MK-1084

2025年10月10日，古都南京迎来一场承载全球医药行业绿色转型使命的盛会——“第二届药石科技绿色化学论坛”盛大启幕，海内外的100余位嘉宾齐聚一堂。这场由药石科技主办的全球级交流平台，是对全球医药可持续发展时代命题的深度回应：首届论坛于美国药石播下绿色化学的跨洋火种，本届则回归药石科技南京总部，这一从海外启幕到本土深耕的战略流转，既是绿色化学理念在全球版图上的扎根延展，更是中国企业以技术实力与行业担当，推动全球医药绿色共识从理念共鸣走向实践协同的重要坐标。 药石科技研发总监王苑先博士作为第二届绿色化学论坛主持人，率先开场。他提到当前医药产业正加速绿色化、低碳化转型，而绿色化学正是这一转型中的行业发展关键，本届论坛将聚焦绿色化学新理念、新技术与新应用，随后预告药石科技创始人杨民民博士与中科院院士郭子建教授将相继登台致辞。 领导致辞 药石科技创始人、董事长兼首席执行官杨民民博士，向现场齐聚的全球学术界专家、企业界伙伴及行业同仁，致以诚挚敬意。他深刻表示，创新是贯穿药石科技十余年发展历程的核心脉络，且围绕产业核心环节，已走出两段具有行业突破性的创新实践。第一段创新实践聚焦药物发现的效率瓶颈，药石科技自创业初期便系统设计、研发出成千上万种新颖分子砌块，为客户研发项目注入生机，如今更迈向创新2.0阶段，计划依托AI技术从蛋白靶点阶段直接锁定候选分子，进一步缩短临床候选药物的发现周期，让药物研发更具精准性与高效性。第二段创新实践则直面传统制药的行业矛盾，持续探索更安全、更环保且更低碳的药品放大生产路径，力求实现制药守护健康与生产守护环境的双向统一。杨民民博士表达绿色制药的突破离不开跨领域知识的融合与多方力量的协作，这正是举办本次论坛的核心初衷——通过汇聚科研界、企业界和客户的智慧，共同探讨药品研发生产的绿色化、高效化路径，为医药产业全链条绿色变革凝聚共识、探索方向。 中国科学院院士、南京大学教授郭子建院士受邀致辞，首先祝贺药石科技的绿色化学实践成果，肯定其作为国际化CDMO企业，凭连续流工艺等技术创新连续斩获美国化学协会CMO绿色化学卓越奖，切实践行化学提供解决方案的理念。郭子建院士强调，绿色化学的核心是以少求多的产业革命，即凭更少资源实现更高价值、减少污染浪费，其领域每一项突破，都在拉近人类与可持续世界的距离。他进一步表示，本次论坛汇聚多国顶尖研究者、业界先驱与青年学者，将集中分享绿色化学最新成果，为药物研发减少环境影响，促跨学科协作提供平台。他坚信论坛能进一步强化学术界与产业界联结，为全球医药行业可持续发展贡献力量。 篇章一·绿色化学实践 01 Complex Target-Oriented Synthesis as an Engine for Discovery Chemistry 美国国家科学院院士、美国艺术与科学院院士、苏黎世联邦理工学院教授、《美国化学会志》(JACS) 主编Erick M. Carreira博士，围绕反应发现与可持续合成展开分享。 Erick M. Carreira博士秉持“Less is more”的简洁性反应设计理念，该理念贯穿于烯烃官能团化与不对称烯丙基化的反应开发中，过程中摒弃复杂配体，仅通过简单光敏剂、催化剂及添加剂构建高效反应体系，同时强调机理分析对反应发现的关键支撑作用，在简化操作流程的同时降低实验成本。此外其团队实现光HAT化学领域的创新应用拓展——成功开发光环异构化等新型反应，这些反应可适配单取代、多取代乃至复杂烯烃，还能直接用于合成含邻位季碳中心的系列天然产物。 在不对称催化体系领域，重点优化钌催化烯丙基化体系，通过改良苯氧基恶唑啉、苯氧基噻唑啉等配体，实现反应的高收率、高对映选择性与高区域选择性，且能以aqueous ammonia这类具有挑战性的亲核试剂完成烯丙基胺化，兼容脂肪胺、苄胺及药物/天然产物衍生物的反应需求，还可高效合成γ-内酰胺、α-甲基氨基酸衍生物等重要中间体。 最后，为推动可持续合成实践整合，团队创新性地将生命周期评估（LCA）融入复杂分子合成过程，以抗病毒药物来特莫韦为案例，通过多轮LCA迭代分析对比不同合成路线，显著降低全球变暖潜能值、生态系统影响等环境负担，并提出借助逆合成填补数据缺口的方法，为绿色化学导向的复杂分子合成提供了可落地的实践路径。 02 Sample-then-Select Strategy for Site-Precise C−H Transformation 北京大学特聘研究员许言博士聚焦传统C−H转化领域的核心痛点——惰性C−H键数量多、反应性低且难以区分，导致位点选择性普遍受限，而经典动力学框架依赖位点选择性C−H断裂步骤的局限，提出了“先取样后筛选”（Sample-then-Select）的创新策略。 该策略受Curtin-Hammett原理启发，打破传统机制束缚：首先通过非位点选择性的C−H断裂生成多种C−H断裂中间体，再引入速率可调的C−H重组步骤与位点敏感的中间体转化步骤，将选择性决定步骤从C−H断裂转移至中间体转化，最终实现单一目标产物的高效生成。 许言博士还展示了该策略的实践成果：已成功应用于未活化C−H键的直接CN转移、硼基转移、酰基转移及C−H环化等反应，并将其应用于40余项实例中，位点选择性均>20:1，展现出不受其他活化C−H键干扰、1,4 -转移选择性稳定等独特优势；同时，该策略可简化分子合成流程，例如将雌激素受体激动剂关键中间体合成步骤优化等实际应用中，实现3D酮类化合物的直接骨架编辑，相关成果发表于Nature，并获Chem Catal.和2023年国家自然科学基金年报重点关注，为新型位点选择性C−H转化反应设计提供了全新思路，助力分子合成与修饰向更高效、精准的方向发展。 篇章二·前沿技术探索 01 Radical Ideas: The Origins and Evolution of Visible-Light Photocatalysis 不列颠哥伦比亚大学Corey Stephenson教授分享团队的可见光光催化研究工作。2007年他与同事开展自由基开环反应合成项目，早期探索马来酸衍生物传统合成，后在液氮真空阱发现胺类兼具电子供体与氢供体双功能，进而开发活化与非活化烯烃催化氢化方法。团队不断推进光催化设备发展并强调高强度光源防护，针对光催化放大难题，指出传统光源光穿透不足致大型容器反应耗时，通过小管径连续流反应器解决，并与礼来公司合作建成反应器，实现公斤级自由基三氟甲基化，分离收率可达60-65%，破解有机合成放大难题。 此外Corey Stephenson教授团队开发自动化反应筛选分析系统，以石英管实现纳米液滴多组分反应组装，结合低成本机器人将产物注入质谱分析，该系统还用于动力学研究，为反应建模与停留时间优化提供依据。 该团队与企业合作优化ORL-1拮抗剂中间体合成路线，解决原料昂贵等问题，开发形成C-C键关键反应；后期聚焦亚磺酰胺自由基生成，通过调控反应极性、多循环质子转移拓展底物范围，计算发现亚磺酰胺S/N反应性能量差异以实现高对映选择性，观察到酰胺与亚磺酰亚胺形成的黄色卤键复合物，验证其对光反应效率无显著影响，同时通过量子化学计算过渡态、研究Wolf重排构型保持完善反应机理。基础研究方面，团队早期建立光氧化还原催化作为形成有机自由基的通用方法，推动光化学获有机化学界认可，多项成果发表于Angew. Chem.、J. Am. Chem. Soc.、Nat. Commun.等期刊。 02 Pursuing Greener Process--- Innovation Driven by Enzyme Catalysis 勃林格殷格翰（Boehringer Ingelheim）工艺开发经理肖青博士，介绍酶作为自然最佳催化剂在医药等领域的应用，同时指出天然酶稳定性与催化效率低、依赖辅酶等局限，而工业需酶具备长期活性、适应多环境等特性。勃林格殷格翰设有生物催化枢纽及多地区化学开发团队，分别负责早中期项目筛选、后期转移与生产支持，聚焦绿色工艺与减少合成步骤。酶应用遵循筛选初始酶—酶工程改造—反应优化—供应保障的流程，重点以COBE转化为 (S)-CHBE 为例详细阐述其团队解决方案。最后总结酶工程关键步骤，并提及未来将借AI工具辅助酶发现，推动绿色工艺发展。 03 Repurposing Thiamine-dependent Enzymes Using Radicals 南京大学特聘研究员黄小强博士聚焦硫胺素依赖酶（ThDP依赖酶）的功能重构，旨在通过自由基化学与生物催化的交叉融合，解决传统酶催化中光酶种类有限、化学催化中自由基不对称控制难的核心痛点。 其团队以酶的非天然反应性开发为核心，通过光/电化学调控与酶工程改造双轮驱动：一方面借助光催化或电催化，打破硫胺素依赖酶天然的双电子反应机制，构建光/电驱动的单电子自由基反应体系；另一方面通过酶库筛选与定点突变技术，优化酶的活性与选择性，成功实现醛类底物的不对称自由基反应，后续进一步拓展至C-H键活化、三组分偶联、1,n -自由基转移等反应场景，部分反应收率可达59%-92%范围区间，对映体过量值（ee）最高达99%。 此外，团队还解决电酶合成中的酶稳定性、异相电子转移等兼容性问题，在1mmol 规模反应中实现55%-58% 收率与94% ee值，相关机制通过EPR实验验证为自由基-自由基交叉偶联。这些成果已发表于Nature、Nat. Synth.和JACS等期刊，不仅为硫胺素依赖酶赋予全新自由基催化功能，更搭建了生物催化与化学催化的协同桥梁，为绿色化学领域的非天然不对称转化提供了创新解决方案。 04 Automated Carcinogenic Potency Categorization Tool Assisted Assessment for Nitrosamine Drug Substance-related Impurities in API Development 百济神州首席科学家屈阳博士围绕API研发中亚硝胺类药物相关杂质（NDSRIs）的自动化致癌效力分类工具辅助评估展开分享。 他明确亚硝胺类化合物的风险属性——作为强遗传毒性物质，被ICH M7指南列为关注群组，同时提及FDA 2020年《人用药品中亚硝胺杂质的控制》与 2023 年《NDSRIs的推荐可接受摄入量限值》指南的相关要求；屈阳博士接着详细解读致癌效力分类方法（CPCA），并重点介绍自动化CPCA工具的功能与优势，用户可输入SMILES字符串或使用结构编辑器，工具无需人工干预即可自动检查亚硝胺结构、α-碳氢原子数量，并计算效力分数及对应类别，支持一键分类与批量评估。工具验证显示，247个受检案例中245个符合FDA推荐的AI限值与类别对应关系，准确性较高；最后，提及ICH M7关于亚硝胺杂质风险评估与控制的补充计划，指出该自动化工具可为API研发中NDSRIs的评估提供高效准确支持，助力企业符合监管要求。 篇章三·低碳与可持续战略 01 PharmaBlock's Green Chemistry Journey 药石科技高级副总裁、美国药石总经理李静博士，以近10年见证企业成长的深度视角，结合全球医药产业绿色转型背景，系统阐述药石科技从绿色化学理念生根到技术创新引领的完整发展旅程，展现中国医药CDMO企业以化学创新驱动行业可持续发展的实践路径与责任担当。 药石科技自2008年成立以来，从新颖分子砌块与定制合成业务起步，伴随全球医药行业对大规模、高稳定性中间体及API的需求升级，以及客户端与各国政府日益严格的EHS合规要求，逐步完成战略转型，将CDMO业务确立为关键业务。 在绿色化学实践层面，药石科技于2016年正式引入绿色化学原则并以PMI为核心评估指标，逐步构建起连续流化学、金属催化、生物催化、微填充床技术协同发力的一体化绿色技术平台——流动化学领域已迭代至研发出商用级自动化连续流反应器并应用于超500个项目；微填充床技术覆盖公斤至吨级商业化及GMP项目，实现高效绿色生产。 作为ACS绿色化学研究所制药圆桌会议供应链团队活跃成员，药石科技更将自身实践延伸至行业生态构建，积极推动原材料供应商绿色创新，从企业技术实践升级为行业绿色转型的推动者，为全球医药产业绿色化发展提供兼具技术可行性与商业价值的中国实践范式。 02 Building a More Sustainable Future for People, Society and the Planet AstraZeneca（阿斯利康）前副总裁David Ennis博士，围绕阿斯利康可持续发展战略展开分享，详细介绍阿斯利康2024年的可持续发展框架，通过重要性评估识别对企业和利益相关方最关键的可持续议题，以“零碳愿景”（Ambition Zero Carbon）为核心支撑，明确三大目标方向：加速净零医疗体系建设、主动管理环境影响、投资自然与生物多样性。 为推进 “零碳愿景”，阿斯利康与可再生能源供应商合作；推行产品可持续性指数（PSI）评估产品环境影响并指导改进，优化小分子、单克隆抗体产品的原料药/药物活性成分生产工艺资源效率，重新设计包装提升可持续性。同时采用生命周期评估（LCA）覆盖产品全生命周期，量化环境影响以支撑PSI和Scope 3报告，结果显示小分子口服固体制剂（OSD）气候变化影响主要来自原料药生产，生物制剂（mAb）主要来自BDS生产阶段；针对两类产品，提出绿色化学、下一代制造、供应商可再生能源、海运替代空运、运输高浓度原料药、减少合成步骤等减排行动。此外，阿斯利康在自然资源管理上聚焦降影响、投自然、循环商业模式、提效率、负责任采购；循环经济实践中，将循环原则融入产品与流程设计，减少材料消耗与废物产生，通过指标监测进展，提升废物回收率、消除填埋废物，增加材料复用与回收含量，优先再生自然并以可再生资源替代不可再生资源。 03 Managing Product Carbon Footprints in API Manufacturing / Pharma R&D Merck KGaA（默克集团）可持续发展评估全球负责人Benjamin Kuehne博士，围绕API生产与制药研发中的产品碳足迹（PCF）管理展开分享。他首先介绍默克的可持续发展承诺，提及公司聚焦创新技术可持续性、可持续供应链，高度关注联合国可持续发展目标（SDGs）落地；指出化学制造的气候变化影响是行业长期关注点，PCF是衡量化学品环境影响的关键指标，默克已通过多年行业合作推动PCF管理技术与标准完善。 随后Benjamin Kuehne博士详解默克PCF管理路径，研发阶段用GreenSpeed构建API前体生命周期清单、核查原材料环境足迹数据并结合ELN数据做工艺评估，商业产品阶段用AllocNow实现规模化PCF核算与管理。最后他提及行业对API前体原材料环境足迹信息需求持续增长，除温室气体排放外，水资源消耗、酸化等环境影响也受关注；Pharma LCA联盟在PEG和SMI支持下，正开发2025年制药产品类别规则PAS2090以建立统一药物LCA标准，后续将通过共享建模原则、开展供应链LCA教育，推动行业数据共享与能力提升，助力医药产业可持续发展。 篇章四·行业应用实践 01 Development of a Scalable Process for an Atropisomeric API RayThera化学工艺研发高级总监Michal Achmatowicz博士，分享了其曾就职于Mirati Therapeutics期间参与的KRAS G12C抑制剂MRTX1719的工艺放大开发工作。该项目的核心难点集中在关键中间体——蝶形双环吡咯烷醇结构单元的合成上，不仅存在立体选择性控制难的问题，还面临反应路径长的工艺瓶颈。 为攻克这些难题，药石科技与Mirati项目团队紧密协作，开发出创新不对称合成方法：通过4-氯苯甲酰氯去对称化策略，将原始路线优化为7步反应，同时借助镁基试剂实现选择性金属化，并在反应后期引入环丙基醚片段降低原料成本，最终成功实现公斤级别生产。该工艺路线不仅将总收率提升至40%以上，更通过创新SPACE技术，从外消旋游离碱中制备出BDP盐，手性控制达到优异水平，相关成果已发表于国际知名期刊《Organic Process Research & Development》。 02 Green through Innovation: Novel Asymmetric Synthesis of KRAS G12C Inhibitor MK-1084 via Crystallization-induced Diastereomer Transformations (CIDT) MSD首席科学家Hongming Li博士围绕工艺质量指数（PMI）及KRAS G12C抑制剂MK-1084的不对称合成工艺开发展开演讲。理想反应的PMI为1.0，而制药领域API合成的PMI普遍偏高。MK-1084作为强效且选择性的共价KRAS G12C-GDP抑制剂，目前处于III期临床阶段，可联合KEYTRUDA用于治疗转移性非小细胞肺癌，其工艺开发初期面临手性N-C阻转异构体构建的核心难题——初期尝试的不对称C-N偶联与盐拆分均未获得可行结果。 为攻克该难题，团队采用结晶诱导非对映异构体转化（CIDT）策略，选用成本低且易获取的二苯甲酰-D-酒石酸，在DME/庚烷溶剂体系中实现了99% ee的产物，且上清液中残留低于0.5%；同时开发一锅法CIDT/羰基化工艺，优化环化条件后，使LCAP（液相色谱纯度）达95%，有效规避了产物消旋的风险。此外，团队还改进了片段21的合成工艺，用KOH水溶液替代原工艺中的过氧化氢、腐蚀性条件及叔丁醇，成功实现几十公斤规模生产，收率达85%。 最终确立的MK-1084反应路线，PMI降至176，较初始阶段大幅降低92%，同时实现71%的成本节省，该反应路线中PMI的构成中溶剂占67%、水占27%、其他成分占6%。 篇章五·深度对话 药石科技CMC专家江虹博士主持本轮深度对话环节，现场邀请的参与嘉宾包括劲方医药首席技术官李景荣博士、Novartis（苏州诺华）Associate Director 李威博士、阿斯利康前副总裁 David Ennis博士、药石科技副总裁兼CDMO负责人陈志华博士。 开场后，江虹博士首先抛出核心问题，提问各位嘉宾如何看待绿色化学供应链中的要求、评价标准，以及CDMO供应商需提升的方向。李景荣博士从创新药企视角出发，强调质量合规是供应链管理的首要责任，在API与中间体质量达标的前提下，需通过绿色技术优化成本；他同时提及绿色化学对员工安全与环境的积极意义，举例说明与CDMO合作时，借助酶催化技术解决消旋体拆分问题，避免外消旋体拆分导致的产物损失，既提升原子经济性，也间接助力成本控制。随后李威博士详细介绍诺华的可持续发展目标，包括推进碳中和与温室气体减排，且诺华2022年便已将可持续标准纳入供应商合同，计划年底覆盖所有相关供应商；他提到公司要求供应商加入科学碳倡议、设定科学碳目标，减少污染物排放并优先使用环保材料，同时希望CDMO供应商能依据药物开发不同阶段需求（临床早期优先速度与工艺安全、晚期聚焦商业化路线合规），在连续流化学、酶催化、光催化等绿色技术领域承接需求，此外还建议CDMO加强对欧美环保法规的追踪，例如关注DCM的分类审议进展。David Ennis博士则补充说明，2023年可持续市场倡议框架下，阿斯利康、诺华等多家药企联合制定了供应商最低目标，核心涵盖2025年前公开披露排放量并承诺科学碳目标、设定废物减少与材料复用目标，2030年前实现生产基地至少80%可再生能源供应；他提到这些目标需由供应商传导至上游二级/三级供应商，阿斯利康已明确新供应商需符合该承诺，同时指出供应链中环保认知与教育需逐步渗透，才能推动全价值链绿色转型。 在各位嘉宾分享完企业端的供应链要求后，江虹博士进一步提出关于药石科技在构建绿色化学供应链中的定位和发展问题。陈志华博士回应称，药石科技定位为全球医药开发与制造领域的创新技术平台，依托分子砌块设计、合成化学、低碳绿色化学技术优势，计划将业务拓展至新材料、新能源、绿色农业等领域，最终构建跨行业绿色化学技术驱动的生态体系；他分享两个实战案例具体说明，强调药石并非被动响应下游客户的绿色需求，而是主动以分子砌块、连续流、固定床加氢等核心技术，从药物合成源头提供更高效、更绿色的解决方案，其他嘉宾也对药石的绿色实践给予积极点评。 篇章六·生态伙伴分享 01 End-to-end Real-time Data-driven Automation and Intelligentization of Process Development 梅特勒托利多自动化化学部产品主管张瑞博士详细介绍了梅特勒构建端到端数据驱动的工艺开发平台，该平台整合自动化反应工作站、PAT传感器（如 ReactIR、ParticleTrack）与模拟软件（Dynochem），通过实时采集反应浓度、粒径等关键数据，为工艺优化与放大提供精准支撑；不仅能指导结晶工艺的开发与规模放大，还曾助力辉瑞Paxlovid、默克等企业的工艺开发，同时为FDA结晶过程质量风险控制提供技术支持，此外其DirectInject-LC技术可自动化完成多相体系取样与分析，进一步强化对工艺的深度理解。 02 Raman PAT Empowers Biopharmaceutical Quality Improvement and Efficiency Enhancement 赛默飞光谱应用专家刘俊博士分享介绍赛默飞基于拉曼散射原理推出的过程拉曼分析技术。这项技术可广泛应用于化药与生物制药生产监测：在化药领域，能实时监测API合成趋势与反应终点、追踪结晶过程与晶型变化，还可精准检测物料混合均匀性；在生物制药领域，结合配套软件能实现CHO细胞培养中葡萄糖浓度的实时闭环补料控制，全程无需人工干预，有效提升生产效率与质量稳定性。 结束语 本次论坛以绿色化学的新理念、新技术、新应用为核心锚点：一方面立足绿色化学12原则这一行业公认基石，深入探寻如何从药物研发的路线设计、工艺开发源头优化原子经济性，削减物耗与能耗，构筑更安全、更高效的生产体系；另一方面紧扣全球碳中和目标与技术革命浪潮，将产品碳足迹核算与管理纳入关键议题，探索人工智能、数智化技术等颠覆性力量为绿色化学注入的新动能，同时聚焦光催化、酶催化、智能工艺开发等前沿技术的产业转化，力求以科学为基、以技术为翼，推动医药行业实现贯穿全球供应链的深度绿色变革。 作为论坛主办者，药石科技的深耕笃行与行业积淀，为这场全球盛会提供了坚实支撑。自 2008年运营以来，药石科技的发展历程清晰展现其对绿色化学和低碳技术的持续深耕：从首创分子砌块概念、为全球新药研发贡献海量新颖分子砌块、助力客户加速临床药物分子发现，到近年顺应全球碳排放与环境可持续性关注升级，将战略重心拓展至绿色与低碳技术的研究与转化——逐步成长为新技术CDMO的坚定实践者、ESG浪潮的积极引领者，最终成为创新药物的新一代赋能者。 南京药石科技股份有限公司（股票代码：300725，公司简称：药石科技）是全球医药研发和制造领域创新化学产品和服务供应商。公司始终致力于通过研发和生产过程中的化学和低碳技术的创新，帮助合作伙伴提高新药发现及开发效率，确保产品质量的稳定，持续降低研发和生产成本，并积极推动行业的绿色、可持续发展。 自2008年投入运营以来，药石科技已成功与全球几乎所有排名前二十的制药公司及数千家中小型生物技术公司达成合作。药石科技的业务源自其新颖、独特且具有前瞻性的分子砌块，这些分子砌块对药物发现的推进起到关键作用；随着运用这些分子砌块的候选化合物进入临床开发和商业化阶段，药石科技成功开发了数千种分子砌块产品的放大工艺，并实现规模化生产，从而帮助客户迅速推进药物开发项目。凭借在分子砌块领域的深厚积累、客户的高度信赖，以及上游原料供应和化学经验等独特优势，药石科技不断拓展业务领域，为药物发现提供化学研发服务，为临床前、临床开发和商业化项目提供高效、高品质的中间体、原料药和药物制剂的工艺开发和生产服务。同时，公司整合多年来在连续流化学、微填充床技术、催化技术、智能制造等前沿技术上的能力积累，积极探索生物医药领域绿色、安全和智能化的先进制造及服务模式，促进行业创新发展。 欢迎点击阅读原文，了解药石科技！

