Balstilimab

中国抗癌协会近距离放射治疗专业委员会. 复发转移性宫颈癌诊疗指南（2025版）[J]. 中华放射肿瘤学杂志, 2025, 34(8): 751-764. DOI: 10.3760/cma.j.cn113030-20250428-00166. 复发转移性宫颈癌诊疗指南（2025版） 中国抗癌协会近距离放射治疗专业委员会 摘 要 宫颈癌经过规范治疗，仍有30%~40%的治疗失败率。复发转移性宫颈癌（r/mCC）的治疗是宫颈癌治疗过程中最具挑战的阶段，患者的治疗与既往治疗方式、无瘤间隔时间、患者状态、复发转移的部位和范围、治疗中肿瘤缓解的情况等相关，涉及手术、放疗、系统药物治疗等，需要采用个体化的综合治疗模式。近年来，r/mCC的治疗效果有了显著提升。因此，中国抗癌协会近距离放射治疗专业委员会组织国内专家，结合最新临床实践经验和研究进展，根据循证医学原则，编写本指南，以期为临床医生提供合理、规范化的诊疗指导意见和建议，进一步提升r/mCC的诊疗水平，改善预后。 关键词 宫颈肿瘤；复发与转移；放射疗法；手术治疗；系统治疗；指南 基金项目：浙江省“尖兵”“领雁”研发攻关科技合作项目（2022C04001）；云南省基础研究计划昆医联合专项项目（202201AY070001‑157）；广州地区临床特色技术项目（2023PTS26） 实践指南注册：国际实践指南注册与透明化平台（PREPARE‑2025CN413） 一、指南制定的目的和方法 近年来，国内外在复发转移性宫颈癌（recurrent/ metastatic cervical cancer，r/mCC）的诊断及综合治疗等方面均取得了显著进展。因此，中国抗癌协会近距离放射治疗专业委员会组织妇科肿瘤领域专家，包括外科、放疗科、肿瘤内科专家，在结合最新临床实践经验和研究进展的基础上，根据循证医学原则，编写本指南，旨在为我国r/mCC的规范化诊疗提供指导意见，提升诊治水平，进一步改善患者预后。 参与本指南制定的专家组成员由全国30余位宫颈癌诊治领域资深专家组成，均不存在利益冲突并进行了声明，专家组集体推选出组长和副组长，对r/mCC诊治领域存在的常见临床问题进行凝练，最终确定10个相关临床问题，并根据临床问题的解决方案及专家特点分为外科组、放疗组、系统药物治疗组，每组配备1位秘书。3个专业组分别进行系统性文献检索，检索的数据库包括Pubmed、Embace、Web of Science、Scopus、中国知网、万方、维普数据库，检索时间从建库开始到2025年3月22日，检索关键词为宫颈肿瘤、复发与转移、放射疗法、手术治疗、化学治疗、靶向治疗、免疫检查点抑制剂、抗体偶联药物。优先纳入高级别证据文献（随机对照Ⅲ期临床试验或高质量、稳健的荟萃分析），高级别证据文献缺乏的情况下纳入较低水平证据级别的文献（优先程度依次为单臂多中心II期临床试验、单中心小样本Ⅱ期临床试验、非干预观察性研究、回顾性研究、个案报道），文献提供给所有专家组成员进行审阅。3个专业组主要参考美国国家综合癌症网（National Comprehensive Cancer Network，NCCN）对相关问题提供汇总意见，全组专家进行了3次会议讨论形成初步意见，最终专家组成员进行投票，根据表1所述的共识程度整合证据等级，形成推荐等级分类，共分为1类、2A类、2B类、3类4个等级。 表1   中国抗癌协会近距离放射治疗专业委员会临床应用证据等级及推荐等级分类 二、复发转移性宫颈癌的概况 全球范围的女性恶性肿瘤中，宫颈癌的发病率和死亡率位居第四［1］，是全球女性因恶性肿瘤死亡的主要疾病之一。2022年中国恶性肿瘤疾病排名，宫颈癌的发病率为第五位，死亡率为第六位，发病及死亡均有上升趋势［2］。近20年来，随着宫颈癌诊疗技术的提高，预后有明显改善，全球癌症生存趋势监测数据显示，在2000—2004年、2005—2009年、2010—2014年3个时间段，中国宫颈癌的5年生存率有所提高，分别为53.3%、63.0%、67.6%［3］。宫颈癌依然存在较高的治疗失败率，国际妇产科协会（International Federation of Gynecology and Obstetrics，FIGO）各期的10年复发率依次为ⅠB期10%、ⅡA~ⅡB期21%、Ⅲ期44%、ⅣA期85%［4］。约75%的宫颈癌复发在初治后2年内。 三、复发转移性宫颈癌的定义和分类 宫颈癌复发指宫颈癌患者经治疗后在治疗区域内或邻近区域出现与原肿瘤相同病理类型的肿瘤。根据首次治疗方法的不同，分为放疗后复发和手术后复发两大类。放疗后复发指经放疗后宫颈肿瘤完全消失，在放疗结束6个月以后在放疗区再次出现肿瘤。放疗后未控是指宫颈癌在接受足量放疗后3~6个月内，放疗区域内仍有明显肿瘤持续存在。手术后复发指手术后，术区又出现肿瘤。盆腔内复发者，分为中心性复发（包括宫颈、阴道、子宫体的复发）和非中心性复发（盆壁、盆腔淋巴结）。 宫颈癌转移指宫颈的原发肿瘤细胞通过淋巴系统、血液循环或体腔等途径，扩散到远处器官或组织，形成与宫颈原发肿瘤同样类型的肿瘤。寡转移指出现数量≤5个、病灶部位局限，且原发性肿瘤可控或已控，这些转移灶可以通过局部治疗，获得潜在治愈或长期控制的机会［5］。 根据复发转移病灶是否接受过放疗，将复发病灶分为放疗野内病灶和放疗野外病灶。 早期宫颈癌复发转移率低，一项欧洲回顾性研究对556例FIGO 2009分期ⅠB1期的宫颈癌长期随访显示，共49例复发转移（9%），其中局部复发占53%、远处转移占39%、复发合并转移占8%［6］。另一项国内研究对975例FIGO 2009分期ⅠB2/ⅡA2期宫颈癌的回顾性观察显示，140例患者复发转移（14.3%），其中55例为局部复发（5.6%），71例为远处转移（7.3%）［7］。局部晚期宫颈癌复发转移率较高，分析1359例接受根治性放疗的宫颈癌患者，出现治疗失败的共249例（18.3%），其中远处转移率为77.5%，局部复发率为36.9%，局部复发以中心性复发最常见，复发部位依次为宫颈32例（12.9%）、盆腔淋巴结32例（12.9%）、阴道21例（8.4%）、宫旁12例（4.8%），远处转移的常见部位依次为肺71例（28.5%）、腹主动脉旁52例（20.9%）、左锁骨上淋巴结32例（12.9%）、骨26例（10.4%）［8］。 现代宫颈癌的放疗技术普遍采用调强放疗为基础的体外放疗和图像引导的近距离放疗。在精准治疗模式（RetroEMBRACE研究）背景下，与传统放疗技术比较，总治疗失败率、仅盆腔复发率、仅远处转移率、盆腔复发合并远处转移率分别为30%比35%、6%比16%、17%比12%、7%比7%，显示局部晚期宫颈癌的治疗失败模式，由以盆腔复发为主，转变为以远处转移为主［9］。 四、复发转移性宫颈癌的诊断 宫颈癌复发转移诊断的金标准是组织病理学，原则上应检尽检，无法穿刺或穿刺阴性但临床高度怀疑复发转移者可结合临床症状、影像结果、肿瘤指标和短期观察变化等进行综合判断，并递交多学科诊疗讨论后进行诊断。 宫颈癌复发转移的临床症状通常是非特异性的，甚至无症状和体征。症状和体征与复发转移的部位相关，可以表现为但不局限于以下情况：阴道排液、阴道出血、下肢水肿、呼吸道症状、声音嘶哑、骨盆/下肢/躯体疼痛、瘘、体重减轻、贫血、浅表淋巴结增大等。 浅表淋巴结的检查首选B超，CT或MRI检查是发现及诊断肺、脑、肝、盆腹腔等深部复发转移病灶的主要检查方法。与CT或MRI相比，正电子发射计算机体层成像（positron emission computed tomography，PET‐CT）诊断的灵敏度和特异性更高，诊断的阳性预测值和阴性预测值明显优于常规显像手段，敏感度为85.7%~96.1%［10-12］，可以在病灶的解剖大小发生变化之前检测到生物和分子变化，有助于对CT或MRI上模糊的成像结果进行定性，并制订复发转移阶段的治疗方案［13-14］。成纤维细胞活化蛋白抑制剂（fibroblast activation protein inhibitor，FAPI）PET‐CT在特定肿瘤和纤维化疾病中表现更佳，可以更好地鉴别放疗后的复发转移病灶。 监测肿瘤标志物水平的变化可一定程度地反映宫颈癌的疗效、预后和复发转移。鳞状细胞癌抗原（squamous cell carcinoma antigen，SCC‐Ag）在宫颈鳞癌中的水平升高常早于临床症状或影像学改变，约46%~92%的宫颈鳞癌复发时首先表现为血清SCC‐Ag水平升高，比临床发现早2~7.8个月［15］，宫颈鳞癌治疗后SCC‐Ag水平持续升高或再次升高，强烈提示复发或转移。在部分宫颈癌患者中，复发时癌胚抗原（carcinoembryonic antigen，CEA）、糖类抗原（carbohydrate antigen，CA）125或CA19‐9水平会升高，尤其与腺癌相关，有助于监测腺癌的复发和转移。然而，检测单一标志物的敏感性和特异性有限，联合检测多种标志物并结合临床和影像学检查结果，能更准确地判断病情，制订有效的治疗方案。 宫颈细胞学阳性及临床可疑中心性复发病例应进一步行宫颈组织病理检查；盆腔肿块、肺、肝、淋巴结等可疑转移病灶争取在B超/CT引导下穿刺活检，病灶毗邻重要器官、血管者需要评估穿刺的安全性。复发转移病灶的组织切片推荐进行程序性死亡受体配体1（programmed death‐ligand 1，PD‐L1）、人表皮生长因子受体2、P16、错配修复（mismatch repair，MMR）等免疫组化的检测，必要时可进行二代基因测序寻找基因突变及治疗靶点。 五、鉴别诊断 足量放疗后宫颈肿瘤的组织细胞学退变需要一定时间，且放疗后不同程度的纤维化，导致放疗后未控、复发、局部放疗反应有时难以区别，放疗剂量过高时临床上甚至可见到半年甚至更长时间的伤口不愈合，宫颈表面多为灰白色坏死物质，甚至形成溃疡或空洞，有时肿瘤组织埋存在坏死组织之下，病理检查仅显示炎症细胞、核异质细胞或坏死物质，而不能明确诊断，需要加强阴道及宫颈的局部冲洗，密切随诊，必要时可多次活检。宫旁组织在放疗后通常存在纤维化，表现为宫旁单侧或双侧弹性欠佳，呈条索状、结节状增厚，甚至冰冻骨盆，后两种情况与宫旁复发难以鉴别，MRI及PET‐CT是鉴别诊断的首选检查，必要时行B超/CT引导下宫旁及盆壁肿块穿刺活检。远处转移灶需要警惕双原发癌的可能，尤其是距离初始治疗的时间间隔越久者，要加强影像学的鉴别，最终由病理学和分子生物学确认肿瘤的性质。 六、治疗 推荐意见：系统性治疗是r/mCC患者的基本治疗，建议寡转移、寡复发者接受局部治疗（2A类）。所有患者均推荐参加临床研究。 r/mCC的治疗需综合考虑以下因素：初始的治疗类型、患者的体能状况与症状、复发部位、累及范围、无瘤间隔时间、肿瘤类型、治疗中肿瘤的缓解情况等。局部治疗包括手术、放疗、射频消融等，系统性治疗包括传统化疗、靶向治疗、免疫治疗等。总治疗原则是个体化综合治疗，目的是延长患者的生存期，改善患者的生活质量（图1）。 图1   复发、转移宫颈癌治疗流程图 注：CCRT为同步放化疗；a局部治疗针对系统治疗反应良好，预估局部治疗可以改善疗效者；b寡转移经治疗后进展为广泛转移；c广泛转移经治疗后转归为寡转移 （一） 局部治疗 1.手术治疗：手术主要针对可完全切除的局部病灶，也适于疾病过程中出现严重影响患者生活质量的病灶或并发症，如骨转移、脑转移的姑息减症手术，如膀胱阴道瘘、直肠阴道瘘等的对症处理。 （1）宫颈癌根治术后的盆腔复发 推荐意见：未接受过放疗的局限盆腔复发，选择手术＋术后辅助放化疗（2A类）；若为盆腔多处复发，病变广泛患者，无法达到完全切除，则手术效果差，生存期短，手术不作为首选治疗方式（2A类）。 宫颈癌术后盆腔复发者，中心性复发占比约为30%~45%，多位于阴道残端、膀胱和直肠之间。盆腔中心性复发患者手术切除后再辅助放化疗，能取得较满意的疗效，文献报道5年总生存（overall survival，OS）率为6%~77%［16］。国内报道16例宫颈癌术后盆腔复发者接受手术治疗，2年OS率为37.5%，5年OS率为18.8%［17］。 （2）放疗后盆腔未控/复发：在盆腔未控/复发的患者中，约70%的患者初治接受过放疗，即为放疗野内未控/复发，再次放疗预后较差，在一些特定患者人群，可以选择手术切除局部病灶达到治疗目的。 1）中心性未控/复发的手术治疗 推荐意见：病灶未浸润膀胱和/或直肠、预计可以完全切除的中心性未控/复发患者，行广泛性子宫切除术或全子宫切除术（2A类）。 回顾性分析50例宫颈癌放疗后中心性未控/复发的患者，肿瘤最大径的中位数为2.5 cm（范围为0~8 cm），接受了根治性子宫切除，术后5年和10年总OS率分别为72%和60%，预后与肿瘤大小相关，复发肿瘤最大径<2 cm者的5年OS率为90%，而更大肿瘤患者为64%（P<0.01），泌尿道的损伤比较多见，28%的患者出现了膀胱阴道瘘或直肠阴道瘘［18］。国内研究显示36例宫颈癌放疗后局部未控或中心性复发患者接受手术，中位生存时间为22个月，5年OS率为40.4%，其中筋膜外子宫全切除术29例，中位OS期为22个月，5年OS率为40.4%；子宫广泛或次广泛切除术患者7例，中位OS期为26个月，5年OS率为40.0%，差异均无统计学意义（均P=0.348），但子宫广泛或次广泛切除术的手术时间长、出血量多、并发症发生率高（P=0.007）［19］。部分放疗后局部未控或中心性复发者可从手术治疗中获益，甚至是唯一获得根治的机会，手术方式为筋膜外子宫全切除术、子宫次广泛切除术或子宫广泛切除术。 推荐意见：病灶浸润膀胱和/或直肠但无盆壁受侵、无盆腔外转移、预计可以完全切除的中心性未控/复发患者，盆腔脏器切除术（pelvic exenteration，PE）是首选治疗（2A类）。 1948年，Brunschwig博士报道了对中心性复发宫颈癌施行PE，旨在通过切除女性生殖道及其相邻的盆腔器官［如下尿路（尿道、膀胱、输尿管）和/或肛管、直肠］来切除肿瘤，并实现显微镜下无瘤边缘。根据切除的范围分为前PE、后PE、全PE。因放疗后盆腔纤维化、毛细血管闭塞，解剖异化、血管生成不良，易出现周围器官损伤及缺血性坏死，手术后的总并发症率接近70%［20-21］。5年OS率在20%~73%之间［22-24］。Jurado等［25］报道了48例放疗后复发的患者接受PE治疗，20例中心型复发的患者中，65%实现了完全的肿瘤切除，28例盆壁复发的患者中，仅28.6%实现了完全切除，中位随访114.6个月（范围为3.0~244.9个月），中心型复发患者中，10年局部控制率和疾病特异性生存率分别为43.1%和27.2%，中心性复发及盆侧壁复发10年的远处失败率分别为56.6%和83.2%（P=0.178）。一项来自美国国家癌症数据库的资料显示，517例患者接受PE，中位OS期为29.6个月，围手术期死亡率已下降，淋巴结状态、切缘阴性是主要的预后因素，淋巴结无转移、转移者的中位OS期分别为73.2、17.8个月，切缘阳性是预后的独立影响因素（HR=1.5，95%CI为1.04~2.27，P=0.029）［26］，其他因素包括距离首次治疗的时间间隔、年龄等［23，26-27］。 2）非中心性未控/复发的手术治疗：非中心性未控/复发通常是肿瘤直接蔓延至盆壁或者盆壁淋巴结。除非病灶局限，多数情况因肿瘤无法切除、无法切净、切缘阳性率高，手术效果差［28］。Höckel等［29］在2003年描述了侧向扩大盆腔内切除术（laterally extended endopelvic resection，LEER）的术式，用于治疗局部晚期或盆壁复发的患者，该手术在PE基础上，手术进一步向盆侧延伸，切除盆壁筋膜和肌肉，如闭孔内肌和耻骨尾肌、髂尾肌和尾肌等，保证有足够安全的手术切缘，在侧方肿瘤固定的情况下，包括切除骨以及髂内血管，确保完整切除。