【信达雅-文献导读】刘少正：卡博替尼治疗碘难治性分化型甲状腺癌 (COSMIC-

　　【编者按】：中国医师协会核医学医师分会青年委员会主办文献导读栏目，备受全国核医学及相关领域的专家、老师、同学们的一致好评。为了给广大读者进一步深入了解和学习文献导读宣讲的文献内容，信达雅栏目推出文献导读所读文献摘译的中英文对照，供大家参考。本期发布的是文献导读中第14篇文献”卡博替尼治疗放射性碘难治性分化型甲状腺癌 (COSMIC-311试验)：一项随机、双盲、安慰剂对照、3期临床试验”的摘译，翻译者为南昌大学第一附属医院核医学科博士生刘少正, 校译者为南昌大学第一附属医院核医学科张庆教授，审核者为山西医科大学第一医院，刘海燕主任医师。因组稿时间仓促、译者水平限制及审校者经验不足，译文中定有不当之处，敬请各位专家批评指正！207

　　

　　Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial

　　(Marcia S Brose , Bruce Robinson , Steven I Sherman, et al. Lancet Oncol, 2021, 22(8):1126-1138.)

　　摘要：

　　背景：本研究的目的是评估酪氨酸激酶抑制剂卡博替尼在接受血管内皮生长因子受体（VEGFR）靶向治疗后疾病进展且没有合适治疗标准的放射性碘难治性分化型甲状腺癌（RR-DTC）患者中的作用。

　　Background：Patients with radioiodine-refractory differentiated thyroid cancer (DTC) previously treated with vascular endothelial growth factor receptor (VEGFR)-targeted therapy have aggressive disease and no available standard of care. The aim of this study was to evaluate the tyrosine kinase inhibitor cabozantinib in this patient population.

　　方法：在这项全球、随机、双盲、安慰剂对照的3期试验中，年龄在16岁及以上的放射性碘难治性DTC（乳头状或滤泡状及其亚型）患者和ECOG体能状态为0或1的患者被随机分配（2:1）口服卡博替尼（60 mg，每日一次）或匹配的安慰剂，根据是否使用仑伐替尼治疗和年龄进行分层。随机方案使用了区组大小为6的分层排列块和交互式语音网络响应系统；患者和研究人员双盲进行研究。这些患者既往接受过仑伐替尼或索拉非尼治疗，并且最多接受过两种VEGFR TKI治疗，在治疗期间或之后出现疾病进展。安慰剂组患者可以在疾病进展时（由盲法独立放射学委员会[BIRC]确认）交叉到开放标签卡博替尼组治疗。主要终点是前100名随机分配的患者的客观缓解率（ORR）（根据【RECIST】1.1版的疗效评估标准确定的疗效）（客观缓解率意向治疗【OITT】人群）和所有患者（意向治疗【ITT】人群）的无进展生存期（根据RECIST 1.1版疾病进展或死亡更早出现的时间），均由BIRC评估。本报告介绍了主要的客观缓解率分析和同时进行的预先计划的中期无进展生存分析。

　　Methods：In this global, randomised, double-blind, placebo-controlled, phase 3 trial, patients aged 16 years and older with radioiodine-refractory DTC (papillary or follicular and their variants) and an Eastern Cooperative Oncology Group  performance status of 0 or 1 were randomly assigned (2:1) to oral cabozantinib (60 mg once daily) or matching placebo, stratified by previous lenvatinib treatment and age. The randomisation scheme used stratified permuted blocks of block size six and an interactive voice-web response system; both patients and investigators were masked to study treatment.Patients must have received previous lenvatinib or sorafenib and progressed during or after treatment with up to two VEGFR tyrosine kinase inhibitors. Patients receiving placebo could cross over to open-label cabozantinib on disease progression confirmed by blinded independent radiology committee (BIRC). The primary endpoints were objective response rate (confirmed response per Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) in the first 100 randomly assigned patients(objective response rate intention-to-treat [OITT] population) and progression-free survival (time to earlier of disease progression per RECIST version 1.1 or death) in all patients (intention-to-treat [ITT] population), both assessed by BIRC. This report presents the primary objective response rate analysis and a concurrent  preplanned interim progression-free survival analysis. The study is registered with ClinicalTrials.gov, NCT03690388, and is no longer enrolling patients.