RAHWAY, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced new research from more than 100 abstracts across more than 20 types of cancer and multiple treatment settings from the company’s broad and differentiated portfolio and pipeline will be presented at the European Society for Medical Oncology (ESMO) Congress 2025 in Berlin, Germany, from Oct. 17-21. These data showcase Merck’s commitment to rapidly advancing research across multiple tumor types to help improve outcomes for patients across stages of cancer. “Our data at ESMO this year affirm the continued impact and potential of KEYTRUDA in certain types of cancer and serve as a testament to the progress we’re making in our rapidly advancing pipeline with several notable presentations of data for our investigational antibody-drug conjugates,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “We are particularly proud that at this year’s ESMO, research evaluating our oncology medicines in certain bladder, ovarian and lung cancers was selected for discussion during three Presidential Symposium presentations.” Presentations at the Congress will feature new or updated findings from Merck’s broad portfolio of cancer medicines, including data for KEYTRUDA® (pembrolizumab); LENVIMA® (lenvatinib), in collaboration with Eisai; WELIREG® (belzutifan); and KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph). Key data being presented on existing medicines in Merck’s portfolio: First-time data from the Phase 3 KEYNOTE-905/EV-303 study evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, plus Padcev (enfortumab vedotin-ejfv) as a treatment for patients with cisplatin-ineligible muscle-invasive bladder cancer when given before and after surgery (Presentation #LBA2, Proffered paper session: Presidential Symposium I), which will be featured in an ESMO Presidential Symposium. 1 First-time data from the Phase 3 KEYNOTE-B96 study evaluating KEYTRUDA in combination with chemotherapy (paclitaxel) with or without bevacizumab as a treatment for patients with platinum-resistant recurrent ovarian cancer (Presentation #LBA3, Proffered paper session: Presidential Symposium I), which will be featured in an ESMO Presidential Symposium. 2 Five-year exploratory follow-up data from the Phase 3 KEYNOTE-775/Study 309 trial evaluating KEYTRUDA plus LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor (TKI) discovered by Eisai, as a treatment for certain patients with advanced endometrial cancer (Presentation #1119P, Poster session: Gynaecological cancers). 3 Ten-year and eight-year exploratory follow-up data from multiple clinical trials evaluating KEYTRUDA monotherapy for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) (Presentation #3208P, Poster session: NSCLC, metastatic). Five-year exploratory follow-up results from the Phase 3 KEYNOTE-671 trial evaluating KEYTRUDA in the perioperative setting (neoadjuvant KEYTRUDA plus chemotherapy followed by resection and adjuvant KEYTRUDA as a single agent) for early-stage NSCLC (Presentation #LBA67, Mini oral session 2: Non-metastatic NSCLC). First presentation of results from cohort A1 of the Phase 2 LITESPARK-015 trial evaluating WELIREG, Merck’s oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, as a treatment for patients with advanced pheochromocytoma and paraganglioma (PPGL) (Presentation #1705O, Proffered paper session: NETs and endocrine tumours). Patient-reported preference outcomes from the Phase 2 MK-3475A-F11 trial evaluating patient preference for KEYTRUDA QLEX™ injection for subcutaneous use versus intravenous KEYTRUDA across multiple tumor types (Presentation #3145P, Poster session: General interest). Additionally, new data for investigational antibody-drug conjugates (ADCs) from Merck’s innovative pipeline will be presented at the Congress, including data for raludotatug deruxtecan (R-DXd), a CDH6 directed DXd ADC, and ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, both discovered by Daiichi Sankyo. Notably, research evaluating sacituzumab tirumotecan (sac-TMT), a TROP2-directed ADC being developed in collaboration with Kelun-Biotech will be shared in four presentations in certain patients with lung, breast, cervical and prostate cancer. Key data being presented on investigational candidates from Merck’s pipeline: Findings from the Phase 2 (dose optimization) part of the Phase 2/3 REJOICE-Ovarian01 trial evaluating R-DXd for patients with platinum-resistant, high-grade ovarian, primary peritoneal or fallopian tube cancer (Presentation #LBA42, Proffered paper session: Gynaecological cancers). 4 Results from the Phase 2 IDeate-Lung01 trial, led by Daiichi Sankyo, evaluating I-DXd for patients with pretreated extensive-stage small cell lung cancer and baseline brain metastases (Presentation #2760MO, Mini oral session 1: Non-metastatic NSCLC). 4 Data from the Phase 3 OptiTROP-Lung04 study evaluating sac-TMT as a treatment for patients with previously treated advanced EGFR-mutated NSCLC (Presentation #LBA5, Proffered paper session: Presidential Symposium II). 5 Primary results from the Phase 3 OptiTROP-Breast02 study evaluating sac-TMT as a treatment for patients with previously treated unresectable locally advanced or metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (Presentation #LBA23, Proffered paper session 1: Breast cancer, metastatic). 5 Efficacy and safety data from the Phase 1/2 MK-2870-001 study evaluating sac-TMT for patients with advanced or metastatic cervical cancer (Presentation #1168P, Poster session: Gynaecological cancers). 5 Findings from cohort D of the Phase 2 MK-2870-002/SKB264-II-06 study evaluating sac-TMT plus KEYTRUDA for patients with metastatic castration-resistant prostate cancer (Presentation #2421P, Poster session: Prostate cancer). 5 Details on presentations listed above and additional key presentations for Merck Breast cancer Sacituzumab tirumotecan (sac-TMT) vs investigator's choice of chemotherapy (ICC) in previously treated locally advanced or metastatic hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer (BC): Results from the randomized, multi-center Phase 3 OptiTROP-Breast02 study. Y. Fan.​​5 Presentation #LBA23, Proffered paper session 1: Breast cancer, metastatic Patient-reported outcomes (PROs) with sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in patients (pts) with previously untreated PD-L1+ metastatic triple-negative breast cancer (mTNBC) in the Phase 3 ASCENT-04/KEYNOTE-D19 study. E. De Azambuja.6 Presentation #LBA22, Mini oral session: Breast cancer, metastatic Genitourinary cancers Perioperative (periop) enfortumab vedotin (EV) plus pembrolizumab (pembro) in participants (pts) with muscle-invasive bladder cancer (MIBC) who are cisplatin-ineligible: The Phase 3 KEYNOTE-905 study. C. Vulsteke.1 Presentation #LBA2, Proffered paper session: Presidential Symposium I Sacituzumab tirumotecan (sac-TMT) + pembrolizumab (pembro) in metastatic castration-resistant prostate cancer (mCRPC): Results from Phase 2 MK-2870-002/SKB264-II-06 study. X. Bian.5 Presentation #2421P, Poster session: Prostate cancer Final analysis of lenvatinib + pembrolizumab (L+P) vs sunitinib (S) in patients with advanced renal cell carcinoma (aRCC) with or without bone metastases in CLEAR. C. G. Porta.3 Presentation #2603P, Poster session: Renal cancer Belzutifan for advanced clear cell renal cell carcinoma (ccRCC) after a PD-(L)1 inhibitor and ≥2 VEGFR-TKIs in LITESPARK-005. G. A. De Velasco Oria. Presentation #2607P, Poster session: Renal cancer EV-103 cohort K: Efficacy and safety of enfortumab vedotin (EV) with or without pembrolizumab (P) in cisplatin (cis)-ineligible pts with previously untreated locally advanced or metastatic urothelial cancer (la/mUC) with a median (m) follow-up (FU) of ≈3.5 y. T. Friedlander.1 Presentation #3074P, Poster session: Urothelial cancer First-line pembrolizumab-based regimens for advanced clear cell renal cell carcinoma: KEYMAKER-U03 substudy 03A. C.S. Rodriguez. Presentation #LBA96, Proffered paper session 2: GU tumours, renal & urothelial Belzutifan plus lenvatinib for Chinese participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): Updated results of cohort 1 of the LITESPARK-010 study. X. Sheng.3 Presentation #2615P, Poster session: Renal cancer Gynecologic cancers Pembrolizumab vs placebo plus weekly paclitaxel ± bevacizumab in platinum-resistant recurrent ovarian cancer: Results from the randomized double-blind Phase 3 ENGOT-ov65/KEYNOTE-B96 study. N. Colombo.2 Presentation #LBA3, Proffered paper session: Presidential Symposium I Raludotatug deruxtecan (R-DXd) in patients with platinum-resistant ovarian cancer (PROC): Primary analysis of the Phase 2, dose-optimization part of the REJOICE-Ovarian01 study. I. L. Ray-Coquard​​.4 Presentation # LBA42, Proffered paper session: Gynaecological cancers Efficacy and safety of sacituzumab tirumotecan (sac-TMT) monotherapy in advanced/metastatic cervical cancer: Results from a Phase 1/2 study (MK-2870-001/KL264-01). Z. Yang.5 Presentation #1168P, Poster session: Gynaecological cancers Lenvatinib plus pembrolizumab (L + P) vs treatment of physician’s choice (TPC) for advanced endometrial cancer (EC): 5-year outcomes from Study 309/KEYNOTE-775. V. Makker.3 Presentation #1119P, Poster session: Gynaecological cancers Sacituzumab tirumotecan (sac-TMT) monotherapy in advanced/metastatic endometrial carcinoma (EC): Results from a Phase 1/2 study (MK-2870-001/KL264-01). K. Wang.5 Presentation #1111P, Poster session: Gynaecological cancers Tisotumab vedotin plus carboplatin or pembrolizumab in recurrent or metastatic cervical cancer: 5-year results from the innovaTV 205/GOG-3024/ENGOT-cx8 study. B. J. Monk.2,7 Presentation #1166P, Poster session: Gynaecological cancers Patient-reported outcomes (PROs) with 1L pembrolizumab (pembro) + chemotherapy (chemo) then maintenance pembro + olaparib (ola) in advanced BRCA1/2-nonmutated epithelial ovarian cancer (EOC): Phase 3 ENGOT-ov43/GOG-3036/KEYLYNK-001 Study. S. Topuz.2 Presentation #1072P, Poster session: Gynaecological cancers Head and neck cancer Neoadjuvant-adjuvant (neoadj-adj) pembrolizumab (pembro) plus standard-of-care (SOC) in resectable locally advanced head and neck squamous cell carcinoma (LA HNSCC): Participant-reported outcomes (PRO) in KEYNOTE-689. Y. Tao. Presentation #1330MO, Mini oral session: Head & neck cancer Lung cancer Sacituzumab tirumotecan (sac-TMT) vs platinum-based chemotherapy in EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) following progression on EGFR-TKIs: Results from the randomized, multi-center Phase 3 OptiTROP-Lung04 study. L. Zhang. 5 Presentation #LBA5, Proffered paper session: Presidential Symposium II Perioperative pembrolizumab in early-stage non-small-cell lung cancer (NSCLC): 5-year follow-up from KEYNOTE-671. H. Wakelee. Presentation #LBA67, Mini oral session 2: Non-metastatic NSCLC 10-year outcomes from clinical trials of pembrolizumab (pembro) monotherapy for locally advanced or metastatic non-small-cell lung cancer (NSCLC). E. B. Garon.