Scleritis

29岁的林女士，这一年多来总是双眼反复发红、刺痛、畏光，几乎每个月都要跑一次眼科门诊。她被诊断为“虹膜睫状体炎”，点了无数眼药水，症状稍缓后又反复。“是不是干眼症太严重？”、“是不是过敏？”、“是不是老熬夜？”她问过许多医生，也试过各种护眼方式，但病情始终反复。直到这一次来院复查，眼科医生发现她眼部异常并不仅仅是炎症那么简单。双眼表层巩膜呈散在结节状充血，后部角膜缘竟出现了新生血管和“影子血管”，更关键的是：她还提到了“最近常常头晕”！“有没有听力下降？耳鸣？耳闷？”医生一问，林女士一愣：“确实有点耳闷，没太在意。”种种线索拼在一起，医生高度怀疑：这不是单纯的眼病，而是罕见的Cogan综合征！累及眼、听觉-前庭系统的综合征1945年Cogan首次详细描述一种听觉-前庭障碍伴发非梅毒性基质性角膜炎的独立临床病例，将其命名为Cogan综合征。该病是一种累及眼、听觉-前庭系统的综合征，属于自身免疫性疾病，主要表现为非梅毒性角膜基质炎、前庭功能障碍、听力下降以及全身症状。该病临床上较罕见，好发于青壮年，无年龄差异，文献报道白种人居多。角膜基质炎大多数患者都会出现眼红、畏光及眼痛等，很少无症状。该病患者大多数都是双眼相继或同时发病，症状随病程进展逐日加重。分型Cogan综合征分为典型与非典型两种类型。典型Cogan综合征表现为非梅毒性角膜炎和美尼尔听觉-前庭障碍。诊断典型的综合征主要依据非梅毒性角膜基质炎、急性发作的感音神经性听力损失、类似美尼尔病的前庭症状及发病两年内听力进行性损失致聋。眼部症状除了基质性角膜炎外，还可有结膜炎、虹膜炎和睑板腺囊肿等。非典型的Cogan综合征眼部损伤多表现为不伴基质性角膜炎的其他病变。另一种非典型的Cogan综合征眼部表现具有典型的基质性角膜炎症状，但耳部症状为非美尼尔听觉-前庭障碍，或者眼耳症状不同时发生（一般2年内先后发生）。至今该病仍然没有确切的诊断标准，但是可以根据患者的症状体征及鉴别诊断对其进行确诊。临床表现该病首发症状可以是眼部炎症性反应，也可以是眼部症状伴发内耳症状。1.内耳症状：表现为骤然出现的类似美尼尔病样发作：眩晕，恶心，呕吐，共济失调，耳鸣，突发性感音神经性聋。内耳症状可与眼部症状同时出现，也可以晚于眼部症状数周或2年内先后出现。2.眼部表现：可出现较多变异，但最典型的眼部症状是非梅毒性间质性角膜炎，表现为眼红、畏光、眼睛不适、疼痛和视物模糊。在裂隙灯下可见斑片状颗粒状角膜浸润，反复发作患者可出现云状角膜变性。3.耳部损害：听力进行性下降为最主要的耳部损害，发病2年内，有54%典型的和37%非典型的Cogan综合征患者会发生单耳或双耳的耳聋。经过抗炎与全身激素治疗，听力较视力下降的改善较差。4.全身其他系统：引起其他系统症状。如，呼吸系统的上呼吸道感染，可见胸痛、呼吸困难等；心血管系统可见主动脉炎、心包炎或者心律失常、高血压等；消化系统可见腹部疼痛不适、消化不良、腹泻、便血、肝脾肿大等；以及皮肤可见红斑、风疹，也可出现多发性关节炎或关节痛。治疗糖皮质激素是治疗CS的基本药物，宜早期大量应用，起效后逐渐减量维持。糖皮质激素无效时可联用免疫抑制剂。结膜炎、巩膜炎、角膜炎、前葡萄膜炎局部应用糖皮质激素有效。无效时可用环孢霉素A滴眼液，严重眼部炎症需服用泼尼松。参考资料1. 范梓晰，靳荷，黄里佳,等. Cogan综合征二例. 中国实用眼科杂志，2015，33(02):200-201.2. 李雪静,陈楠.老年Cogan综合征1例[J].中国现代医学杂志,2019,29(09):126.3.毛秋月,杨涛,彭安全,等.Cogan综合征诊治的研究进展[J].中华耳科学杂志,2023,21(01):115-120.来源 | 梅斯医学编辑 | wanny神经系统罕见病交流群↓点击下方“阅读原文”，下载梅斯医学APP吧！

摘要：带状疱疹性眼病（HZO）是由水痘 - 带状疱疹病毒（VZV）在感觉神经节潜伏感染再激活引起的，是带状疱疹（HZ）的一种特殊类型，会累及三叉神经的眼支 。约 4 - 20% 的 HZ 患者会发展为 HZO，其中约 50% 的 HZO 患者会出现眼部疾病，部分患者还会发展为慢性或复发性疾病。常见眼部表现有结膜炎、角膜炎和葡萄膜炎等，严重时可能导致视力丧失 。早期识别并及时使用抗病毒药物治疗至关重要，接种疫苗是预防 HZO 的有效手段 。目前有重组佐剂疫苗（RZV）和减毒活疫苗（ZVL），RZV 在预防 HZ 和 HZO 方面比 ZVL 更有效，但成人疫苗接种覆盖率仍不理想 。一、引言带状疱疹（HZ）是由儿童时期初次感染水痘 - 带状疱疹病毒（VZV）后，病毒在感觉神经节潜伏，日后重新激活引发的疾病 。带状疱疹性眼病（HZO）则是 HZ 中病毒累及三叉神经眼支的特殊类型，可导致严重的长期眼部并发症，甚至永久性视力丧失 。因此，一旦怀疑 HZO，需紧急进行眼科会诊 。早期识别和治疗对预防严重并发症十分关键，而接种疫苗可以有效预防 HZ 和 HZO 。本文将对 HZO 的负担、并发症、识别、治疗和预防策略进行综述 。二、流行病学HZ 的发病率随年龄增长而增加，这与 VZV 特异性细胞免疫功能下降有关 。全球范围内，50 - 54 岁人群中 HZ 的发病率约为 5.15/1000 人，85 岁及以上人群则高达 11.27/1000 人 。在 HZ 患者中，HZO 的发生率约为 4 - 20% 。HZO 的发病率同样随年龄增长而上升，美国一项回顾性研究显示，21 - 50 岁成年人中 HZO 的发病率为每 10 万人年 13.2 - 32.3 例，50 岁以上人群则为每 10 万人年 54.6 - 131.6 例，且约 70% 的 HZO 病例发生在 50 岁以上人群中 （原文 Fig. 2，展示美国 1994 - 2018 年不同年龄段 HZO 的发病率，直观呈现发病率与年龄的关系）。此外，HZ 和 HZO 在女性中的发病率高于男性，不同种族之间 HZO 的发生率也存在差异，如美国白人中 HZO 的发病率较高，而非洲裔、亚裔和西班牙裔人群发病率较低 。三、危险因素虽然目前尚未明确 HZO 的特定危险因素，但已知一些 HZ 的危险因素，如免疫抑制（如 HIV/AIDS、恶性肿瘤、器官移植、使用免疫抑制药物等）、家族病史、身体创伤、年龄增长等，这些因素大概率也适用于 HZO 。免疫抑制状态与 HZO 的严重表现相关，例如在 HIV/AIDS 患者中，HZO 较为常见（发生率约为 22.1%），且可能出现急性视网膜坏死（ARN）和进行性外层视网膜坏死（PORN）等严重并发症 。另外，有研究表明，COVID - 19 感染后，HZ 的发病风险可能会小幅增加，部分研究也报道了 COVID - 19 疫苗接种后 HZ 和 HZO 的发病风险有所上升，但也有研究持不同观点 。四、临床症状HZO 的典型症状包括单侧面部疱疹性皮疹，常伴有神经痛、发热和头痛，有时疼痛会先于皮疹出现 。皮疹通常在这些早期症状出现 2 - 3 天后出现，形成水疱，数天后结痂 。当皮疹延伸至鼻尖（即 Hutchinson 征）时，表明鼻睫神经分支受累，增加了眼部受累的可能性 。大约 50% 的 HZO 患者会出现眼部病变，可累及从角膜到视网膜的所有眼部结构，引发多种眼部疾病，如结膜炎、角膜炎、葡萄膜炎、巩膜炎、视网膜炎等（原文 Table 1，展示 HZO 常见和不常见的眼部表现及相应发病率，帮助读者了解眼部病变情况）。眼睑/结膜：皮疹出现 1 - 2 周内，眼睑和结膜通常会受到影响，出现特征性水疱、睑缘炎、单侧结膜炎，有时还会伴有点状出血和眶周水肿 。慢性炎症可能导致后期并发症，如结膜或皮肤瘢痕形成，进而引起干眼、睑位异常和倒睫等问题 。巩膜 / 表层巩膜：发病第一周内，可能出现表层巩膜炎或巩膜炎，表现为局部发红。角膜：HZO 患者的角膜可能会受到多种影响。初期，上皮层受影响，出现浅层点状角膜炎（SPK），之后发展为假树枝状病变，与单纯疱疹病毒（HSV）感染的树枝状病变不同 。疾病后期，更深层的角膜组织可能受累，出现前基质角膜炎、深基质角膜炎和内皮炎等，还可能导致角膜水肿、瘢痕形成，甚至角膜穿孔。此外，还可能引发神经营养性角膜病变，导致慢性角膜溃疡，难以用常规方法治疗 。葡萄膜：前葡萄膜炎可单独出现或与角膜炎同时发生（即角膜葡萄膜炎），通常在 HZO 发病后 2 - 4 周出现 。葡萄膜炎常导致眼压升高，患者会出现眼痛、眼红、视力模糊等症状。在后部节段，HZO 可能导致急性视网膜坏死（ARN），表现为周边视网膜的片状炎症迅速融合，伴有闭塞性血管炎和玻璃体炎症 。免疫功能低下的个体尤其容易发生进行性外层视网膜坏死（PORN） 。其他并发症：HZO 还可能引起其他眼部并发症，如罕见的颅神经麻痹，影响第七、第三（最常见）、第四和第六颅神经；眼眶炎症和肌炎、视神经炎等，这些症状在没有水疱皮疹时也可能是 HZO 的首发表现 。此外，还可能出现带状疱疹后神经痛，表现为皮疹消退后 3 个月以上仍存在的皮节疼痛，并伴有感觉异常等症状 。鉴别诊断：一些疾病的症状与 HZO 相似，需要进行鉴别诊断 。当患者仅出现疼痛时，需排除紧张性头痛、偏头痛、丛集性头痛和巨细胞动脉炎等；出现皮疹时，要考虑接触性皮炎、脓疱疮和 HSV 感染等，其中 HSV 感染通常累及多个皮节，且有典型的角膜树枝状病变，而 HZO 为假树枝状病变；当仅有眼部表现而无皮疹时，需考虑眶蜂窝织炎、眼眶肿瘤、海绵窦血栓形成等多种疾病 。五、视力损害与疾病复发视力损害：HZO 患者中，中度视力丧失并不少见，而严重视力丧失相对较少，完全失明则更为罕见 。多项研究表明，葡萄膜炎、年龄增长、Hutchinson 征阳性、角膜感觉缺失、角膜上皮病变等因素与视力丧失相关，其中葡萄膜炎是视力丧失的重要预测因素 。疾病复发：相当一部分 HZO 患者会经历慢性或复发性疾病，比例高达 25% 。回顾性研究显示，慢性 HZO 患者症状持续时间较长，平均为 304 天，而复发性疾病患者中大多数也患有慢性疾病 。常见的复发性表现包括基质角膜炎、上皮角膜炎、内皮炎和结膜炎 / 巩膜炎等 。白内障手术与 HZO 的复发有关，术后复发的患者发作更频繁，疾病缓解期更短 。六、早期诊断和转诊的重要性HZO 一般通过临床诊断，通常不需要实验室检查来确诊 。当诊断不确定时，如在无疹型带状疱疹或复发性前葡萄膜炎患者中，可考虑对皮肤或眼部病变进行 PCR 分析 。早期将具有特征性眼部疼痛皮疹的患者转诊给眼科医生至关重要，这有助于预防 HZO 相关并发症导致的长期不可逆损伤 。