　　结果：2019年2月27日至2020年8月18日期间，对227名患者进行了资格评估，最终入选187名患者，来自25个国家的164家医疗机构，并随机分为卡博替尼组（125例）或安慰剂组（62例）。在数据截止点（2020年8月19日）对主要的ORR和中期PFS分析，ITT人群的中位随访时间为6.2个月（IQR 3.4–9.2），OITT人群的中位随访时间为8.9个月（7.1–10.5）。在OITT人群中，卡博替尼组客观缓解率（15%；99%CI 5.8-29.3）对比安慰剂组（0%；0-14.88）（p=0.028），但未达到预先规定的显著性水平（α=0.01）。在中期分析中，ITT人群达到了无进展生存的主要终点；卡博替尼在无进展生存期方面比安慰剂有显著提高，但与安慰剂1.9个月（1.8-3.6）相比中位PFS未达到（96%可信区间5.7-不可估计[NE]）；风险比0.22（96%可信区间0.13-0.36；P<0.0001）。125名接受卡博替尼治疗的患者中有71名（57%）发生3级或4级不良事件，安慰剂组16名（26%）发生3级或4级不良事件；其中最常见的是掌-足底红斑感觉障碍（13[10%]vs 0）、高血压（11[9%]vs 2[3%]）和疲劳（10[8%]vs 0）。卡博替尼组16%（20/125）患者和安慰剂组2%（1/62）患者发生严重的治疗相关不良事件；未发生用药相关死亡。

　　Findings：Between Feb 27, 2019, and Aug 18, 2020, 227 patients were assessed for eligibility, of whom 187 were enrolled from 164 clinics in 25 countries and randomly assigned to cabozantinib (n=125) or placebo (n=62).At data cutoff  (Aug 19, 2020) for the primary objective response rate and interim progression-free survival analyses, median follow-up was6.2months (IQR 3.4-9.2) for the ITT population and8.9months (7.1-10.5) for the OITT population. An  objective response in the OITT population was achieved in ten (15%; 99% CI 5.8-29.3) of 67 patients in the  cabozantinib group versus 0 (0%; 0-14.8) of 33 in the placebo (p=0.028) but did not meet the prespecified significance level (α=0.01). At interim analysis, the primary endpoint of progression-free survival was met in the ITT population; cabozantinib showed significant improvement in progression-free survival over placebo: median not reached (96% CI 5.7-not estimable [NE]) versus 1.9months (1.8-3.6); hazard ratio 0.22(96% CI 0.13-0.36;p<0.0001). Grade 3 or 4  adverse events occurred in 71 (57%) of 125  patients receiving cabozantinib and 16 (26%)of 62 receiving placebo, the most frequent of which were palmar-plantar erythrodysaesthesia (13 [10%] vs 0), hypertension (11[9%] vs 2 [3%]), and  fatigue (ten [8%] vs 0). Serious treatment-related adverse events occurred in 20(16%) of 125 patients in the cabozantinib group and one (2%) of 62 in the placebo group. There were no treatment-related deaths.

　　结论：最终的结果表明，卡博替尼显著延长PFS，并可能为尚无标准治疗的RR-DTC患者提供一种新的治疗选择。

　　Interpretation：Our results show that cabozantinib significantly prolongs progression-free survival and might provide  a new treatment option for patients with radioiodine-refractory DTC who have no available standard of care.

　　背景介绍

　　索拉非尼和仑伐替尼靶向血管内皮生长因子受体（VEGFR）和其他参与肿瘤增殖、存活和血管生成的激酶受体。虽然大多数RR-DTC患者最初使用索拉非尼或仑伐替尼实现疾病控制，但大多数患者最终会产生治疗耐药性并出现疾病进展。这些患者几乎没有治疗选择，没有标准的护理，是一个医疗需求高度未满足的人群。疾病进展可能与衰弱症状有关，RR-DTC患者的中位总生存期少于5年。

　　Sorafenib and lenvatinib target the vascular endothelial growth factor receptor (VEGFR) and other kinase receptors involved in tumour proliferation, survival, and angiogenesis.8–10 Although the majority of patients with radioiodine-refractory DTC initially achieve disease control with sorafenib or lenvatinib, most will eventually develop treatment resistance and have disease progression.These patients have few treatment options with no standard of care and are a population with high unmet medical need.Disease progression can be associated with debilitating symptoms, and median overall survival for patients with radioiodine-refractory metastatic DTC is less than 5 years.