​​ Presentation #3208P, Poster session: metastatic NSCLC Intracranial activity of ifinatamab deruxtecan (I-DXd) in patients (pts) with extensive-stage (ES) small cell lung cancer (SCLC) and baseline (BL) brain metastases (BM): Primary analysis of IDeate-Lung01. P. F. S. da Rocha.4 Presentation #2760MO, Mini oral session 1: Non-metastatic NSCLC Updated results from a Phase 1/2 study of gocatamig for small cell lung cancer (SCLC) and other neuroendocrine cancers. H. Beltran.4 Presentation #2758MO, Mini oral session 1: Non-metastatic NSCLC Sacituzumab tirumotecan (sac-TMT) + pembrolizumab (pembro) for treatment-naïve advanced PD-L1-positive NSCLC: Results from the Phase 2 MK-2870-003/SKB264-II-04 Study. W. F. Fang.5 Presentation #1949P, Poster session: NSCLC, metastatic Sacituzumab tirumotecan (sac-TMT) in participants (pts) with previously treated, advanced KRAS-mutant NSCLC: Results from cohort 5d of the SKB264-II-08 Study. T. Zhou.5 Presentation #1945P, Poster session: NSCLC, metastatic Melanoma and other skin cancers IO102-IO103 cancer vaccine plus pembrolizumab for first line (1L) advanced melanoma: Primary Phase 3 results (IOB-013/KN-D18). J. C. Hassel​.8 Presentation #LBA53, Proffered paper session: Melanoma and other skin tumours Pembrolizumab versus placebo as adjuvant therapy for resected stage IIB or IIC melanoma: 5-year follow-up of the Phase 3 KEYNOTE-716 study. A. M. Eggermont. Presentation #1611P, Poster session: Melanoma and other skin tumours 3-year survival with neoadjuvant-adjuvant pembrolizumab from SWOG S1801. V. K. Sondak.9 Presentation #1601O, Proffered paper session: Melanoma and other skin tumours ECOB-ACRIN EA6174: STAMP: Surgically treated adjuvant Merkel cell carcinoma with pembrolizumab, a Phase III trial. J. M. Mehnert.9 Presentation # LBA56, Proffered paper session: Melanoma and other skin tumours Multi-tumor A Phase 2 study of participant (pt)-reported preference for pembrolizumab (pembro) administered subcutaneously (SC) or intravenously (IV). I. A. Casarini. Presentation #3145P, Poster session: General interest MK-1084 monotherapy in participants (pts) with KRAS G12C-mutated advanced solid tumors: Activity and safety in the Phase 1 KANDLELIT-001 study. M. Simonelli.10 Presentation #926MO, Mini oral session: Developmental therapeutics IO102-IO103 cancer vaccine plus pembrolizumab for first line (1L) treatment of advanced solid tumors: Final results of a Phase 2 basket trial. J. W. Riess.8 Presentation #1557P, Poster session: Investigational immunotherapy Pheochromocytoma and Paraganglioma LITESPARK-015: Belzutifan in advanced pheochromocytoma and paraganglioma. C. Jimenez. Presentation #1705O, Proffered paper session: NETs and endocrine tumours Belzutifan for advanced pancreatic neuroendocrine tumors (panNETs): Results from cohort A2 of the Phase 2 LITESPARK-015 study. J. Capdevila. Presentation #1710MO, Mini oral session: NETs and endocrine tumours Thymic Perioperative pembrolizumab for locally advanced thymic epithelial tumors. S. Park. Presentation #2967O, Proffered paper session: Mesothelioma and thymic tumours: Targeting and breaking through 1 In collaboration with Astellas/Pfizer 2 In collaboration with the European Network for Gynaecological Oncology Trial (ENGOT) groups and the GOG Foundation, Inc. (GOG) 3 In collaboration with Eisai 4 In collaboration with Daiichi Sankyo 5 Led by Kelun-Biotech, conducted in China 6 In collaboration with Gilead 7 In collaboration with Genmab/Pfizer 8 In collaboration with IO Biotech 9 In collaboration with National Cancer Institute’s Cancer Therapy Evaluation Program 10 In collaboration with Taiho Pharmaceutical Co. Ltd and Astex Pharmaceuticals (UK), a wholly owned subsidiary of Otsuka Pharmaceutical Co., Ltd 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. About KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) injection for subcutaneous use, 165 mg + 2,000 units/mL KEYTRUDA QLEX is a fixed-combination drug product of pembrolizumab and berahyaluronidase alfa. Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody and berahyaluronidase alfa enhances dispersion and permeability to enable subcutaneous administration of pembrolizumab. KEYTRUDA QLEX is administered as a subcutaneous injection into the thigh or abdomen, avoiding the 5 cm area around the navel, over one minute every three weeks (2.4 mL) or over two minutes every six weeks (4.8 mL). Selected KEYTRUDA® (pembrolizumab) and KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) Indications in the U.S. Melanoma KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with unresectable or metastatic melanoma. KEYTRUDA and KEYTRUDA QLEX are each indicated for the adjuvant treatment of adult and pediatric patients 12 years and older with stage IIB, IIC, or III melanoma following complete resection. Non-Small Cell Lung Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with pemetrexed and platinum chemotherapy, for the first-line treatment of adult patients with metastatic nonsquamous non–small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, for the first-line treatment of adult patients with metastatic squamous NSCLC. KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the first-line treatment of adult 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 and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult 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 or KEYTRUDA QLEX. KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult 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 and KEYTRUDA QLEX, as single agents, are each indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC. Head and Neck Squamous Cell Cancer KEYTRUDA is indicated for the treatment of adult patients with resectable locally advanced head and neck squamous cell carcinoma (HNSCC) whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with radiotherapy (RT) with or without cisplatin and then as a single agent. KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with platinum and fluorouracil (FU), for the first-line treatment of adult patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC). KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the first-line treatment of adult 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 and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. Urothelial Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with enfortumab vedotin, for the treatment of adult patients with locally advanced or metastatic urothelial cancer. KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult 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 and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult 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. Cervical Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with chemoradiotherapy (CRT), for the treatment of adult patients with locally advanced cervical cancer involving the lower third of the vagina, with or without extension to pelvic sidewall, or hydronephrosis/non-functioning kidney, or spread to adjacent pelvic organs (FIGO 2014 III-IVA). KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with or without bevacizumab, for the treatment of adult patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult 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. Merkel Cell Carcinoma KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). For this indication, KEYTRUDA also is indicated for the treatment of pediatric patients, and KEYTRUDA QLEX also is indicated for the treatment of pediatric patients 12 years and older. Renal Cell Carcinoma KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with axitinib, for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with lenvatinib, for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). KEYTRUDA and KEYTRUDA QLEX are each indicated for the adjuvant treatment of adult patients with renal cell carcinoma (RCC) at intermediate high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. Endometrial Carcinoma KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with carboplatin and paclitaxel, followed by KEYTRUDA or KEYTRUDA QLEX as a single agent, for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with lenvatinib, for the treatment of adult patients with advanced endometrial carcinoma that is pMMR or not MSI-H 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. KEYTRUDA and KEYTRUDA QLEX, as a single agent, are each indicated for the treatment of adult 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. Triple-Negative Breast Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then each continued as a single agent as adjuvant treatment after surgery. KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with chemotherapy, for the treatment of adult patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test. See additional selected KEYTRUDA and KEYTRUDA QLEX indications in the U.S. after the Selected Important Safety Information. Selected Important Safety Information for KEYTRUDA and KEYTRUDA QLEX Contraindications KEYTRUDA QLEX is contraindicated in patients with known hypersensitivity to berahyaluronidase alfa, hyaluronidase or to any of its excipients. Severe and Fatal Immune-Mediated Adverse Reactions KEYTRUDA and KEYTRUDA QLEX are monoclonal antibodies that belong 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 or KEYTRUDA QLEX 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 and KEYTRUDA QLEX depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA and KEYTRUDA QLEX require 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 and KEYTRUDA QLEX 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. Immune-mediated pneumonitis occurred in 5% (13/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including fatal (0.4%), Grade 3 (2%), and Grade 2 (1.2%) adverse reactions. 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 and KEYTRUDA QLEX 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. Immune-mediated colitis occurred in 1.2% (3/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 3 (0.8%) and Grade 2 (0.4%) adverse reactions. Hepatotoxicity and Immune-Mediated Hepatitis KEYTRUDA and KEYTRUDA QLEX 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. Immune-mediated hepatitis occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (0.4%) adverse reactions. KEYTRUDA or KEYTRUDA QLEX With Axitinib KEYTRUDA and KEYTRUDA QLEX, when either is used 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 or KEYTRUDA QLEX 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 and KEYTRUDA QLEX can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA and KEYTRUDA QLEX 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. Adrenal insufficiency occurred in 2% (5/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 3 (0.4%) and Grade 2 (0.8%) adverse reactions. Hypophysitis KEYTRUDA and KEYTRUDA QLEX 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 and KEYTRUDA QLEX 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 and KEYTRUDA QLEX 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 and KEYTRUDA QLEX 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 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. Thyroiditis occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (0.4%). Hyperthyroidism occurred in 8% (20/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (3.2%). Hypothyroidism occurred in 14% (35/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (11%). 