Trastuzumab vedotin

摘要：抗体药物偶联物（ADCs）已经彻底改变了包括乳腺癌在内的许多类型癌症的治疗方法。最近，两种新的ADC药物获得批准，曲妥珠单抗德鲁替康和萨西图珠单抗戈维替康；两者在总生存期方面都展示了令人印象深刻的改善，曲妥珠单抗德鲁替康在所有三种亚型的转移性乳腺癌中，萨西图珠单抗戈维替康在亮面和三阴性转移性乳腺癌中。这些药物是ADC三个组成部分——单克隆抗体、有效载荷和连接体——构建方面取得显著进展和创新的结果，并且是新靶点抗原发现的结果。ADC工程学深刻改变了癌症治疗的范式，一方面对被认为天生对药物有效载荷类别具有抗性的肿瘤有效，另一方面在目标表达非常低的肿瘤中也显示出活性。然而，我们可能只是处于一个新时代的开始，随着新靶点的识别以及新的ADC结构和组合的引入，ADC领域将在未来几年迅速扩展。 1.  引言 在过去十年中，杂交瘤技术的快速发展，以及更多亲水性和血液稳定的连接体的开发，以及更广泛高效载荷的引入，导致了第三代抗体-药物偶联物（ADCs）的开发，与传统疗法相比，ADCs具有多个优点。鉴于每个组分与肿瘤和肿瘤微环境的复杂相互作用，新一代ADCs的活性超越了选择性地向肿瘤传递高细胞毒性载荷，并扩展到被认为天生对治疗药物类别具有抗性的肿瘤。事实上，由于连接体偶联不影响抗原结合位点，抗体骨架保持了其自身的肿瘤靶点调节功能，并通过其Fc区域激活抗体依赖性细胞毒性（ADCC）、抗体依赖性细胞吞噬作用和补体依赖性细胞毒性（CDC）。此外，可切割连接体的日益增长的使用允许亲脂性载荷穿过细胞膜扩散，有可能杀死不表达ADC靶标的邻近细胞，即所谓的旁观者效应。最后，新偶联技术的快速发展和亲水性连接体的日益增长的使用导致了更加均匀和稳定的ADCs，具有更高的药物对抗体比例和更低的免疫原性。目前，已有14种ADCs在不同国家获得批准，用于实体瘤和血液肿瘤的治疗，其中3种被批准用于早期或转移性乳腺癌（BC）的治疗，在所有三种BC亚型中展示了总生存期（OS）的显著改善。然而，我们只是处于一个新时代的开始，ADC领域可能会迅速丰富，基于新技术和靶点抗原的新有希望的化合物将会出现。不幸的是，ADCs也导致了新的毒性，这可能会影响患者的生活质量，并需要教育以实现其最佳管理。目前，大量试验正在评估新的ADCs和基于ADC的组合，以进一步提高疗效结果，并更好地理解未识别的抗性机制、特定毒性和缺乏预测性生物标志物。在这篇综述中，我们讨论了ADCs在乳腺癌治疗中的未来之路。 2.  目前，针对乳腺癌的已批准ADCs 2.1.  靶向HER2 Ado-trastuzumab emtansine（T-DM1），一种第二代抗HER2 ADC，是首个被批准用于治疗HER2阳性乳腺癌患者的ADC。T-DM1，一种基于曲妥珠单抗的ADC，携带一种细胞毒性微管抑制剂作为有效载荷，通过硫醚不可切割连接体显著改善了无进展生存期（PFS）和总生存期（OS），用于二线及以后治疗的HER2阳性乳腺癌患者。在III期临床试验TH3RESA中，606名经过大量预处理（平均4线）的患者被随机分配接受T-DM1（n=404）或医生选择的治疗（n=198）。实验组的中位OS明显更长（22.7比15.8个月；HR 0.68，95%CI 0.54–0.85），尽管对照组有47%的患者在疾病进展时接受了T-DM1。在III期EMILIA试验中，T-DM1与当时二线最常用的治疗方案拉帕替尼加卡培他滨进行了比较，在991名曾接受曲妥珠单抗和紫杉醇治疗的HER2阳性乳腺癌患者中。T-DM1在客观反应率（ORR，43.6%比30.8%）、中位PFS（9.6比6.4个月；HR 0.65，95%CI 0.55–0.77）和OS（29.9比25.9个月；HR 0.75，95%CI 0.64–0.88）方面明显优于标准治疗。鉴于其美登素载荷，T-DM1最常见的不良事件（AEs）是血小板减少（3级，14%）和肝毒性（3级，5%）。基于在转移环境中的积极结果，T-DM1作为辅助治疗在新辅助化疗后仍有残留浸润性疾病的HER2阳性乳腺癌患者中进行了测试。改变实践的KATHERINE试验表明，与辅助曲妥珠单抗相比，辅助T-DM1将复发风险减半。 最近，第二种抗HER2 ADC，trastuzumab-deruxtecan（T-DXd）彻底改变了转移性乳腺癌的治疗。T-DXd由一种可切割的四肽连接体和一种exatecan衍生物组成，这是一种喜树碱类似物，通过抑制拓扑异构酶I（TOPO1）导致DNA断裂。在II期单组DESTINY-Breast01研究的显著结果之后，该研究促成了2019年12月的FDA加速批准，进一步的研究证实了T-DXd在HER2阳性和HER2低表达（免疫组化1+或2+和原位杂交阴性结果）患者中相较于标准治疗的更大疗效。关键的III期DESTINY-Breast03试验比较了T-DXd和T-DM1在转移性HER2阳性乳腺癌中的疗效，这些患者之前曾接受过紫杉醇和曲妥珠单抗治疗。共有524名患者被随机分配接受T-DXd或T-DM1。与T-DM1相比，T-DXd的中位PFS延长了4倍（28.8比6.8个月；HR 0.33，95% CI 0.26–0.43）。在平均研究随访28.4个月（范围，0.0–46.9个月）时，两组均未达到中位OS，但差异显著（HR 0.64，95% CI 0.47–0.87）。此外，III期DESTINY-Breast02研究比较了T-DXd与医生选择的治疗在曾接受过T-DM1的HER2阳性转移性乳腺癌患者中的疗效，证实了T-DXd在后续治疗线中的更大疗效，中位PFS为17.8个月，而标准治疗为6.9个月（HR 0.36，95% CI 0.28–0.45）。 基于T-DXd旁观者效应的临床前证据以及I期的初步数据，III期DESTINY-Breast04试验评估了T-DXd在经治的HER2低表达转移性乳腺癌患者中的疗效，这些患者曾接受过一线或两线的化疗。共有557名患者被随机分配接受T-DXd或医生选择的化疗。在激素受体（HR）阳性的患者亚组中（n=494），T-DXd改善了中位PFS（10.1比5.4个月；HR 0.51，95%CI 0.40–0.64）和OS（23.9比17.5个月；HR 0.64，95%CI 0.48–0.86）。这些益处也见于HR阴性乳腺癌患者，中位PFS为9.9（比5.1个月；HR 0.50，95%CI 0.40–0.63）和OS为23.4（比16.8个月；HR 0.64，95%CI 0.49–0.84），尽管这是对58名患者的探索性分析的限制。有趣的是，T-DXd在HER2阴性乳腺癌患者中也显示出活性，如II期DAISY研究所示，在该研究中，转移性乳腺癌患者根据HER2表达被分为三个队列接受T-DXd治疗。在高HER2表达队列中注册的患者（免疫组化[IHC] 3+或IHC2+/ISH+），ORR为69.1%，中位PFS为11.1个月。HER2低表达队列中的患者（IHC1+或IHC2+/ISH-肿瘤）的ORR为33.3%，中位PFS为6.7个月。在HER2非表达队列中（IHC 0），ORR为30.6%，中位PFS为4.2个月。总的来说，T-DXd具有普遍可控的安全性概况，血液学、低级别胃肠道不良事件是最常见的。间质性肺毒性（ILD）是最令人关注的不良事件。在九项I/II期T-DXd单药治疗的汇总分析中，ILD的总发生率为15.4%，其中大多数为低级别；77.4%为1级或2级，在极少数情况下是致命的（5级，2.2%）。可能与增加ILD风险相关的因素包括年龄<65岁，在日本招募，T-DXd剂量>6.4 mg/kg，氧饱和度<95%，中度/重度肾功能不全，存在肺部合并症，以及自最初诊断以来的时间>4年。尽管ILD的发病机制仍不清楚并正在调查中，但T-DXd可能通过不依赖靶标的摄取进入肺泡巨噬细胞可能是关键机制。 2.2.  靶向TROP-2 滋养层细胞表面抗原2（Trop-2）是一种跨膜糖蛋白，作为钙信号转导因子。在正常组织中含量较低，但在上皮性肿瘤中高度表达，包括80%的乳腺癌患者，Trop-2的过度表达与肿瘤的侵袭性和生长有关，这是由于间充质至上皮的转录调控。Sacituzumab govitecan是一种针对Trop-2的首创ADC，其中抗Trop-2抗体通过可水解连接体与SN-38偶联，SN-38是拓扑异构酶I抑制剂伊立替康的活性代谢产物。在ASCENT试验中，在至少接受过两种系统治疗的转移性三阴性乳腺癌（TNBC）患者中，与医生选择的单药化疗相比，sacituzumab govitecan展示了增加的中位PFS（5.6个月对1.7个月；HR 0.41，95% CI 0.32–0.52）、OS（12.1个月对6.7个月（HR 0.48，95% CI 0.38–0.59））和ORR（35%对5%）。在TROPiCS-02试验中，在至少接受过一种基于内分泌治疗的转移性HR阳性乳腺癌患者中，包括之前的CDK4/6抑制剂，以及2至4线的转移性疾病化疗，sacituzumab govitecan与研究者的选择进行了比较。在中期分析中，sacituzumab govitecan显示出统计学上显著的PFS改善（5.5对4.0个月：HR 0.66，95% CI 0.53–0.83）和OS改善（14.4对11.2个月；HR 0.79，95%CI 0.65–0.96，p=0.02）优于标准化疗。在III期ASCENT和TROPiCS-02试验中，最临床相关的3级及以上不良事件是中性粒细胞减少、腹泻和脱发，主要与SN-38有关。尽管在开处sacituzumab govitecan时不需要药物基因组筛查，但在ASCENT试验中，携带UGT1A1*28等位基因纯合子的患者严重中性粒细胞减少症的发生率是其他患者的两倍。 3.  未来乳腺癌中的ADCs 在过去的十年中，我们见证了ADCs的前所未有快节奏的扩张，大量新型ADC结构进入了临床开发，利用新的抗体骨架，通常针对多个抗原或不同的表位，新载荷概念，包括非化疗药物，以及更广泛的适用靶点，不仅在肿瘤中，也在肿瘤微环境中。以下是目前正在BC中探索的新型ADC结构的主要属性，特别关注进一步的潜在临床开发（表1）。 3.1.  针对已知抗原的新ADC结构 几项正在进行的试验一直在评估针对已知抗原的新ADC结构，即HER2和Trop-2，旨在提高治疗的疗效和耐受性。 3.1.1.  HER2 最近至少有8种不同的针对HER2的ADCs进入了临床开发，显示出不同的活性和毒性特征。Vic-trastuzumab duocarmazine（SYD985）由一个DNA烷基化剂载荷通过可切割连接体附在曲妥珠单抗上。在I期试验中显示出对经过大量预处理的HER2阳性和HER2低表达乳腺癌患者显著的临床活性，并获得了FDA快速通道指定后，在III期TULIP试验中与标准治疗相比表现良好。该研究达到了其主要终点，通过增加中位PFS（7.0对4.9个月；HR 0.64，95%CI 0.49–0.84）并显示出OS获益的趋势（HR 0.83，95%CI 0.62–1.09）。最常见的治疗相关不良事件是眼部毒性，76%的患者报告了任何级别的结膜炎和角膜炎，12.2%和5.6%的患者报告了3级或更高级别的角膜炎和结膜炎。值得注意的是，接受Vic-trastuzumab duocarmazine治疗的患者中有7.6%（5.2% 1-2级）报告了ILD，包括两名5级患者。正在评估不同的缓解措施，如预防性使用眼药水。 Disitamab Vedotin（RC48）由一种新型人源化单克隆抗体组成，针对HER2，hertuzumab，其特点是对HER2的亲和力更高，ADCC更强，以及通过可切割连接体偶联的单甲基奥瑞他汀E（MMAE）载荷。