患者可能出现全身症状（如前驱症状、皮疹、皮节疼痛等）和眼部症状（如疼痛、眼红、畏光、视力下降等），当患者出现由第五颅神经第一分支支配区域的丘疹或丘疱疹皮疹，尤其是皮疹出现前有刺痛和触痛加剧，并伴有头痛和全身不适时，应考虑 HZO 的诊断 。HZO 的早期症状（如受影响区域的瘙痒、刺痛或疼痛）可能在典型 HZ 皮疹出现前几天就出现，少数情况下，可能不会出现皮疹（即 “无疹型带状疱疹”），这增加了诊断的难度 。眼部症状通常不具有特异性，且常在皮疹出现几天后才出现 。出现 Hutchinson 征、结膜或睫状疼痛、视力变化（复视、畏光或视力下降）以及异常的眼外肌运动（提示第三、第四或第六颅神经麻痹）时，应及时转诊眼科医生。患者就诊后，需进行全面的眼科检查，包括裂隙灯检查、眼压测定和颅神经检查。目前关于转诊时间的报道并不统一，有研究显示从出疹到就诊并转诊至眼科医生的中位时间为 5 天，也有分析表明 75.8% 的患者在确诊 HZO 后 7 天内就诊 。（原文 Fig. 3，展示 HZO 随时间的进展和并发症，辅助读者理解疾病发展过程）七、早期和适当治疗的重要性HZO 的治疗目标是减轻症状的严重程度和持续时间，促进病变愈合，提高生活质量，对于眼部病变，还需限制眼部结构的受累程度、保护视力并预防疾病复发 。在 HZO 症状出现后 72 小时内开始抗病毒治疗，有助于预防眼部并发症 。抗病毒治疗药物包括口服阿昔洛韦、伐昔洛韦和泛昔洛韦等；对于播散性 HZ 或免疫功能低下的患者，可使用静脉注射阿昔洛韦，若对阿昔洛韦耐药，可考虑使用静脉注射膦甲酸钠 。早期使用抗病毒治疗能有效限制疾病进展，降低慢性眼部并发症的发生风险 （原文 Fig. 4，展示初级护理人员和眼科医生对 HZO 患者的协作护理治疗流程，清晰呈现治疗步骤）。除了抗病毒和止痛药物，全身和局部眼科糖皮质激素可作为辅助抗炎药物使用，但存在一定争议 。美国眼科学会（AAO）建议谨慎使用局部糖皮质激素，并密切监测是否出现基质角膜炎和葡萄膜炎 。然而，在没有抗病毒药物的情况下，不应使用糖皮质激素，因为其可能抑制免疫，促进病毒复制，甚至导致急性视网膜坏死，不过急性视网膜坏死的发病率较低。对于急性视网膜坏死，这是一种进展迅速的眼科急症，可能会扩散到对侧眼睛，建议立即使用静脉注射阿昔洛韦进行治疗，随后口服抗病毒药物，完成 3 - 4 个月的疗程，以阻止病毒复制并防止双眼受累，也可考虑玻璃体内注射抗病毒药物 。对于视神经病变或眼眶病变，可使用静脉注射阿昔洛韦，剂量为 10 - 15mg/kg，每日三次，持续 2 - 3 周，视网膜炎的治疗类似，但需增加数月的口服抗病毒治疗 。目前尚无随机、安慰剂对照研究支持长期使用口服抗病毒药物进行抑制性治疗，相关研究正在进行中 。初次诊断 HZO 后，应根据临床表现安排随访 。若未出现眼部受累，可在 10 - 14 天进行验光评估；若出现眼部受累，随访间隔则取决于眼部受累的类型和严重程度，AAO 建议在急性期每 1 - 7 天随访一次，之后每 3 - 12 个月监测是否出现延迟并发症（如眼压升高、白内障和角膜瘢痕形成等） 。八、预防的重要性预防 HZ 是预防 HZO 的有效方法，因为 HZO 是 HZ 的一种特殊类型 。目前有两种疫苗被批准用于预防成人 HZ，分别是 2006 年获批的减毒活疫苗（ZVL，Zostavax）和 2017 年获批的重组佐剂疫苗（RZV，Shingrix） 。1.疫苗预防 HZ 的效果：在随机、多中心、3 期试验中，单剂量 ZVL 预防 HZ 的效果在 50 - 59 岁成年人中为 69.8% ，在 60 岁及以上成年人中为 51.3% ，但随着时间推移，其效力会逐渐减弱 。ZVL 一般禁用于免疫功能低下的个体，其常见的不良反应包括注射部位反应、头痛和四肢疼痛等，大多为轻度 。RZV 需接种两剂，用于预防 50 岁及以上成年人以及 18 岁及以上 HZ 高风险人群（如免疫功能低下者）的 HZ 。在随机、对照、多中心、3 期试验中，50 岁及以上和 70 岁以上成年人接种 RZV 预防 HZ 的效果分别为 97.2% 和 91.3% ，且在接种后 6 - 10 年仍有 81.6% 的效力 。RZV 可用于免疫功能低下的个体，常见的局部不良反应包括疼痛、发红和肿胀，常见的全身不良反应包括肌痛、疲劳、头痛等，大多持续时间较短 。2.疫苗预防 HZO 的效果：两项荟萃分析评估了疫苗对 HZO 的预防效果 。一项对 9,536,086 名患者的系统评价显示，基于两项研究数据，ZVL 预防 HZO 的效力为 30% 。另一项网络荟萃分析表明，RZV 预防 HZO 的效力显著优于安慰剂，疫苗效力达 88% 。美国的真实世界观察性研究也评估了疫苗预防 HZO 的有效性，ZVL 在 65 岁及以上医疗保险受益人群中，接种后前 3 年预防 HZO 的有效性为 31% ，4 年及以后降至 21%；在 50 岁以上人群中，接种后第 1 年有效性为 71% ，8 - 10 年降至 12%，10 年期间的总体有效性为 37% 。RZV 在 65 岁及以上医疗保险受益人群中的有效性为 67% ；在两项针对商业健康保险数据库、中位随访期为 2 年的研究中，50 岁以上人群接种 RZV 预防 HZO 的有效性分别为 89% 和显著降低发病率（接种者为 11.9 例 / 10 万人年，未接种者为 72.1 例 / 10 万人年） 。然而，目前尚无针对有 HZO 病史个体接种疫苗有效性的评估数据 。九、当前预防 HZ 的指导建议在过去二十年中，针对老年人接种疫苗预防 HZ 的建议不断演变 。最初，ZVL 是唯一可用的疫苗，美国免疫实践咨询委员会（ACIP）曾推荐 60 岁以上个体接种 。RZV 获批后，ACIP 推荐所有 50 岁及以上成年人接种 RZV，无论之前是否接种过 ZVL，这是因为 RZV 在临床试验中表现出更高的效力，且 ZVL 的效力会随时间减弱 。此外，随着 RZV 被批准用于免疫功能低下的个体，ACIP 推荐 19 岁及以上免疫缺陷和免疫抑制的成年人接种 RZV 以预防 HZ 及相关并发症 。澳大利亚、加拿大和德国等国的权威机构也更倾向于推荐 RZV 。AAO 建议 50 岁及以上患者接种 HZ 疫苗，并倡导眼科医生与其他医疗专业人员合作，推荐符合条件的患者接种 。对于有 HZ 病史的患者，虽然疫苗在这部分人群中的有效性数据有限，但仍建议接种疫苗 。不过，关于接种时间的指导存在差异，ACIP 建议在急性 HZ 病情缓解后接种，而澳大利亚免疫技术咨询小组（ATAGI）则建议在 HZ 发作后至少延迟 12 个月（免疫功能低下者为 3 个月）接种 。对于有 HZO 病史的个体，接种疫苗可能存在疾病加重或复发的风险，有研究报道接种 RZV 后 56 天内疾病加重或复发的风险增加 。因此，AAO 建议这类个体在接种 HZ 疫苗前后几周内接受眼科医生的检查，且在眼部疾病得到良好控制之前，不应急于接种疫苗 。临床医生应根据当前建议，结合患者的 HZO 症状缓解情况和免疫状态，做出专业判断 。尽管有这些建议，但成人 HZ 疫苗的接种覆盖率仍不理想 。接种障碍包括患者对 HZ 的认知（如认为 HZ 风险低、自身很少生病或已有免疫力）、对疫苗的担忧（如对有效性、不良反应或过敏反应的担心，甚至认为疫苗会导致带状疱疹）以及与医疗保健提供者相关的因素（如未与初级保健医生讨论接种需求或难以见到医生） 。其中，患者拒绝接种的一个主要原因是初级保健医生未给予推荐 。因此，初级保健医生应积极主动地向所有符合条件的患者推荐 HZ 疫苗接种，在患者接种季节性流感疫苗时，是推荐和接种 HZ 疫苗的便利时机，护士也应协助识别符合接种条件的患者 。十、结论HZO 是一种可能威胁视力的疾病，且部分患者会经历慢性或复发性病程 。对于出现 HZ 症状且伴有眼部体征或鼻睫神经分支受累的患者，应及时转诊至眼科医生处进行治疗和随访 。及时启动抗病毒治疗并进行随访，对于限制 HZO 的进展和并发症至关重要 。目前有有效的疫苗可用于预防成人 HZ 和 HZO，初级保健医生应将符合条件患者的疫苗接种作为成人综合疫苗接种计划的一部分，积极推进，以降低 HZO 的发生风险，保护患者视力健康 。识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观不本站。

PRINCETON, N.J.--( BUSINESS WIRE )-- Bristol Myers Squibb (NYSE: BMY) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended approval of Opdivo ® (nivolumab) plus Yervoy ® (ipilimumab) for the first-line treatment of adult patients with microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR) unresectable or metastatic colorectal cancer (mCRC). Of significance, the CheckMate -8HW trial results showed reduction in the risk of disease progression or death by 79% (HR: 0.21; 95% CI: 0.14-0.32; p<0.0001) compared to chemotherapy in this patient population. The European Commission (EC), which has the authority to approve medicines for the European Union (EU), will now review the recommendation and make their decision. “Approximately 5-7% of metastatic colorectal cancer patients have dMMR or MSI-H tumors, and current treatment options often do not provide sufficient benefit,” said Dana Walker, M.D., M.S.C.E., vice