文献报道61例复发或肿瘤持续的宫颈癌患者接受LEER，5年OS率为58%，近一半的患者出现Ⅱ度以上并发症，其利弊尚有争议［30］。 （3）直肠阴道瘘和膀胱阴道瘘：直肠阴道瘘和膀胱阴道瘘是放疗并发症或肿瘤侵犯所导致的相关事件，通常需要手术处理，快速缓解肠道内容物或尿液外溢导致的系列症状。作为姑息减症手段，建议尽早实施手术，通过肠道或尿道改道引流，避免进一步的恶化，如感染性休克、周围脏器受到腐蚀等，改善生活质量。手术方案需权衡尿道、肠道修复的可能性与患者整体预后。 （4）远处转移的手术治疗 推荐意见：手术切除适合孤立或寡转移灶（≤5个）、有减症需求的病灶（2B类）。 手术切除是孤立的腹主动脉旁淋巴结转移、肺转移、脑转移等可选择的治疗方式，具有直接切除肿瘤，潜在治愈的意义。 Yamamoto等［31］报道29例肺转移患者，手术切除后的5年生存率为32.9%；分组研究显示，1~2个肺转移灶患者的5年OS率（42.2%）多于3~4个肺转移灶患者（0%），且鳞癌患者优于腺癌或腺鳞癌（47.4%比0%），孤立性肺转移或虽为多处转移但局限于一个肺叶者也可尝试手术治疗。脑转移在r/mCC中少见但严重威胁生命，发生率不足1%~2%，中位OS期约3~6个月［32-33］。外科手术在脑转移瘤治疗中发挥着重要作用［34］，尤其是有症状或大型脑转移瘤，可以迅速减轻颅内压和缓解肿块占位效应引起的继发性症状，单个脑转移或寡转移患者手术治疗可明显提高患者生存率。手术治疗主要适用于：卡诺夫斯凯计分≥70分；原发宫颈病灶稳定（无广泛全身转移或未控盆腔病灶）；单发脑转移灶（偶可考虑2~3个相邻病灶），直径≥3 cm且占位效应显著。如患者存在严重颅内高压症状或脑疝风险，或者神经功能障碍（如肢体偏瘫），则有急诊手术指征。脑转移瘤单纯手术治疗的复发率超过50%，推荐术后补充局部放疗。近年来，有研究报道免疫检查点抑制剂（immune checkpoint inhibitors，ICI）可以在中枢神经系统中诱导强大的免疫反应，已成为脑转移者有效的治疗方法［35-36］。骨转移通常发生在脊柱、骨盆和长骨，患者常表现为骨痛、病理性骨折或神经压迫症状，手术治疗适用于获取组织进行病理确诊、存在骨折风险或已发生骨折、存在神经压迫症状（如脊髓压迫导致的神经功能障碍）的情况［37］，此外，双膦酸盐和地舒单抗等减少了骨相关不良事件（如骨折、骨痛）［38-39］。 综上所述，手术治疗可能取得较好疗效的r/mCC特征如下［19，28，30］：①病灶局限于盆腔而既往无放疗史；②根治性放疗后中心性未控/复发，无盆壁受侵；③可切除的远处转移灶。由于切缘阳性的r/mCC的手术获益并不明显，且PE和LEER创伤大，涉及切除后不同程度的盆底、会阴/阴道、肠道、尿道的重建［28］，并发症发生率高，患者生活质量受影响，因此需严格筛选可从PE和LEER中获益的患者［40］。 2.放射治疗：同步放化疗（concurrent chemo‐radiotherapy，CCRT）的治疗模式在未接受过放疗的病灶中具有治疗优势［41-42］，如根治术后的盆腔复发，进行CCRT+近距离放疗，可达到根治的目的［43］。接受过放疗的病灶，则可以考虑手术，无法手术或手术获益不大，则考虑再程放疗［44-46］。可选的放疗技术主要为体外放疗技术和近距离放疗技术。体外照射技术包括三维适形放疗（three dimensional conformal radiation therapy，3DCRT）、调强放疗（intensity modulated radiation therapy，IMRT）、立体定向放疗（stereotactic body radiation therapy，SBRT）、射波刀等。近距离放疗主要应用于阴道残端、阴道壁、外阴、盆腔复发病灶，偶用于浅表肿大淋巴结、腹膜后淋巴结、脏器转移等深部病灶。 （1）根治性手术后盆腔复发 推荐意见：CCRT（含顺铂和/或紫杉醇）是宫颈癌根治性手术后（未接受辅助放疗且无远处转移）盆腔复发的首选治疗方法（2A类）。 宫颈癌根治性手术后盆腔复发的预后优于放疗后复发。在传统放疗和化疗年代，41例宫颈癌根治术后复发患者接受了放疗和化疗（氟尿嘧啶联合或不联合丝裂霉素），58%的患者对治疗有完全反应，5例复发，中位随访57个月时，45%患者无复发生存［47］。一项多中心的回顾性研究显示，72例根治性子宫切除术后局部区域复发的宫颈癌患者在接受了基于IMRT的挽救性CCRT后，5年OS率为65.9%、5年无进展生存（progression free survival，PFS）率为57.6%［48］。CCRT+近距离放疗是中心性复发患者的首选治疗方式，体外照射联合近距离放疗（包含插植技术）可以赋予阴道残端、阴道、阴道旁复发病灶根治放疗剂量80~90 Gy，联合同步化疗，达到与初治局部晚期宫颈癌类似的疗效。 （2）寡转移灶的放射治疗 推荐意见：原发肿瘤获得控制的寡转移灶，首选局部放疗，SBRT是一种可选择的放疗技术，无瘤间隔时间长者优选（2A类）。 腹主动脉旁淋巴结（para‐aortic lymph node，PALN）是常见的复发转移部位。在仅发生PALN转移的患者中，CCRT的安全性和有效性已得到肯定［49-51］。孤立的PALN病灶，27%的患者生存时间超过5年，接受CCRT、单纯放疗、姑息化疗或者无治疗者的5年OS率分别为40%、30%、0%（P<0.001）［52］。韩国对67例PALN转移患者进行回顾性研究：3年总OS率为42.7%，32例孤立PALN转移的3年OS率为60.8%，21例PALN转移合并其他淋巴结转移者为42.1%，14例PALN转移伴远处转移者为7.7%；在多变量分析中，鳞癌（P=0.028）、无症状复发（P=0.024）、孤立的PALN转移（P=0.008）和无瘤间隔时间（disease free interval，DFI）（P=0.008）是影响生存的预后因素［53］。因此，PALN转移（未曾接受过放疗）者，建议同步含铂化疗联合局部放疗。 对寡转移性病灶进行根治性放疗，可以实现局部控制获得良好的预后，甚至使部分患者达到长期生存，放疗相关的不良反应发生率小。Ning等［54］报道了38例接受根治性放疗的同时或异时寡转移的宫颈癌患者，根治性放疗的定义为采用常规分割或立体定向技术进行大分割放疗，给予放疗剂量≥50.4 Gy（中位剂量60 Gy），38例患者的中位PFS期为21.7个月，1、2年PFS率分别为63%、48%，2、3年OS率分别为74%、65%。KROG 14‐11研究对85例寡转移或复发的宫颈癌患者进行SBRT的多中心研究，中位OS期为32.7个月，2年OS率为57.5%［55］。58例首次寡复发、寡转移的宫颈癌患者接受放疗，放疗中位剂量为44 Gy（范围为31~68 Gy），其中56%的患者接受了全身化疗，中位PFS期、OS期分别为16、28个月［56］。越来越多的证据支持对寡转移性病变使用根治目的的局部放疗。体部立体定向消融放疗（stereotactic ablative body radiotherapy，SABR）可以获得良好的局部控制，不良反应发生率低，是首选的治疗方法［57］。寡转移病灶经过局部治疗得到良好控制，而进行了系统治疗的患者依然会出现广泛复发［58］，因此加强系统治疗非常必要，可减少广泛复发转移的风险。 除外手术，放疗是肺转移主要的局部治疗手段，SBRT/SABR是适宜技术。NRG‐BR001 Ⅰ期临床研究采用的剂量方案为中央型肺转移灶50 Gy分5次，周围性转移灶45 Gy分3次，安全性良好［59］。肺转移者行SBRT可参考以下选择标准：①肺转移灶的最大直径不超过5 cm；②肺转移灶的数量不超过3个；③无肺外远处转移，或远处转移已被控制；④未发现明显肺间质性疾病［60］。合并广泛转移或多器官转移者可接受姑息性放疗，以改善肺部、胸膜转移引起的咳嗽、咯血或胸痛等症状。 （3）初治ⅣB期的处理 推荐意见：ⅣB期患者行系统性治疗，单纯淋巴结转移者，联合根治性放疗；血行转移者，如果对系统治疗有较好的反应，可对系统治疗后的寡转移病灶或仍存在活性的病灶进行局部治疗，包括放疗、手术、热消融等（2A类）。 初治ⅣB期是r/mCC的一种特殊情况，5年OS率为14.7%［61］，通常接受系统药物治疗，局部治疗的益处尚不确定。一项研究对美国国家癌症数据库的患者进行倾向评分匹配分析，比较仅化疗、体外放疗+化疗、体外放疗+近距离放疗+化疗三种不同的治疗方式，发现随着放疗的加入和强化，中位OS期有延长倾向［62］。从美国国立癌症研究所监测、流行病学和最终结果（surveillance，epidemiology and end results，SEER）数据库获得的数据也表明，与单独盆腔放疗相比，接受近距离放疗或近距离放疗联合EBRT治疗的患者有OS优势［63］。在精准治疗模式下，严重的胃肠道和泌尿生殖道不良反应的发生率可控制在8.5%和6.8%［64］。在免疫治疗时代，通过放疗等实现局部肿瘤控制尤为重要，可能带来更高的生存概率，且不良反应可以接受。 回顾性评估左锁骨上淋巴结转移的ⅣB期宫颈癌患者25例，其接受了CCRT+左锁骨上区域放疗，平均剂量59.4 Gy，3年OS率和无瘤生存（disease‐free survival，DFS）率分别为49%和33%，宫颈肿瘤完全控制患者的3年OS率为68%，未完全控制者为29%，原发肿瘤的局部控制与生存结果相关，急性血液不良反应发生率高，但可恢复，晚期不良反应可接受［65］。另有研究分析了164例患者：76.2%有PALN转移且无远处转移，23.8%有远处转移；患者接受了盆腔放疗±腹主动脉旁放疗+图像引导自适应近距离放疗，对于有脏器或膈上淋巴结转移者，则先接受化疗后进行放化疗，两组之间的生存率差异无统计学意义；中位随访时间为36个月，OS率、PFS率、3年局部控制（local control，LC）率分别为55.5%、40.6%、90%；在多变量分析中，高危临床靶区D90%的剂量≥80 Gy与OS相关（HR=0.96，95%CI为0.94~0.98，P<0.001）；研究表明，转移性肿瘤负荷低，或对化疗反应良好的ⅣB期患者，可能会从强化局部治疗中获益，达到与ⅢC2期相同的治疗效果，且大多数不良反应为轻至中度［66］。 （4）再程放射治疗 推荐意见：再程放疗仅针对累及病变区域，如无病变证据，不考虑淋巴引流区的照射（2A类）。 再程放疗是指对原先放疗过的区域内再次出现的肿瘤，或曾经放疗区域的邻近区域出现新的肿瘤（与原照射野有部分重叠）的再次放疗，这类肿瘤通常无法通过手术或其他局部治疗手段进行控制［67］。再程放疗的实施需要综合考虑患者的一般状况、预期生存期、既往治疗史（放疗剂量、放疗范围及正常组织的受量）、肿瘤特征（病理、部位、范围、大小、周边解剖关系等）、距离前次放疗的时间间隔及治疗相关不良反应。具体的放疗剂量及采用的放疗技术（IMRT、SBRT、近距离放疗等）需根据上述的实际情况调整［68］。再程放疗通常仅照射累及病变野，如无病变证据，不考虑淋巴引流区的照射。再程放疗的不良反应往往比首次放疗更急切且强烈，需谨慎施行［69］。危及器官的剂量需要严格控制，以防严重并发症如出血和瘘的发生。距离前次放疗的时间间隔越长，再程放疗的可行性及安全性越高。 （5）姑息减症放射治疗：随着近年来r/mCC生存期的延长以及肿瘤转移等事件的出现，放疗在缓解转移灶相关的症状、体征方面具有无创的优势，疗效明确，如：可缓解颅内高压导致的恶心呕吐、食管压迫导致的进食障碍、血管受压导致的静脉回流障碍等［70］；缓解骨转移、胸膜转移、盆壁转移导致的局部或躯体疼痛。放疗是首选的姑息减症的局部治疗方法［71］。 （6）术中放射治疗（intraoperative radiotherapy，IORT）：IORT是盆壁和淋巴引流区复发灶行手术切除时，因手术安全边界不够或者切缘阳性，避开正常组织，针对术区的补充放疗，以增加局部控制效果。IORT推荐剂量从10~20 Gy不等。Haddock等［72］的研究显示，显微镜下残留病灶者IORT后的5年OS率约为37%，而大体残留病灶患者为10%。对17例复发性妇科恶性肿瘤行PE或者肿瘤切除，13例完整切除，所有患者接受高剂量率（high dose rate，HDR）IORT，中位剂量为14 Gy（范围为12~15 Gy），结果显示，3年LC率为67%，在完全切除的患者中，3年LC率为83%，而残留肿瘤者为25%（P<0.01），提示可以完全切除的盆壁和淋巴引流区复发者能从手术+术中放疗这种治疗模式中获益［73］。IORT可以通过2种技术实现：电子线和HDR近距离放疗。 （二） 药物治疗 推荐意见：大多数r/mCC患者都需要接受药物治疗，控制其复发转移阶段已经存在或潜在的肿瘤全身扩散（1类）。 r/mCC的系统性药物治疗经历了4个关键发展阶段：从单药顺铂化疗，到紫杉醇+顺铂（taxel+cisplatin，TP）/紫杉醇+卡铂（taxel+carboplatin，TC）联合化疗，再到TP/TC化疗±贝伐珠单抗，直至目前的TP/TC化疗±贝伐珠单抗+ICI，每个阶段，患者的预后都得到进一步的提升。 1.传统药物治疗：早期妇科肿瘤学组（Gynecologic Oncology Group，GOG）研究报道的单药顺铂化疗的OS期为6.1~7.1个月［74］，反应率在17%~38%之间，与剂量有微弱关系，50 mg/m2的总反应率为20.7%，100 mg/m2的反应率为31.4%，但PFS和OS无显著改善［75］。2004年，GOG169研究对260例r/mCC患者进行顺铂+紫杉醇（顺铂50 mg/m2，紫杉醇135 mg/m2）与顺铂单药两个队列的疗效比较，总反应率分别为36%、19%（P=0.002），中位PFS期分别为4.8、2.8个月（P<0.001），中位OS期分别为8.8、9.7个月，差异无统计学意义，顺铂+紫杉醇在反应率和PFS以及持续生活质量方面优于单独使用顺铂［76］。GOG204研究比较了顺铂分别联合紫杉醇、长春瑞滨、吉西他滨和托泊替康的疗效，与其他组相比，顺铂+紫杉醇的组合显示出明显更长的3年中位OS期（12.87个月）和更高的客观反应率（objective response rate，ORR；29.1%）［77］。由此奠定了顺铂+紫杉醇是r/mCC的标准化疗方案。日本临床肿瘤组（Japanese Clinical Oncology Group，JGOG）0505试验用卡铂［曲线下面积=5 mg/（ml·min）］代替顺铂，显示了紫杉醇+卡铂在生存率上非劣效于紫杉醇+顺铂［78］。对于顺铂不能耐受者，可考虑用卡铂代替顺铂与紫杉醇联合治疗。GOG240研究显示，在紫杉醇和顺铂的方案中添加贝伐珠单抗，中位OS期可达17.5个月［79］，贝伐珠单抗与TP的联合方案在2014年被美国食品药品监督管理局（Food and Drug Administration，FDA）批准为一线r/mCC的系统药物治疗方案。 2.免疫治疗 （1）二线r/mCC治疗：KEYNOTE‐158试验中，帕博利珠单抗治疗在77例复发或转移性疾病治疗后进展的PD‐L1阳性患者中具有抗肿瘤活性，ORR为14.6%［80］。2018年6月FDA批准帕博利珠单抗用于PD‐L1阳性［联合阳性评分（combined positivity score，CPS）≥1］并在化疗期间或化疗后进展的晚期宫颈癌患者。对于PD‐L1阳性或高频微卫星不稳定（microsatellite instability‐high，MSI‐H）/错配修复缺陷（mismatch repair‐deficient，dMMR）的晚期宫颈癌，NCCN 2022指南和中国临床肿瘤学会（Chinese Society of Clinical Oncology，CSCO）指南均将帕博利珠单抗作为二线治疗的优先选择。