在剂量递增的C001 CANCER I期试验中，RC48在不同HER2表达水平的患者中显示出活性。在HER2阳性亚组中，RC48 1.5、2.0和2.5 mg/kg剂量的ORR分别为22.2%、42.9%和40.0%，中位PFS分别为4.0、5.7和6.3个月。在HER2低表达亚组中，RC48 2.0 mg/kg的ORR和中位PFS分别为39.6%和5.7个月。这种化合物还获得了中国国家药品监督管理局（NMPA）的有条件批准，用于治疗HER2阳性局部晚期或转移性胃癌患者和转移性尿路上皮癌患者。 ARX788是一种基于非天然氨基酸的位点特异性共轭技术的ADC，因此具有很高的均匀性。它由一种人源化HER2抗体组成，结合了一种微管抑制剂amberstatin（AS269）。在一项只招募HER2阳性乳腺癌患者的I期试验中，ORR为65.5%，中位PFS为17.0个月。最常见的3-4级不良事件是眼部不良事件（5.7%）和肺炎（4.3%）。正在进行的2期ACE-Breast-03（NCT04829604）研究正在评估ARX788在对T-DM1、T-DXd和/或含tucatinib方案耐药的转移性HER2阳性乳腺癌患者的活性和安全性。然而，ARX788的开发目前处于暂停状态。 其他两种含有MMAE载荷的ADCs在临床开发中也显示出对HER2阳性乳腺癌患者有希望的活性。首先，ALT-P7在一项招募了27名接受过至少两种抗HER2治疗的HER2阳性乳腺癌患者的I期试验中，ORR为77%，中位PFS为6.2个月。最常见的不良事件包括肌痛（33.3%）、疲劳（25.9%）、感觉神经病变（22.2%）、脱发（22.2%）、瘙痒（22.2%）和中性粒细胞减少症（22.2%）。第二种，MRG002，在HER2低表达乳腺癌患者中显示出显著的活性，IHC 1+和2+的ORR分别为34.1%和37.5%。报告的不良事件包括中性粒细胞减少症（53.6%）、天门冬氨酸氨基转移酶和丙氨酸氨基转移酶增加（分别为46.4%和32.1%）以及脱发（39.3%）。 3.1.2.  靶向TROP-2 Datopotamab deruxtecan（Dato-DXd）是一种第三代ADC，靶向Trop-2，由一个IgG1单抗与一个拓扑异构酶I抑制剂（MAAA-1181a，一种exatecan衍生物）通过一个基于四肽的可切割连接体偶联，药物与抗体的比例约为4:1。目前，作为单药或与免疫检查点抑制剂联合使用，正在进行多个I-III期研究。在正在进行的I期多队列研究TROPION-PanTumor01（NCT03401385）中，44名经过大量预处理的TNBC患者观察到32%的ORR和80%的疾病控制率（DCR）。值得注意的是，在接受过靶向拓扑异构酶I的ADC治疗的13名患者中，也有9名报告了肿瘤缩小。最常见的任何级别的不良事件包括口腔炎（73%）、恶心（66%）、呕吐（39%）、疲劳（34%）和脱发（36%）；3级口腔炎在11%的病例中报告。在先前接受过RH+/HER2-转移性乳腺癌治疗的患者队列中，ORR为29%，DCR为85%。最常见的不良事件包括口腔炎（80%）、恶心（56%）、疲劳（46%）和脱发（37%）。目前正在进行两项III期试验，评估Dato-DXd与标准护理相比作为晚期TNBC患者的一线治疗（NCT05374512）以及作为晚期HR阳性乳腺癌患者的二线或三线治疗（NCT05104866）。此外，一项III期试验正在评估Dato-DXd联合或不联合durvalumab治疗接受过新辅助系统治疗后仍有残留浸润性疾病的I至III期TNBC患者（NCT05629585）。 3.2.  新型选择性靶点 3.2.1  HER3 HER3是一种跨膜生长因子受体，在50%的乳腺癌中过度表达。HER3介导对EGFR、HER2、PI3K/AKT/mTOR导向治疗和内分泌治疗的抗性，其变构功能对HER2放大的癌症生长至关重要[38–40]。HER3过度表达与不同肿瘤类型（包括乳腺癌）的癌症进展风险更高和预后更差有关。Patritumab deruxtecan（U3-1402，HER3-DXd）是一种靶向HER3的ADC，由一个人类IgG1单抗（mAb，patritumab）与一个拓扑异构酶I抑制剂载荷（MAAA-1181a，一种exatecan衍生物）通过一个基于四肽的可切割连接体链接，具有高达8的药物与抗体比例。1/2期研究U3-1402-J101研究包括HER3+（IHC 2+或3+）的经过大量预处理的转移性乳腺癌患者：113例亮面型，53例TNBC和14例HER2阳性乳腺癌。ORR分别为30%、23%和43%。有趣的是，HER3-DXd的活性与HER3表达无关。同样，在TOT-HER3研究中，测试了HER3-DXd单剂量在未经治疗的早期亮面型乳腺癌患者的临床和生物学活性，ORR与基线HER3 IHC和ERBB3 mRNA表达水平无关。目前正在早期和转移性环境中进行进一步的II期和III期研究（NCT05569811, NCT04965766, NCT04699630）。 3.2.2.  LIV-1 LIV-1是一种具有金属蛋白酶活性的跨膜蛋白，属于ZIP（Zrt, Irt-like proteins）锌转运蛋白的一个亚家族，在不同正常组织中表达异质。中/高LIV-1表达在约90%的HR阳性乳腺癌和TNBC中被发现，它与淋巴结和远处转移进展相关，与其在上皮-间充质转化中的作用一致，通过E-钙粘蛋白下调。Ladiratuzumab vedotin（SGN-LIV1A）是一种ADC，由一个针对LIV-1的人源化单抗组成，通过一个可被蛋白酶切割的连接体与一种强效的微管破坏剂，单甲基奥瑞他汀E（MMAE）载荷偶联，是dolastatin 10的合成类似物，它决定了G2/M细胞周期停滞并最终导致细胞凋亡。 目前正在积极招募经过大量预处理的转移性LIV-1阳性TNBC或HR阳性内分泌抵抗性乳腺癌患者进行I期开放标签剂量递增和扩展研究（NCT01969643）。纳入剂量递增和扩展队列的44名TNBC患者的中期分析显示，ORR为32%，中位PFS为11.3周（95%CI 6.1–17.1周），最常见的所有级别不良事件为疲劳（59%）、恶心（51%）和周围神经病变（44%），而中性粒细胞减少（25%）和贫血（15%）是最常见的3级和4级不良事件。确定的RP2D为每3周2.5 mg/kg，然而也在研究每周一次的计划，以确定它是否扩大了治疗窗口。在适应性平台试验I-SPY2中，与标准臂相比，新辅助疗法使用4个周期的SNG-LIV1A 2.5 mg/kg每3周，然后是4个周期的多柔比星+环磷酰胺，并没有增加病理完全缓解率。尽管正常的凋亡死亡是非免疫原性的，但临床前证据表明SGN-LIV1在LIV-1阳性细胞中诱导ER应激并释放免疫原性细胞死亡（ICD）标志物，如ATP和HMGB1。基于这些数据，2项正在进行的研究正在评估SGN-LIV1A与pembrolizumab（NCT03310957）或atezolizumab（NCT03424005）的组合在TNBC患者中的活性，作为一线或二线治疗，无论PD-L1和LIV-1表达如何。 3.2.3.  Nectin-4 Nectin-4是一种参与细胞增殖、迁移和粘附的跨膜糖蛋白。在60%的膀胱癌和乳腺癌中报告了中度至强染色，而其在正常组织中的表达较低。Enfortumab vedotin（EV）是一种靶向nectin-4的第三代ADC，由一个完全人源化的IgG1抗体与一个微管抑制剂（MMAE）通过一个可被蛋白酶切割的连接体偶联。2021年9月，它获得了FDA批准用于治疗转移性尿路上皮癌患者。目前，一项多队列的2期研究（NCT04225117）正在评估EV在不同局部晚期实体瘤患者中的活性和毒性，包括接受过预处理的HR阳性乳腺癌和TNBC患者。Nectin-4表达不是研究纳入标准，而是作为探索性生物标志物进行评估。 3.2.4.  CEACAM5 另一个新兴靶点是癌胚抗原（CEA）相关的细胞黏附分子5（CEACAM5），一种跨膜糖蛋白，在包括胃肠道、肺和乳腺在内的多种肿瘤类型中高度表达，其中它参与肿瘤侵袭和转移，而其在正常组织中的表达较低。Tusamitamab ravtansine（SAR408701）是一种新型靶向CEACAM5的ADC。它包含一个与DM4偶联的人源化单抗，通过一个可切割的N-succinimidyl 4-(2-pyridyldithio)丁酸酯（SPDB）连接体。在I期研究中，92名不同CEACAM 5表达水平的患者接受了逐步增加剂量的SAR-408701治疗，包括1名乳腺癌患者。总体上，在低表达和高表达队列中分别观察到2个部分缓解（ORR 7.1%）和13个PRs（ORR 20.3%）。最常见的治疗相关不良事件是乏力、食欲下降、角膜炎和恶心，每项在25%的参与者中观察到。目前正在对SAR-408701进行非小细胞肺癌和其他实体瘤的II期和III期临床试验（NCT04154956, NCT04659603, NCT04394624, NCT05071053, NCT04524689）。 3.3.  新ADC构建 3.3.1.  抗体技术 ADC的抗体部分技术不断发展，目标是优化细胞内吞率、肿瘤渗透性和从肿瘤微环境中招募细胞。 双特异性ADCs，即针对同一癌细胞上的两种不同受体，或双特异性ADCs，即针对同一受体上的两种不同表位，旨在提高靶向特异性、内吞作用，同时最小化对健康组织的毒性。MEDI4276结合了一种双特异性抗体，针对HER2上的两个不重叠表位，特异性共轭到一种基于tubulysin的微管抑制剂载荷。通过增加内吞作用和溶酶体的运输及降解，它在体内模型中显示出强大的抗肿瘤潜力，特别是在T-DM1耐药或HER2表达低的情况下。在一项针对接受过抗HER2药物治疗的晚期或转移性HER2阳性乳腺癌患者的I期试验中，MEDI4276导致了1/47的完全反应（0.5 mg/kg）和2/47的部分反应（0.6和0.75 mg/kg），但主要由于肝功能测试增加而产生不可接受的毒性。另一个概念是使用一个内吞作用差但特异性的抗原与一个内吞作用快速的抗原。这样，快速内吞的抗原加速了内吞作用差的抗原的摄取。从这个意义上说，一种靶向HER2和催乳素受体（PRLR）的双特异性ADC比靶向HER2的ADC更有效地杀死癌细胞。与HER2相比，PRLR快速且持续地内吞，PRLR在细胞表面的水平足以确保内吞作用。使用一种结合了两种受体的双特异性ADC，非共价交叉结合HER2和PRLR到细胞表面，显著提高了内吞作用和细胞毒性潜力。 Probody药物偶联物是扩大治疗窗口的另一项创新技术。它们是一类利用肿瘤蛋白酶活性来传递其治疗效果到肿瘤微环境而不是健康组织的新一类蛋白酶激活的重组抗体前药。在肿瘤内靶向肿瘤可以减少不良反应，从而提高安全性和/或剂量。最近，CX-2009，一种针对CD166（ALCAM）的Probody药物偶联物，与DM4共轭，在涉及92名患者（其中39名患有晚期乳腺癌）的I期试验中进行了研究。在5名乳腺癌患者中观察到部分反应，消化和剂量依赖性眼部毒性是最频繁的不良事件。目前，CX-2009的开发已中断。 另一种发展方向是用小分子替换抗体骨架。小分子药物偶联物（SMDCs）仍处于开发的早期阶段，但它们可能具有较小的免疫原性、更容易合成，以及穿透实体瘤和解剖屏障的高潜力。 3.4.  新载荷 免疫刺激抗体偶联物（ISACs）使用免疫刺激剂，如Toll样受体（TLR）激动剂、干扰素刺激基因激动剂（STING）作为载荷。这些免疫刺激剂不能安全地系统性给药，但通过使用特异性靶向抗体，它们可以被传递到肿瘤细胞或微环境细胞。在临床前小鼠模型中，BDC-1001是一个由双TLR7/8激动剂与靶向HER2的抗体共轭而成的ISAC，引发了局部免疫反应，导致肿瘤中髓系和T细胞的减少和免疫记忆。