president, global program lead, gastrointestinal and genitourinary cancers, Bristol Myers Squibb. “This is the first dual checkpoint inhibitor treatment for first-line metastatic colorectal cancer, delivering a transformative benefit for MSI-H/dMMR patients in this population. We are focused on bringing Opdivo plus Yervoy to these patients in the European Union and look forward to EC’s upcoming decision.” The positive opinion is based on results from the CheckMate -8HW trial, which were presented at medical congresses earlier this year. These data formed the basis for the Company’s Type II variation application, which was validated by the European Medicines Agency (EMA) . In the study, Opdivo plus Yervoy demonstrated a statistically significant and clinically meaningful improvement in the dual primary endpoint of progression-free survival (PFS) compared to the investigator’s choice of chemotherapy as assessed by Blinded Independent Central Review. In addition to the risk of disease progression or death the results noted, the safety profile for the dual immunotherapy combination remained consistent with previously reported data and was manageable with established protocols, with no new safety signals identified. In October 2024, it was announced that Opdivo plus Yervoy also demonstrated a statistically significant and clinically meaningful improvement in the dual endpoint of PFS per BICR compared to Opdivo monotherapy across all lines of therapy. The study is ongoing to assess various secondary endpoints, including overall survival (OS). Bristol Myers Squibb thanks the patients and investigators involved in the CheckMate -8HW clinical trial. About CheckMate -8HW CheckMate -8HW (NCT04008030) is a Phase 3 randomized, open-label trial evaluating Opdivo plus Yervoy compared to Opdivo alone or the investigator’s choice chemotherapy (mFOLFOX-6 or FOLFIRI with or without bevacizumab or cetuximab) in patients with microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR) unresectable or metastatic colorectal cancer (mCRC). 839 patients were randomized to receive either Opdivo monotherapy ( Opdivo 240 mg Q2W for six doses, followed by Opdivo 480 mg Q4W), Opdivo plus Yervoy (Opdivo 240 mg plus Yervoy 1 mg/kg Q3W for four doses, followed by Opdivo 480 mg Q4W ), or investigator’s choice of chemotherapy. The dual primary endpoints of the trial are progression-free survival (PFS) per blinded independent central review (BICR) for Opdivo plus Yervoy compared to investigator’s choice of chemotherapy in the firstline setting and PFS per BICR for Opdivo plus Yervoy compared to Opdivo alone across all lines of therapy. CheckMate-8HW has also met its other dual primary point of PFS per BICR Opdivo plus Yervoy compared to Opdivo across all lines therapy in randomized subjects with centrally confirmed MSI-H/dMMR mCRC at the second interim analysis in September 2024, and data disclosure is planned for an upcoming medical conference. The trial also evaluates several secondary safety and efficacy endpoints, including overall survival, which is ongoing. About dMMR or MSI-H Colorectal Cancer Colorectal cancer (CRC) is cancer that develops in the colon or the rectum, which are part of the body’s digestive or gastrointestinal system. CRC is the third most commonly diagnosed cancer in the world. In 2020, it is estimated that there were approximately 1,931,000 new cases of the disease; it is the second leading cause of cancer-related deaths among men and women combined. Mismatch repair deficiency (dMMR) occurs when the proteins that repair mismatch errors in DNA replication are missing or non-functional, leading to microsatellite instability-high (MSI-H) tumors. Approximately 5-7% of metastatic CRC patients have dMMR or MSI-H tumors. These patients are less likely to benefit from conventional chemotherapy and typically have a poor prognosis. Bristol Myers Squibb: Creating a Better Future for People with Cancer Bristol Myers Squibb is inspired by a single vision — transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine and, through innovative digital platforms, are turning data into insights that sharpen their focus. Deep understanding of causal human biology, cutting-edge capabilities and differentiated research programs uniquely position the company to approach cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. As a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future. About