然而帕博利珠单抗在r/mCC总人群中的ORR仅为12.2%（KEYNOTE‐158试验），在PD‐L1阳性患者中的ORR分别为17%（KEYNOTE‐028试验）［81］和14.6%（KEYNOTE‐158试验）［80］。纳武利尤单抗在r/mCC患者中的ORR为26.3%（CheckMate 358试验）［82］。NCT03104699试验显示巴替利单抗在r/mCC患者中的ORR为15%［83］；西米普利单抗在复发性宫颈癌患者中的ORR为16.4%。不管PD‐L1状态如何，西米普利单抗较医生选择的化疗有生存获益（12.0个月比8.5个月，任何原因死亡的HR=0.69，95%CI为0.56~0.84，P<0.001）［84］。NCCN指南推荐西米普利单抗（350 mg）作为首选的二线治疗选择，纳武利尤单抗或帕博利珠单抗可用于PD‐L1阳性患者。由此可见，ICI在r/mCC中虽然ORR普遍偏低，但显示出有效性，是化疗和靶向药物之外的新治疗选择。在一项程序性死亡受体1（programmed death‐1，PD‐1）/细胞毒性T淋巴细胞相关抗原4（cytotoxic T lymphocyte antigen 4，CTLA‐4）双特异性抗体卡度尼利单抗的研究中，99例r/mCC患者的ORR为32.3%，中位PFS期为3.7个月，12个月OS率为59.9%，63例PD‐L1阳性（CPS≥1）患者的ORR为42.9%［85］。另一项PD‐1/CTLA‐4双功能组合抗体艾帕洛利托沃瑞利单抗治疗二线r/mCC（QL1706‐206）的研究，在2024年欧洲妇科肿瘤学会（European Society of Gynaecological Oncology，ESGO）大会的报道中称148例r/mCC的ORR为33.8%，中位PFS期为5.4个月，12个月OS率为65.4%。基于以上的研究证据，ICI可用于二线r/mCC的治疗（表2）。 表2   复发转移性宫颈癌系统治疗方案 注：药物剂量可以根据患者的实际情况做合理、可解释的调整；PD‐L1为程序性死亡受体配体1；TMB‐H为高肿瘤突变负荷；MSI‐H为高频微卫星不稳定；dMMR为错配修复缺陷；HER2为人表皮生长因子受体2；AUC为曲线下面积 （2）一线r/mCC治疗：2023年，KEYNOTE‐826研究报道，接受TP/TC化疗±贝伐珠单抗+帕博利珠单抗（PD‐L1阳性，CPS≥1）的患者中位OS期达到28.6个月［86］，r/mCC患者的药物治疗效果得到了显著的提升。该研究将617例未经治疗的r/mCC患者随机分配接受使用或不使用帕博利珠单抗治疗，帕博利珠单抗或安慰剂200 mg，每3周一次，最多35个周期，加上TP/TC标准化疗±贝伐珠单抗。中位随访39.1个月，在CPS≥1（548例）、所有人群（617例）和CPS≥10（317例）人群中，帕博利珠单抗组与安慰剂组的中位OS期分别为28.6比16.5、26.4比16.8、29.6比17.4个月，中位PFS期分别为10.5比8.2、10.4比8.2、10.4比8.1个月。结果表明，帕博利珠单抗进一步改善了r/mCC患者的OS和PFS，两组24个月的OS率分别为52.1%、38.7%（P<0.001），无论是否使用贝伐珠单抗，帕博利珠单抗均改善了OS率。≥3级不良事件的发生率，帕博利珠单抗组为82.4%，安慰剂组为75.4%。在帕博利珠单抗组中未观察到对生活质量的负面影响［86-87］。2021年10月13日，FDA批准帕博利珠单抗用于PD‐L1阳性的一线r/mCC患者，帕博利珠单抗+化疗±贝伐珠单抗的方案已成为r/mCC（PD‐L1阳性，CPS≥1）人群的一线标准治疗方案［88］。 BEATcc（ENGOT‐cx10/GEICO 68‐C/JGOG1084/GOG‐3030）研究比较了阿替利珠单抗+紫杉醇联合铂类化疗+贝伐珠单抗与紫杉醇联合铂类化疗+贝伐珠单抗作为r/mCC的两种一线治疗方案的疗效［89］。该研究与KEYNOTE‐826研究的主要区别在于缺乏安慰剂对照，不测分子生物标记物，所有患者必须接受贝伐珠单抗，结果显示在化疗+贝伐珠单抗基础上，添加阿替利珠单抗显著延长了患者的PFS期（中位13.7比10.4个月，P<0.001）和OS期（中位32.1比22.8个月，P=0.005）。 COMPASSION‐16试验是在国内进行的Ⅲ期、随机、双盲、安慰剂对照试验，评估了双特异性抗体卡度尼利单抗/安慰剂+紫杉醇联合铂类化疗±贝伐珠单抗的疗效和安全性，结果显示卡度尼利单抗联合化疗±贝伐珠单抗一线治疗全人群的中位OS显著优于安慰剂组（P=0.001）［90］。 基于以上研究，ICI在r/mCC中的疗效明确，一线r/mCC治疗的标准方案为紫杉醇+顺铂/卡铂±贝伐珠单抗+ICI（表2）。 3.免疫后时代药物：抗体药物偶联物（antibody‐drug conjugate，ADC）正在逐步取代传统细胞毒素药物，成为先前使用过贝伐珠单抗、ICI、铂类化疗后r/mCC的治疗药物。 组织因子（tissue factor，TF）在宫颈癌组织中几乎普遍表达，包括淋巴结和远处转移灶［91］。替索单抗‐韦多汀（tisotumab vedotin，TV）是一种靶向TF并与微管抑制剂共价连接的单克隆抗体。2021年，基于对101例受试者的单臂Ⅱ期innovaTV 204（ENGOT‐cx6/GOG‐3023）试验，TV的ORR为24%（95%CI为0.16~0.33），其中7例（7%）完全缓解、17例（17%）部分缓解，中位缓解持续时间为8.3个月［92］。TV获得了FDA的加速批准，用于在化疗期间或之后进展的r/mCC。innovaTV 301（ENGOT‐cx12/GOG‐3057）试验是一项Ⅲ期验证性临床试验，将502例一线系统治疗后进展的r/mCC患者1∶1随机分为TV组或医生选择的化疗组（托泊替康、长春瑞滨、吉西他滨、伊立替康、培美曲塞），中期分析发现TV的疗效优于化疗，两组中位OS时间为11.5比9.5个月（P=0.004），中位PFS时间为4.2比2.9个月（P<0.001），ORR为17.8%比5.2%（P<0.001）［93］，TV相关的特殊不良事件包括眼部不良反应、周围神经病变和出血。2024年4月29日，美国FDA批准了TV用于治疗一线含铂化疗后进展的r/mCC，这是继西米普利单抗（EMPOWER‐Cervical研究）之后，再次有药物在二线r/mCC治疗中，显示出OS优于医生选择的化疗。 DESTINY‐PanTumor02研究中，入组一线系统治疗失败且人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）免疫组化表达的r/mCC受试者40例，接受德曲妥珠单抗（trastuzumab deruxtecan）（DS‐8201）的治疗，这是一种HER2导向的ADC，具有拓扑异构酶Ⅰ抑制剂的有效载荷，研究者评估的ORR为50%，HER2免疫组化表达3+和2+的患者分别为8例和20例，其相应的ORR分别为75%和40%［94］，虽然宫颈癌HER2的突变率低［95］，但也显示出抗肿瘤活性。因此，2024年4月5日FDA加速批准德曲妥珠单抗用于治疗HER2免疫组化3+/2+的实体肿瘤。在r/mCC，ADC与ICI临床研究的发展基本平行，目前聚焦在二线r/mCC，ADC与ICI等的组合试验正在进行中。 （三） 综合治疗策略 r/mCC接受治疗时可能是寡转移、寡复发或广泛转移复发转态，鉴于其潜在转移的可能，均建议接受系统性药物治疗±局部治疗。在寡转移、寡复发患者，更注重局部治疗；在广泛复发转移者，则注重系统治疗，经过系统性药物治疗，如转化为寡转移、寡复发状态，此时有必要介入合适的局部治疗。姑息支持治疗贯穿在r/mCC的全过程管理中。经综合治疗后，根据r/mCC疾病转归的自然规律，表现为进展、好转、消失等不同的趋势，广泛复发转移者和寡转移、寡复发之间可以互相转化，需要根据病情变化调整治疗策略。 1. 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DOI: 10.1016/j.ygyno. 2020.07.025. 指南编纂专家组组长 曹新平：中山大学肿瘤防治中心 盛修贵：中国医学科学院肿瘤医院深圳医院 雷   新：陆军军医大学大坪医院 孙志华：江苏省肿瘤医院 魏丽春：空军军医大学西京医院 张福泉：北京协和医院 楼寒梅：浙江省肿瘤医院 指南编纂专家组副组长 胡   克：北京协和医院 程淑霞：河南省肿瘤医院 李大鹏：山东省肿瘤医院 张云艳：哈尔滨医科大学附属肿瘤医院 朱   红：中南大学湘雅医院 刘   孜：西安交通大学第一附属医院 吕晓娟：浙江省肿瘤医院 指南编纂专家组秘书 欧阳翼：中山大学肿瘤防治中心 倪   镌：浙江省肿瘤医院 徐寒子：江苏省肿瘤医院 指南编纂专家组成员 （排名不分先后， 按姓氏汉语拼音排序） 曹新平：中山大学肿瘤防治中心 程淑霞：河南省肿瘤医院 樊晓妹：河北医科大学第四医院 高玉华：辽宁省肿瘤医院 胡   克：北京协和医院 黄   奕：湖北省肿瘤医院 黄曼妮：中国医学科学院肿瘤医院 柯桂好：复旦大学附属肿瘤医院 雷   新：陆军军医大学大坪医院 李大鹏：山东省肿瘤医院 刘   孜：西安交通大学第一附属医院 楼寒梅：浙江省肿瘤医院 吕晓娟：浙江省肿瘤医院 邱   惠：武汉大学中南医院 盛修贵：中国医学科学院肿瘤医院深圳医院 宋红林：广西医科大学附属肿瘤医院 孙   力：中国医学科学院肿瘤医院深圳医院 孙志华：江苏省肿瘤医院 田小飞：陕西省肿瘤医院 王亚利：西安交通大学第二附属医院 魏丽春：空军军医大学西京医院 吴星娆：云南省肿瘤医院 徐   沁：福建省肿瘤医院 叶奕菁：广东省中山市人民医院 张福泉：北京协和医院 张继东：山西省肿瘤医院 张云艳：哈尔滨医科大学附属肿瘤医院 郑光浩：阿克苏地区第一人民医院 朱   红：中南大学湘雅医院 通信作者简介 楼寒梅 浙江省肿瘤医院 主任医师，浙江省肿瘤医院妇瘤放疗科主任。毕业于原浙江医科大学，浙江大学医学院硕士。 浙江省“新世纪151 人才工程”第三层次培养人员，美国MD安德森肿瘤中心访问学者，浙江省中医药大学硕导。 中国抗癌协会近距离放射治疗专委会副主任委员，中国抗癌协会近距离放射治疗专委会青年委员会主任委员，中国初级卫生保健基金会妇科肿瘤专委会副主任委员，浙江省抗癌协会近距离放射治疗专委会主任委员，浙江省医学会妇科肿瘤学分会副主任委员，浙江省医学会放射肿瘤治疗学分会委员，中华医学会放射治疗分会妇科肿瘤学组委员，中国医师协会放射治疗分会妇科肿瘤、近距离放射治疗学组委员，浙江省康复医学会淋巴水肿康复专委会主任委员。 长期从事妇科肿瘤的诊疗工作，擅长子宫颈癌、子宫内膜癌、外阴癌、阴道癌以及卵巢癌等的综合治疗，尤其在妇科恶性肿瘤的放射治疗领域，致力于规范化放射治疗以及特殊放疗精准技术的开发，牵头及参与多项免疫及ADC药物注册临床研究。研究方向为妇科恶性肿瘤放化疗策略、宫颈癌放疗疗效相关关键因素等。 近5年，承担及参与国家级、省厅级课题10余项，第一或通讯作者发表SCI及一级刊物30余篇。多项宫颈癌药物注册临床研究的leadingPI及分中心PI， 作为主要参与者成果多次发表在Lancet Oncology、Clinical Cancer Research。 曹新平 中山大学肿瘤防治中心 医学博士，主任医师，主诊教授，临床大PI，博士后合作导师。 中国抗癌协会理事会理事，中国抗癌协会近距离放疗专委会主任委员，中国抗癌协会整合放射治疗工作委员会副主任委员，中华医学会放射肿瘤治疗学分会近距离治疗学组副组长，中国医师协会近距离放疗学组副组长，国家癌症中心国家肿瘤质控中心宫颈癌质控委员会委员，中华医学会广东省放射肿瘤分会近距离放疗学组组长，广东省健康管理学会妇瘤MDT专委会副主任委员，广州市抗癌协会放射治疗分会候任主任委员，北京大学医学部客座教授。 责编：吕媛媛 审阅：崔敬璐 终审：何海青 -The End- 投稿网址：medpress.yiigle.com 编辑部电话： 010-87788294 邮箱：cjron@cmaph.org 谨防诈骗 任何以“某编辑”名义用个人邮箱 与您联系者均为假冒！ 任何收费相关的疑似假冒行为， 请拨打电话确认！ 声明：本文由“肿瘤界”整理与汇编，欢迎分享转载，如需使用本文内容，请务必注明出处。 来源：《中华放射肿瘤学杂志》官微 原标题：指南全文 | 复发转移性宫颈癌诊疗指南（2025版） 编辑：lagertha 审核：南星

Second quarter performance driven by strong portfolio royalty revenue growth of 57% 2025 full year revenue guidance increased to $200 million - $225 million (previously $180 million - $200 million) and adjusted earnings per diluted share1 increased to $6.70 - $7.00 (previously $6.00 - $6.25) Conference call begins at 8:30 a.m. Eastern Time today JUPITER, Fla., Aug. 07, 2025 (GLOBE NEWSWIRE) -- Ligand Pharmaceuticals Incorporated (Nasdaq: LGND) today reported financial results for the three and six months ended June 30, 2025, and provided an operating forecast and business update. Ligand management will host a conference call and webcast today at 8:30 a.m. Eastern Time to discuss the results and answer questions. “We are pleased to announce an increase to our 2025 guidance reflecting the continued strength and growth of our commercial-stage royalty portfolio.” said Todd Davis, CEO of Ligand. “This quarter there were several key milestones across our portfolio including the commercial launch of Zelsuvmi by our partner Pelthos and Merck's recently announced acquisition of our partner, Verona, which is expected to further accelerate the launch trajectory of Ohtuvayre in COPD and its clinical development in other indications. These achievements reflect the significant value of our