Purpura, Thrombocytopenic, Idiopathic

▎药明康德内容团队报道3月28日，诺诚健华公布了2023年业绩报告和公司进展。2023年，该公司研发费用同比增加17.5%，达到7.5亿元，研发费用的增加主要是持续推进重要管线的全球临床试验和加大早期研发产品投资。此外，根据诺诚健华新闻稿，该公司在2024年有望递交4个新药NDA。血液瘤管线产品进展奥布替尼（BTK抑制剂）奥布替尼2023年4月获批用于既往至少接受过一次治疗的边缘区淋巴瘤（MZL）患者，成为奥布替尼获批的第三个适应症。奥布替尼一线治疗慢性淋巴细胞白血病（CLL）/小淋巴细胞淋巴瘤 （SLL）的3期注册临床试验2023年上半年完成患者入组，预计2024年第三季度递交新药上市申请（NDA）。 在美国，奥布替尼用于既往至少接受过一次治疗的套细胞淋巴瘤（MCL）患者的 2期注册临床试验2023年上半年完成患者入组，预计2024年第三季度向美国FDA递交NDA上市申请。诺诚健华正启动奥布替尼一线治疗MCL的全球3期临床试验。奥布替尼在新加坡获批用于既往至少接受过一次治疗的MCL患者，标志着诺诚健华商业化走向国际。预计2024年将在新加坡提交既往至少接受过一次治疗的MZL的NDA上市申请。诺诚健华正启动奥布替尼针对MZL的三期确证性临床试验。联合BCL2抑制剂ICP-248一线治疗CLL/SLL。奥布替尼一线治疗弥漫大B细胞淋巴瘤（DLBCL）MCD亚型3期注册研究目前在中国45个中心开展。坦昔妥单抗（tafasitamab，CD19单抗）坦昔妥单抗联合来那度胺治疗复发/难治性DLBCL注册临床试验在中国完成患者入组，预计2024年第二季度递交BLA上市申请，预计2025年上半年获批上市。坦昔妥单抗治疗方案在中国香港地区获批上市，并在海南博鳌和粤港澳大湾区获批使用，并分别在两地先行区的医院开出首方。ICP-248（BCL2抑制剂）ICP-248的初步研究结果展示了良好的安全性和药代动力学（PK），展示了和其他BCL2抑制剂的差异化。截至目前，17名患者完成给药，在完成评估的六名患者中，总缓解率（ORR）达到100%，三名患者达到完全缓解（CR），其中两名患者的微小残留病灶已检测不到（uMRD）。2024年1月，ICP-248获美国FDA批准开展临床研究。2024年3月，ICP-248联合奥布替尼一线治疗CLL/SLL在中国获批临床。ICP-248是一款新型口服高选择性BCL2抑制剂，旨在单药或与BTK抑制剂等其他药物联合治疗CLL/SLL、MCL、急性髓性白血病（AML）和其他NHL患者。ICP-B02（CD20xCD3双特异性抗体）ICP-B02（CM355）是诺诚健华和康诺亚合作开发的CD20xCD3双特异性抗体。初步数据显示，ICP-B02的静脉输注（IV）制剂和皮下注射（SC）制剂在滤泡性淋巴瘤（FL）和DLBCL患者中都展示了良好的疗效。在接受至少一剂6毫克以上剂量的13名患者中，ORR为100%。9名可评估的皮下注射患者中，7名患者完全缓解（CR），其中2名DLBCL患者完全缓解。基于ICP-B02单药令人鼓舞的结果，诺诚健华计划在更早线NHL患者中开展ICP-B02联合其他免疫化疗的剂量扩展研究。目前，诺诚健华已提交联合疗法的新药研究申请（IND）。ICP-490（CRBN E3连接酶调节剂）ICP-490是诺诚健华自主研发的创新药，源自分子胶平台，旨在治疗MM等血液肿瘤。诺诚健华正在进行多发性骨髓瘤（MM）患者1期剂量递增研究，展示了良好的安全性和耐受性。药效学（PD）分析显示主要药理靶点Aiolos（IKZF3）和Ikaro（IKZF1）的降解更深。2023年9月，ICP-490联合地塞米松在中国获批临床。作为单一疗法或与其他疗法联用，ICP-490有望在血液肿瘤领域展现强劲的潜力。ICP-B05（CCR8单抗）ICP-B05（CM369）是一款抗趋化因子受体8（CCR8）单克隆抗体，由诺诚健华和康诺亚共同开发，拟作为单一疗法或与其他疗法联合治疗高发的晚期实体瘤和NHL。在正在进行的1期临床试验中，该药展示了良好的耐受性，未观察到剂量限制毒性（DLT）。初步结果展现了良好的PK，同时观察到作为药效学（PD）生物标志物的Treg被清除。 实体瘤研究中的剂量递增已升至150毫克，这也是针对NHL患者的初始剂量。ICP-B05在NHL患者中观察到初步疗效。自身免疫性疾病管线进展自身免疫性疾病几乎可以影响身体的每个器官，且在生命的任何阶段都会发生。诺诚健华正进一步加强药物发现平台，通过B细胞和T细胞通路开发自身免疫性疾病领域的全球前沿靶点，打造差异化的自身免疫性疾病管线，旨在为大量未满足的临床需求提供创新疗法。奥布替尼奥布替尼治疗原发免疫性血小板减少症（ITP）已获得概念验证（PoC），并启动3期注册临床，预计2024年年底完成患者入组。2023年6月，奥布替尼治疗ITP的2期研究成果在第28届欧洲血液学协会（EHA）年会上进行口头报告。最新数据显示，50毫克组别中，40%的患者达到主要终点。在达到主要终点的患者中，83.3%的患者获得持久缓解。在对糖皮质激素（GC）或静脉注射免疫球蛋白（IVIG）敏感的患者中，50毫克剂量组中，75.0%的患者达到主要终点。奥布替尼治疗系统性红斑狼疮（SLE）的2a期临床试验取得积极效果，研究显示SLE反应指数-4（SRI-4）呈剂量依赖性的改善趋势，同时观察到尿蛋白呈下降趋势。2b期试验持续推进中，预计2024年年中完成患者入组。奥布替尼治疗多发性硬化（MS）全球2期试验的24周数据与之前报告的12周的数据在有效性和安全性方面趋势均一致。奥布替尼治疗MS三个剂量组的24周数据都达到主要终点，奥布替尼显著降低了多发性硬化（MS）患者的疾病活动，呈现剂量依赖性（Cmax driven）的改善趋势。与安慰剂组（第12周后每天一次50毫克奥布替尼）相比，每天一次80毫克剂量组在第24周时钆增强T1脑部累计新发病灶（Gd+ T1）减少了92.3%。与其他已批准或处于开发阶段的MS药物相比，这种减少最为显著。所有奥布替尼剂量组在治疗4周后均达到T1新病灶控制，且效果可持续长达24周。每天一次80毫克剂量组显示了最优的有效性，并且在整个24周内病灶控制效果最佳，安全性也最好，这表明每天一次80毫克有潜力成为治疗MS的最佳剂量。奥布替尼治疗视神经脊髓炎谱系疾病（NMOSD）的2期临床试验正在中国进行。ICP-332ICP-332治疗中重度特应性皮炎（AD）2期临床的最新数据在2024年美国皮肤病学会（AAD）年会以重磅口头报告形式发布。ICP-332展示了较好的疗效和安全性，达到多个有效性终点，包括EASI（湿疹面积和严重程度指数）较基线变化百分比、EASI 50、EASI 75、EASI 90（EASI评分较基线改善≥50%，75%，90%）、研究者整体评估（IGA）0/1（即皮损完全清除或基本清除）且较基线改善≥2分、以及瘙痒NRS评分较基线变化等。80毫克和120毫克两个治疗组EASI评分较基线改善的百分比变化分别为78.2%和 72.5%，与安慰剂组的16.7%相比，具备显著的统计学差异；两个治疗组EASI 75应答率均为64.0%，较安慰剂组（8.0%）改善了56.0%，优于多种获批创新药物单药治疗12周或16周的疗效（非头对头比较）。ICP-332 80毫克组EASI 90和IGA 0/1且较基线改善≥2分的应答率较安慰剂组分别改善40.0%和32.0%，具有统计学意义。ICP-332展示了良好的安全性和耐受性。两个治疗组的总体不良事件发生率、感染及侵染类疾病的不良事件发生率均与安慰剂组相当。预计2024年在中国启动ICP-332治疗AD的3期临床试验，在美国启动临床试验，以及针对第二个适应症白癜风的2期试验。ICP-332是一种新型酪氨酸激酶2（TYK2）抑制剂，开发用于治疗各种T细胞相关的自身免疫性疾病。ICP-488已完成ICP-488治疗银屑病患者的1期研究，在接受治疗4周的患者中，ICP-488展示了有效性。在每日一次6毫克剂量组中，银屑病面积和严重程度指数（PASI）评分较基线变化百分比的最小二乘均值改善38%，而安慰剂组为14%，具有统计学意义。6毫克组PASI 50的应答率为42%。已完成单剂量爬坡（1毫克到36毫克）和多剂量爬坡（2毫克到12毫克）研究，观察到ICP-488血浆暴露与剂量成比例。给药期同时服用标准高脂肪、高热量膳食，没有观察到明显的食物效应。ICP-488展示了良好的安全性和耐受性，治疗组与安慰剂组的不良事件相当。ICP-488治疗银屑病的2期研究预计2024年上半年完成患者入组。ICP-488是一款强效的高选择性TYK2变构抑制剂，通过结合TYK2 JH2结构域，阻断IL-23、IL-12和I型干扰素等炎性细胞因子的信号转导。ICP-B02（CM355）在1/2期临床试验中，ICP-B02在复发难治性NHL患者中首次输注（SC和IV）后，诱导外周B细胞的深度且持续清除。鉴于B细胞在多种严重自身免疫性疾病中发挥的关键作用，ICP-B02有潜力在严重的自身免疫性疾病中具有更广泛的应用。ICP-923（新靶点）IL-17是一种促炎细胞因子，在免疫应答中发挥重要作用。靶向IL-17的口服小分子对患者而言更便利，可替代IL-17靶向单克隆抗体。这款新型口服小分子可有效阻断IL-17AA和IL-17AF与IL-17R的结合。创新的实体瘤管线通过靶向治疗和免疫肿瘤学方法，诺诚健华致力于拓展管线的深度和广度，涵盖实体瘤疾病领域。为了使更广泛的患者受益，诺诚健华开发的早期管线包括基石疗法ICP-192、ICP-189和ICP-B05，有望为实体瘤患者提供新的治疗解决方案。Zurletrectinib（ICP-723）诺诚健华正加速推进zurletrectinib在中国的注册临床试验，预计2024年年底递交NDA。截至报告期，zurletrectinib展示了良好的有效性和安全性，ORR为80%~90%。Zurletrectinib被证明可以克服第一代TRK抑制剂的耐药性，为接受第一代TRK抑制剂后耐药的患者带来希望。除成年患者之外，zurletrectinib在青少年（12周岁到18周岁）患者和儿童患者（2周岁到12周岁）中开展临床研究，已覆盖所有年龄的NTRK基因融合阳性患者。儿童患者入组正进行中，已观察到部分缓解。ICP-189诺诚健华与ArriVent达成临床合作协议，ICP-189联合第三代EGFR抑制剂伏美替尼治疗晚期或转移性非小细胞肺癌（NSCLC）患者的疗效和安全性。这一联合用药临床研究正推进中。ICP-189是诺诚健华自主研发的新型蛋白酪氨酸磷酸酶SHP2变构抑制剂，可用作单药疗法及/或和其他抗肿瘤药的联合疗法，旨在为肺癌、头颈癌及消化道肿瘤等实体瘤提供新的临床治疗方法。ICP-189单药治疗观察到初步疗效。截至报告期，剂量已增至120毫克，未观察到DLT，并显示出良好的PK和长半衰期。160毫克剂量组的患者入组正在进行中。SHP2抑制剂是和多种靶向药和免疫疗法联合治疗实体瘤的理想药物。ICP-189在KRAS G12C突变和EGFR过表达驱动的肿瘤模型具有显著的抗肿瘤作用。Gunagratinib（ICP-192）2023年ASCO-GI会议公布gunagratinib治疗胆管癌（CCA）患者的最新临床数据 。在既往接受过治疗的局部晚期或转移性的FGFR2基因融合/重排的胆管癌患者中，gunagratinib显示出良好的安全性和有效性。参考资料：[1]诺诚健华2023年业绩报告：以高质量创新药赋能新质生产力发展. Retrieved Mar 28 , 2024, from https://mp.weixin.qq.com/s/EFabBdlejaGGbn4puCUKiQ本文由药明康德内容团队根据公开资料整理编辑，欢迎个人转发至朋友圈。转发授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

March 28, 2024 6:45 am ET Decision marks the first approval in Europe for an anti-PD-1/L1 therapy in resectable NSCLC based on positive overall survival results and represents the sixth approval for KEYTRUDA in lung cancer in Europe RAHWAY, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the European Commission (EC) has approved KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with platinum-containing chemotherapy as neoadjuvant treatment, then continued as monotherapy as adjuvant treatment, for resectable non-small cell lung cancer (NSCLC) at high risk of recurrence in adults. This approval by the EC follows the positive recommendation from the Committee for Medicinal Products for Human Use received in February 2024 and was based on results from the Phase 3 KEYNOTE-671 trial. At a median follow-up of 29.8 months (range, 0.4 to 62.0 months), KEYTRUDA plus chemotherapy in the neoadjuvant setting followed by KEYTRUDA as monotherapy after surgical resection significantly improved overall survival (OS), reducing the risk of death by 28% (HR=0.72 [95% CI, 0.56-0.93]; one-sided p=0.00517) in patients with resectable stage II, IIIA or IIIB NSCLC versus placebo plus chemotherapy in the neoadjuvant setting followed by placebo after surgical resection, regardless of PD-L1 expression. For patients who received the KEYTRUDA-based regimen, median OS was not reached (95% CI, NR-NR) versus 52.4 months (95% CI, 45.7-NR) for patients who received the chemotherapy-placebo regimen. The KEYTRUDA-based regimen also improved event-free survival (EFS), reducing the risk of disease recurrence, progression or death by 41% (HR=0.59 [95% CI, 0.48-0.72]) compared to the chemotherapy-placebo regimen. For patients who received the KEYTRUDA-based regimen, median EFS was improved by nearly two and a half years compared to the chemotherapy-placebo regimen (47.2 months [95% CI, 32.9-NR] versus 18.3 months [95% CI, 14.8-22.1], respectively). “Despite the clinical advances for patients with metastatic lung cancer, lung cancer continues to be the leading cause of cancer death in Europe, reinforcing the need to treat these patients in earlier stages of their disease, where we may have the most impact,” said Dr. Solange Peters, chair of the medical oncology and thoracic malignancies department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. “The approval of this KEYTRUDA-based regimen is an important milestone for patients diagnosed with resectable non-small cell lung cancer at high risk of recurrence, regardless of PD-L1 expression, providing a new option for these patients that has shown, through the results of the Phase 3 KEYNOTE-671 trial, the potential to help extend their lives.” This approval allows marketing of this KEYTRUDA regimen for this indication in all 27 EU member states, as well as Iceland, Liechtenstein, Norway and Northern Ireland. KEYTRUDA is now approved for six indications in NSCLC, and for 27 indications overall in the EU. In October 2023 , KEYTRUDA was approved in the U.S. for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. “Today’s approval of the first anti-PD-1/L1 therapy as part of a treatment regimen in Europe for the neoadjuvant followed by adjuvant treatment of resectable NSCLC based on positive overall survival results demonstrates our continued progress to advance treatments in earlier stages of lung cancer,” said Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “We are eager to build on this momentum as we plan to seek additional approvals of this regimen around the world, and to work together with the cancer community to help drive earlier diagnoses of lung cancer, an urgent need.” About the KEYNOTE-671 study design KEYNOTE-671 is a randomized, double-blind Phase 3 trial (ClinicalTrials.gov, NCT03425643 ) evaluating KEYTRUDA in combination with neoadjuvant chemotherapy, followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent, versus placebo plus neoadjuvant chemotherapy, followed by resection and adjuvant placebo, in patients with resectable stage II, IIIA or IIIB (T3-4N2) NSCLC (per the eight edition of the American Joint Committee on Cancer [AJCC] Cancer Staging Manual). The trial’s dual primary endpoints are EFS, per RECIST v1.1 by investigator assessment, and OS. Key secondary endpoints include pathologic complete response (pCR) and major pathological response (mPR). The study enrolled 797 patients who were randomly assigned (1:1) to receive either: KEYTRUDA (200 mg intravenously [IV] every three weeks [Q3W]) plus chemotherapy (cisplatin [75 mg/m 2 , IV; given on Day 1 of each cycle] and either gemcitabine [1,000 mg/m 2 , IV; given on Days 1 and 8 of each cycle] or pemetrexed [500 mg/m 2 , IV; given on Day 1 of each cycle]) for up to four cycles as neoadjuvant therapy prior to surgery. Within 4-12 weeks following surgery, KEYTRUDA (200 mg) was administered every three weeks for up to 13 cycles, or; Placebo (saline IV Q3W) plus chemotherapy (cisplatin [75 mg/m 2 , IV; given on Day 1 of each cycle] and either gemcitabine [1,000 mg/m 2 , IV; given on Days 1 and 8 of each cycle] or pemetrexed [500 mg/m 2 , IV; given on Day 1 of each cycle]) for up to four cycles as neoadjuvant therapy prior to surgery. Within 4‑12 weeks following surgery, placebo was administered every three weeks for up to 13 cycles. About lung cancer Lung cancer is the leading cause of cancer death worldwide. In 2022 alone, there were approximately 2.4 million new cases and 1.8 million deaths from lung cancer globally. Non-small cell lung cancer is the most common type of lung cancer, accounting for about 80% of all cases. In recent decades, the overall five-year survival rate for patients diagnosed with lung cancer increased from 11% to 15% on average across EU countries. Improved survival rates are due, in part, to earlier detection and screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. About Merck’s research in lung cancer Merck is advancing research aimed at transforming the way lung cancer is treated, with a goal of improving outcomes for patients affected by this deadly disease. Through nearly 200 clinical trials evaluating more than 36,000 patients around the world, Merck is at the forefront of lung cancer research. In NSCLC, KEYTRUDA has six approved U.S. indications (see indications below) and is approved for advanced disease in more than 95 countries. Among Merck’s research efforts are trials focused on evaluating KEYTRUDA in earlier stages of lung cancer as well as identifying new combinations and coformulations with KEYTRUDA. About Merck’s early-stage cancer clinical program Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is studying KEYTRUDA in earlier disease states, with more than 25 ongoing registrational studies across multiple types of cancer. About KEYTRUDA ® (pembrolizumab) injection, 100 mg KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD- L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells. Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers. Selected KEYTRUDA ® (pembrolizumab) Indications in the U.S. Non-Small Cell Lung Cancer KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC. KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is: stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic. KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. KEYTRUDA is indicated for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA, as a single agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC. See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information. Selected Important Safety Information for KEYTRUDA Severe and Fatal Immune-Mediated Adverse Reactions KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy. Immune-Mediated Pneumonitis KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients. Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution. Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution. Immune-Mediated Colitis KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients. Hepatotoxicity and Immune-Mediated Hepatitis KEYTRUDA as a Single Agent KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients. KEYTRUDA With Axitinib KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event. Immune-Mediated Endocrinopathies Adrenal Insufficiency KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypophysitis KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Thyroid Disorders KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism. The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment, including Grade 3 (0.2%) hyperthyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism. Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Immune-Mediated Nephritis With Renal Dysfunction KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients. Immune-Mediated Dermatologic Adverse Reactions KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients. Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection. Infusion-Related Reactions KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA. Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between anti–PD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT. Increased Mortality in Patients With Multiple Myeloma In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an anti–PD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials. Embryofetal Toxicity Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose. Adverse Reactions In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%). In KEYNOTE-054, when KEYTRUDA was administered as a single agent to patients with stage III melanoma, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE-716, when KEYTRUDA was administered as a single agent to patients with stage IIB or IIC melanoma, adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054. In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%). In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407. In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%). In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%). In KEYNOTE-671, adverse reactions occurring in patients with resectable NSCLC receiving KEYTRUDA in combination with platinum-containing chemotherapy, given as neoadjuvant treatment and continued as single-agent adjuvant treatment, were generally similar to those occurring in patients in other clinical trials across tumor types receiving KEYTRUDA in combination with chemotherapy. The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, and hypothyroidism. In the neoadjuvant phase of KEYNOTE-671, when KEYTRUDA was administered in combination with platinum-containing chemotherapy as neoadjuvant treatment, serious adverse reactions occurred in 34% of 396 patients. The most frequent (≥2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death due to unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%). Permanent discontinuation of any study drug due to an adverse reaction occurred in 18% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy; the most frequent adverse reactions (≥1%) that led to permanent discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%) and pneumonia (1.3%). Of the KEYTRUDA-treated patients who received neoadjuvant treatment, 6% of 396 patients did not receive surgery due to adverse reactions. The most frequent (≥1%) adverse reaction that led to cancellation of surgery in the KEYTRUDA arm was interstitial lung disease (1%). In the adjuvant phase of KEYNOTE-671, when KEYTRUDA was administered as a single agent as adjuvant treatment, serious adverse reactions occurred in 14% of 290 patients. The most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction of pulmonary hemorrhage occurred. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 12% of patients who received KEYTRUDA as a single agent, given as adjuvant treatment; the most frequent adverse reactions (≥1%) that led to permanent discontinuation of KEYTRUDA were diarrhea (1.7%), interstitial lung disease (1.4%), increased aspartate aminotransferase (1%), and musculoskeletal pain (1%). Adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred. In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%). In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%). In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism. In KEYNOTE-204, KEYTRUDA was discontinued due to adverse reactions in 14% of 148 patients with cHL. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA; those ≥1% were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients died from causes other than disease progression: 2 from complications after allogeneic HSCT and 1 from unknown cause. The most common adverse reactions (≥20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, rash, and cough (20% each). In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% were pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression: 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%). In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%). In KEYNOTE-A39, when KEYTRUDA was administered in combination with enfortumab vedotin to patients with locally advanced or metastatic urothelial cancer (n=440), fatal adverse reactions occurred in 3.9% of patients, including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin; the serious adverse reactions in ≥2% of patients were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Permanent discontinuation of KEYTRUDA occurred in 27% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash (3.4%). The most common adverse reactions (≥20%) occurring in patients treated with KEYTRUDA in combination with enfortumab vedotin were rash (68%), peripheral neuropathy (67%), fatigue (51%), pruritus (41%), diarrhea (38%), alopecia (35%), weight loss (33%), decreased appetite (33%), nausea (26%), constipation (26%), dry eye (24%), dysgeusia (21%), and urinary tract infection (21%). In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%). In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%). In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (≥20%) were fatigue (29%), diarrhea (24%), and rash (24%). Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-158 and KEYNOTE-164, adverse reactions occurring in patients with MSI-H or dMMR cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. In KEYNOTE-811, when KEYTRUDA was administered in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 6% of 217 patients with locally advanced unresectable or metastatic HER2+ gastric or GEJ adenocarcinoma. The most common adverse reaction resulting in permanent discontinuation was pneumonitis (1.4%). In the KEYTRUDA arm versus placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for diarrhea (53% vs 44%) and nausea (49% vs 44%). In KEYNOTE-859, when KEYTRUDA was administered in combination with fluoropyrimidine- and platinum-containing chemotherapy, serious adverse reactions occurred in 45% of 785 patients. Serious adverse reactions in >2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who received KEYTRUDA including infection (2.3%) and thromboembolism (1.3%). KEYTRUDA was permanently discontinued due to adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were infections (1.8%) and diarrhea (1.0%). The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were peripheral neuropathy (47%), nausea (46%), fatigue (40%), diarrhea (36%), vomiting (34%), decreased appetite (29%), abdominal pain (26%), palmar-plantar erythrodysesthesia syndrome (25%), constipation (22%), and weight loss (20%). In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil to patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued due to adverse reactions in 15% of 370 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in combination with chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%). Adverse reactions occurring in patients with esophageal cancer who received KEYTRUDA as a monotherapy were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-A18, when KEYTRUDA was administered with CRT (cisplatin plus external beam radiation therapy [EBRT] followed by brachytherapy [BT]) to patients with FIGO 2014 Stage III-IVA cervical cancer, fatal adverse reactions occurred in 1.4% of 292 patients, including 1 case each (0.3%) of large intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious adverse reactions occurred in 30% of patients; those ≥1% included urinary tract infection (2.7%), urosepsis (1.4%), and sepsis (1%). KEYTRUDA was discontinued for adverse reactions in 7% of patients. The most common adverse reaction (≥1%) resulting in permanent discontinuation was diarrhea (1%). For patients treated with KEYTRUDA in combination with CRT, the most common adverse reactions (≥10%) were nausea (56%), diarrhea (50%), vomiting (33%), urinary tract infection (32%), fatigue (26%), hypothyroidism (20%), constipation (18%), decreased appetite and weight loss (17% each), abdominal pain and pyrexia (12% each), hyperthyroidism, dysuria, rash (11% each), and pelvic pain (10%). In KEYNOTE-826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (n=307), to patients with persistent, recurrent, or first-line metastatic cervical cancer regardless of tumor PD-L1 expression who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent, fatal adverse reactions occurred in 4.6% of patients, including 3 cases of hemorrhage, 2 cases each of sepsis and due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab; those ≥3% were febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each). KEYTRUDA was discontinued in 15% of patients due to adverse reactions. The most common adverse reaction resulting in permanent discontinuation (≥1%) was colitis (1%). For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common adverse reactions (≥20%) were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea (39%), hypertension and thrombocytopenia (35% each), constipation and arthralgia (31% each), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%). For patients treated with KEYTRUDA in combination with chemotherapy with or without bevacizumab, the most common adverse reactions (≥20%) were peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension and urinary tract infection (24% each), and rash (22%). In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with previously treated recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%). In KEYNOTE-394, KEYTRUDA was discontinued due to adverse reactions in 13% of 299 patients with previously treated hepatocellular carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was ascites (2.3%). The most common adverse reactions in patients receiving KEYTRUDA (≥10%) were pyrexia (18%), rash (18%), diarrhea (16%), decreased appetite (15%), pruritis (12%), upper respiratory tract infection (11%), cough (11%), and hypothyroidism (10%). In KEYNOTE-966, when KEYTRUDA was administered in combination with gemcitabine and cisplatin, KEYTRUDA was discontinued for adverse reactions in 15% of 529 patients with locally advanced unresectable or metastatic biliary tract cancer. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was pneumonitis (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 55% of patients. The most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood cell count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary obstruction (2.3%). In KEYNOTE-017 and KEYNOTE-913, adverse reactions occurring in patients with MCC (n=105) were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent. In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%). In KEYNOTE-564, when KEYTRUDA was administered as a single agent for the adjuvant treatment of renal cell carcinoma, serious adverse reactions occurred in 20% of patients receiving KEYTRUDA; the serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% including 1 case of pneumonia. Discontinuation of KEYTRUDA due to adverse reactions occurred in 21% of 488 patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). The most common adverse reactions (≥20%) were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%), and hypothyroidism (21%). Adverse reactions occurring in patients with MSI-H or dMMR endometrial carcinoma who received KEYTRUDA as a single agent were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent. Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-522, when KEYTRUDA was administered with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent (n=778) to patients with newly diagnosed, previously untreated, high-risk early-stage TNBC, fatal adverse reactions occurred in 0.9% of patients, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA; those ≥2% were febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients due to adverse reactions. The most common reactions (≥1%) resulting in permanent discontinuation were increased ALT (2.7%), increased AST (1.5%), and rash (1%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%). In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting (n=596), fatal adverse reactions occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy; the serious reactions in ≥2% were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse reactions. The most common reactions resulting in permanent discontinuation (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%). Lactation Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the last dose. Pediatric Use In KEYNOTE-051, 173 pediatric patients (65 pediatric patients aged 6 months to younger than 12 years and 108 pediatric patients aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 25 months). Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults were pyrexia (33%), leukopenia (31%), vomiting (29%), neutropenia (28%), headache (25%), abdominal pain (23%), thrombocytopenia (22%), Grade 3 anemia (17%), decreased lymphocyte count (13%), and decreased white blood cell count (11%). Geriatric Use Of the 564 patients with locally advanced or metastatic urothelial cancer treated with KEYTRUDA in combination with enfortumab vedotin, 44% (n=247) were 65-74 years and 26% (n=144) were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years of age or older and younger patients. Patients 75 years of age or older treated with KEYTRUDA in combination with enfortumab vedotin experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 4% in patients younger than 75 and 7% in patients 75 years or older. Additional Selected KEYTRUDA Indications in the U.S. Melanoma KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma. KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB, IIC, or III melanoma following complete resection. Head and Neck Squamous Cell Cancer KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC). KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test. KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. Classical Hodgkin Lymphoma KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL). KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy. Primary Mediastinal Large B-Cell Lymphoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. Urothelial Cancer KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC). KEYTRUDA, as a single agent, is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma: who are not eligible for any platinum-containing chemotherapy, or who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. KEYTRUDA, as a single agent, is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. Microsatellite Instability-High or Mismatch Repair Deficient Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test. Gastric Cancer KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval of this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. KEYTRUDA, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. Esophageal Cancer KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either: in combination with platinum- and fluoropyrimidine-based chemotherapy, or as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test. Cervical Cancer KEYTRUDA, in combination with chemoradiotherapy (CRT), is indicated for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer. KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. Hepatocellular Carcinoma KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen. Biliary Tract Cancer KEYTRUDA, in combination with gemcitabine and cisplatin, is indicated for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer (BTC). Merkel Cell Carcinoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). Renal Cell Carcinoma KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. Endometrial Carcinoma KEYTRUDA, as a single agent, is indicated for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. Tumor Mutational Burden-High Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established. Cutaneous Squamous Cell Carcinoma KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation. Triple-Negative Breast Cancer KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test. Merck’s focus on cancer Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials . About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter) , Facebook , Instagram , YouTube and LinkedIn . Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2023 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site ( www.sec.gov ). Please see Prescribing Information for KEYTRUDA (pembrolizumab) at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf and Medication Guide for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf . Media Contacts: Julie Cunningham (617) 519-6264 Sienna Choi (908) 873-4311 Investor Contacts: Peter Dannenbaum (732) 594-1579 Damini Chokshi (732) 594-1577 Source: Merck & Co., Inc.

BEIJING--(BUSINESS WIRE)-- InnoCare Pharma (HKEX: 09969; SSE: 688428), a leading biopharmaceutical company focusing on cancer and autoimmune diseases, today announced the 2023 annual results as of 31 December 2023. Financial Highlights Revenue increased by 18.1% to RMB738.5 million in 2023, including RMB670.7 million from orelabrutinib, an increase of 18.5%, mainly due to the continuous and rapid ramp-up of orelabrutinib sales. Gross Profit increased by 26.6% to RMB610.1 million in 2023, with a gross profit margin of 82.6%, representing an increase of 5.5%, mainly due to the increase of orelabrutinib sales and the reduction in the unit cost of sales. Research and Development Expenses increased by 17.5% to 751.2 million in 2023, primarily due to heightened spending on global clinical trials that have made significant progress and strategic investments in early-stage candidates poised to become key future assets. The Loss decreased by 27.8% to RMB645.6 million. Cash and Bank Balance stood at approximately RMB8.2 billion. With this robust cash position, the Company is well-positioned to expedite the clinical development of key projects and invest in a competitive pipeline. Accelerating Pipeline Development for the Benefit of Patients In 2023, InnoCare has continued to advance its robust pipeline across various clinical stages, continuously unleashing the power of innovation to meet unmet medical needs. Orelabrutinib has