Opdivo Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers. Opdivo ’s leading global development program is based on Bristol Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has treated more than 35,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression. In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 65 countries, including the United States, the European Union, Japan and China. In October 2015, the Company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union. About Yervoy Yervoy is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activity. Yervoy binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including the anti-tumor immune response. On March 25, 2011, the U.S. Food and Drug Administration (FDA) approved Yervoy 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy is approved for unresectable or metastatic melanoma in more than 50 countries. There is a broad, ongoing development program in place for Yervoy spanning multiple tumor types. INDICATIONS OPDIVO® (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic melanoma. OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic melanoma. OPDIVO® is indicated for the adjuvant treatment of adult and pediatric patients 12 years and older with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma. OPDIVO® (nivolumab), in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC). OPDIVO® (nivolumab) in combination with platinum-doublet chemotherapy, is indicated for neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements, followed by single-agent OPDIVO® as adjuvant treatment after surgery. OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. OPDIVO® (nivolumab) is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO. OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM). OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma (RCC). OPDIVO® (nivolumab), in combination with cabozantinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). OPDIVO® (nivolumab) is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy. OPDIVO® (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. OPDIVO® (nivolumab) is indicated for the treatment of adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy. OPDIVO® (nivolumab) is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. OPDIVO® (nivolumab), as a single agent, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC. OPDIVO® (nivolumab), in combination with cisplatin and gemcitabine, is indicated as first-line treatment for adult patients with unresectable or metastatic urothelial carcinoma. OPDIVO® (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. OPDIVO® (nivolumab) is indicated for the treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy. OPDIVO® (nivolumab) is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult patients who have received neoadjuvant chemoradiotherapy (CRT). OPDIVO® (nivolumab), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC). OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC). OPDIVO® (nivolumab), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. IMPORTANT SAFETY INFORMATION Severe and Fatal Immune-Mediated Adverse Reactions Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. 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 OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, 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 immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below. Immune-Mediated Pneumonitis OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune- mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune- mediated pneumonitis occurred in 7% (31/456) of patients, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2 (4.4%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune- mediated pneumonitis occurred in 3.9% (26/666) of patients, including Grade 3 (1.4%) and Grade 2 (2.6%). In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, immune- mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%). Four patients (0.7%) died due to pneumonitis. In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO, including Grade 3 (n=1) and Grade 2 (n=12). Immune-Mediated Colitis OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) 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. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated colitis occurred in 9% (60/666) of patients, including Grade 3 (4.4%) and Grade 2 (3.7%). Immune-Mediated Hepatitis and Hepatotoxicity OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune- mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 7% (48/666) of patients, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%). OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. In patients receiving OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. Immune-Mediated Endocrinopathies OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. 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 clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, adrenal insufficiency occurred in 7% (48/666) of patients, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In patients receiving OPDIVO and cabozantinib, adrenal insufficiency occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and Grade 2 (1.9%). In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456), including Grade 3 (2.4%) and Grade 2 (6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in 4.4% (29/666) of patients, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%). In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, thyroiditis occurred in 2.7% (22/666) of patients, including Grade 3 (4.5%) and Grade 2 (2.2%). In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hyperthyroidism occurred in 9% (42/456) of patients, including Grade 3 (0.9%) and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hyperthyroidism occurred in 12% (80/666) of patients, including Grade 3 (0.6%) and Grade 2 (4.5%). In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypothyroidism occurred in 18% (122/666) of patients, including Grade 3 (0.6%) and Grade 2 (11%). In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%). Immune-Mediated Nephritis with Renal Dysfunction OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated nephritis with renal dysfunction occurred in 4.1% (27/666) of patients, including Grade 4 (0.6%), Grade 3 (1.1%), and Grade 2 (2.2%). Immune-Mediated Dermatologic Adverse Reactions OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes. Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated rash occurred in 16% (108/666) of patients, including Grade 3 (3.5%) and Grade 2 (4.2%). 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 OPDIVO monotherapy or OPDIVO in combination with YERVOY or were reported with the use of other PD-1/PD-L1 blocking antibodies. 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; 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, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection. In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified: nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune): conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis. Some ocular IMAR 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, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss. Infusion-Related Reactions OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30- minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 8% (4/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, infusion-related reactions occurred in 5.1% (28/547) of patients. In MSI- H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, infusion-related reactions occurred in 4.2% (5/119) of patients. In MPM patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, infusion-related reactions occurred in 12% (37/300) of patients. Complications of Allogeneic Hematopoietic Stem Cell Transplantation Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO or YERVOY. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO or YERVOY and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT. Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose. Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials. Lactation There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose. Serious Adverse Reactions In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). In Checkmate 238, serious adverse reactions occurred in 18% of patients receiving OPDIVO (n=452). Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. In Checkmate 816, serious adverse reactions occurred in 30% of patients (n=176) who were treated with OPDIVO in combination with platinum-doublet chemotherapy. Serious adverse reactions in >2% included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received OPDIVO in combination with platinum-doublet chemotherapy. In Checkmate 77T, serious adverse reactions occurred in 21% of patients who received OPDIVO in combination with platinum-doublet chemotherapy as neoadjuvant treatment (n=228). The most frequent (≥2%) serious adverse reactions was pneumonia. Fatal adverse reactions occurred in 2.2% of patients, due to cerebrovascular accident, COVID-19 infection, hemoptysis, pneumonia, and pneumonitis (0.4% each). In the adjuvant phase of Checkmate 77T, 22% of patients experienced serious adverse reactions (n=142). The most frequent serious adverse reaction was pneumonitis/ILD (2.8%). One fatal adverse reaction due to COVID-19 occurred. In Checkmate 227, serious adverse reactions occurred in 58% of patients (n=576). The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. In Checkmate 9LA, serious adverse reactions occurred in 57% of patients (n=358). The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia. In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 057, fatal adverse reactions occurred; these included events of infection (7 patients, including one case of Pneumocystis jirovecii pneumonia), pulmonary embolism (4 patients), and limbic encephalitis (1 patient). In Checkmate 743, serious adverse reactions occurred in 54% of patients receiving OPDIVO plus YERVOY. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis. In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY (n=547). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. In Checkmate 9ER, serious adverse reactions occurred in 48% of patients receiving OPDIVO and cabozantinib (n=320). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 274, serious adverse reactions occurred in 30% of patients receiving OPDIVO (n=351). The most frequent serious adverse reaction reported in ≥2% of patients receiving OPDIVO was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). In Checkmate 901, serious adverse reactions occurred in 48% of patients receiving OPDIVO in combination with chemotherapy. The most frequent serious adverse reactions reporting in ≥2% of patients who received OPDIVO with chemotherapy were urinary tract infection (4.9%), acute kidney injury (4.3%), anemia (3%), pulmonary embolism (2.6%), sepsis (2.3%), and platelet count decreased (2.3%). Fatal adverse reactions occurred in 3.6% of patients who received OPDIVO in combination with chemotherapy; these included sepsis (1%). OPDIVO and/or chemotherapy were discontinued in 30% of patients and were delayed in 67% of patients for an adverse reaction. In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in ≥2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. In Checkmate 040, serious adverse reactions occurred in 59% of patients receiving OPDIVO with YERVOY (n=49). Serious adverse reactions reported in ≥4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. In Attraction-3, serious adverse reactions occurred in 38% of patients receiving OPDIVO (n=209). Serious adverse reactions reported in ≥2% of patients who received OPDIVO were pneumonia, esophageal fistula, interstitial lung disease, and pyrexia. The following fatal adverse reactions occurred in patients who received OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%). In Checkmate 577, serious adverse reactions occurred in 33% of patients receiving OPDIVO (n=532). A serious adverse reaction reported in ≥2% of patients who received OPDIVO was pneumonitis. A fatal reaction of myocardial infarction occurred in one patient who received OPDIVO. In Checkmate 648, serious adverse reactions occurred in 62% of patients receiving OPDIVO in combination with chemotherapy (n=310). The most frequent serious adverse reactions reported in ≥2% of patients who received OPDIVO with chemotherapy were pneumonia (11%), dysphagia (7%), esophageal stenosis (2.9%), acute kidney injury (2.9%), and pyrexia (2.3%). Fatal adverse reactions occurred in 5 (1.6%) patients who received OPDIVO in combination with chemotherapy; these included pneumonitis, pneumatosis intestinalis, pneumonia, and acute kidney injury. In Checkmate 648, serious adverse reactions occurred in 69% of patients receiving OPDIVO in combination with YERVOY (n=322). The most frequent serious adverse reactions reported in ≥2% who received OPDIVO in combination with YERVOY were pneumonia (10%), pyrexia (4.3%), pneumonitis (4.0%), aspiration pneumonia (3.7%), dysphagia (3.7%), hepatic function abnormal (2.8%), decreased appetite (2.8%), adrenal insufficiency (2.5%), and dehydration (2.5%). Fatal adverse reactions occurred in 5 (1.6%) patients who received OPDIVO in combination with YERVOY; these included pneumonitis, interstitial lung disease, pulmonary embolism, and acute respiratory distress syndrome. In Checkmate 649, serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy (n=782). The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with OPDIVO in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation. In Checkmate 76K, serious adverse reactions occurred in 18% of patients receiving OPDIVO (n=524). Adverse reactions which resulted in permanent discontinuation of OPDIVO in >1% of patients included arthralgia (1.7%), rash (1.7%), and diarrhea (1.1%). A fatal adverse reaction occurred in 1 (0.2%) patient (heart failure and acute kidney injury). The most frequent Grade 3-4 lab abnormalities reported in ≥1% of OPDIVO-treated patients were increased lipase (2.9%), increased AST (2.2%), increased ALT (2.1%), lymphopenia (1.1%), and decreased potassium (1.0%). Common Adverse Reactions In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). In Checkmate 238, the most common adverse reactions (≥20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%),headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). In Checkmate 816, the most common (>20%) adverse reactions in the OPDIVO plus chemotherapy arm (n=176) were nausea (38%), constipation (34%), fatigue (26%), decreased appetite (20%), and rash (20%). In Checkmate 77T, the most common adverse reactions (reported in ≥20%) in patients receiving OPDIVO in combination with chemotherapy (n= 228) were anemia (39.5%), constipation (32.0%), nausea (28.9%), fatigue (28.1%), alopecia (25.9%), and cough (21.9%). In Checkmate 227, the most common (≥20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In Checkmate 9LA, the most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 743, the most common adverse reactions (≥20%) in patients receiving OPDIVO plus YERVOY were fatigue (43%), musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea (27%), nausea (24%), decreased appetite (24%), cough (23%), and pruritus (21%). In Checkmate 214, the most common adverse reactions (≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%). In Checkmate 9ER, the most common adverse reactions (≥20%) in patients receiving OPDIVO and cabozantinib (n=320) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), cough (20%) and upper respiratory tract infection (20%). In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO (n=236) were cough (14%) and dyspnea (14%) at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 274, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=351) were rash (36%), fatigue (36%), diarrhea (30%), pruritus (30%), musculoskeletal pain (28%), and urinary tract infection (22%).In Checkmate 901, the most common adverse reactions (≥20%) were nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy. In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent (n=74), the most common adverse reactions (≥20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), the most common adverse reactions (≥20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%). In Checkmate 040, the most common adverse reactions (≥20%) in patients receiving OPDIVO with YERVOY (n=49), were rash (53%), pruritus (53%), musculoskeletal pain (41%), diarrhea (39%), cough (37%), decreased appetite (35%), fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%), nausea (20%), dizziness (20%), hypothyroidism (20%), and weight decreased (20%). In Attraction-3, the most common adverse reactions (≥20%) in OPDIVO-treated patients (n=209) were rash (22%) and decreased appetite (21%). In Checkmate 577, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=532) were fatigue (34%), diarrhea (29%), nausea (23%), rash (21%), musculoskeletal pain (21%), and cough (20%). In Checkmate 648, the most common adverse reactions (≥20%) in patients treated with OPDIVO in combination with chemotherapy (n=310) were nausea (65%), decreased appetite (51%), fatigue (47%), constipation (44%), stomatitis (44%), diarrhea (29%), and vomiting (23%). In Checkmate 648, the most common adverse reactions reported in ≥20% of patients treated with OPDIVO in combination with YERVOY were rash (31%), fatigue (28%), pyrexia (23%), nausea (22%), diarrhea (22%), and constipation (20%). In Checkmate 649, the most common adverse