢Nature Medicine | 刷新认知！体内巨细胞病毒，竟是抗癌“隐形队友”？揭秘CMV与免疫疗法生存奇迹！Science | cycleHCR技术实现深层组织RNA与蛋白质同步高分辨成像Nature Methods | 质谱分析终结者？CHIMERYS统一DDA、DIA、PRM数据，破译蛋白质密码Cell | 颠覆认知！没核没线的红细胞竟有复杂程序性死亡：Spectosis 机制大公开Nature Biotechnology | 突破传统极限：远红外生物传感器带你“看清”活细胞内激酶的秘密

Patients lived significantly longer without high-risk disease recurrence or progression after one year of IMFINZI treatment plus Bacillus Calmette-Guérin (BCG) induction and maintenance therapy vs. BCG alone WILMINGTON, DE, USA I May 09, 2025 I Positive high-level results from the POTOMAC Phase III trial showed one year of treatment with AstraZeneca’s IMFINZI ® (durvalumab) plus standard-of-care BCG induction and maintenance therapy demonstrated a statistically significant and clinically meaningful improvement in disease-free survival (DFS) for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) compared to BCG induction and maintenance therapy alone.​ The trial was not statistically powered to formally test overall survival (OS) however a descriptive analysis demonstrated no detriment. More than 70% of bladder cancer patients are diagnosed with NMIBC, an early-stage cancer where the tumor is in the tissue that lines the inner surface of the bladder but has not invaded the muscle wall. 1-2 About half of patients with NMIBC are classified as high-risk for disease progression or recurrence because of certain characteristics of their cancer, such as tumor grade, stage and specific tumor features. 3 Maria De Santis, MD, Head of the Interdisciplinary Uro-Oncology Section at Charité Universitätsmedizin Berlin, Germany, and a principal investigator in the POTOMAC trial, said: “These exciting data show that adding one year of durvalumab to the current standard treatment significantly extends the time patients live without high-risk disease recurrence or progression. While most patients with non-muscle invasive bladder cancer are treated with curative intent, 80 percent see their disease return and almost half may require life-altering surgery to remove the bladder, underscoring the urgent need to improve treatment.” Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: “The positive results for IMFINZIin the POTOMAC trial represent a significant advance that will potentially allow more patients with early-stage bladder cancer to benefit from this important immunotherapy. Building on the NIAGARA data, this outcome demonstrates our strategy of bringing novel therapies to patients with early-stage disease where there is the greatest potential for long-term benefit.” The safety and tolerability of IMFINZI plus BCG induction and maintenance therapy was consistent with the known safety profiles of the individual medicines, with no new safety concerns identified. The addition of IMFINZI did not compromise patients’ ability to complete BCG induction and maintenance therapy. The second experimental arm evaluating IMFINZIplus BCG induction-only therapy compared to BCG induction and maintenance therapy alone did not meet the endpoint of DFS. These data will be presented at a forthcoming medical meeting and shared with global regulatory authorities. IMFINZIis approved in the US and other countries for patients with muscle-invasive bladder cancer (MIBC) based on results from the NIAGARA Phase III trial and continues to be investigated across early and late-stage bladder cancer in various treatment combinations, including in patients with MIBC who are ineligible or refuse to take cisplatin (VOLGA) and in locally advanced or metastatic disease (NILE). Indications: IMFINZI, as a single agent, is indicated for the treatment of adult patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT). IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by IMFINZI continued as a single agent as adjuvant treatment after surgery, is indicated for the treatment of adult patients with resectable (tumors ≥4 cm and/or node positive) NSCLC and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements. IMFINZI, in combination with IMJUDO and platinum-based chemotherapy, is indicated for the treatment of adult patients with metastatic NSCLC with no sensitizing EGFR mutations or ALK genomic tumor aberrations. IMFINZI, as a single agent, is indicated for the treatment of adult patients with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT). IMFINZI, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). IMFINZI, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC). IMFINZI in combination with IMJUDO is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC). IMFINZI in combination with carboplatin and paclitaxel followed by IMFINZI as a single agent is indicated for the treatment of adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) as determined by an FDA-approved test. IMFINZI in combination with gemcitabine and cisplatin as neoadjuvant treatment, followed by single-agent IMFINZI as adjuvant treatment following radical cystectomy, is indicated for the treatment of adult patients with muscle-invasive bladder cancer (MIBC). Please see additional Important Safety Information throughout and Full Prescribing Information including Medication Guide for IMFINZI and IMJUDO . Notes Bladder cancer Bladder cancer is the 9th most common cancer in the world, with more than 614,000 cases diagnosed each year. 4 The most common type is urothelial carcinoma, which begins in the urothelial cells of the urinary tract. 