　　卡博替尼是几种酪氨酸激酶的抑制剂，这些酪氨酸激酶介导DTC肿瘤生长和血管生成，包括VEGFR2、AXL、MET和RET。MET和AXL也与VEGF通路抑制的耐药性有关；导致RET融合蛋白的RET基因重排是一部分甲状腺乳头状癌患者的致癌驱动因素。卡博替尼尼对先前接受VEGFR靶向治疗的实体瘤患者，包括肾细胞癌、肝细胞癌和甲状腺髓样癌，显示出临床疗效。1期和2期的研究表明，卡博替尼在RR-DTC患者（包括之前接受VEGFR靶向治疗的患者）中的临床益处。在此，我们报告了对COSMIC-311的客观缓解率的初步分析和无进展生存期的中期分析，COSMIC-311是一项3期试验，用于评估卡博替尼对经过治疗的RR-DTC患者的疗效和安全性。

　　Cabozantinib is an inhibitor of several tyrosine kinases that mediate tumour growth and angiogenesis in DTC, including VEGFR2, AXL, MET, and RET. MET and AXL have also been implicated in resistance to vascular endothelial growth factor (VEGF) pathway inhibition;and RET gene rearrangements resulting in RET fusion proteins are oncogenic drivers in a subset of patients with papillary thyroid cancer.Cabozantinib has shown clinical benefit in patients with solid tumours previously treated with VEGFR-targeted therapy, including renal cell carcinoma, hepatocellular carcinoma, and medullary thyroid cancer.Phase 1 and 2 studies have shown the clinical activity of cabozantinib in patients with radioiodine-refractory DTC, including those previously treated with VEGFR-targeted therapy Here, we report the primary analysis of objective response rate and interim analysis of progression-free survival from COSMIC-311, a phase 3 trial that evaluated the efficacy and safety of cabozantinib in patients with previously treated radioiodine-refractory DTC.

　　方法

　　研究设计与研究对象

　　COSMIC-311是一项全球性、多中心、随机、双盲、安慰剂对照的3期试验。来自25个国家164家临床机构的患者，年龄在16岁或以上，确诊为DTC（乳头状或滤泡状及其组织学亚型），根据实体瘤反应评估标准（RECIST）1.1版本，有可测量的病灶，之前接受过碘-131治疗或被认为不适合使用碘-131治疗。患者必须之前接受过仑伐替尼或索拉非尼治疗，并且允许使用最多两种VEGFR TKI。在使用VEGFR TKI治疗期间或之后，患者必须按照RECIST版本1.1评估影像学进展。患者ECOG的体能状态为0或1分，适当的器官和骨髓功能，必须接受甲状腺素抑制治疗，血清促甲状腺素浓度低于参考范围下限或低于0.50mIU/L。通过回顾血液学、化学和尿液实验室结果，在筛查时评估器官功能。主要排除标准包括之前使用选择性BRAF抑制剂进行治疗，同时使用口服抗凝剂或血小板抑制剂进行治疗（不包括低剂量阿司匹林和低剂量低分子量肝素），是否存在未经治疗的脑转移，以及未控制的严重并发疾病。研究方案由各中心的机构审查委员会或伦理委员会批准，试验按照良好的临床实践进行，包括国际协调会议和赫尔辛基宣言。所有患者均提供书面知情同意书。

　　COSMIC-311 was a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Patients from 164 clinics in 25 countries (appendix pp 2–3) were eligible for enrolment if they were aged 16 years or older, had a confirmed diagnosis of DTC (papillary or follicular and their histological variants), had measurable disease according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, and were previously treated with or deemed ineligible for treatment with iodine-131. Patients must have received previous treatment with lenvatinib or sorafenib, and up to two previous VEGFR TKIs were allowed. Patients must have had radiographic progression per RECIST version 1.1 during or following treatment with a VEGFR TKI. Patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate organ and bone marrow function, and must have been receiving thyroxine replacement therapy with serum thyroid-stimulating hormone concentrations below the lower cutoff of the reference range or less than 0.50 mIU/L. Organ function was assessed at screening through review of haematology, chemistry, and urine laboratory results. Key exclusion criteria included previous treatment with selective BRAF inhibitors, concurrent treatment with oral anticoagulants or platelet inhibitors (excluding low-dose aspirin and low-dose low-molecular-weight heparins), presence of untreated brain metastases, and uncontrolled, significant intercurrent illness. Additional eligibility criteria are listed in the appendix (pp 4–8) and the study protocol (appendix). The study protocol was approved by the institutional review board or ethics committee at each centre and the trial was done in accordance with Good Clinical Practice, including the International Conference on Harmonisation and the Declaration of Helsinki. All patients provided written informed consent.