目前正在进行一项1/2期剂量递增/扩展研究，以评估BDC-1001 ± pembrolizumab在接受标准治疗后病情进展的HER2表达实体瘤患者中的疗效（NCT04278144）。SBT6050也是一个由TLR8激动剂与靶向HER2的单克隆抗体共轭而成的ISAC。它在体外和体内显示出令人鼓舞的结果，特别是在与曲妥珠单抗联合使用时。其他含有细胞毒素放射性同位素的ADCs已显示出临床活性，如ibritumomab tiuxetan，一种与碘-131链接的抗CD20抗体，用于治疗淋巴瘤。然而，据我们所知，目前没有含有细胞毒素放射性同位素的ADCs在乳腺癌中进行开发。 4.  乳腺癌中未来ADCs组合策略 4.1.  ADCs和免疫检查点抑制剂 大量临床前证据支持将ADCs与免疫疗法结合使用。首先，大多数ADCs诱导ICD，ICD包括细胞表面暴露或死亡细胞释放损伤相关分子模式（DAMPs）。DAMPs被免疫系统识别，并最终导致吞噬肿瘤细胞的抗原呈递细胞和交叉呈递给细胞毒性T细胞。其次，抗体骨架通常保持其免疫效应功能，能够通过其Fc部分激活ADCC和CDC。最后，微管抑制剂载荷（美登素类、多拉司他汀、奥瑞他汀）和拓扑异构酶I抑制剂载荷能够直接诱导树突细胞激活。总的来说，这些证据为将ADCs和免疫疗法结合提供了强有力的理由，这种组合可以进一步增加肿瘤微环境中的T细胞浸润。 在乳腺癌中将免疫检查点抑制剂与ADC结合的最早试验是在HER2阳性乳腺癌患者中进行的。随机II期KATE2试验招募了330名接受过治疗的HER2阳性乳腺癌患者，结果显示，将atezolizumab添加到T-DM1中，无论是在意向治疗人群（HR 0.82, 95%CI 0.55–1.23和HR 0.74, 95%CI 0.42–1.30）还是PDL1阳性人群中（HR 0.60, 95%CI 0.32–1.11和HR 0.55, 95%CI 0.22–1.38），都没有带来统计学意义上的PFS和OS益处。组合臂中的不良事件更为常见，主要涉及血小板减少症（13%对4%）、天门冬氨酸氨基转移酶增加（8%对3%）和贫血（5%对0%），导致研究因无效而终止。T-DM1和atezolizumab单药治疗的药代动力学和免疫原性结果符合预期；值得注意的是，1.7%和12.1%的患者报告了针对T-DM1和atezolizumab的治疗性抗体。一个较小的Ib期试验（NCT03032107）评估了T-DM1和pembrolizumab在20名接受过治疗的HER2阳性乳腺癌患者中的组合，报告了20%的ORR（95% CI 5.7–43.7%）和9.6个月的中位PFS（95% CI 2.8–16个月）。所有治疗相关的不良事件均为2级和3级（分别为65%和20%）。PDL-1和肿瘤浸润性淋巴细胞与这个小队列的反应无关。最近，一项1b期研究（NCT03523572）评估了T-DXd和nivolumab在经过大量预处理的HER2表达（HER2阳性或HER2低）转移性乳腺癌和尿路上皮癌患者中的组合。ORR分别为65.6%（95% CI, 46.8–81.4）和50%（95% CI, 24.7–75.3），中位PFS分别为11.6个月（95% CI, 6.9-未达到）和7.0个月（95% CI, 2.3–10.8）。然而，与T-DXd单药治疗在HER2阳性患者中的疗效结果（DESTINY-Breast02中的ORR 60.9%和PFS 16.4个月）相比，这些结果令人失望。每种研究药物单药治疗的安全概况符合预期。治疗相关的不良事件发生在≥3级的比例为48.9%；ILD发生在7名患者中（14.6%），其中6名为2级，1名为5级。相比之下，T-DXd和durvalumab的组合在Ib期研究BEGONIA中显示出有希望的结果，这是一项多臂试验，评估了转移性乳腺癌一线治疗中的不同治疗组合。在HR-/HER2低BC队列中，ORR为57%（26/46），中位PFS为12.6个月（95% CI, 8-未达到），与PDL1状态无关。所有等级中最常见的不良事件为恶心（73%）、疲劳（46%）和呕吐（30%）。5名患者（9%）经历了与治疗相关的间质性肺病或肺炎，大多数为1级或2级，1例与COVID相关的5级病例。 ADCs与免疫检查点抑制剂的组合也在TNBC中进行了评估。在Ib期试验（NCT03310957）中，对51名未经治疗的晚期TNBC患者进行了拉迪拉图单抗vedotin和pembrolizumab的组合评估。在这项进行中的试验中，至少有3个月随访的26名患者的ORR为54%（95% CI 33.4–73.4），超过了pembrolizumab单药治疗在PDL-1阳性TNBC患者中的疗效（ORR 21.4% [95% CI 13.9–31.4] ）。最常见的≥3级不良事件是中性粒细胞减少症（16%）、腹泻、疲劳、低钾血症和斑丘疹（各8%），以及腹痛、丙氨酸氨基转移酶增加和尿路感染（各6%）。同样，在BEGONIA试验的TNBC队列中，47名接受Dato-DXd和durvalumab组合治疗的患者，无论PD-L1表达如何，ORR为79%（95% CI, 61%-91%）。100%的完全或部分反应患者在6个月随访时仍处于反应状态。任何级别的最常见不良事件是胃肠道（恶心55%和口腔炎51%）。没有报告间质性肺病/肺炎或血小板减少症的病例。 其他组合正在I-II期试验中评估，例如：T-DXd与pembrolizumab（NCT04042701）或durvalumab或durvalumab加紫杉醇（NCT04538742），在转移性HER2阳性BC中；T-DXd与durvalumab加紫杉醇在转移性HER2低BC中（NCT04556773）；sacituzumab govitecan与pembrolizumab（NCT04468061）或与atezolizumab（NCT03424005）。 4.2.  ADCs和靶向疗法 靶向疗法和ADCs的组合主要在HER2阳性BC中进行了评估。T-DM1和pertuzumab在细胞培养模型中显示出协同活性，并在Ib/II期研究中具有可接受的安全性。在纳入接受过治疗的HER2阳性BC患者的MARIANNE试验中，将pertuzumab添加到T-DM1中没有实现临床上显著的OS益处（51.8 vs 53.7个月），两组之间的治疗相关不良事件相似（48.6 vs 47.1%）。T-DM1和pertuzumab的组合也在两个试验的新辅助环境中进行了评估。KRISTINE研究比较了新辅助T-DM1 plus pertuzumab与多西他赛、卡铂、曲妥珠单抗 plus pertuzumab在444名II/III期HER2阳性BC患者中的疗效。T-DM1和pertuzumab的组合与多西他赛-卡铂-曲妥珠单抗-pertuzumab（TCHP）治疗相比，在手术前局部区域进展更多（6.7 vs. 0%）的情况下，无事件生存期更短（HR 2.61, 95%CI 1.36–4.98）。相比之下，手术后的无侵袭疾病生存期相似（HR 1.11, 95%CI 0.52–2.40）。T-DM1臂的病理完全缓解率为44.4%，而标准方案为55.7%。在I-SPY II期试验中也取得了类似的结果，该试验将临床II/III期HER2阳性BC患者随机分配到T-DM1 plus pertuzumab、紫杉醇 plus pertuzumab和曲妥珠单抗，或紫杉醇 plus 曲妥珠单抗，然后进行多柔比星/环磷酰胺治疗，然后手术。T-DM1臂的3年无事件生存率为88%（95% CI 79–99%），而紫杉醇 plus pertuzumab和曲妥珠单抗为92%（95% CI 84–100%），紫杉醇 plus 曲妥珠单抗为87%（95% CI 75–100%）。值得注意的是，基线时HER2通路信号和磷酸化程度与T-DM1 plus pertuzumab组合的反应相关，并可以进一步识别对这种组合高度敏感的患者。此外，T-DM1与pertuzumab的不足疗效可能受到肿瘤内HER2异质性的驱动。实际上，HER2异质性，定义为ERBB2扩增区域>5%但<50%的肿瘤细胞，或FISH检测的HER2阴性区域，在接受T-DM1和pertuzumab新辅助治疗的非异质性亚组中，完全缓解率分别为0%和55%。 最后，T-DM1在II期NSABP Foundation Trial FB-10中与neratinib联合。在这项研究中纳入的27名HER2阳性BC患者中，有19名患者可评估反应，ORR为63.2%。该研究内进行的转化研究表明，HER2抗体的抗性机制可能是HER2受体的丢失和p95HER2的高表达。 在开发有效的靶向疗法和ADCs后，TNBC中ADCs加靶向疗法组合的开发也加快了。聚腺苷二磷酸核糖聚合酶（PARP）抑制剂，即olaparib和talazoparib，在OLYMPIAD和EMBRACA试验中将HER2阴性BC和BRCA胚系突变患者的PFS大约减半[87, 88]。在Ib期SEASTAR研究中报告了两例TNBC患者接受rucaparib plus sacituzumab govitecan的组合。第一名患者有有害的同源重组修复基因（HRR）突变，部分反应，第二名患者没有HRR突变，在24周时病情稳定。正在进行的I/II期试验NCT04039230正在评估sacituzumab govitecan加talazoparib在转移性TNBC患者中的组合。 其他几个I/II期试验正在进行中，正在不同的BC亚组中测试基于ADC的组合与单克隆抗体、酪氨酸激酶抑制剂或内分泌疗法。 4.3.  ADCs和化疗 ADC与化疗组合的首个临床证据来自ECHELON-1试验，表明brentuximab vedotin改善了晚期霍奇金淋巴瘤患者的结果。此后，在实体瘤中评估了ADC和化疗的组合，并显示出有希望的疗效。很少有试验涉及BC中化疗和ADC的组合。I期试验，STELA，在14名可评估患者中，使用T-DM1 plus nab-paclitaxel和lapatinib治疗，ORR为85.7%。值得注意的是，T-DM1的药代动力学没有受到组合的影响。正在进行的篮式试验，包括转移性TNBC患者，正在评估ADC与化疗的组合（NCT02996825, NCT03102320, NCT04538742, NCT04556773）。 探索ACD组合的所有临床试验在表2中进行了总结。 5.  结论和展望 在过去的几年里，我们见证了实体瘤中，特别是在乳腺癌中，新ADCs的惊人发展，这得益于ADC生产新技术的可用性和新合适靶点的识别。然而，一方面治疗格局正在迅速被新的ADCs和新的ADC组合填补，另一方面我们迫切需要了解ADC的作用机制和抗性，以更好地定义临床实践中未来的ADC连续策略。抗性机制可能涉及目标抗原、ADC内吞、运输途径、细胞周期修饰和信号通路、药物外排泵、溶酶体功能、细胞毒素化合物靶标的改变以及凋亡失调。这些抗性机制中的许多目前正在接受第三代ADCs治疗的患者中进行积极评估。在DAISY试验中进行的转化研究揭示了额外的抗性机制。原发性抗性可能与HER2 0细胞的高患病率和空间分布或ERBB2半合子缺失有关，而获得性抗性涉及HER2表达的减少和SLX4突变的发生。同样，报告了两名患者对sacituzumab govitecan的抗性，其中一名缺乏TROP2表达并迅速进展，而另一名是长期反应者，最初TROP-2表达高，TACSTD2/TROP2基因局部扩增。在进展期，对最后一名患者的不同转移亚克隆的分析显示，获得性TOP1 E418K抗性突变和随后的移码TOP1突变，这些突变赋予了对SN-38的抗性，以及TACSTD2/TROP2 T256R错义突变，导致TROP-2的细胞膜定位缺陷。毫无疑问，对ADC抗性机制更全面的知识将使我们在未来能够根据每个患者的具体肿瘤特征和获得性抗性突变，选择最合适的ADC连续策略。由于ADC是模块化的，ADC平台的开发也可能进一步发展为更加个性化的、针对特定患者的化合物，其中抗体骨架、连接体和载荷的选择将基于特定肿瘤和肿瘤微环境激活的途径和表达的蛋白质。