partnerships and our comprehensive asset selection process, which continue to validate our robust and differentiated royalty aggregation model.” Second Quarter 2025 Financial Results Total revenues and other income for the second quarter of 2025 were $47.6 million, compared with $41.5 million for the same period in 2024, with the 15% increase primarily attributable to an increase in royalty revenue. Royalties for the second quarter of 2025 were $36.4 million, compared with $23.2 million for the same period in 2024, with the 57% increase primarily attributable to royalties earned on Recordati’s Qarziba, and Travere Therapeutics’ Filspari. Captisol® sales were $8.3 million for the second quarter of 2025, compared with $7.5 million for the same period in 2024, with the change due to the timing of customer orders. Contract revenue and other income was $2.9 million for the second quarter of 2025, compared with $10.9 million for the same period in 2024, with the difference due to the timing of partner milestone events. Cost of Captisol was $2.9 million and amortization of intangibles was $8.3 million for each of the second quarters of 2025 and 2024. Research and development expenses were $6.6 million for the second quarter of 2025, compared with $5.4 million for the same period in 2024, with the increase primarily attributable to expenses incurred by Pelthos in preparation for the commercial launch of Zelsuvmi. General and administrative expenses were $20.2 million for the second quarter of 2025, compared with $17.6 million for the same period in 2024, with the increase primarily attributable to employee related costs and operating costs associated with incubating the Pelthos business. Fair value adjustment to partner program derivatives was $1.3 million for the second quarter of 2025 primarily due to mark to market adjustments to certain Agenus partnered programs. In the second quarter of 2024 Ligand recorded a $26.5 million financial asset impairment tied to Takeda’s Soticlestat program which resulted from missing its Phase 3 clinical trial primary endpoint. GAAP net income was $4.8 million, or $0.24 per diluted share for the second quarter of 2025, compared with GAAP net loss of $51.9 million, or $2.88 per share, for the same period in 2024. Core adjusted net income for the second quarter of 2025 was $32.0 million, or $1.60 per diluted share, compared to $25.8 million, or $1.40 per diluted share, for the same period in 2024. The increase in core adjusted net income was driven primarily by the 15% increase in revenue and other income. Core adjusted net income represents a non-GAAP financial measure. See the table below for a reconciliation of net income (loss) to core adjusted net income. As of June 30, 2025, Ligand had cash, cash equivalents and short-term investments of $245.0 million, which includes $26.5 million in Viking Therapeutics common stock. Year-to-Date Financial Results Total revenues and other income for the six months ended June 30, 2025 were $93.0 million, compared with $72.5 million for the same period in 2024, with the 28% increase primarily attributable to an increase in royalty revenue and Captisol sales. Royalties for the six months ended June 30, 2025 were $63.9 million, compared with $42.3 million for the same period in 2024, with the 51% increase primarily attributable to royalties earned on Recordati’s Qarziba, and Travere Therapeutics’ Filspari. Captisol sales were $21.7 million for the six months ended June 30, 2025, compared with $16.7 million for the same period in 2024, with the change due to the timing of customer orders. Contract revenue and other income was $7.3 million for the six months ended June 30, 2025, compared with $13.5 million for the same period in 2024, with the difference due to the timing of partner milestone events. Cost of Captisol was $7.8 million for the six months ended June 30, 2025, compared with $5.8 million for the same period in 2024, with the change due to an increase in Captisol sales. Amortization of intangibles was $16.5 million for the six months ended June 30, 2025, compared with $16.4 million for the same period in 2024. Research and development expenses were $56.7 million for the six months ended June 30, 2025, compared with $11.3 million for the same period in 2024, with the increase primarily attributable to a $44.3 million one-time charge in connection with Ligand’s previously announced royalty financing agreement with Castle Creek Biosciences to fund the Phase 3 clinical study of D-Fi (FCX-007), which was accounted for as a research and development funding arrangement under ASC 730-20, Research and Development Arrangements. General and administrative expenses were $39.0 million for the six months ended June 30, 2025, compared with $28.6 million for the same period in 2024, with the increase primarily attributable to employee related costs and operating costs associated with incubating the Pelthos business. Fair value adjustment to partner program derivatives was $0.8 million for the six months ended June 30, 2025 primarily due to mark to market adjustments to certain Agenus partnered programs. Financial royalty assets impairment was $26.5 million for the six months ended June 30, 2024 due to Takeda’s Soticlestat missing its Phase 3 clinical trial primary endpoint of reducing the frequency of convulsive seizures for patients with Dravet Syndrome. GAAP net loss was $37.6 million, or $1.95 per share for the six months ended June 30, 2025, compared with GAAP net gain of $34.2 million, or $1.87 per diluted share, for the same period in 2024. Core adjusted net income for the six months ended June 30, 2025 was $58.6 million, or $2.94 per diluted share, compared to $47.6 million, or $2.61 per diluted share, for the same period in 2024. Core adjusted net income excluded gains from the sale of Viking Therapeutics common stock during the six months ended June 30, 2024. Ligand did not sell any shares of Viking Therapeutics common stock during the six months ended June 30, 2025. The increase in core adjusted net income was driven primarily by the 28% increase in revenue and other income. Core adjusted net income represents a non-GAAP financial measure. See the table below for a reconciliation of net income (loss) to core adjusted net income. 