　　随机方案

　　患者被随机分配（2:1）接受卡博替尼或匹配的安慰剂。选择2:1随机分组是为了减少分配给安慰剂的患者比例，因为这些患者没有标准的护理。随机分组按是否使用仑伐替尼治疗和年龄进行分层(≤65岁与>65岁）。随机化方案使用区组为6的分层排列区块，研究治疗通过交互式语音-网络响应系统集中分配。随机时间表的制定被分配给一个独立临床研究组织。由临床研究组织生成的实时时间表已上传到交互式响应技术供应商的安全服务器上，该供应商负责交互式语音-网络响应服务。研究人员在授权并记录揭盲之前（2021年 4月16日），无法访问实时时间表、区组或区组大小的主列表。在每个瓶子或包装上预先打印出独特的药包编号，并通过交互式语音网络响应系统分配给患者，以确保患者、研究人员、现场工作人员和研究赞助人均无法知晓治疗分配方案。研究人员可以要求患者在经BIRC确认的放射学进展时揭盲。

　　患者每天口服一次60 mg卡博替尼片或与其匹配的安慰剂片。两组都得到了最好的支持性护理（镇痛、抗感染、贫血输血、营养支持，以及酌情通过药物或咨询提供心理支持）。不良事件通过剂量调整和支持性护理进行管理，根据研究者的判断，允许在任何时候进行。对于与治疗相关的不良事件，建议中断、减少剂量。对于不能耐受的2级不良事件、3级或4级不良事件，建议进行剂量调整。允许剂量中断长达8周或更长时间，但必须得到研究者的批准，剂量可以从每天60毫克减少到40毫克，然后再减少到每天20毫克。患者继续接受治疗，直到根据RECIST版本1.1确认疾病进展，或直到出现不可耐受的毒性。中止治疗的其他原因包括患者的决定、依从性差或妊娠。在放射学进展中被揭盲并被发现属于安慰剂组的患者，如果符合条件，可以交叉接受卡博替尼。卡博替尼组只要研究者认为患者可以临床获益的有影像学进展的患者也可以过渡到开放标签卡博替尼治疗。

　　Randomisation and masking

　　Patients were randomly assigned (2:1) to receive cabozantinib or matching placebo. The 2:1 randomisation was selected to reduce the proportion of patients assigned to placebo because these patients have no standard of care. Randomisation was stratified by previous lenvatinib treatment (yes vs no) and age (≤65 vs >65 years). The randomisation scheme used stratified permuted blocks of block size six and study treatment was centrally assigned through an interactive voice–web response system. Generation of the randomisation schedule was assigned

　　to a clinical research organisation who maintained an unmasked team independent from the study. The live schedule, generated by the clinical research organisation, was uploaded to a secured server for the interactive response technology vendor who was responsible for interactive voice–web response services. Study personnel did not have access to the live schedule, the master list of blocks or block sizes, until authorised and documented unmasking (April 16, 2021). Unique drug pack numbers were preprinted onto each bottle or package and assigned to the patient by the interactive voice–web response system to ensure patients, investigators, site staff, and the study sponsor remained masked to treatment assignment. Investigators could request that patients be unmasked at the time of radiographic progression confirmed by blinded independent radiology committee (BIRC)

　　Patients self-administered 60 mg of cabozantinib tablets or matching placebo tablets orally once per day. Both groups also received best supportive care (analgesia, antibiotics for infections, transfusions for anaemia, nutritional support, and psychological support with medication or counseling as appropriate). Adverse events were managed with dose modification and supportive care, which were allowed at any time per investigator judgment. Dose interruptions, reductions, or both, were recommended for treatment-related adverse events. Dose modification was recommended for intolerable grade 2 adverse events and grade 3 or 4 adverse events. Dose interruptions were allowed for up to 8 weeks, or longer but only with sponsor approval, and the dose could be reduced from 60 mg to 40 mg daily and then to 20 mg daily. Patients continued to receive treatment until disease progression was confirmed per RECIST version 1.1 or until unacceptable toxicity. Other reasons for treatment discontinuation included patient decision, non-compliance, or pregnancy. Patients who were unmasked at radiographic progression and found to be in the placebo group could cross over, if eligible, to receive open-label cabozantinib. Patients in the cabozantinib group who had radiographic progression could also transition to openlabel cabozantinib as long as they were deriving clinical benefit in the opinion of the investigator。