RAHWAY, N.J.--( BUSINESS WIRE )--Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the Japanese Ministry of Health, Labor and Welfare (MHLW) has approved new indications for KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, in certain lung and urothelial cancers: KEYTRUDA in combination with chemotherapy as a neoadjuvant treatment, then continued as monotherapy as an adjuvant treatment, for patients with non-small cell lung carcinoma (NSCLC) based on results from the Phase 3 KEYNOTE-671 trial; KEYTRUDA in combination with Padcev (enfortumab vedotin-ejfv) for the first-line treatment of patients with radically unresectable urothelial carcinoma based on results from the Phase 3 KEYNOTE-A39 trial (also known as EV-302), which was conducted in a research collaboration with Pfizer (previously Seagen) and Astellas; KEYTRUDA monotherapy in patients with radically unresectable urothelial carcinoma who are not eligible for any platinum-containing chemotherapy based on results from the Phase 2 KEYNOTE-052 trial. “ For certain patients in Japan who are diagnosed with resectable non-small cell lung carcinoma and radically unresectable urothelial carcinoma, there is a need for new, effective treatment options,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “ With these new approvals, we look forward to providing KEYTRUDA as monotherapy and in combination with other treatment regimens as we aim to address the unmet needs of these patients.” Approval as perioperative treatment regimen in non-small cell lung carcinoma The approval of KEYTRUDA in combination with chemotherapy as a neoadjuvant treatment, then continued as monotherapy as an adjuvant treatment for patients with NSCLC is based on results from the Phase 3 KEYNOTE-671 trial. In this study, KEYTRUDA plus chemotherapy in the neoadjuvant setting followed by KEYTRUDA as monotherapy after surgical resection significantly improved overall survival (OS), reducing the risk of death by 28% (HR=0.72 [95% CI, 0.56-0.93]; one-sided p=0.00517) in patients with stage II, IIIA or IIIB NSCLC, regardless of PD-L1 expression, versus placebo plus chemotherapy in the neoadjuvant setting followed by placebo after surgical resection at a median follow-up of 29.8 months (range, 0.4 to 62.0 months). For patients who received the KEYTRUDA-based regimen, median OS was not reached (95% CI, NR-NR) versus 52.4 months (95% CI, 45.7-NR) for patients who received the chemotherapy-placebo regimen. The KEYTRUDA-based regimen also improved event-free survival, reducing the risk of disease recurrence, progression or death by 42% (HR=0.58 [95% CI, 0.46-0.72]; p<0.00001) compared to the chemotherapy-placebo regimen. Lung cancer is the leading cause of cancer death worldwide. In 2022, there were approximately 2.4 million new cases and 1.8 million deaths from lung cancer globally. In Japan alone, there were approximately 130,000 new cases of lung cancer diagnosed in 2019 and about 75,000 deaths from the disease in 2020. The overall five-year survival rate for lung cancer patients in Japan is about 35%. Non-small cell carcinoma is the most common type of lung cancer, accounting for about 85% of all cases. Non-small cell lung carcinoma is more common, whereas small cell lung cancer is less common and typically grows more quickly. Approvals in radically unresectable urothelial carcinoma The approval of KEYTRUDA in combination with enfortumab vedotin for the first-line treatment of patients with radically unresectable urothelial carcinoma is based on results from the first interim analysis of the Phase 3 KEYNOTE-A39 trial, which evaluated the combination compared to gemcitabine plus cisplatin or carboplatin in 886 chemotherapy-naïve patients with radically unresectable urothelial carcinoma. In this study, the KEYTRUDA plus enfortumab vedotin combination significantly improved OS and progression-free survival (PFS), reducing the risk of death by 53% (HR=0.47 [95% CI, 0.38-0.58]; p<0.00001) and also reducing the risk of disease progression or death by 55% (HR=0.45 [95% CI, 0.38-0.54]; p<0.00001) versus gemcitabine plus cisplatin or carboplatin. The approval of KEYTRUDA as monotherapy for patients with radically unresectable urothelial carcinoma who are not eligible for any platinum-containing chemotherapy is based on results from the phase 2 KEYNOTE-052 trial, which evaluated KEYTRUDA monotherapy compared to chemotherapy alone in 370 chemotherapy-naïve patients with radically unresectable urothelial carcinoma who were not eligible for any platinum-containing chemotherapy. Urothelial carcinoma, a type of bladder cancer, begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis and some other organs. Globally, it is estimated that approximately 614,300 new cases of bladder cancer are reported annually. In Japan, 25,000 people are estimated to be diagnosed with bladder cancer each year, and in the U.S., it is estimated that approximately 83,190 people will be diagnosed with bladder cancer in 2024. Of those patients diagnosed in the U.S., approximately 12% of cases are locally advanced or metastatic urothelial carcinoma at diagnosis, and many patients who are diagnosed at an advanced stage face a poor prognosis. About KEYTRUDA ® (pembrolizumab) injection, 100 mg KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD- L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells. Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers. Selected KEYTRUDA ® (pembrolizumab) Indications in the U.S. Non-Small Cell Lung Cancer KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC. KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is: Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic. KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. KEYTRUDA is indicated for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA, as a single agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC. Urothelial Cancer KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer. KEYTRUDA, as a single agent, is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma: who are not eligible for any platinum-containing chemotherapy, or who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. KEYTRUDA, as a single agent, is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information. Selected Important Safety Information for KEYTRUDA Severe and Fatal Immune-Mediated Adverse Reactions KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy. Immune-Mediated Pneumonitis KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients. Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution. Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution. Immune-Mediated Colitis KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients. Hepatotoxicity and Immune-Mediated Hepatitis KEYTRUDA as a Single Agent KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients. KEYTRUDA With Axitinib KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event. Immune-Mediated Endocrinopathies Adrenal Insufficiency KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypophysitis KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Thyroid Disorders KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism. The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment, including Grade 3 (0.2%) hyperthyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism. Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Immune-Mediated Nephritis With Renal Dysfunction KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients. Immune-Mediated Dermatologic Adverse Reactions KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti– PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients. Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection. Infusion-Related Reactions KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA. Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatments. Transplant- related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between anti–PD-1/PD-L1 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 its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose. Adverse Reactions In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%). In KEYNOTE-054, when KEYTRUDA was administered as a single agent to patients with stage III melanoma, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE-716, when KEYTRUDA was administered as a single agent to patients with stage IIB or IIC melanoma, adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054. In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%). In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407. In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%). In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%). In KEYNOTE-671, adverse reactions occurring in patients with resectable NSCLC receiving KEYTRUDA in combination with platinum-containing chemotherapy, given as neoadjuvant treatment and continued as single-agent adjuvant treatment, were generally similar to those occurring in patients in other clinical trials across tumor types receiving KEYTRUDA in combination with chemotherapy. The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar- plantar erythrodysesthesia, urinary tract infection, and hypothyroidism. In the neoadjuvant phase of KEYNOTE-671, when KEYTRUDA was administered in combination with platinum-containing chemotherapy as neoadjuvant treatment, serious adverse reactions occurred in 34% of 396 patients. The most frequent (≥2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death due to unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%). Permanent discontinuation of any study drug due to an adverse reaction occurred in 18% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy; the most frequent adverse reactions (≥1%) that led to permanent discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%). Of the KEYTRUDA-treated patients who received neoadjuvant treatment, 6% of 396 patients did not receive surgery due to adverse reactions. The most frequent (≥1%) adverse reaction that led to cancellation of surgery in the KEYTRUDA arm was interstitial lung disease (1%). In the adjuvant phase of KEYNOTE-671, when KEYTRUDA was administered as a single agent as adjuvant treatment, serious adverse reactions occurred in 14% of 290 patients. The most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction of pulmonary hemorrhage occurred. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 12% of patients who received KEYTRUDA as a single agent, given as adjuvant treatment; the most frequent adverse reactions (≥1%) that led to permanent discontinuation of KEYTRUDA were diarrhea (1.7%), interstitial lung disease (1.4%), increased aspartate aminotransferase (1%), and musculoskeletal pain (1%). Adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred. In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%). In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%). In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism. In KEYNOTE-204, KEYTRUDA was discontinued due to adverse reactions in 14% of 148 patients with cHL. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA; those ≥1% were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients died from causes other than disease progression: 2 from complications after allogeneic HSCT and 1 from unknown cause. The most common adverse reactions (≥20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, rash, and cough (20% each). In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% were pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression: 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%). In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%). In KEYNOTE-A39, when KEYTRUDA was administered in combination with enfortumab vedotin to patients with locally advanced or metastatic urothelial cancer (n=440), fatal adverse reactions occurred in 3.9% of patients, including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin; the serious adverse reactions in ≥2% of patients were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Permanent discontinuation of KEYTRUDA occurred in 27% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash (3.4%). The most common adverse reactions (≥20%) occurring in patients treated with KEYTRUDA in combination with enfortumab vedotin were rash (68%), peripheral neuropathy (67%), fatigue (51%), pruritus (41%), diarrhea (38%), alopecia (35%), weight loss (33%), decreased appetite (33%), nausea (26%), constipation (26%), dry eye (24%), dysgeusia (21%), and urinary tract infection (21%). In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%). In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%). In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (≥20%) were fatigue (29%), diarrhea (24%), and rash (24%). Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-158 and KEYNOTE-164, adverse reactions occurring in patients with MSI-H or dMMR cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. In KEYNOTE-811, when KEYTRUDA was administered in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 6% of 217 patients with locally advanced unresectable or metastatic HER2+ gastric or GEJ adenocarcinoma. The most common adverse reaction resulting in permanent discontinuation was pneumonitis (1.4%). In the KEYTRUDA arm versus placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA vs standard of care for diarrhea (53% vs 44%) and nausea (49% vs 44%). In KEYNOTE-859, when KEYTRUDA was administered in combination with fluoropyrimidine- and platinum-containing chemotherapy, serious adverse reactions occurred in 45% of 785 patients. Serious adverse reactions in >2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who received KEYTRUDA including infection (2.3%) and thromboembolism (1.3%). KEYTRUDA was permanently discontinued due to adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were infections (1.8%) and diarrhea (1.0%). The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were peripheral neuropathy (47%), nausea (46%), fatigue (40%), diarrhea (36%), vomiting (34%), decreased appetite (29%), abdominal pain (26%), palmar-plantar erythrodysesthesia syndrome (25%), constipation (22%), and weight loss (20%). In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil to patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued due to adverse reactions in 15% of 370 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in combination with chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%). Adverse reactions occurring in patients with esophageal cancer who received KEYTRUDA as a monotherapy