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 and KEYTRUDA QLEX 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. Type 1 DM occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy. Immune-Mediated Nephritis With Renal Dysfunction KEYTRUDA and KEYTRUDA QLEX 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 and KEYTRUDA QLEX 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 and KEYTRUDA QLEX 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. Immune-mediated dermatologic adverse reactions occurred in 1.6% (4/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 4 (0.8%) and Grade 3 (0.8%) adverse reactions. 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, KEYTRUDA QLEX, 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 (2.8%), 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. Hypersensitivity and Infusion- or Administration-Related Reactions KEYTRUDA and KEYTRUDA QLEX can cause severe or life-threatening administration-related reactions, including hypersensitivity and anaphylaxis. With KEYTRUDA and KEYTRUDA QLEX, monitor for signs and symptoms of infusion- and administration-related systemic reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Infusion-related reactions have been reported in 0.2% of 2799 patients receiving KEYTRUDA. 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. Hypersensitivity and administration related systemic reactions occurred in 3.2% (8/251) of patients receiving KEYTRUDA QLEX in combination with platinum doublet chemotherapy, including Grade 2 (2.8%). Interrupt injection (if not already fully administered) and resume if symptoms resolve for mild or moderate systemic reactions. For severe or life-threatening systemic reactions, stop injection and permanently discontinue KEYTRUDA QLEX. 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 treatments 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 their mechanism of action, KEYTRUDA and KEYTRUDA QLEX can each 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 or KEYTRUDA QLEX and advise them to use effective contraception during treatment and for 4 months after the last dose. Adverse Reactions In study MK-3475A-D77, when KEYTRUDA QLEX was administered with chemotherapy in metastatic non–small cell lung cancer (NSCLC), serious adverse reactions occurred in 39% of patients. Serious adverse reactions in ≥1% of patients who received KEYTRUDA QLEX were pneumonia (10%), thrombocytopenia (4%), febrile neutropenia (4%), neutropenia (2.8%), musculoskeletal pain (2%), pneumonitis (2%), diarrhea (1.6%), rash (1.2%), respiratory failure (1.2%), and anemia (1.2%). Fatal adverse reactions occurred in 10% of patients including pneumonia (3.2%), neutropenic sepsis (2%), death not otherwise specified (1.6%), respiratory failure (1.2%), parotitis (0.4%), pneumonitis (0.4%), pneumothorax (0.4%), pulmonary embolism (0.4%), neutropenic colitis (0.4%), and seizure (0.4%). KEYTRUDA QLEX was permanently discontinued due to an adverse reaction in 16% of 251 patients. Adverse reactions which resulted in permanent discontinuation of KEYTRUDA QLEX in ≥2% of patients included pneumonia and pneumonitis. Dosage interruptions of KEYTRUDA QLEX due to an adverse reaction occurred in 45% of patients. Adverse reactions which required dosage interruption in ≥2% of patients included neutropenia, anemia, thrombocytopenia, pneumonia, rash, and increased aspartate aminotransferase. The most common adverse reactions (≥20%) were nausea (25%), fatigue (25%), and musculoskeletal pain (21%). 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 or chemoradiotherapy 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, hypothyroidism, radiation skin injury, dysphagia, dry mouth, and musculoskeletal pain. 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. Adverse reactions observed in KEYNOTE-483 were generally similar to those occurring in other patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. 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-689, the most common adverse reactions (≥20%) in patients receiving KEYTRUDA were stomatitis (48%), radiation skin injury (40%), weight loss (36%), fatigue (33%), dysphagia (29%), constipation (27%), hypothyroidism (26%), nausea (24%), rash (22%), dry mouth (22%), diarrhea (22%), and musculoskeletal pain (22%). In the neoadjuvant phase of KEYNOTE-689, of the 361 patients who received at least one dose of single agent KEYTRUDA, 11% experienced serious adverse reactions. Serious adverse reactions that occurred in more than one patient were pneumonia (1.4%), tumor hemorrhage (0.8%), dysphagia (0.6%), immune-mediated hepatitis (0.6%), cellulitis (0.6%), and dyspnea (0.6%). Fatal adverse reactions occurred in 1.1% of patients, including respiratory failure, clostridium infection, septic shock, and myocardial infarction (one patient each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 2.8% of patients who received KEYTRUDA as neoadjuvant treatment. The most frequent adverse reaction which resulted in permanent discontinuation of neoadjuvant KEYTRUDA in more than one patient was arthralgia (0.6%). Of the 361 patients who received KEYTRUDA as neoadjuvant treatment, 11% did not receive surgery. Surgical cancellation on the KEYTRUDA arm was due to disease progression in 4%, patient decision in 3%, adverse reactions in 1.4%, physician’s decision in 1.1%, unresectable tumor in 0.6%, loss of follow-up in 0.3%, and use of non-study anti-cancer therapy in 0.3%. Of the 323 KEYTRUDA-treated patients who received surgery following the neoadjuvant phase, 1.2% experienced delay of surgery (defined as on-study surgery occurring ≥9 weeks after initiation of neoadjuvant KEYTRUDA) due to adverse reactions, and 2.8% did not receive adjuvant treatment due to adverse reactions. In the adjuvant phase of KEYNOTE-689, of the 255 patients who received at least one dose of KEYTRUDA, 38% experienced serious adverse reactions. The most frequent serious adverse reactions reported in ≥1% of KEYTRUDA- treated patients were pneumonia (2.7%), pyrexia (2.4%), stomatitis (2.4%), acute kidney injury (2.0%), pneumonitis (1.6%), COVID-19 (1.2%), death not otherwise specified (1.2%), diarrhea (1.2%), dysphagia (1.2%), gastrostomy tube site complication (1.2%), and immune-mediated hepatitis (1.2%). Fatal adverse reactions occurred in 5% of patients, including death not otherwise specified (1.2%), acute renal failure (0.4%), hypercalcemia (0.4%), pulmonary hemorrhage (0.4%), dysphagia/malnutrition (0.4%), mesenteric thrombosis (0.4%), sepsis (0.4%), pneumonia (0.4%), COVID-19 (0.4%), respiratory failure (0.4%), cardiovascular disorder (0.4%), and gastrointestinal hemorrhage (0.4%). Permanent discontinuation of adjuvant KEYTRUDA due to an adverse reaction occurred in 17% of patients. The most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant KEYTRUDA were pneumonitis, colitis, immune-mediated hepatitis, and death not otherwise specified. 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, fatal adverse reactions occurred in 3 patients who received KEYTRUDA in combination with trastuzumab and CAPOX (capecitabine plus oxaliplatin) or FP (5-FU plus cisplatin) and included pneumonitis in 2 patients and hepatitis in 1 patient. KEYTRUDA was discontinued due to adverse reactions in 13% of 350 patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma. Adverse reactions resulting in permanent discontinuation of KEYTRUDA in ≥1% of patients were pneumonitis (2.0%) and pneumonia (1.1%). In the KEYTRUDA arm vs placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA vs standard of care for diarrhea (53% vs 47%), rash (35% vs 28%), hypothyroidism (11% vs 5%), and pneumonia (11% vs 5%). 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 294 patients, including 1 case each (0.3%) of large intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious adverse reactions occurred in 34% of patients; those ≥1% included urinary tract infection (3.1%), urosepsis (1.4%), and sepsis (1%). KEYTRUDA was discontinued for adverse reactions in 9% 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 (51%), urinary tract infection (35%), vomiting (34%), fatigue (28%), hypothyroidism (23%), constipation (20%), weight loss (19%), decreased appetite (18%), pyrexia (14%), abdominal pain and hyperthyroidism (13% each), dysuria and rash (12% each), back and pelvic pain (11% each), and COVID-19 (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%), pruritus (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-581, when KEYTRUDA was administered in combination with lenvatinib to patients with advanced renal cell carcinoma (n=352), fatal adverse reactions occurred in 4.3% of patients. Serious adverse reactions occurred in 51% of patients; the most common (≥2%) were hemorrhagic events (5%), diarrhea (4%), hypertension, myocardial infarction, pneumonitis, and vomiting (3% each), acute kidney injury, adrenal insufficiency, dyspnea, and pneumonia (2% each). Permanent discontinuation of KEYTRUDA, lenvatinib, or both due to an adverse reaction occurred in 37% of patients; 29% KEYTRUDA only, 26% lenvatinib only, and 13% both. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA, lenvatinib, or the combination were pneumonitis, myocardial infarction, hepatotoxicity, acute kidney injury, rash (3% each), and diarrhea (2%). The most common adverse reactions (≥20%) observed with KEYTRUDA in combination with lenvatinib were fatigue (63%), diarrhea (62%), musculoskeletal disorders (58%), hypothyroidism (57%), hypertension (56%), stomatitis (43%), decreased appetite (41%), rash (37%), nausea (36%), weight loss, dysphonia and proteinuria (30% each), palmar-plantar erythrodysesthesia syndrome (29%), abdominal pain and hemorrhagic events (27% each), vomiting (26%), constipation and hepatotoxicity (25% each), headache (23%), and acute kidney injury (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%). In KEYNOTE-868, when KEYTRUDA was administered in combination with chemotherapy (paclitaxel and carboplatin) to patients with advanced or recurrent endometrial carcinoma (n=382), serious adverse reactions occurred in 35% of patients receiving KEYTRUDA in combination with chemotherapy, compared to 19% of patients receiving placebo in combination with chemotherapy (n=377). Fatal adverse reactions occurred in 1.6% of patients receiving KEYTRUDA in combination with chemotherapy, including COVID-19 (0.5%) and cardiac arrest (0.3%). KEYTRUDA was discontinued for an adverse reaction in 14% of patients. Adverse reactions occurring in patients treated with KEYTRUDA and chemotherapy were generally similar to those observed with KEYTRUDA alone or chemotherapy alone, with the exception of rash (33% all Grades; 2.9% Grades 3-4). In KEYNOTE-775, when KEYTRUDA was administered in combination with lenvatinib to patients with advanced endometrial carcinoma that was pMMR or not MSI-H (n=342), fatal adverse reactions occurred in 4.7% of patients. Serious adverse reactions occurred in 50% of these patients; the most common (≥3%) were hypertension (4.4%) and urinary tract infections (3.2%). Discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of these patients. The most common adverse reaction leading to discontinuation of KEYTRUDA (≥1%) was increased ALT (1.2%). The most common adverse reactions for KEYTRUDA in combination with lenvatinib (reported in ≥20% patients) were hypothyroidism and hypertension (67% each), fatigue (58%), diarrhea (55%), musculoskeletal disorders (53%), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), abdominal pain and weight loss (34% each), urinary tract infections (31%), proteinuria (29%), constipation (27%), headache (26%), hemorrhagic events (25%), palmar-plantar erythrodysesthesia (23%), dysphonia (22%), and rash (20%). 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 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). The safety and effectiveness of KEYTRUDA QLEX for the treatment of pediatric patients 12 years and older who weigh greater than 40 kg have been established for: Stage IIB, IIC, or III melanoma following complete resection Unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors Recurrent locally advanced or metastatic Merkel cell carcinoma Use of KEYTRUDA QLEX in pediatric patients for these indications is supported by evidence from adequate and well-controlled studies of KEYTRUDA in adults and additional pharmacokinetic and safety data for KEYTRUDA in pediatric patients 12 years and older. Pembrolizumab exposures in pediatric patients 12 years and older who weigh greater than 40 kg are predicted to be within range of those observed in adults at the same dosage. The safety and effectiveness of KEYTRUDA as a single agent have been established in pediatric patients with melanoma, MCC, and MSI-H or dMMR cancer. Use of KEYTRUDA in pediatric patients for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients. The safety and effectiveness of KEYTRUDA QLEX and KEYTRUDA have not been established in pediatric patients younger than 12 years of age for the treatment of melanoma. The safety and effectiveness of KEYTRUDA QLEX have not been established in pediatric patients younger than 12 years of age for the treatment of, MCC and MSI-H or dMMR cancer. The safety and effectiveness of KEYTRUDA and KEYTRUDA QLEX have not been established in pediatric patients for other approved indications shown. Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults were pyrexia (33%), leukopenia (30%), 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 and KEYTRUDA QLEX Indications in the U.S. Malignant Pleural Mesothelioma KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with pemetrexed and platinum chemotherapy, for the first-line treatment of adult patients with unresectable advanced or metastatic malignant pleural mesothelioma (MPM). Microsatellite Instability-High or Mismatch Repair Deficient Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult 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. For this indication, KEYTRUDA also is indicated for the treatment of pediatric patients, and KEYTRUDA QLEX also is indicated for the treatment of pediatric patients 12 years and older. Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test. Gastric Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, 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. KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. Esophageal Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult 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 for patients with tumors that express PD-L1 (CPS ≥1), 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. Hepatocellular Carcinoma KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult 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 and KEYTRUDA QLEX are each indicated, in combination with gemcitabine and cisplatin, for the treatment of adult patients with locally advanced unresectable or metastatic biliary tract cancer (BTC). Cutaneous Squamous Cell Carcinoma KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation. 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. Please see Prescribing Information for KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) at https://www.merck.com/product/usa/pi_circulars/k/keytruda_qlex/keytruda_qlex_pi.pdf and Medication Guide for KEYTRUDA QLEX™ at https://www.merck.com/product/usa/pi_circulars/k/keytruda_qlex/keytruda_qlex_mg.pdf. About LENVIMA® (lenvatinib); available as 10 mg and 4 mg capsules LENVIMA, discovered and developed by Eisai, is an orally available multiple receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4, the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. In syngeneic mouse tumor models, LENVIMA decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone. The combination of LENVIMA and everolimus showed increased antiangiogenic and antitumor activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse xenograft models of human renal cell cancer greater than each drug alone. LENVIMA® (lenvatinib) Indications in the U.S. For the treatment of adult patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). In combination with pembrolizumab, for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). In combination with everolimus, for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy. For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H), 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. Selected Safety Information for LENVIMA Warnings and Precautions Hypertension. In differentiated thyroid cancer (DTC), hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In advanced renal cell carcinoma (RCC), hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% of patients, and 21% had diastolic blood pressure ≥100 mmHg. In unresectable hepatocellular carcinoma (HCC), hypertension occurred in 45% of LENVIMA-treated patients (24% grade 3). Grade 4 hypertension was not reported in HCC. Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiation. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue based on severity. Cardiac Dysfunction. Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC, and HCC, grade 3 or higher cardiac dysfunction occurred in 3% of LENVIMA-treated patients. Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity. Arterial Thromboembolic Events. Among patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in RCC and HCC and 5% in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials. Among patients receiving LENVIMA with KEYTRUDA, arterial thrombotic events of any severity occurred in 5% of patients in CLEAR, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%). Permanently discontinue following an arterial thrombotic event. The safety of resuming after an arterial thromboembolic event has not been established and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. Hepatotoxicity. Across clinical studies enrolling 1,327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of patients. In HCC, hepatic encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade 3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated patients. 2% of patients discontinued LENVIMA due to hepatic encephalopathy and 1% discontinued due to hepatic failure. Monitor liver function prior to initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity. Renal Failure or Impairment. Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment was reported in 14% and 7% of LENVIMA-treated patients in DTC and HCC, respectively. Grade 3-5 renal failure or impairment occurred in 3% of patients with DTC and 2% of patients with HCC, including 1 fatal event in each study. In RCC, renal impairment or renal failure was reported in 18% of LENVIMA + everolimus–treated patients (10% grade 3). Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at reduced dose upon recovery or permanently discontinue for renal failure or impairment based on severity. Proteinuria. In DTC and HCC, proteinuria was reported in 34% and 26% of LENVIMA-treated patients, respectively. Grade 3 proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA + everolimus (8% grade 3). Monitor for proteinuria prior to initiation and periodically during treatment. If urine dipstick proteinuria ≥2+ is detected, obtain a 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity. Diarrhea. Of the 737 LENVIMA-treated patients in DTC and HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea occurred in 81% of LENVIMA + everolimus–treated patients (19% grade 3). Diarrhea was the most frequent cause of dose interruption/reduction, and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity. Fistula Formation and Gastrointestinal Perforation. Of the 799 patients treated with LENVIMA or LENVIMA + everolimus in DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred in 2%. Permanently discontinue in patients who develop gastrointestinal perforation of any severity or grade 3-4 fistula. QT Interval Prolongation. In DTC, QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In RCC, QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA + everolimus and QTc interval >500 ms occurred in 6%. In HCC, QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%. Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose upon recovery based on severity. Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation with or without dose interruption or dose reduction. In RCC, grade 3-4 hypocalcemia occurred in 6% of LENVIMA + everolimus–treated patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity. Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Across clinical studies of 1,823 patients who received LENVIMA as a single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity and persistence of neurologic symptoms. Hemorrhagic Events. Serious including fatal hemorrhagic events can occur with LENVIMA. In DTC, RCC, and HCC clinical trials, hemorrhagic events, of any grade, occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In DTC, grade 3-5 hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5 hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients, including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage occurred in 5% of LENVIMA-treated patients, including 7 fatal hemorrhagic events. Serious tumor-related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-treated patients in clinical trials and in the postmarketing setting. In postmarketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than other tumors. Safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials. Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg, carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity. Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction. LENVIMA impairs exogenous thyroid suppression. In DTC, 88% of patients had baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. In RCC and HCC, grade 1 or 2 hypothyroidism occurred in 24% of LENVIMA + everolimus–treated patients and 21% of LENVIMA-treated patients, respectively. In patients with normal or low TSH at baseline, elevation of TSH was observed post baseline in 70% of LENVIMA-treated patients in HCC and 60% of LENVIMA + everolimus–treated patients in RCC. Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard medical practice. Impaired Wound Healing. Impaired wound healing has been reported in patients who received LENVIMA. Withhold LENVIMA for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of LENVIMA after resolution of wound healing complications has not been established. Osteonecrosis of the Jaw (ONJ). ONJ has been reported in patients receiving LENVIMA. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease or invasive dental procedures, may increase the risk of ONJ. Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment. Advise patients regarding good oral hygiene practices and to consider having preventive dentistry performed prior to treatment with LENVIMA and throughout treatment with LENVIMA. Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk. Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures, if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk of ONJ. Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution. Embryo‐Fetal Toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of LENVIMA during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus; and advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for 30 days after the last dose. Adverse Reactions In DTC, the most common adverse reactions (≥30%) observed in LENVIMA-treated patients were hypertension (73%), fatigue (67%), diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%), decreased weight (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%), proteinuria (34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31%), and dysphonia (31%). The most common serious adverse reactions (≥2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of LENVIMA-treated patients; 18% discontinued LENVIMA. The most common adverse reactions (≥10%) resulting in dose reductions were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%). In RCC, the most common adverse reactions (≥20%) observed in LENVIMA + KEYTRUDA-treated patients were fatigue (63%), diarrhea (62%), musculoskeletal pain (58%), hypothyroidism (57%), hypertension (56%), stomatitis (43%), decreased appetite (41%), rash (37%), nausea (36%), decreased weight (30%), dysphonia (30%), proteinuria (30%), palmar-plantar erythrodysesthesia syndrome (29%), abdominal pain (27%), hemorrhagic events (27%), vomiting (26%), constipation (25%), hepatotoxicity (25%), headache (23%), and acute kidney injury (21%). Fatal adverse reactions occurred in 4.3% of patients receiving LENVIMA in combination with KEYTRUDA, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm and subarachnoid hemorrhage. Serious adverse reactions occurred in 51% of patients receiving LENVIMA and KEYTRUDA. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Permanent discontinuation of LENVIMA, KEYTRUDA, or both due to an adverse reaction occurred in 37% of patients; 26% LENVIMA only, 29% KEYTRUDA only, and 13% both drugs. The most common adverse reactions (≥2%) leading to permanent discontinuation of LENVIMA, KEYTRUDA, or both were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%). Dose interruptions of LENVIMA, KEYTRUDA, or both due to an adverse reaction occurred in 78% of patients receiving LENVIMA in combination with KEYTRUDA. LENVIMA was interrupted in 73% of patients and both drugs were interrupted in 39% of patients. LENVIMA was dose reduced in 69% of patients. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), palmar-plantar erythrodysesthesia (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%), abdominal pain (6%), vomiting (6%), increased ALT (5%), and increased amylase (5%). In RCC, the most common adverse reactions (≥30%) observed in LENVIMA + everolimus–treated patients were diarrhea (81%), fatigue (73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%), peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic events (32%), and proteinuria (31%). The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients. In HCC, the most common adverse reactions (≥20%) observed in LENVIMA-treated patients were hypertension (45%), fatigue (44%), diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31%), decreased weight (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia (24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea (20%). The most common serious adverse reactions (≥2%) were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%). Adverse reactions led to dose reductions or interruption in 62% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to an adverse reaction occurred in 20% of patients. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%). In endometrial carcinoma, the most common adverse reactions (≥20%) observed in LENVIMA + KEYTRUDA-treated patients were hypothyroidism (67%), hypertension (67%), fatigue (58%), diarrhea (55%), musculoskeletal disorders (53%), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), decreased weight (34%), abdominal pain (34%), urinary tract infection (31%), proteinuria (29%), constipation (27%), headache (26%), hemorrhagic events (25%), palmar‐plantar erythrodysesthesia (23%), dysphonia (22%), and rash (20%). Fatal adverse reactions among these patients occurred in 4.7% of those treated with LENVIMA and KEYTRUDA, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction. Serious adverse reactions occurred in 50% of these patients receiving LENVIMA and KEYTRUDA. Serious adverse reactions with frequency ≥3% were hypertension (4.4%), and urinary tract infection (3.2%). Discontinuation of LENVIMA due to an adverse reaction occurred in 26% of these patients. The most common (≥1%) adverse reactions leading to discontinuation of LENVIMA were hypertension (2%), asthenia (1.8%), diarrhea (1.2%), decreased appetite (1.2%), proteinuria (1.2%), and vomiting (1.2%). Dose reductions of LENVIMA due to adverse reactions occurred in 67% of patients. The most common (≥5%) adverse reactions resulting in dose reduction of LENVIMA were hypertension (18%), diarrhea (11%), palmar-plantar erythrodysesthesia syndrome (9%), proteinuria (7%), fatigue (7%), decreased appetite (6%), asthenia (5%), and weight decreased (5%). Dose interruptions of LENVIMA due to an adverse reaction occurred in 58% of these patients. The most common (≥2%) adverse reactions leading to interruption of LENVIMA were hypertension (11%), diarrhea (11%), proteinuria (6%), decreased appetite (5%), vomiting (5%), increased alanine aminotransferase (3.5%), fatigue (3.5%), nausea (3.5%), abdominal pain (2.9%), weight decreased (2.6%), urinary tract infection (2.6%), increased aspartate aminotransferase (2.3%), asthenia (2.3%), and palmar-plantar erythrodysesthesia (2%). Use in Specific Populations Because of the potential for serious adverse reactions in breastfed children, advise women to discontinue breastfeeding during treatment and for 1 week after last dose. LENVIMA may impair fertility in males and females of reproductive potential. No dose adjustment is recommended for patients with mild (creatinine clearance [CLcr] 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or endometrial carcinoma and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with DTC, RCC, or endometrial carcinoma and severe renal impairment. There is no recommended dose for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end stage renal disease. No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. No dose adjustment is recommended for patients with DTC, RCC, or endometrial carcinoma and mild or moderate hepatic impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment. Reduce the dose for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment. Please see Prescribing Information for LENVIMA (lenvatinib) at http://www.lenvima.com/pdfs/prescribing-information.pdf. About LYNPARZA® (olaparib) LYNPARZA is a first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Inhibition of PARP with LYNPARZA leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. LYNPARZA is being tested in a range of tumor types with defects and dependencies in the DDR. LYNPARZA, which is being jointly developed and commercialized by AstraZeneca and Merck, has a broad clinical trial development program, and AstraZeneca and Merck are working together to understand how it may affect multiple PARP-dependent tumors as a monotherapy and in combination across multiple cancer types. Independently, Merck is developing LYNPARZA in combination with its anti-PD-1 therapy, KEYTRUDA. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS There are no contraindications for LYNPARZA. WARNINGS AND PRECAUTIONS Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in approximately 1.2% of patients with various BRCAm, gBRCAm, HRR gene-mutated or HRD-positive cancers who received LYNPARZA as a single agent or as part of a combination regimen, consistent with the approved indications, and the majority of events had a fatal outcome. The median duration of therapy in patients who developed MDS/AML was approximately 2 years (range: <6 months to >4 years). All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy. In SOLO-1, patients with newly diagnosed advanced BRCAm ovarian cancer, the incidence of MDS/AML was 1.9% (5/260) in patients who received LYNPARZA and 0.8% (1/130) in patients who received placebo based on an updated analysis. In PAOLA-1, of patients with newly diagnosed advanced ovarian cancer with HRD-positive status, the incidence of MDS/AML was 1.6% (4/255) in patients who received LYNPARZA and 2.3% (3/131) in the control arm. In SOLO-2, patients with BRCAm platinum-sensitive relapsed ovarian cancer, the incidence of MDS/AML was 8% (15/195) in patients who received LYNPARZA and 4% (4/99) in patients who received placebo. The duration of LYNPARZA treatment prior to the diagnosis of MDS/AML ranged from 0.6 years to 4.5 years. Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed. Pneumonitis: Occurred in 0.8% of patients exposed to LYNPARZA monotherapy, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately. Venous Thromboembolism (VTE): Including severe or fatal pulmonary embolism (PE) occurred in patients treated with LYNPARZA. In the combined data of two randomized, placebo-controlled clinical studies (PROfound and PROpel) in patients with metastatic castration-resistant prostate cancer (N=1180), VTE occurred in 8% of patients who received LYNPARZA, including pulmonary embolism in 6%. In the control arms, VTE occurred in 2.5%, including pulmonary embolism in 1.5%. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism, and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated. Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. Verify pregnancy status in females of reproductive potential prior to initiating treatment. Females Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose. Males Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time. ADVERSE REACTIONS—First-Line Maintenance BRCAm Advanced Ovarian Cancer Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA in the first-line maintenance setting for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%), upper respiratory tract infection/influenza/nasopharyngitis/bronchitis (28%), dysgeusia (26%), decreased appetite (20%), dizziness (20%), neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), urinary tract infection (13%), thrombocytopenia (11%), and stomatitis (11%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the first-line maintenance setting for SOLO-1 were: decrease in hemoglobin (87%), increase in mean corpuscular volume (87%), decrease in leukocytes (70%), decrease in lymphocytes (67%), decrease in absolute neutrophil count (51%), decrease in platelets (35%), and increase in serum creatinine (34%). ADVERSE REACTIONS—First-Line Maintenance Advanced Ovarian Cancer in Combination with Bevacizumab Most common adverse reactions (Grades 1-4) in ≥10% of patients treated with LYNPARZA/bevacizumab and at a ≥5% frequency compared to placebo/bevacizumab in the first-line maintenance setting for PAOLA-1 were: nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%), and leukopenia (18%). In addition, the most common adverse reactions (≥10%) for patients receiving LYNPARZA/bevacizumab irrespective of the frequency compared with the placebo/bevacizumab arm were: diarrhea (18%), neutropenia (18%), urinary tract infection (15%), and headache (14%). In addition, venous thromboembolic events occurred more commonly in patients receiving LYNPARZA/bevacizumab (5%) than in those receiving placebo/bevacizumab (1.9%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients for LYNPARZA in combination with bevacizumab in the first-line maintenance setting for PAOLA-1 were: decrease in hemoglobin (79%), decrease in lymphocytes (63%), increase in serum creatinine (61%), decrease in leukocytes (59%), decrease in absolute neutrophil count (35%), and decrease in platelets (35%). ADVERSE REACTIONS—Maintenance gBRCAm Recurrent Ovarian Cancer Most common adverse reactions (Grades 1-4) in ≥20% of patients who received LYNPARZA in the maintenance setting for SOLO-2 were: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the maintenance setting for SOLO-2 were: increase in mean corpuscular volume (89%), decrease in hemoglobin (83%), decrease in leukocytes (69%), decrease in lymphocytes (67%), decrease in absolute neutrophil count (51%), increase in serum creatinine (44%), and decrease in platelets (42%). ADVERSE REACTIONS—Adjuvant Treatment of gBRCAm, HER2-Negative, High-Risk Early Breast Cancer Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA in the adjuvant setting for OlympiA were: nausea (57%), fatigue (including asthenia) (42%), anemia (24%), vomiting (23%), headache (20%), diarrhea (18%), leukopenia (17%), neutropenia (16%), decreased appetite (13%), dysgeusia (12%), dizziness (11%), and stomatitis (10%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the adjuvant setting for OlympiA were: decrease in lymphocytes (77%), increase in mean corpuscular volume (67%), decrease in hemoglobin (65%), decrease in leukocytes (64%), and decrease in absolute neutrophil count (39%). ADVERSE REACTIONS—gBRCAm, HER2-Negative Metastatic Breast Cancer Most common adverse reactions (Grades 1-4) in ≥20% of patients who received LYNPARZA in the metastatic setting for OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%). Most common laboratory abnormalities (Grades 1-4) in >25% of patients who received LYNPARZA in the metastatic setting for OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%). ADVERSE REACTIONS—First-Line Maintenance gBRCAm Metastatic Pancreatic Adenocarcinoma Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA in the first-line maintenance setting for POLO were: fatigue (60%), nausea (45%), abdominal pain (34%), diarrhea (29%), anemia (27%), decreased appetite (25%), constipation (23%), vomiting (20%), back pain (19%), arthralgia (15%), rash (15%), thrombocytopenia (14%), dyspnea (13%), neutropenia (12%), nasopharyngitis (12%), dysgeusia (11%), and stomatitis (10%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the first-line maintenance setting for POLO were: increase in serum creatinine (99%), decrease in hemoglobin (86%), increase in mean corpuscular volume (71%), decrease in lymphocytes (61%), decrease in platelets (56%), decrease in leukocytes (50%), and decrease in absolute neutrophil count (25%). ADVERSE REACTIONS—HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA for PROfound were: anemia (46%), fatigue (including asthenia) (41%), nausea (41%), decreased appetite (30%), diarrhea (21%), vomiting (18%), thrombocytopenia (12%), cough (11%), and dyspnea (10%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA for PROfound were: decrease in hemoglobin (98%), decrease in lymphocytes (62%), decrease in leukocytes (53%), and decrease in absolute neutrophil count (34%). ADVERSE REACTIONS—Metastatic Castration-Resistant Prostate Cancer in Combination with Abiraterone and Prednisone or Prednisolone Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA/abiraterone with a difference of ≥5% compared to placebo for PROpel were: anemia (48%), fatigue (including asthenia) (38%), nausea (30%), diarrhea (19%), decreased appetite (16%), lymphopenia (14%), dizziness (14%), and abdominal pain (13%). Most common laboratory abnormalities (Grades 1-4) in ≥20% of patients who received LYNPARZA/abiraterone for PROpel were: decrease in hemoglobin (97%), decrease in lymphocytes (70%), decrease in platelets (23%), and decrease in absolute neutrophil count (23%). DRUG INTERACTIONS Anticancer Agents: Clinical studies of LYNPARZA with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. CYP3A Inhibitors: Avoid coadministration of strong or moderate CYP3A inhibitors when using LYNPARZA. If a strong or moderate CYP3A inhibitor must be coadministered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment. CYP3A Inducers: Avoid coadministration of strong or moderate CYP3A inducers when using LYNPARZA. USE IN SPECIFIC POPULATIONS Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose. Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients. Hepatic Impairment: No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C). Renal Impairment: No dosage modification is recommended in patients with mild renal impairment (CLcr 51-80 mL/min estimated by Cockcroft-Gault). In patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the dose of LYNPARZA to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min). INDICATIONS LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated: First-Line Maintenance BRCAm Advanced Ovarian Cancer For the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. First-Line Maintenance HRD-Positive Advanced Ovarian Cancer in Combination with Bevacizumab In combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either: a deleterious or suspected deleterious BRCA mutation, and/or genomic instability Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. Maintenance BRCA-mutated Recurrent Ovarian Cancer For the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. Adjuvant Treatment of gBRCAm, HER2-Negative, High-Risk Early Breast Cancer For the adjuvant treatment of adult patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative high-risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. gBRCAm, HER2-Negative Metastatic Breast Cancer For the treatment of adult patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. First-Line Maintenance gBRCAm Metastatic Pancreatic Cancer For the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer For the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. BRCAm Metastatic Castration-Resistant Prostate Cancer in Combination with Abiraterone and Prednisone or Prednisolone In combination with abiraterone and prednisone or prednisolone (abi/pred) for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC). Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. Please see complete Prescribing Information, including Medication Guide. About WELIREG® (belzutifan) 40 mg tablets, for oral use Indications in the U.S. Certain von Hippel-Lindau (VHL) disease-associated tumors WELIREG is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. Advanced Renal Cell Carcinoma (RCC) WELIREG is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) with a clear cell component following a programmed death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). Pheochromocytoma or Paraganglioma (PPGL) WELIREG is indicated for the treatment of adult and pediatric patients 12 years and older with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL). Selected Safety Information for WELIREG Warning: Embryo-Fetal Toxicity Exposure to WELIREG during pregnancy can cause embryo-fetal harm. Verify pregnancy status prior to the initiation of WELIREG. Advise patients of these risks and the need for effective non-hormonal contraception as WELIREG can render some hormonal contraceptives ineffective. Anemia WELIREG can cause severe anemia that can require blood transfusion. Monitor for anemia before initiation of, and periodically throughout, treatment. Transfuse patients as clinically indicated. For patients with hemoglobin <8 g/dL, withhold WELIREG until ≥8 g/dL, then resume at the same or reduced dose or permanently discontinue WELIREG, depending on the severity of anemia. For life-threatening anemia or when urgent intervention is indicated, withhold WELIREG until hemoglobin ≥8 g/dL, then resume at a reduced dose or permanently discontinue WELIREG. In LITESPARK-004 (N=61), decreased hemoglobin occurred in 93% of patients with VHL disease and 7% had Grade 3 events. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months). The safety of erythropoiesis-stimulating agents (ESAs) for treatment of anemia in patients with VHL disease treated with WELIREG has not been established. In LITESPARK-005 (n=372), decreased hemoglobin occurred in 88% of patients with advanced RCC with a clear cell component and 29% had Grade 3 events. Median time to onset of anemia was 29 days (range: 1 day to 16.6 months). Of the patients with anemia, 22% received transfusions only, 20% received ESAs only, and 12% received both transfusion and ESAs. In LITESPARK-015, anemia occurred in 96% of patients and 22% had Grade 3 events. Median time to onset of anemia was 29 days (range: 1 day to 22.1 months). Of the patients with anemia, 20% received transfusions only, 26% received ESAs only, and 6% received both transfusion and ESAs. Hypoxia WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization. Monitor oxygen saturation before initiation of, and periodically throughout, treatment. For decreased oxygen saturation with exercise (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg), consider withholding WELIREG until pulse oximetry with exercise is greater than 88%, then resume at the same dose or a reduced dose. For decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg) or when urgent intervention is indicated, withhold WELIREG until resolved and resume at a reduced dose or discontinue. For life-threatening hypoxia or recurrent symptomatic hypoxia, permanently discontinue WELIREG. Advise patients to report signs and symptoms of hypoxia immediately to a healthcare provider. In LITESPARK-004, hypoxia occurred in 1.6% of patients. In LITESPARK-005, hypoxia occurred in 15% of patients and 10% had Grade 3 events. Of the patients with hypoxia, 69% were treated with oxygen therapy. Median time to onset of hypoxia was 30.5 days (range: 1 day to 21.1 months). In LITESPARK-015, hypoxia occurred in 13% of patients and 10% had Grade 3 hypoxia. Median time to onset of hypoxia was 35 days (range: 6 days to 23.9 months). Of the patients with hypoxia, 67% were treated with oxygen therapy. Embryo-Fetal Toxicity Based on findings in animals, WELIREG can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. WELIREG can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose. Adverse Reactions Adverse Reactions in LITESPARK-004 Serious adverse reactions occurred in 15% of patients, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each). WELIREG was permanently discontinued due to adverse reactions in 3.3% of patients for dizziness and opioid overdose (1.6% each). Dosage interruptions due to an adverse reaction occurred in 39% of patients. Those which required dosage interruption in >2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness. Dose reductions due to an adverse reaction occurred in 13% of patients. The most frequently reported adverse reaction which required dose reduction was fatigue (7%). The most common adverse reactions (≥25%), including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin (93%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%). Adverse Reactions in LITESPARK-005 Serious adverse reactions occurred in 38% of patients. The most frequently reported serious adverse reactions were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%), and pleural effusion (2.2%). Fatal adverse reactions occurred in 3.2% of patients who received WELIREG, including sepsis (0.5%) and hemorrhage (0.5%). WELIREG was permanently discontinued due to adverse reactions in 6% of patients. Adverse reactions which resulted in permanent discontinuation (≥0.5%) were hypoxia (1.1%), anemia (0.5%), and hemorrhage (0.5%). Dosage interruptions due to an adverse reaction occurred in 39% of patients. Of the patients who received WELIREG, 28% were 65 to 74 years, and 10% were 75 years and over. Dose interruptions occurred in 48% of patients ≥65 years of age and in 34% of younger patients. Adverse reactions which required dosage interruption in ≥2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%), fatigue (3.2%), and hemorrhage (2.2%). Dose reductions due to an adverse reaction occurred in 13% of patients. Dose reductions occurred in 18% of patients ≥65 years of age and in 10% of younger patients. The most frequently reported adverse reactions which required dose reduction (≥1.0%) were hypoxia (5%) and anemia (3.2%). The most common (≥25%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin (88%), fatigue (43%), musculoskeletal pain (34%), increased creatinine (34%), decreased lymphocytes (34%), increased alanine aminotransferase (32%), decreased sodium (31%), increased potassium (29%), and increased aspartate aminotransferase (27%). Adverse Reactions in LITESPARK-015 Serious adverse reactions occurred in 36% of patients. The most frequently reported serious adverse reactions were anemia and hypertension (4.2% each) and pyelonephritis, pneumonia, hypoxia, dyspnea and hemorrhage (2.8% each). WELIREG was permanently discontinued due to adverse reactions in 2 patients (2.8%). Adverse reactions which resulted in permanent discontinuation were increased alanine aminotransferase and paraparesis (1.4% each). Dosage interruptions due to an adverse reaction occurred in 40% of patients. Of the patients who received WELIREG, 13% were ≥65 years old and 4.2% were ≥75 years. Adverse reactions which required dosage interruption in >3% of patients were hypoxia, nausea and fatigue (4.2% each). Dose reductions due to an adverse reaction occurred in 14% of patients. The most frequently reported adverse reaction which required dose reduction was hypoxia (4.2%). The most common (≥25%) adverse reactions, including laboratory abnormalities, that occurred in patients were anemia (96%), fatigue (56%), musculoskeletal pain (56%), decreased lymphocytes (54%), increased alanine aminotransferase (51%), increased aspartate aminotransferase (42%), increased calcium (34%), dyspnea (33%), increased potassium (31%), decreased leukocytes (30%), headache (29%), increased alkaline phosphatase (25%), dizziness (26%) and nausea (25%). Drug Interactions Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases plasma exposure of belzutifan, which may increase the incidence and severity of adverse reactions. Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended. Coadministration of WELIREG with CYP3A4 substrates decreases concentrations of CYP3A4 substrates, which may reduce the efficacy of these substrates or lead to therapeutic failures. Avoid coadministration with sensitive CYP3A4 substrates. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information. Coadministration of WELIREG with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding. Lactation Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with WELIREG and for 1 week after the last dose. Females and Males of Reproductive Potential WELIREG can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating treatment with WELIREG. Use of WELIREG may reduce the efficacy of hormonal contraceptives. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose. Based on findings in animals, WELIREG may impair fertility in males and females of reproductive potential and the reversibility of this effect is unknown. Pediatric Use The safety and effectiveness of WELIREG have been established in pediatric patients aged 12 years and older for the treatment of locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma. Renal Impairment For patients with severe renal impairment (eGFR 15-29 mL/min estimated by MDRD), monitor for increased adverse reactions and modify the dosage as recommended. Hepatic Impairment WELIREG has not been studied in patients with severe hepatic impairment (total bilirubin >1.5 x ULN and any AST). For patients with moderate and severe hepatic impairment, monitor for increased adverse reactions and modify the dosage as recommended. Please see Prescribing Information, including information for the Boxed Warning about embryo-fetal toxicity, for WELIREG (belzutifan) at https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_pi.pdf and Medication Guide for WELIREG at https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_mg.pdf. About the Astellas, Pfizer and Merck collaboration Merck previously entered a clinical collaboration agreement with Seagen and Astellas to evaluate the combination of Merck’s KEYTRUDA® (pembrolizumab) and Seagen’s and Astellas’ Padcev® (enfortumab vedotin-ejfv) in patients with muscle-invasive bladder cancer (MIBC) who are not eligible for or declined cisplatin-based chemotherapy. Padcev® and the Padcev device are trademarks jointly owned by Agensys, Inc., and Seagen Inc. Pfizer Inc. completed its acquisition of Seagen on December 14, 2023. About the Daiichi Sankyo and Merck collaboration Daiichi Sankyo and Merck entered into a global collaboration in October 2023 to jointly develop and commercialize patritumab deruxtecan (HER3-DXd), ifinatamab deruxtecan (I-DXd) and raludotatug deruxtecan (R-DXd), except in Japan where Daiichi Sankyo will maintain exclusive rights. Daiichi Sankyo will be solely responsible for manufacturing and supply. In August 2024, the global co-development and co-commercialization agreement was expanded to include gocatamig (MK-6070/DS3280), which the companies will jointly develop and commercialize worldwide, except in Japan where Merck will maintain exclusive rights. Merck will be solely responsible for manufacturing and supply for gocatamig. About the Merck and Eisai strategic collaboration In March 2018, Eisai and Merck, known as MSD outside of the United States and Canada, through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA. Under the agreement, the companies jointly develop, manufacture and commercialize LENVIMA, both as monotherapy and in combination with Merck’s anti-PD-1 therapy KEYTRUDA. Eisai and Merck are studying the KEYTRUDA plus LENVIMA combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program. Merck’s focus on cancer Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit https://www.merck.com/research/oncology. 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 evaluating our portfolio of medicines and pipeline candidates in earlier disease states, with more than 30 ongoing registrational studies across multiple types of cancer. About Merck 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 innovation 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, 2024 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).