　　评估

　　（A）甲状腺球蛋白评估：基线检查、第5周、第9周以及每8周评估一次血清甲状腺球蛋白。在基线实验室检测包括血液学、生化、凝血、尿液和甲状腺功能测试，开始每2周进行一次，第9周后每4周进行一次。

　　（B）研究人员和BIRC根据RECIST版本1.1对图像进行评估：基线检查后，每8周通过MRI或CT评估肿瘤反应和进展，持续1年，然后改为每12周进行一次。

　　（C）在第9周之前，每2周评估一次安全性，之后每4周评估一次，并在治疗中断后30天进行治疗后随访。研究人员根据美国国家癌症研究所不良事件通用术语标准第 5 版对不良事件进行了严重程度分级。在最后一次治疗后随访后，每 12 周评估一次OS。

　　Tumour response and progression were assessed by MRI or CT at baseline, every 8 weeks after randomisation for 12 months, and then every 12 weeks thereafter. Images were evaluated per RECIST version 1.1 by the investigators and BIRC. Serum thyroglobulin was assessed at baseline, week 5, week 9, and then every 8 weeks. Quantification of serum thyroglobulin was done by Covance Central Laboratory Services (Indianapolis, IN, USA), and was established by chemiluminescence immunoassay by means of IMMULITE 2000 (Siemens Medical Solutions Diagnostics, Los Angeles, CA, USA). Laboratory tests, including haematology, chemistry, coagulation, urine, and thyroid function tests, were done at baseline, every 2 weeks until week 9, and then every 4 weeks thereafter. Safety was assessed every 2 weeks until week 9, then every 4 weeks thereafter, with a posttreatment follow-up visit 30 days after treatment discontinuation. Adverse events were assessed by investigators with severity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5. Overall survival was assessed every 12 weeks after the last post-treatment visit.

　　研究终点

　　主要研究终点：基于BIRC的评估，前100名随机分配患者的ORR（客观缓解率意向治疗[OITT]人群）和所有随机分配患者的PFS(意向治疗[ITT]人群）。达到客观缓解率或无进展生存期这两个终点中的任何一个都表明卡博替尼治疗优于安慰剂。

　　无进展生存期：从随机分组到按照RECIST版本1.1的放射学进展或任何原因导致的死亡中较早者的时间

　　客观缓解率：OITT人群中至少随访6个月后按照RECIST版本1.1确认CR与PR的患者比例。

　　总生存期：从随机分组到因任何原因死亡的时间。

　　反应持续时间：至少28天后确认的首次客观反应记录到疾病进展或因任何原因死亡的最早的时间，以及血清甲状腺球蛋白浓度的变化（定义为根据基线、第5周第1天和第9周第1天的评估得出的血清甲状腺球蛋白浓度的最佳下降百分比），并在OITT和ITT人群中进行评估。

　　疾病稳定率：患者在至少16周的时间内达到确切反应（完全或部分）或稳定疾病的比例。

　　对至少接受一剂试验方案的所有患者（安全人群）进行安全性和耐受性评估。

　　The multiple primary endpoints were objective response rate in the first 100 randomly assigned patients (the objective response rate intention-to-treat [OITT] population) and progression-free survival in all randomly assigned patients (the intention-to-treat [ITT] population), both based on evaluations by BIRC. Meeting either of the endpoints of objective response rate or progression-free survival would indicate superiority of cabozantinib treatment over placebo. Progression-free survival was defined as time from randomisation to the earlier of either radiographic progression per RECIST version 1.1 or death from any cause, and objective response rate was defined as the proportion of patients with a confirmed complete or partial response per RECIST version 1.1 after a minimum of 6 months of follow-up in the OITT population. Other prespecified efficacy endpoints included overall survival (defined as the time from randomisation to death from any cause), duration of response (defined as the time from first documentation of objective response that is confirmed at least 28 days later to the earliest date of disease progression or death from any cause), and changes in serum thyroglobulin concentrations (defined as the best percentage decrease in serum thyroglobulin concentrations on the basis of assessments at baseline, week 5 day 1, and week 9 day 1) and were evaluated in the OITT and ITT populations. The disease stabilisation rate was a prespecified supportive analysis and was defined as the proportion of patients achieving a confirmed response (complete or partial) or stable disease with a duration of at least 16 weeks. Safety and tolerability were evaluated in all patients who received at least one dose of the trial regimen (the safety population). Additional endpoints included the pharmacokinetics of cabozantinib, the association of biomarkers with outcomes, health-related quality of life, and health-care utilisation; analyses of these endpoints are in progress.

　　结果（部分）：

　　在227名接受资格评估的患者中，187名患者被纳入研究，并随机分为卡博替尼组（125例）或安慰剂组（62例）。前100名随机分配的患者（卡博替尼组67名，安慰剂组33名）组成OITT人群。基线人口统计学和临床特征如表1所示。ITT人群的平均年龄为66岁（IQR 56–72）。关于先前的治疗，187名患者中有118名（63%）曾服用过仑伐替尼，113名（60%）患者曾服用过索拉非尼，44名（24%）患者同时服用了仑伐替尼和索拉非尼。大多数患者（142例（76%）在接受索拉非尼或仑伐替尼作为其最近的治疗时出现疾病进展。两个治疗组先前全身非放射抗癌治疗的中位数（IQR）为2（2–3）。在数据截止点，89名患者继续接受卡博替尼治疗，26名患者继续接受安慰剂治疗。两个治疗组中断治疗的最常见原因是疾病进展。根据BIRC，卡博替尼组的两名患者和安慰剂组的19名患者在放射学进展中被揭盲，并过渡到接受开放标签卡博替尼。ITT人群的中位随访时间为6.2个月（IQR 3.4–9.2），OITT人群的中位随访时间为8.9个月（7.1–10.5）。

　　Of 227 patients assessed for eligibility, 187 patients were enrolled and randomly assigned to cabozantinib (n=125) or to placebo (n=62). These patients comprise the ITT and safety populations, since all randomised patients received at least one dose of their assigned study treatment. The first 100 randomly assigned patients (67 in the cabozantinib group and 33 in the placebo group) comprise the OITT population.

　　Baseline demographics and clinical characteristics are shown in table 1. Median age was 66 years (IQR 56–72) in the ITT population. Regarding previous therapy, 118 (63%) of 187 patients had received previous lenvatinib, 113 (60%) patients had received previous sorafenib, and 44 (24%) patients had received both lenvatinib and sorafenib. Most patients (142 [76%] had had disease progression while receiving sorafenib or lenvatinib as their most recent previous therapy . The median (IQR) number of previous systemic non-radiation anticancer therapies was two (2–3) in both treatment groups.

　　At data cutoff, 89 patients were continuing masked cabozantinib treatment, and 26 were continuing masked placebo treatment (figure 1). The most common reason for treatment discontinuation was disease progression in both treatment groups. Two patients in the cabozantinib group and 19 in the placebo group had been unmasked at radiographic progression per BIRC and transitioned to receive open-label cabozantinib. Median follow-up was 6·2 months (IQR 3·4–9·2) for the ITT population and 8·9 months (7·1–10·5) for the OITT population.

　　在OITT人群中，卡博替尼组67名患者中有10名（15%）经BIRC证实有部分应答，而安慰剂组33名患者中无应答。卡博替尼组BIRC的客观缓解率为15%（99%可信区间5.8–29.3），安慰剂组为0%（0–14.8）（p=0.028，表2）；这种差异不显著（观察到的p值>临界p值0·01）。在数据截止点处，卡博替尼组的中位反应持续时间尚未达到，10名患者中有9名在数据截止点处保持反应，而1名患者有疾病进展。卡博替尼组58名患者中有44名（76%）至少进行了一次基线后靶病变评估，而安慰剂组31名患者中有9名（29%）靶病变减少

　　In the OITT population, ten (15%) of 67 patients had confirmed partial responses by BIRC in the cabozantinib group, and there were no confirmed responses among 33 patients in the placebo group. The objective response rate by BIRC was 15% (99% CI 5·8–29·3) in the cabozantinib group versus 0% (0–14·8) in the placebo group (p=0·028, table 2); this difference was not significant (the observed p value >the critical p value of 0·01). Median duration of response in the cabozantinib group had not been reached at the data cutoff, with nine of ten patients maintaining response at data cutoff while one patient had disease progression. 44 (76%) of 58 patients with at least one post-baseline target lesion assessment in the cabozantinib group had a reduction in target lesions compared with nine (29%) of 31 patients in the placebo group (figure 2).

　　重要结果： 

　　（纵坐标 与基线相比，靶病变的最佳百分比变化（直径之和）） 

　　图2：个体患者靶病变中从基线检查时起最大肿瘤减少百分比的瀑布图（治疗人群的目标反应率）（A） 卡博替尼组。（B） 安慰剂组。由盲法独立放射学委员会根据实体瘤1.1版中的反应评估标准评估肿瘤反应。瀑布图显示了在疾病进展或开始任何非方案抗癌药物治疗之前，目标病变直径总和相对于基线的最大百分比减少或最小增加。仅显示至少有一项基线和基线后评估的患者。在卡博替尼组的58名患者和安慰剂组的31名患者中，至少有一项基线后评估，卡博替尼组的一名患者和安慰剂组的两名患者被排除，没有纳入瀑布图。

　　*确认部分反应。

　　Waterfall plot for maximum percentage tumour reduction from baseline in target lesions for individual patients (objective response rate intention-to-treat population) (A) Cabozantinib group. (B) Placebo group. Tumour response was assessed with Response Evaluation Criteria in Solid Tumours version 1.1 by blinded independent radiology committee. The waterfall plots show the maximum percentage reduction or minimum increase from baseline in sum of diameters of target lesions before progressive disease or initiation of any non-protocol anti-cancer medication. Only patients with at least one baseline and post-baseline assessment are shown. Of the 58 patients in the cabozantinib group and 31 in the placebo group with at least one-post baseline assessment, one patient in the cabozantinib group and two patients in the placebo group did not have a qualifying sum of diameter for inclusion in the waterfall plot. *Confirmed partial response

　　BIRC对ITT人群无进展生存期的中期分析显示，卡博替尼与安慰剂相比有显著改善。与安慰剂组的1.9个月（1.8–3.6）相比，卡博替尼组未达到中位无进展生存期（96%可信区间5.7–不可估计[NE]）（HR 0.22[96%可信区间0.13–0.36]，p<0.0001），无进展生存期6个月预估值为57%（96%可信区间43–69）；而安慰剂组6个月预估为17%（7–30）（图3A）

　　Interim analysis of progression-free survival by BIRC in the ITT population showed a significant improvement with cabozantinib versus placebo. Median progressionfree survival was not reached (96% CI 5·7–not estimable [NE]) in the cabozantinib group compared with 1.9 months (1·8–3·6) in the placebo group (HR 0·22 [96% CI 0·13–0·36], p<0·0001), with progression-free survival estimates of 57% (96% CI 43–69) versus 17% (7–30) at 6 months (figure 3A)。

　　数据截止时，卡博替尼组125名患者中有17名（14%）死亡，安慰剂组62名患者中有14名（23%）死亡。两个治疗组均未达到中位总生存率（95%可信区间NE-NE）（HR 0.54；95%可信区间0.27-1.11），卡博替尼组的总生存率估计为85%（95%可信区间75.0-91.0），安慰剂组为73%（58.4-83.7）（图3B）。卡博替尼组125名患者中有3名（2%）使用后续全身抗癌治疗，安慰剂组62名患者中有4名（6%）使用后续全身抗癌治疗；这还不包括安慰剂组中19名（31%）交叉使用开放标签卡博替尼的患者。

　　At data cutoff, there were 17 (14%) deaths among 125 patients in the cabozantinib group and 14 (23%) deaths among 62 patients in the placebo group. Median overall survival was not reached (95% CI NE–NE) in either treatment group (HR 0·54; 95% CI 0·27–1·11), with overall survival estimates of 85% (95% CI 75·0–91·0) in the cabozantinib group versus 73% (58·4–83·7) in the placebo group at 6 months (figure 3B). The number of patients who used subsequent systemic anticancer therapy was three (2%) of 125 in the cabozantinib group and four (6%) of 62 in the placebo group; this does not include the 19 patients (31%) in the placebo group who crossed over to open-label cabozantinib。

　　

　　图3：Kaplan-Meier对意向治疗人群无进展生存期（A）和总生存期（B）的估计

　　疾病稳定率：OITT人群：卡博替尼组60%（95%CI 47-71.5），安慰剂27%（95%CI13.3-45.5），P=0.028。ITT人群：卡博替尼组9%（95%CI 4.5-15.2），安慰剂0（95%CI 0-5.8），P=0.017.