2025 Financial Guidance Ligand is increasing its 2025 full year financial guidance. The Company now expects total revenue of $200 million to $225 million (previously $180 million to $200 million) and is raising its guidance on adjusted earnings per diluted share1 to $6.70 to $7.00 (previously $6.00 to $6.25). Royalties are now expected to be in the range of $140 million to $150 million (previously $135 million to $140 million). Sales of Captisol are unchanged from $35 million to $40 million and contract revenue is now in the range of $25 million to $35 million (previously $10 million to $20 million). Second Quarter 2025 and Corporate Highlights Pelthos Therapeutics Transaction On July 2, 2025, Ligand announced the completion of its previously announced merger between the Company's wholly owned subsidiary, LNHC, Inc., and CHRO Merger Sub Inc., a wholly owned subsidiary of Channel Therapeutics Corporation (“Channel”). The combined company operates under the name Pelthos Therapeutics Inc. (“Pelthos”) and trades on the NYSE American exchange under the ticker symbol “PTHS”. Concurrent with the merger, Pelthos raised $50.1 million of equity capital, including a private placement from a group of strategic investors led by Murchinson (“Investor Group” and together with Ligand, the “Investors”). The Investor Group invested $32 million and Ligand invested $18 million in the combined company, respectively. The capital was invested into Pelthos’ Series A Convertible Preferred Stock (“Series A”) and common stock and includes cancellation of approximately $18.8 million in bridge capital that was advanced to Pelthos by several of the Investors (including Ligand) since the beginning of 2025 to support the commercial launch of Zelsuvmi. On July 10, 2025, Pelthos commercially launched Zelsuvmi (berdazimer) topical gel 10.3%, the first and only U.S. Food and Drug Administration (FDA) approved at-home treatment for molluscum contagiosum. Ligand earned a $5 million milestone payment from Pelthos following the commercial launch of Zelsuvmi. Ligand is also entitled to a 13% royalty on worldwide sales of Zelsuvmi, excluding Japan, and up to an additional $5 million in commercial sales milestones. New Royalty Investment in Orchestra BioMed On August 4, 2025, Ligand invested $25 million in strategic capital to fund Orchestra BioMed's late-stage partnered cardiology programs with an additional $15 million to be funded, subject to certain conditions precedent, at the nine-month anniversary of the transaction closing date. Ligand's investment included a $20 million cash payment and an additional $5 million in an equity private placement at the public offering price of $2.75 per share in Orchestra BioMed’s public offering. In exchange, Ligand will receive a low double-digit royalty on the first $100 million in commercial revenues from Orchestra’s AVIM therapy and Virtue SAB programs in all indications. Ligand will also earn a mid-single-digit royalty on annual revenues exceeding $100 million in commercial revenues from AVIM therapy in the uncontrolled hypertension and increased cardiovascular risk indication and Virtue SAB in coronary artery disease indications. Portfolio Updates On July 9, 2025, Merck and Verona announced a definitive agreement under which Merck, through a subsidiary, will acquire Verona for $107 per American Depository Share (ADS), each of which represents eight Verona ordinary shares, for a total transaction value of approximately $10 billion. Verona's portfolio includes Ohtuvayre, which was approved by the FDA in June 2024 for the maintenance treatment of COPD in adult patients. Ligand receives a 3% royalty on Ohtuvayre sales. On July 7, 2025, Agenus announced that its botensilimab and balstilimab (BOT/BAL) combination achieved a two-year survival rate of 42% along with a more mature 21-month median overall survival in an expanded cohort of 123 patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) without active liver metastases (NLM). Agenus also confirmed that it has reached agreement with the FDA on the design of the global BATTMAN Phase 3 trial. The FDA waived the need for a BOT monotherapy arm, allowing for a simple two-arm study design. On June 23, 2025, Palvella Therapeutics announced the full enrollment in SELVA, a Phase 3 trial of Qtorin 3.9% rapamycin anhydrous gel (Qtorin rapamycin) for the treatment of microcystic lymphatic malformations (microcystic LMs). The Phase 3 trial enrolled 51 subjects, exceeding the original target of 40 subjects by over 25%. Top-line results from SELVA are expected in the first quarter of 2026, with a New Drug Application (NDA) submission planned for the second half of 2026. On June 3, 2025, Agenus announced it entered into a partnership agreement with Zydus designed to accelerate clinical development, scale global manufacturing, and expand patient access to BOT/BAL. The strategic collaboration includes an exchange of Agenus’ state-of-the-art biologics CMC facilities in Emeryville, CA and Berkeley, CA for an upfront consideration of $75 million. Moreover, Agenus will receive up to an additional $50 million in contingent payments triggered by BOT/BAL production orders. This collaboration enables Agenus to unlock the value of its manufacturing assets and secure strategic capital to drive BOT/BAL toward global regulatory engagement and commercialization. On May 23, 2025, CSL Vifor announced that the National Institute for Health and Care Excellence (NICE) has published final draft guidance recommending that Filspari can be used in the NHS in England as an option to treat primary IgA nephropathy in adults with a urine protein excretion of 1.0 g/day or more, or a urine protein-to-creatinine ratio of 0.75 g/g or more. On May 16, 2025, Nuance announced top-line results from the Phase 3 ENHANCE-CHINA trial which evaluated nebulized ensifentrine (marketed as Ohtuvayre in the U.S.) for the maintenance treatment of chronic obstructive pulmonary disease (COPD). The ENHANCE-CHINA trial successfully met its primary endpoint, as well as secondary endpoints demonstrating improvements in lung function. On May 15, 2025, Travere announced that the FDA accepted its supplemental New Drug Application (sNDA) for traditional approval of Filspari (sparsentan) for the treatment of focal segmental glomerulosclerosis (FSGS). The FDA has assigned a Prescription Drug User Fee Act (PDUFA) target action date of January 13, 2026, and has indicated that it is currently planning to hold an advisory committee meeting to discuss the application. Additionally, Travere continues to expect a PDUFA target action date of August 28, 2025 for its sNDA requesting modification of liver monitoring and removal of embryo-fetal toxicity monitoring REMS for Filspari for the treatment of adults with primary immunoglobulin A nephropathy (IgAN) who are at risk for disease progression. Adjusted Financial Measures Ligand reports adjusted net income from continuing operations, adjusted