were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-A18, when KEYTRUDA was administered with CRT (cisplatin plus external beam radiation therapy [EBRT] followed by brachytherapy [BT]) to patients with FIGO 2014 Stage III-IVA cervical cancer, fatal adverse reactions occurred in 1.4% of 292 patients, including 1 case each (0.3%) of large intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious adverse reactions occurred in 30% of patients; those ≥1% included urinary tract infection (2.7%), urosepsis (1.4%), and sepsis (1%). KEYTRUDA was discontinued for adverse reactions in 7% of patients. The most common adverse reaction (≥1%) resulting in permanent discontinuation was diarrhea (1%). For patients treated with KEYTRUDA in combination with CRT, the most common adverse reactions (≥10%) were nausea (56%), diarrhea (50%), vomiting (33%), urinary tract infection (32%), fatigue (26%), hypothyroidism (20%), constipation (18%), decreased appetite and weight loss (17% each), abdominal pain and pyrexia (12% each), hyperthyroidism, dysuria, rash (11% each), and pelvic pain (10%). In KEYNOTE-826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (n=307), to patients with persistent, recurrent, or first-line metastatic cervical cancer regardless of tumor PD-L1 expression who had not been treated with chemotherapy except when used concurrently as a radio- sensitizing agent, fatal adverse reactions occurred in 4.6% of patients, including 3 cases of hemorrhage, 2 cases each of sepsis and due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab; those ≥3% were febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each). KEYTRUDA was discontinued in 15% of patients due to adverse reactions. The most common adverse reaction resulting in permanent discontinuation (≥1%) was colitis (1%). For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common adverse reactions (≥20%) were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea (39%), hypertension and thrombocytopenia (35% each), constipation and arthralgia (31% each), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%). For patients treated with KEYTRUDA in combination with chemotherapy with or without bevacizumab, the most common adverse reactions (≥20%) were peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension and urinary tract infection (24% each), and rash (22%). In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with previously treated recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%). In KEYNOTE-394, KEYTRUDA was discontinued due to adverse reactions in 13% of 299 patients with previously treated hepatocellular carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was ascites (2.3%). The most common adverse reactions in patients receiving KEYTRUDA (≥10%) were pyrexia (18%), rash (18%), diarrhea (16%), decreased appetite (15%), pruritis (12%), upper respiratory tract infection (11%), cough (11%), and hypothyroidism (10%). In KEYNOTE-966, when KEYTRUDA was administered in combination with gemcitabine and cisplatin, KEYTRUDA was discontinued for adverse reactions in 15% of 529 patients with locally advanced unresectable or metastatic biliary tract cancer. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was pneumonitis (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 55% of patients. The most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood cell count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary obstruction (2.3%). In KEYNOTE-017 and KEYNOTE-913, adverse reactions occurring in patients with MCC (n=105) were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent. In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%). In KEYNOTE-564, when KEYTRUDA was administered as a single agent for the adjuvant treatment of renal cell carcinoma, serious adverse reactions occurred in 20% of patients receiving KEYTRUDA; the serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% including 1 case of pneumonia. Discontinuation of KEYTRUDA due to adverse reactions occurred in 21% of 488 patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). The most common adverse reactions (≥20%) were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%), and hypothyroidism (21%). 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). Adverse reactions occurring in patients with MSI-H or dMMR endometrial carcinoma who received KEYTRUDA as a single agent were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent. Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-522, when KEYTRUDA was administered with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent (n=778) to patients with newly diagnosed, previously untreated, high-risk early-stage TNBC, fatal adverse reactions occurred in 0.9% of patients, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA; those ≥2% were febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients due to adverse reactions. The most common reactions (≥1%) resulting in permanent discontinuation were increased ALT (2.7%), increased AST (1.5%), and rash (1%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%). In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting (n=596), fatal adverse reactions occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy; the serious reactions in ≥2% were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse reactions. The most common reactions resulting in permanent discontinuation (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%). Lactation Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the last dose. Pediatric Use In KEYNOTE-051, 173 pediatric patients (65 pediatric patients aged 6 months to younger than 12 years and 108 pediatric patients aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 25 months). Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults were pyrexia (33%), leukopenia (31%), vomiting (29%), neutropenia (28%), headache (25%), abdominal pain (23%), thrombocytopenia (22%), Grade 3 anemia (17%), decreased lymphocyte count (13%), and decreased white blood cell count (11%). Geriatric Use Of the 564 patients with locally advanced or metastatic urothelial cancer treated with KEYTRUDA in combination with enfortumab vedotin, 44% (n=247) were 65-74 years and 26% (n=144) were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years of age or older and younger patients. Patients 75 years of age or older treated with KEYTRUDA in combination with enfortumab vedotin experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 4% in patients younger than 75 and 7% in patients 75 years or older. Additional Selected KEYTRUDA Indications in the U.S. Melanoma KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma. KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with Stage IIB, IIC, or III melanoma following complete resection. Malignant Pleural Mesothelioma KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic malignant pleural mesothelioma (MPM). Head and Neck Squamous Cell Cancer KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC). KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test. KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. Classical Hodgkin Lymphoma KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL). KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy. Primary Mediastinal Large B-Cell Lymphoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. Microsatellite Instability-High or Mismatch Repair Deficient Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test. Gastric Cancer KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval of this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. KEYTRUDA, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. Esophageal Cancer KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either: in combination with platinum- and fluoropyrimidine-based chemotherapy, or as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test. Cervical Cancer KEYTRUDA, in combination with chemoradiotherapy (CRT), is indicated for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer. KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. Hepatocellular Carcinoma KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen. Biliary Tract Cancer KEYTRUDA, in combination with gemcitabine and cisplatin, is indicated for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer (BTC). Merkel Cell Carcinoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). Renal Cell Carcinoma KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. Endometrial Carcinoma KEYTRUDA, in combination with carboplatin and paclitaxel, followed by KEYTRUDA as a single agent, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. KEYTRUDA, as a single agent, is 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. Tumor Mutational Burden-High Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established. Cutaneous Squamous Cell Carcinoma KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation. Triple-Negative Breast Cancer KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test. About the Astellas, Pfizer and Merck collaboration Astellas and Seagen entered a clinical collaboration agreement with Merck to evaluate the combination of Astellas’ and Seagen’s Padcev ® (enfortumab vedotin-ejfv) and Merck’s KEYTRUDA ® (pembrolizumab) in patients with previously untreated metastatic urothelial cancer. 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. 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 At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter) , Facebook , Instagram , YouTube and LinkedIn . Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2023 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site ( www.sec.gov ). Please see Prescribing Information for KEYTRUDA (pembrolizumab) at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf and Medication Guide for KEYTRUDA at https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf .