对仑伐替尼联合抗程序性死亡...晚期肉瘤患者的临床疗效观察_徐步舒.pdf

骨科临床与研究杂志 2023 年 3 月第 8 卷第 2 期J Clin Orthop es，March 2023，Vol 8，No2DOI:1019548/j2096-269x 202302004作者单位:510060 广州，中山大学肿瘤防治中心黑色素瘤与肉瘤内科 华南肿瘤学国家重点实验室 肿瘤医学协同创新中心通信作者:张星，E-mail:zhangxing sysucc org cn骨肿瘤诊治对仑伐替尼联合抗程序性死亡受体 1 抗体治疗晚期肉瘤患者的临床疗效观察徐步舒刘梦梦潘花潘求忠彭瑞清张星【摘要】目的探讨应用仑伐替尼联合抗程序性死亡受体 1(PD-1)抗体治疗晚期肉瘤患者的临床效果。方法对2018 年7 月至2021 年12 月中山大学肿瘤防治中心黑色素瘤与肉瘤内科应用仑伐替尼联合抗 PD-1 治疗的晚期肉瘤患者 26 例的临床资料进行回顾性分析。其中男 10 例，女 16 例;中位年龄为 36(18 73)岁;包括软组织肉瘤 24 例和骨肉瘤 2 例;治疗前美国东部肿瘤协作组(ECOG)评分为0 1 分;其中软组织肉瘤的病理类型包括平滑肌肉瘤 6 例、滑膜肉瘤 3 例、横纹肌肉瘤2 例、纤维肉瘤 2 例和其他 11 例。原发灶位于头颈部 1 例、四肢 10 例、躯干 6 例及腹腔或脏器 9 例。依照法国国家癌症中心联盟(FNCLCC)分级方法，13 例(50%)患者为 G3 级。记录患者的临床特征、影像学结果、临床疗效及生存情况等;依据实体瘤疗效评估标准(ECIST)1 1 对疗效进行评估，并对各病理型肉瘤患者的结果进行比较;采用美国国家癌症研究所(NCI)常见不良反应术语评定标准(CTCAE)4 0 对治疗相关不良事件进行评估。结果以仑伐替尼联合抗 PD-1 抗体治疗作为一线治疗方案的患者3 例，作为二线治疗方案的患者 4 例，作为三线及以上治疗方案的患者 19 例。中位随访时间为 11 9 个月(1 1 45 0 个月)。1 例患者失随访。总体客观缓解率(O)为 20 0%，疾病控制率(DC)为 72 0%。末次随访时，疾病进展患者 18 例，达到生存终点患者 8 例，中位无进展生存时间(PFS)为 7 8 个月(95%CI:3 6 12 0)，中位总生存时间(OS)23 3 个月(95%CI:13 1 33 6)。不良反应包括甲状腺功能减退(血 TSH 水平升高)17 例(68 0%)、皮疹 6 例(24 0%)、瘙痒 6 例(24 0%)、疲乏 5 例(20 0%)及高血压 4 例(16 0%)等，其中大部分为轻中度。结论仑伐替尼联合抗 PD-1 抗体的治疗方案对晚期肉瘤患者有效，且不良反应总体可耐受。【关键词】肉瘤;药物疗法;受体蛋白质酪氨酸激酶类;蛋白激酶抑制剂;程序性细胞死亡受体 1;抗体;仑伐替尼基金项目:国家自然科学基金(82102776，82072958)Effect of lenvatinib plus anti-programmed death-1 antibody on advanced sarcomaXu Bushu，LiuMengmeng，Pan Hua，Pan Qiuzhong，Peng uiqing，Zhang Xing Melanoma and Sarcoma Medical OncologyUnit，Sun Yat-sen University Cancer Center，State Key Laboratory of Oncology in South China，CollaborativeInnovation Center for Cancer Medicine，Guangzhou 510060，ChinaCorresponding author:Zhang Xing，E-mail:zhangxing sysucc org cn【Abstract】ObjectiveTo investigate the efficacy and safety of lenvatinib plus anti-programmed death-1(anti-PD-1)antibody in patients with advanced sarcoma MethodsClinical data of 26 patients with advancedsarcoma treated with lenvatinib plus anti-PD-1 antibody in Melanoma and Sarcoma Medical Oncology Unit，SunYat-sen University Cancer Center from July 2018 to December 2021 were retrospectively analyzed There were10 males and 16 females with a median age of 36(18-73)years Twenty-four cases of soft tissue sarcoma and 2cases of bone sarcoma in ECOG status of 0-1 before treatment were included Of the cases of soft tissuesarcoma，6 were leiomyosarcoma，3 were synovial sarcoma，2 were rhabdomyosarcoma，2 were fibrosarcomaand 11 were other pathological subtypes The primary lesion was located in head and neck in one case，limbs in48骨科临床与研究杂志 2023 年 3 月第 8 卷第 2 期J