net income per diluted share and adjusted earnings per diluted share in addition to, not as a substitute for, and does not consider such measures superior to, financial measures calculated in accordance with GAAP. The Company also reports a core calculation for each of the foregoing measures which excludes any realized gain from sales of Viking Therapeutics common stock. Additionally, adjusted earnings per diluted share is a key component of the financial metrics utilized by the Company’s board of directors to measure, in part, management’s performance and determine significant elements of management’s compensation. The Company’s financial measures under GAAP include share-based compensation expense, amortization of debt-related costs, amortization related to acquisitions and intangible assets, changes in contingent liabilities, mark-to-market adjustments for amounts relating to its equity investments in public companies, excess tax benefit from share-based compensation, transaction costs, income tax effect of adjusted reconciling items and others that are listed in the itemized reconciliations between GAAP and non-GAAP adjusted financial measures included at the end of this press release. A reconciliation of forward-looking non-GAAP adjusted earnings per diluted share to the most directly comparable GAAP measures is not available without unreasonable effort, as certain items cannot be reasonably predicted because of their high variability, complexity and low visibility. Specifically, non-cash adjustments that could be made for changes in contingent liabilities, changes in the market value of its investments in public companies, share-based compensation expense and the effects of any discrete income tax items, directly impact the calculations of our adjusted earnings per diluted share, which we expect to have a significant impact on our future GAAP financial results. Conference Call and Webcast Ligand management will host a conference call today beginning at 8:30 a.m. Eastern Time (5:30 a.m. Pacific Time) to discuss this announcement and answer questions. To participate via telephone, please dial (800) 715-9871 using the conference ID 3661098. International participants outside of Canada may use the toll number +1(646) 307-1963. To participate via live or replay webcast, a link is available at www.ligand.com. About Ligand Pharmaceuticals Ligand is a biopharmaceutical company enabling scientific advancement through supporting the clinical development of high-value medicines. Ligand does this by providing financing, licensing our technologies or both. Our business model seeks to generate value for stockholders by creating a diversified portfolio of biotech and pharmaceutical product revenue streams that are supported by an efficient and low corporate cost structure. Our goal is to offer investors an opportunity to participate in the promise of the biotech industry in a profitable and diversified manner. Our business model is based on funding programs in mid- to late-stage drug development in return for economic rights, purchasing royalty rights in development stage or commercial biopharmaceutical products and licensing our technology to help partners discover and develop medicines. We partner with other pharmaceutical companies to attempt to leverage what they do best (late-stage development, regulatory management and commercialization) in order to generate our revenue. We operate two infrastructure-light royalty generating technology IP platform technologies. Our Captisol® platform technology is a chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs. Our NITRICIL™ platform technology facilitates tunable dosing, permitting an adjustable drug release profile to allow proprietary formulations that target a broad range of indications. We have established multiple alliances, licenses and other business relationships with the world’s leading pharmaceutical companies including Amgen, Merck, Pfizer, Jazz, Gilead Sciences and Baxter International. For more information, please visit www.ligand.com. Follow Ligand on X and LinkedIn. We use our investor relations website and X as a means of disclosing material non-public information and for complying with our disclosure obligations under Regulation FD. Investors should monitor our website and our X account, in addition to following our press releases, SEC filings, public conference calls and webcasts. Forward-Looking Statements This press release contains forward-looking statements, as defined in Section 21E of the Securities Exchange Act of 1934, regarding Ligand’s current expectations. All statements, other than statements of historical fact, could be deemed to be forward-looking statements. In some instances, words such as “plans,” “believes,” “expects,” “anticipates,” and “will,” and similar expressions, are intended to identify forward-looking statements. Readers are cautioned not to place undue reliance on these forward-looking statements, which reflect our good faith beliefs (or those of the indicated third parties) and speak only as of the date hereof. These forward-looking statements include, without limitation, Ligand’s ability to expand its portfolio with life sciences royalty opportunities; the timing of clinical and regulatory events of Ligand’s partners and other commercialization and marketing efforts; the timing of the initiation or completion of preclinical studies and clinical trials by Ligand and its partners; the timing of product launches by Ligand or its partners; and guidance regarding projected 2025 financial results. Actual events or results may differ from Ligand’s expectations due to risks and uncertainties inherent in Ligand’s business, including, without limitation: Ligand relies on collaborative partners for milestone payments, royalties, materials revenue, contract payments and other revenue projections and may not receive expected revenue; Ligand may not receive expected revenue from Captisol material sales; Ligand and its partners may not be able to timely or successfully advance any product(s) in its internal or partnered pipeline or receive regulatory approval and there may not be a market for the product(s) even if successfully developed and approved; Ligand may not achieve its financial guidance for 2025; Ligand faces competition in acquiring royalties and locating suitable royalties to acquire; Ligand may not be able to create future revenues and cash flows through the acquisition of royalties or by developing innovative therapeutics; products under development by Ligand or its partners may not receive regulatory approval; the total addressable market