2 In 2024, an estimated 125,000 patients were treated for high-risk NMIBC, for which the current standard of care is transurethral resection of bladder tumor (TURBT) followed by administration of BCG directly into the bladder. 5-6 Up to 80% of patients experience disease recurrence within five years, and rates of progression in high-risk patients can be as high as 45%. 2 There is a critical need for treatment options in this curative-intent setting. POTOMAC POTOMAC is a randomized, open-label, multi-center, global Phase III trial evaluating IMFINZIin combination with BCG therapy as a treatment for 1,018 patients with high-risk, BCG-naïve NMIBC who have undergone TURBT prior to randomization. Patients were randomized 1:1:1 to receive IMFINZI plus BCG induction and maintenance therapy, or IMFINZIplus BCG induction-only therapy, versus standard-of-care BCG induction and maintenance therapy. The trial was conducted in more than 120 centers across 12 countries including Canada and others across Europe and Asia. The primary endpoint was DFS, defined as time from randomization to date of first recurrence of high-risk disease or death from any cause, for IMFINZI plus BCG induction and maintenance therapy compared to BCG induction and maintenance therapy alone. Secondary endpoints included DFS for IMFINZI plus BCG induction only therapy versus the comparator arm, as well as OS at five years and safety across both experimental arms of the trial. IMFINZI IMFINZI ® (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and releasing the inhibition of immune responses. In addition to its indication in MIBC, IMFINZIis the global standard of care based on OS in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiotherapy (CRT). Additionally, IMFINZI is approved as a perioperative treatment in combination with neoadjuvant chemotherapy in resectable NSCLC, and in combination with a short course of IMJUDO (tremelimumab-actl) and chemotherapy for the treatment of metastatic NSCLC. IMFINZIis also approved for limited-stage small cell lung cancer (SCLC) in patients whose disease has not progressed following concurrent platinum-based CRT; and in combination with chemotherapy for the treatment of extensive-stage SCLC. IMFINZI is also approved in combination with chemotherapy in locally advanced or metastatic biliary tract cancer and in combination with IMJUDO in unresectable hepatocellular carcinoma (HCC). IMFINZIis also approved as a monotherapy in unresectable HCC in Japan and the European Union (EU). In March 2025, perioperative IMFINZI added to standard-of-care chemotherapy met the primary endpoint of event-free survival in the MATTERHORN Phase III trial in resectable gastric and gastroesophageal junction cancers. IMFINZIin combination with chemotherapy followed by IMFINZImonotherapy is approved as a 1st-line treatment for primary advanced or recurrent endometrial cancer (mismatch repair deficient disease only in US and EU). IMFINZIin combination with chemotherapy followed by olaparib and IMFINZIis approved for patients with mismatch repair proficient advanced or recurrent endometrial cancer in EU and Japan. Since the first approval in May 2017, more than 374,000 patients have been treated with IMFINZI. As part of a broad development program, IMFINZIis being tested as a single treatment and in combinations with other anti-cancer treatments for patients with NSCLC, bladder cancer, breast cancer, ovarian cancer and several gastrointestinal cancers. AstraZeneca in immuno-oncology (IO) AstraZeneca is a pioneer in introducing the concept of immunotherapy into dedicated clinical areas of high unmet medical need. The Company has a comprehensive and diverse IO portfolio and pipeline anchored in immunotherapies designed to overcome evasion of the anti-tumor immune response and stimulate the body’s immune system to attack tumors. AstraZeneca strives to redefine cancer care and help transform outcomes for patients with IMFINZI as a monotherapy and in combination with IMJUDO as well as other novel immunotherapies and modalities. The Company is also investigating next-generation immunotherapies like bispecific antibodies and therapeutics that harness different aspects of immunity to target cancer, including cell therapy and T-cell engagers. AstraZeneca is pursuing an innovative clinical strategy to bring IO-based therapies that deliver long-term survival to new settings across a wide range of cancer types. The Company is focused on exploring novel combination approaches to help prevent treatment resistance and drive longer immune responses. With an extensive clinical program, the Company also champions the use of IO treatment in earlier disease stages, where there is the greatest potential for cure. AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 125 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on social media @AstraZeneca . References SOURCE: AstraZeneca