reactions (≥20%) in patients treated with OPDIVO in combination with chemotherapy (n=782) were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), and musculoskeletal pain (20%). In Checkmate 76K, the most common adverse reactions (≥20%) reported with OPDIVO (n=524) were fatigue (36%), musculoskeletal pain (30%), rash (28%), diarrhea (23%) and pruritis (20%). Surgery Related Adverse Reactions In Checkmate 77T, 5.3% (n=12) of the OPDIVO-treated patients who received neoadjuvant treatment, did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery in OPDIVO- treated patients were cerebrovascular accident, pneumonia, and colitis/diarrhea (2 patients each) and acute coronary syndrome, myocarditis, hemoptysis, pneumonitis, COVID-19, and myositis (1 patient each). Please see U.S. Full Prescribing Information for OPDIVO and YERVOY . Clinical Trials and Patient Populations Checkmate 227-previously untreated metastatic non-small cell lung cancer, in combination with YERVOY; Checkmate 9LA–previously untreated recurrent or metastatic non-small cell lung cancer in combination with YERVOY and 2 cycles of platinum-doublet chemotherapy by histology; Checkmate 649–previously untreated advanced or metastatic gastric cancer, gastroesophageal junction and esophageal adenocarcinoma; Checkmate 577–adjuvant treatment of esophageal or gastroesophageal junction cancer; Checkmate 238– adjuvant treatment of patients with completely resected Stage III or Stage IV melanoma; Checkmate 76K– adjuvant treatment of patients 12 years of age and older with completely resected Stage IIB or Stage IIC melanoma; Checkmate 274–adjuvant treatment of urothelial carcinoma; Checkmate 275–previously treated advanced or metastatic urothelial carcinoma; Checkmate 142–MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 142–MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Attraction-3–esophageal squamous cell carcinoma; Checkmate 648-previously untreated, unresectable advanced recurrent or metastatic esophageal squamous cell carcinoma in combination with chemotherapy; Checkmate 648-previously untreated, unresectable advanced recurrent or metastatic esophageal squamous cell carcinoma combination with YERVOY; Checkmate 040–hepatocellular carcinoma, in combination with YERVOY; Checkmate 743–previously untreated unresectable malignant pleural mesothelioma, in combination with YERVOY; Checkmate 037–previously treated metastatic melanoma; Checkmate 066—previously untreated metastatic melanoma; Checkmate 067– previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 017– second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057–second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 816–neoadjuvant non-small cell lung cancer, in combination with platinum-doublet chemotherapy; Checkmate 77T–Neoadjuvant treatment with platinum-doublet chemotherapy for non-small cell lung cancer followed by single-agent OPDIVO as adjuvant treatment after surgery; Checkmate 901–Adult patients with unresectable or metastatic urothelial carcinoma; Checkmate 141–recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 025– previously treated renal cell carcinoma; Checkmate 214–previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 9ER–previously untreated renal cell carcinoma, in combination with cabozantinib; Checkmate 205/039–classical Hodgkin lymphoma About the Bristol Myers Squibb and Ono Pharmaceutical Collaboration In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Bristol Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally, except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Ono and Bristol Myers Squibb further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan. About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn , X (formerly Twitter), YouTube , Facebook and Instagram . Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that the CHMP opinion is not binding on the EC, that Opdivo (nivolumab) plus Yervoy (ipilimumab) may not receive regulatory approval for the additional indication described in this release in the currently anticipated timeline or at all, that any marketing approvals, if granted, may have significant limitations on their use, and, if approved, whether such combination treatment for such additional indication will be commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2023, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise. corporatefinancial-news