for our partners’ products may be smaller than estimated; Ligand faces competition with respect to its technology platforms which may demonstrate greater market acceptance or superiority; Ligand is currently dependent on a single source sole supplier for Captisol and failures by such supplier may result in delays or inability to meet the Captisol demands of its partners; Ligand’s partners may change their development focus and may not execute on their sales and marketing plans for marketed products for which Ligand has an economic interest; Ligand’s collaboration partners may become insolvent; Ligand’s and its partners’ products may not be proved to be safe and efficacious and may not perform as expected and uncertainty regarding the commercial performance of such products; Ligand or its partners may not be able to protect their intellectual property and patents covering certain products and technologies may be challenged or invalidated; cyber-attacks or other failures in telecommunications or information technology systems could result in information theft, data corruption and significant disruption to Ligand’s business operations; Ligand’s partners may terminate any of their agreements or the development or commercialization of any of its products; Ligand and its partners may experience delays in the commencement, enrollment, completion or analysis of clinical testing for its product candidates, or significant issues regarding the adequacy of its clinical trial designs or the execution of its clinical trials, challenges, costs and charges associated with integrating acquisitions with Ligand’s existing businesses; Ligand may not be able to successfully implement its strategic growth plan and continue the development of its proprietary programs; restrictions under Ligand’s credit agreement may limit its flexibility in operating its business and a default under the agreement could result in a foreclosure of the collateral securing such obligations; and changes in general economic conditions, including as a result of war, conflict, epidemic diseases, the imposition and/or announcement of tariffs and ongoing or future litigation could expose Ligand to significant liabilities and have a material adverse effect on the Company. The failure to meet expectations with respect to any of the foregoing matters may reduce Ligand’s stock price. Additional information concerning these and other risk factors affecting Ligand can be found in prior press releases available at www.ligand.com as well as in Ligand’s public periodic filings with the Securities and Exchange Commission available at www.sec.gov. Ligand disclaims any intent or obligation to update these forward-looking statements beyond the date of this release, including the possibility of additional license fees and milestone revenues we may receive. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Other Disclaimers and Trademarks The information in this press release regarding certain third-party products and programs, including Filspari, a Travere Therapeutics product, Ohtuvayre, a Verona Pharma product, and QTORIN rapamycin, a Palvella Therapeutics product candidate, comes from information publicly released by the owners of such products and programs. Ligand is not responsible for, and has no role in, the development of such products or programs. Ligand owns or has rights to trademarks and copyrights that it uses in connection with the operation of its business including its corporate name, logos and websites. Other trademarks and copyrights appearing in this press release are the property of their respective owners. The trademarks Ligand owns include Ligand, Captisol, NITRICIL and Zelsuvmi. Solely for convenience, some of the trademarks and copyrights referred to in this press release are listed without the®,© and™ symbols, but Ligand will assert, to the fullest extent under applicable law, its rights to its trademarks and copyrights. References to “Ligand,” the “Company,” “we,” “our” and similar expressions include Ligand Pharmaceuticals Incorporated and our wholly-owned subsidiaries. Contacts: Investors: Melanie Herman investors@ligand.com (858) 550-7761 Media:Kellie Walshmedia@ligand.com(914) 315-6072 LIGAND PHARMACEUTICALS INCORPORATEDCONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS(Unaudited, in thousands, except per share amounts) Three Months Ended June 30, Six Months Ended June 30, 2025 2024 2025 2024 Revenues and other income: Revenue from intangible royalty assets$30,084 $22,603 $51,671 $40,960 Income from financial royalty assets 6,313 559 12,215 1,297 Royalties 36,397 23,162 63,886 42,257 Captisol 8,287 7,500 21,747 16,712 Contract revenue and other income 2,943 10,869 7,327 13,540 Total revenues and other income 47,627 41,531 92,960 72,509 Operating costs and expenses: Cost of Captisol 2,907 2,906 7,756 5,788 Amortization of intangibles 8,258 8,257 16,515 16,443 Research and development 6,567 5,354 56,652 11,325 General and administrative 20,175 17,623 38,976 28,574 Financial royalty assets impairment — 26,491 — 26,491 Fair value adjustments to partner program derivatives 1,276 — 833 — Total operating costs and expenses 39,183 60,631 120,732 88,621 Income (loss) from operations 8,444 (19,100) (27,772) (16,112)Non-operating income and expenses: Gain (loss) from short-term investments 939 (14,256) (11,428) 96,516 Interest income, net 468 1,489 1,372 3,366 Other non-operating expense, net 1,372 (33,523) (1,129) (35,713)Total other income (loss), net 2,779 (46,290) (11,185) 64,169 Income (loss) before income taxes 11,223 (65,390) (38,957) 48,057 Income tax (expense) benefit (6,376) 13,479 1,353 (13,829)Net income (loss)$4,847 $(51,911) $(37,604) $34,228 Basic net income (loss) per share$0.25 $(2.88) $(1.95) $1.91 Shares used in basic per share calculation 19,327 18,028 19,259 17,880 Diluted net income (loss) per share$0.24 $(2.88) $(1.95) $1.87 Shares used in diluted per share calculation 19,926 18,028 19,259 18,282 LIGAND PHARMACEUTICALS INCORPORATEDCONDENSED CONSOLIDATED BALANCE SHEETS(unaudited, in thousands) June 30, 2025 December 31, 2024Assets Current assets: Cash, cash equivalents and short-term investments$245,020 $256,165Accounts receivable, net 41,288 38,376Inventory 15,489 14,114Short-term portion of financial royalty assets, net 10,276 10,025Income taxes receivable 828 4,073Other current assets 4,816 8,806Assets held for sale 35,228 —Total current assets 352,945 331,559 Goodwill and other intangible assets, net 351,674 371,898Long-term portion of financial royalty assets, net 193,556 185,024Noncurrent derivative assets 17,958 10,583Property and