become the first and only BTK inhibitor approved for the treatment of relapsed or refractory Marginal Zone Lymphoma (r/r MZL) in China, an indication which has been included in the updated 2023 National Reimbursement Drug List (NRDL) without a price cut. The Company has continuously forged ahead on the road to improving public health. Additionally, the Phase II study results of our novel TYK2 inhibitor, ICP-332, met the primary endpoints in patients with moderate-to-severe atomic dermatitis. From research, clinical development, manufacturing, commercialization, to global collaboration, InnoCare not only established an integrated platform, but also formulated a clear growth strategy aimed at benefiting patients worldwide as we embark on the Company 2.0 phase. Building A Leading Franchise in Hemato-Oncology With orelabrutinib (BTK inhibitor) serving as the backbone therapy and a key component of InnoCare’s extensive pipeline in hemato-oncology – including tafasitamab (anti-CD19 antibody), ICP-248 (BCL2 inhibitor), ICP-B02 (CD20xCD3 bispecific antibody), ICP-490 (CRBN E3 Ligase modulator), and potential future developments from internal and external sources - InnoCare strives to become a leading player in hemato-oncology both in China and worldwide. Orelabrutinib's exceptional safety and efficacy profiles promise synergistic benefits when combined with other pipeline drugs, such as ICP-248 (BCL2 inhibitor). InnoCare intends to address various segments, such as non-Hodgkin lymphoma (NHL), multiple myeloma (MM), and leukemia, utilizing both single and combination therapies. Orelabrutinib Orelabrutinib was approved for the treatment of relapsed/refractory marginal zone lymphoma (r/r MZL) in April 2023 and included in the NRDL. Orelabrutinib has thus become the first and only BTK inhibitor for r/r MZL in China, which also marks orelabrutinib’s third indication approved in China. Patient enrollment of the Phase III registrational trial of orelabrutinib for the first-line treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was completed in China in the first half of 2023. The Company expects to submit the NDA in the third quarter of 2024. In the U.S., patient enrollment of the Phase II registrational trial for relapsed/refractory mantle cell lymphoma (r/r MCL) was completed. The Company expects to submit the NDA to the U.S. Food and Drug Administration (US FDA) in the third quarter of 2024. The Company is initiating a global Phase III study of orelabrutinib for the first-line treatment of MCL. Orelabrutinib was approved by the Health Sciences Authority (HSA) of Singapore for the treatment of adult patients with r/r MCL, which marks InnoCare’s entrance onto international commercial markets. The Company expects to submit r/r MZL NDA in Singapore in 2024. The Company is initiating a Phase III MZL confirmatory study with orelabrutinib. The strategic combination of orelabrutinib with BCL2 inhibitor, ICP-248, for the first line treatment of CLL/SLL. A Phase III registrational study of orelabrutinib for the first-line treatment of MCD subtype diffuse large B-cell lymphoma (DLBCL) is ongoing in 45 sites in China. Tafasitamab Patient enrollment of the registrational trial of tafasitamab in combination with lenalidomide for the treatment of r/r DLBCL was completed in China. The Company expects to submit the biologics license application (BLA) in the second quarter of 2024 and anticipates BLA approval in the first half of 2025. Tafasitamab in combination with lenalidomide was approved by the Department of Health, the Hong Kong Special Administrative Region, China, and approved for use in Bo’ao and Greater Bay Area with first prescription issued respectively. ICP-248 The preliminary results demonstrated good safety pro achieved favorable pharmacokinetic (PK), demonstrating differentiation from other BCL2 inhibitors. So far, seventeen patients were dosed, and among six evaluated patients, the ORR was 100%, with three complete responses (CR) in which two achieved undetectable minimal residual disease (uMRD). The clinical trial approval of ICP-248 in combination with orelabrutinib as a first-line therapy for CLL/SLL in March 2024. In the U.S., the IND was cleared in January 2024. ICP-248 will become an important asset for the Company’s globalization. ICP-248 is a novel, orally bioavailable BCL2 selective inhibitor, developed as monotherapy or in combination with orelabrutinib for the treatment of CLL/SLL, MCL, AML, and other NHLs. ICP-B02 (CM355) The preliminary data of both the intravenous infusion (IV) and the subcutaneous (SC) formulations have shown good efficacy of ICP-B02 in patients with follicular lymphoma (FL) and DLBCL. All 13 patients who were treated with ICP-B02 at doses ≥6mg achieved response, resulting in an ORR of 100%. Among the nine patients who were evaluable in the SC group, seven achieved a complete response (CR), including two with DLBCL. Based on the encouraging results of ICP-B02 single agent, the Company is planning for dose expansion study of ICP-B02 in combination with other immunochemotherapies for earlier lines of treatment in NHL patients. An IND for the combination therapies has been submitted. ICP-B02 is a CD20xCD3 bispecific antibody co-developed with Keymed. ICP-490 The Phase I dose escalation study is ongoing in China with multiple myeloma (MM) patients, demonstrating a good tolerability and safety profile. Pharmacodynamic (PD) analysis showed deeper degradation of primary pharmacological targets Aiolos (IKZF3) and Ikaro (IKZF1). In September 2023, the IND was approved to conduct a clinical trial of ICP-490 in combination with dexamethasone. ICP-490 shows strong potential in hemato-oncology therapeutics as a monotherapy or in combination with others. ICP-490 was developed from InnoCare’s molecular glue platform for the treatment of MM and other hematological malignancies. ICP-B05 (CM369) The Phase I trial is ongoing, showing good tolerability with no DLT observed. The preliminary results demonstrate favorable PK pro PD biomarker, Treg depletion, was observed. Dose escalation in solid tumors has been escalated up to 150 mg, which is also the initial dose designated for NHL. Preliminary efficacy was observed in NHL. ICP-B05 is an anti-CC chemokine receptor 8 (CCR8) monoclonal antibody, a potential first-in-class drug co-developed with KeyMed as a monotherapy or in combination with other therapies for the treatment of various cancers. Developing B-cell and T-cell Pathways in Autoimmune Diseases Autoimmune diseases can affect almost every organ in the body and can occur at any age. The global market for autoimmune disease therapeutics anticipated to reach $185 billion by 20291. The Company has fortified its powerful discovery engine focusing on global frontier targets for the development of differentiated autoimmune therapeutics through B-cell and T-cell pathways, aiming to offer first-in-class or best-in-class treatments to the massive unmet medical needs with promising market potential worldwide and/or regionally. Orelabrutinib ITP: The Company has achieved proof of concept (PoC) of orelabrutinib for the treatment of primary immune thrombocytopenia purpura (ITP), with a Phase III registrational trial underway in China. The last patient is expected to be enrolled by the end of 2024. In June 2023, the ITP Phase II result was orally presented at the European Hematology Association (EHA) 2023 Hybrid Congress. The results showed that 40% of patients met primary endpoint at 50mg. 83.3% achieved durable response among patients met the primary endpoint. A subgroup analysis of patients who previously responded to glucocorticoids (GC) or intravenous immunoglobulin (IVIG) showed that 75.0% of patients at the 50mg dose achieved the primary endpoint. SLE: The Phase IIa trial for systemic lupus erythematosus (SLE) demonstrated positive results, with remarkable SLE Responder Index (SRI)-4 response rates observed in a dose dependent manner, along with trends indicating a reduction in proteinuria levels. A Phase IIb trial is ongoing, and the Company expects to complete patient enrollment by mid-2024. MS: The 24-week data of orelabrutinib from the multiple sclerosis (MS) global Phase II trial is consistent with the previous reported 12-week data in terms of both efficacy and safety. The primary endpoint was achieved dose-dependently (Cmax driven) in all three active orelabrutinib treatment groups. Notably, a 92.3% relative reduction was achieved in cumulative number of new gadolinium (Gd) + T1 lesions at week 24 at 80mg QD compared to placebo arm (which switched to orelabrutinib 50mg QD after Week 12). This reduction stands out as a leading indicator of efficacy when compared to other MS therapies that are approved or in developmental stages. All orelabrutinib groups achieved T1 new lesion control after 4 weeks of treatment, with effects sustained through 24 weeks. The 80 mg QD cohort showed the highest reduction rate of cumulative number of new lesions Gd+T1 lesions and the best for lesion control throughout 24 weeks, with the best safety profile, indicating orelabrutinib’s potential as a leading MS treatment. NMOSD: The Phase II clinical trial for the treatment of neuromyelitis optica spectrum disorder (NMOSD) is ongoing in China. ICP-332 The latest data of ICP-332 for the treatment of patients with moderate-to-severe atopic dermatitis (AD) has been released at the 2024 American Academy of Dermatology (AAD) Annual Meeting as a late-breaking oral presentation. ICP-332 demonstrated an outstanding efficacy and safety profile. ICP-332 achieved multiple efficacy endpoints in the 80 mg QD and 120 mg QD dosing groups respectively, including the percentage change in Eczema Area and Severity Index (EASI) score from baseline, EASI 50, EASI 75, EASI 90 (improvement of at least 50%, 75% and 90% in EASI score from baseline), Investigator’s Global Assessment (IGA) 0/1 (score of 0 ‘clear’ or 1 ‘almost clear’) with >= 2 points improvement, and Pruritus Numerical Rating Scale (NRS) score from baseline, etc. The mean percentage change from baseline of the EASI score reached 78.2% and 72.5% at the 80 mg QD and 120 mg QD groups respectively, both with a highly significant P value (p<0.0001), compared to 16.7% for the patients receiving placebo. The percentages of patients achieving at least 75% improvement in EASI 75 were significantly higher in the ICP-332 80 mg QD (64.0%, p<0.0001) and 120 mg QD (64.0%, p<0.0001) groups than that of placebo (8.0%), which are better than the reported efficacies of multiple approved innovative drugs treated for 12 weeks or 16 weeks (not a head-to-head comparison). In the ICP-332 80 mg QD group, the response rates of EASI 90 and IGA 0/1 with >=2 points from baseline demonstrated a 40.0% (P=0.0009) and 32.0% (P=0.0047) improvement respectively compared with the placebo group. ICP-332 was safe and well tolerated in AD patients. The overall incidence rates of adverse events (AEs) and AEs related to infections and infestations in the two treatment groups were comparable to that of the placebo group. The Company expects to start the patient enrollment of the Phase III trial for AD in China, initiate US trials, and initiate a Phase II trial for a second indication of vitiligo in 2024. ICP-332 is a novel tyrosine kinase 2 (TYK2) inhibitor that is being developed for the treatment of various T-cell related autoimmune disorders. ICP-488 The Phase I trial has been completed, with preliminary efficacy assessed in psoriasis patients. The least-squares mean percentage change from baseline in the Psoriasis Area and Severity Index (PASI) score indicated preliminary significantly difference between the ICP-488 6 mg once-daily dosing group and placebo group at week 4 (38% vs 14%, p=0.0870). PASI 50 assessments demonstrated a 42% improvement with treatment of ICP-488 at 6 mg QD. Following single ascending doses (1mg to 36mg) and multiple ascending doses (3mg -12mg) once daily, ICP-488 plasma exposures were dose proportional. No significant food effect was observed following co-administration with standard high-fat, high-calorie meals. ICP-488 demonstrated good tolerability and safety. The TRAE rate was the same between the ICP-488 arm and placebo arm. The Phase II study of psoriasis is ongoing, InnoCare targets to finish the patient enrollment in the first half of 2024. ICP-488 is a potent and selective TYK2 allosteric inhibitor that binds to the pseudo kinase JH2 domain of TYK2 and blocks IL-23, IL12, type 1 IFN, and other cytokine receptors. ICP-B02 (CM355) ICP-B02 (SC & IV) induced a profound and sustained depletion of peripheral B- cells after first infusion in Phase I/II clinical trial in r/r NHL patients. Given the critical role of B-cells in a variety of severe autoimmune diseases, ICP-B02 may have wider applications in severe