Clin Orthop es，March 2023，Vol8，No210 cases，trunk in 6 cases and abdominal cavity or organs in 9 cases Thirteen(50%)patients were graded G3according to the French National Federation of Cancer Centers(FNCLCC)grading methodClinicalcharacteristics，imaging results，clinical efficacy and survival of the patients were recorded Efficacy wasevaluated according to esponse Evaluation Criteria in Solid Tumors(ECIST)1 1 Outcomes were comparedamong patients with different pathologic types of sarcoma Common Terminology Criteria Adverse Events ofNational Cancer Institute(NCI-CTCAE)version 4 0 was used to evaluate adverse effects esultsThree(11 5%)patients received lenvatinib plus anti-PD-1 antibody therapy as the first-line therapy，4(15 4%)patients received as second-line therapy and 19(73 1%)patients received as third-line therapy Twenty-fivepatients completed follow-up and the median follow-up period was 11 9 months(1 1-45 0 months)Theoverall objective response rate(O)was 20 0%and the disease control rate(DC)was 72 0%Eighteenpatients had disease progression and 8 patients reached the end point of survival The median progression-freesurvival(PFS)was 7 8(95%CI:3 6-12 0)months，while the median overall survival(OS)was 23 3(95%CI:13 1-33 6)months Main adverse effects of this therapy were hypothyroidism/high thyroid stimulatinghormone(TSH)in 17 cases(68 0%)，rash in 6 cases(24 0%)，itching in 6 cases(24 0%)，fatigue in5 cases(20 0%)and hypertension in 4 cases(16 0%)Most adverse effects were mild to moderateConclusionLenvatinib plus anti-PD-1 antibody is effective in patients with advanced sarcoma，and the adverseeffects are generally tolerable【Key words】Sarcoma;Drug therapy;eceptor protein-tyrosine kinases;Protein kinase inhibitors;Programmed cell death 1 receptor;Antibodies;Lenvatinib【Key words】National Natural Science Foundation of China(82072958)肉瘤是一类间叶组织来源的罕见恶性肿瘤，主要包括软组织肉瘤及骨肉瘤，其分型复杂、预后差、研究进展缓慢且治疗手段局限。尤其是对于晚期肉瘤患者，一线治疗失败后缺乏有效药物。随着肉瘤发病率的不断上升，迫切需要更多针对晚期肉瘤患者的有效治疗方案。仑伐替尼是一种多靶点受体酪氨酸激酶小分子抑制剂1-3。该药被应用于晚期肝癌的一线治疗，并在甲状腺癌、肾癌和胸腺癌等多种恶性肿瘤的治疗中显示出一定的效果4-9。有学者应用仑伐替尼治疗少量骨与软组织肉瘤患者，中位无进展生存时间(progression-free survival，PFS)为3 个月，PFS 为 4 个月患者比例为 29%，与化学治疗联用可进一步提升疗效(PFS 为 4 个月患者比例为51%)10-12。抗 程 序 性 死 亡 受 体 1(programmeddeath-1，PD-1)抗体是一种靶向免疫检查点 PD-1/PD-L1 信号通路的新型免疫检查点抑制剂(immunecheckpoint inhibitor)，可通过激活 T 细胞及调控免疫应答杀伤肿瘤，对肺癌、肾癌、黑色素瘤及血液系统肿瘤等均展现出一定疗效14。近年来，随着对免疫治疗研究的逐步深入，靶向免疫联合治疗成为研究热点。将多种作用机制不同的药物组合使用，可能更大程度提高疗效，给肿瘤患者带来希望。作为靶向免疫联合治疗中最具潜力的组合之一，仑伐替尼与抗 PD-1 抗体已先后经美国食品和药品监督管理局(Foods and Drugs Administry，FDA)批准用于肝癌、肾癌和子宫内膜癌的治疗，且仑