equipment, net 3,632 15,133Operating lease right-of-use assets 5,573 6,907Finance lease right-of-use assets 2,418 2,766Other investments 10,908 10,908Deferred income taxes, net 829 72Other assets 9,111 6,924Total assets$948,604 $941,774 Liabilities and Stockholders' Equity Current liabilities: Accounts payable and accrued liabilities$26,048 $33,139Income taxes payable 305 1,199Deferred revenue 111 1,278Current contingent liabilities 1,465 206Current operating lease liabilities 1,089 1,266Current finance lease liabilities 24 24Liabilities related to assets held for sale 35,692 —Total current liabilities 64,734 37,112 Long-term contingent liabilities 4,097 3,475Long-term operating lease liabilities 4,629 5,815Deferred income taxes, net 32,246 32,524Other long-term liabilities 14,369 32,409Total liabilities 120,075 111,335 Total stockholders' equity 828,529 830,439Total liabilities and stockholders' equity$948,604 $941,774 LIGAND PHARMACEUTICALS INCORPORATEDADJUSTED FINANCIAL MEASURES(Unaudited, in thousands, except per share amounts) Three Months Ended June 30, Six Months Ended June 30, 2025 2024 2025 2024 Net income (loss)$4,847 $(51,911) $(37,604) $34,228 Adjustments: Share-based compensation expense 9,997 11,060 17,833 18,394 Non-cash interest expense(1) 1,054 1,207 1,816 1,291 Amortization of intangible assets 8,258 8,257 16,515 16,443 Amortization of financial royalty assets(2) 4,177 962 6,742 4,224 Change in contingent liabilities(3) 52 1,233 1,931 1,200 Pelthos operating loss 8,467 4,686 13,212 10,846 Loss (gain) from short-term investments (939) 14,256 11,428 (96,516)Realized (loss) gain from short-term investments — (17) (20) 59,962 Provision for current expected credit losses on financial royalty assets (420) (1,419) (750) (4,260)Impairment of financial royalty assets(4) — 26,491 — 26,491 Decrease in investments in Primrose Bio(5) — 33,789 — 36,141 Castle Creek R&D funding — — 44,340 — Other(6) (1,293) (1,500) 154 (1,347)Income tax effect of adjusted reconciling items above (2,276) (21,785) (16,221) (12,588)Discrete tax expense related to increase in unrecognized tax benefits — 426 — 426 Excess tax benefit (shortfall) from share-based compensation(7) 41 98 (813) 563 Adjusted net income 31,965 25,833 58,563 95,498 Realized gains from sales of VKTX stock, net of tax — — — (47,857)Core adjusted net income$31,965 $25,833 $58,563 $47,641 Diluted per-share amounts attributable to common shareholders: Diluted net income (loss) per share$0.24 $(2.88) $(1.95) $1.87 Adjustments: Share-based compensation expense 0.50 0.60 0.89 1.01 Non-cash interest expense(1) 0.05 0.07 0.09 0.07 Amortization of intangible assets 0.41 0.45 0.83 0.90 Amortization of financial royalty assets(2) 0.21 0.05 0.34 0.23 Change in contingent liabilities(3) — 0.07 0.10 0.07 Pelthos operating loss 0.42 0.25 0.66 0.59 Loss (gain) from short-term investments (0.05) 0.77 0.57 (5.28)Realized gain from short-term investments — — — 3.28 Provision for current expected credit losses on financial royalty assets (0.02) (0.08) (0.04) (0.23)Impairment of financial royalty assets(4) — 1.44 — 1.45 Decrease in investments in Primrose Bio(5) — 1.83 — 1.98 Castle Creek R&D funding — — 2.22 — Other(6) (0.05) (0.06) 0.01 (0.07)Income tax effect of adjusted reconciling items above (0.11) (1.17) (0.81) (0.69)Discrete tax expense related to increase in unrecognized tax benefits — 0.02 — 0.02 Excess tax benefit (shortfall) from share-based compensation(7) — 0.01 (0.04) 0.03 Adjustment for shares excluded due to anti-dilution effect on GAAP net loss — 0.03 0.07 — Adjusted diluted net income per share 1.60 1.40 2.94 5.23 Realized gains from sales of VKTX stock, net of tax — — — (2.62)Core adjusted diluted net income per share$1.60 $1.40 $2.94 $2.61 GAAP - weighted average number of common shares - diluted 19,926 18,028 19,259 18,282 Shares excluded due to anti-dilutive effect on GAAP net loss — 413 677 — Adjusted weighted average number of common shares - diluted 19,926 18,441 19,936 18,282 (1) Amounts represent (a) non-cash interest expense in connection with the royalty and milestone payments purchase agreement assumed as part of the Novan acquisition in September 2023; and (b) non-cash debt related costs that are calculated in accordance with the authoritative accounting guidance for our revolving credit facility. (2) Amounts represent the adjustments to the effective interest income recognized to total contractual payments recognized in the period. (3) Amounts represent changes in fair value of contingent consideration related to CyDex and Metabasis transactions. (4) Amounts represent the impairment of financial royalty assets primarily related to the discontinuation of Takeda’s soticlestat program. (5) In June 2024, Primrose Bio announced a Series B preferred stock offering. Management applies the measurement alternative for its investment in the Series A preferred stock of Primrose Bio. Management concluded the Series B financing was a relevant transaction for determining an observable price change and revalued its Series A investment resulting in a downward adjustment of $25.8 million in the price of the Series A preferred stock. The unrealized loss on the Series A preferred stock was an indicator that the losses in common shares (equity method investment) are other than temporary. As a result, management recorded a $5.8 million impairment charge to its equity method investment in addition to Ligand’s share of the net loss of Primrose Bio. (6) Amounts primarily relate to gain or loss from change in fair value or derivative assets, loss on other investment, restructuring costs and other. (7) Excess tax benefit (shortfall) from share-based compensation are recorded as a discrete item within the provision for income taxes on the consolidated statements of operations as a result of the adoption of an accounting pronouncement (ASU 2016-09) on January 1, 2017. Prior to the adoption, the amount was recognized in additional paid-in capital on the consolidated statement of stockholders' equity. 1 A reconciliation of forward-looking non-GAAP adjusted earnings per diluted share to the most directly comparable GAAP measure is not available without unreasonable effort, as certain items cannot be reasonably predicted because of their high variability, complexity and low visibility. Specifically, non-cash adjustments that could be made for changes in contingent liabilities, changes in the market value of investments in public companies, share-based compensation expense and the effects of any discrete income tax items, directly impact the calculation of our adjusted earnings per diluted share.