autoimmune diseases. ICP-923 (New Target) IL-17 is a pro-inflammatory cytokine that plays an important role in immune functional responses. Orally administered small molecules targeting IL-17 may represent a convenient alternative to IL-17-targeting monoclonal antibodies for patients. This novel orally available small molecule can potently block the binding of both IL-17AA and IL-17AF to IL-17R. Building Innovative Solid Tumor Assets InnoCare strives to expand the breadth of its pipeline to cover solid tumor diseases areas through a combination of targeted therapy and immune-oncology approaches. The Company believes that potential best-in-class molecule, zurletrectinib (ICP-723), will enable InnoCare to establish a solid footprint in the field of solid tumor treatment. To benefit a broader range of patients, InnoCare’s rapidly maturing early-stage pipeline, including the cornerstone therapy ICP-192, ICP-189 and ICP-B05 immune-oncology treatment, aims to offer competitive treatment solutions for a large array of solid tumors, both in China and worldwide. Zurletrectinib (ICP-723) InnoCare is accelerating the registrational trial of zurletrectinib in China. The NDA is expected to be submitted by the end of 2024. An outstanding efficacy of 80-90% ORR was observed in adult patients with various cancers carrying NTRK gene fusion who received ≥8 mg dosages. Zurletrectinib was shown to overcome acquired resistance to the first generation TRK inhibitors, bringing hope for patients who failed prior TRKi therapy. The Company is conducting a clinical trial of zurletrectinib for pediatric (2 to 12 years old) and adolescent patients (12 to 18 years old). Patient enrollment of pediatric patients is ongoing, with PR observed. ICP-189 InnoCare and ArriVent reached a clinical development collaboration to evaluate the anti-tumor activity and safety of the combination of InnoCare’s novel SHP2 allosteric inhibitor, ICP-189, with ArriVent’s third generation EGFR inhibitor furmonertinib in patients with advanced non-small cell lung cancer (NSCLC). Currently, the combo study is underway. NSCLC is the predominant subtype of lung cancer, accounting for approximately 85% of all cases2. The novel SHP2 allosteric inhibitor, ICP-189, is being developed for the treatment of solid tumors as a single agent and/or in combination with other antitumor agents. Preliminary efficacy was observed in ICP-189 monotherapy. As of this announcement, the dosage has been escalated up to 120 mg with no DLT observed, and it has shown a favorable PK pro a long half-life. The patient enrollment at 160mg QD is ongoing. As a potential first-in-class SHP2 inhibitor, ICP-189 is an ideal partner for combination with multiple targeted and immune-oncology therapies in solid tumors. ICP-189 has demonstrated significant anti-tumor effect in tumor models driven by KRASG12C mutation and EGFR over-expression. Gunagratinib (ICP-192) The latest data of gunagratinib in patients with cholangiocarcinoma (CCA) was presented at 2023 ASCO-GI3. Gunagratinib showed good efficacy and safety in previously treated patients with locally advanced or metastatic CCA harboring FGR2 gene fusions or rearrangements. Other Corporate Development InnoCare appointed Xin Fu and Jeff Chen as Chief Financial Officer and Chief Commercial Officer respectively. InnoCare was approved by the Hong Kong Stock Exchange to remove "B" from the stock code from May 12, 2023. This is another important milestone in the Company's development. Following the approval for commercial production, InnoCare Guangzhou quickly launched the manufacturing of orelabrutinib, which is now available to patients in China. This achievement allows InnoCare to cover the entire industry chain from in-house research and development to production. Dr. Jasmine Cui, the Co-founder, Chairwoman and CEO of InnoCare, said, "We must maintain the entrepreneurial spirit and persist in continuous innovation, focusing on key objectives with high quality growth, so as to make our contributions to patients, partners, and the broader biopharmaceutical industry. We’re committed to deepening our focus on original innovation, pushing forward multiple innovative molecules to further strengthen our pipeline; we will accelerate the registrational trials both in China and worldwide, aiming to submit multiple NDAs; we will increase market penetration to achieve our long-term strategy and realize significant sales increases; we will amplify our global presence and push more projects to reach international markets.” To know more about the detailed financial data and business updates of InnoCare 2023 annual results, please log in to . Conference Call Information InnoCare will host a conference call at 8:30 p.m. Beijing time on March 28 in English and at 9:30 p.m. Beijing time in Chinese on March 29, 2024. Participants must register in advance of the conference call. Details are as follows: For English conference call, please register through the below link: For Chinese conference call, please register through the below link: Forward-looking Statement This report contains the disclosure of some forward-looking statements. Except for statements of facts, all other statements can be regarded as forward-looking statements, that is, about our or our management's intentions, plans, beliefs, or expectations that will or may occur in the future. Such statements are assumptions and estimates made by our management based on its experience and knowledge of historical trends, current conditions, expected future development and other related factors. This forward-looking statement does not guarantee future performance, and actual results, development and business decisions may not match the expectations of the forward-looking statement. Our forward-looking statements are also subject to a large number of risks and uncertainties, which may affect our short-term and long-term performance. About InnoCare InnoCare (HKEX: 09969; SSE: 688428) is a commercial stage biopharmaceutical company committed to discovering, developing, and commercializing first-in-class and/or best-in-class drugs for the treatment of cancer and autoimmune diseases with unmet medical needs in China and worldwide. InnoCare has branches in Beijing, Nanjing, Shanghai, Guangzhou, Hong Kong, and United States. ___________________________________ 1 iHealthcareAnalyst, Inc., Oct. 3, 2023 2 Cancer-free 3 2023 ASCO GI Abstract