　　在ITT人群中，卡博替尼组125名患者中有78名（62%）患者的血清甲状腺球蛋白浓度下降，而安慰剂组62名患者中有12名（19%）患者的血清甲状腺球蛋白浓度下降，与基线检查时相比，中位最佳百分比变化为?46%（IQR）?卡博替尼组为70%至0%，安慰剂组为14%（0%至58%）。

　　In addition, 78 (62%) of 125 patients in the cabozantinib group versus 12 (19%) of 62 in the placebo group had a decrease in serum thyroglobulin concentrations in the ITT population with a median best percentage change from baseline of ?46% (IQR ?70 to 0) in the cabozantinib group and 14% (0 to 58) in the placebo group. 17 patients in the cabozantinib group and ten patients in the placebo group were not evaluable for change from baseline in serum thyroglobulin.

　　卡博替尼组的治疗暴露时间中位数为4.4个月（IQR 2.1–7.3），而安慰剂组为2.3个月（1.6–5.6）。卡博替尼组的中位日剂量为42.0 mg（IQR 32.2–54.5），安慰剂组为60.0 mg（52.9–60.0）。卡博替尼组125名患者中有70名（56%）和安慰剂组62名患者中有3名（5%）因不良事件而需要减少药物剂量，125名患者中有28名（22%）和62名患者中有1名（2%）需要再次减少剂量。导致卡博替尼剂量减少的最常见不良事件包括手掌-足底红斑感觉障碍（125例中24例，占19%）、腹泻（13例，占10%）和疲劳（9例，占7%）。在安慰剂组中，导致剂量减少的不良事件包括疲劳、呼吸困难、吞咽困难和瘙痒（每62例中有1例[2%]）。卡博替尼组首次剂量减少的中位时间为57天（IQR 35–90），安慰剂组为85天（30–153）。卡博替尼组125名患者中有6名（5%）因与DTC无关的治疗突发不良事件而中断治疗，而安慰剂组无一名患者中断治疗。导致卡博替尼停药的治疗相关不良事件包括疲劳（n=2）、关节痛（n=1）、腹泻（n=1）、高钙血症（n=1）、高血压（n=1）、大肠穿孔（n=1）、增加肝功能检测（n=1）、肌痛（n=1）和肾功能损害（n=1）

　　Median duration of treatment exposure in the safety population was4.4months (IQR 2.1-7.3) in the cabozantinib group versus 2.3 months (1.6-5.6) in the placebo group. The median daily dose was 42 mg (IQR 32.2-54.5) with cabozantinib and 60mg (52.9-60) with placebo. Dose reductions to manage adverse events were required by 70 (56%) of 125 patients in the cabozantinib group and three (5%) of 62 in the placebo group, and 28 (22%) of 125 and one (2%) of 62 patients required a second dose reduction, respectively. The most common adverse events resulting in dose reduction of cabozantinib included palmar-plantar erythrodysaesthesia (24 [19%] of 125), diarrhoea (13 [10%]), and fatigue (nine [7%]). In the placebo group, adverse events resulting in dose reduction included fatigue, dyspnoea, dysphagia, and pruritus (one [2%] of 62 for each). The median time to the first dose reduction was 57 days (IQR 35–90) in the cabozantinib group and 85 days (30–153) in the placebo group. Six (5%) of 125 patients in the cabozantinib group and no patients in the placebo group discontinued treatment due to treatment-emergent adverse events unrelated to DTC. Treatment-related adverse events leading to discontinuation of cabozantinib included fatigue (n=2), arthralgia (n=1), diarrhoea (n=1), hypercalcaemia (n=1), hypertension (n=1), large-intestine perforation (n=1), increased liver function test (n=1), myalgia (n=1), and renal impairment (n=1).

　　卡博替尼组125名患者中有117名（94%）和安慰剂组62名患者中有58名（93%）发生任何因果关系和任何级别的不良事件，125名患者中有71名（57%）发生3级或4级不良事件，62名患者中有16名（26%）发生4级不良事件，125名患者中有7名（6%）和62名患者中有2名（3%）发生4级不良事件（表3）。最常见的3级或4级不良事件包括手掌-足底红斑感觉障碍（125例中卡博替尼组13例，安慰剂组0%）、高血压（11例，分别为9%和2例，分别为3%和3%）、疲劳（10例，分别为8%和0%）、腹泻（9例，分别为7%和0%）、低钙血症（9例，分别为7%和1例，分别为2%）。卡博替尼组20名（16%）患者和安慰剂组1名（2%）患者出现严重的治疗相关不良事件。

　　最后一次给药后30天内共有16例死亡：卡博替尼组125例中有9例（7%）死亡，安慰剂组62例中有7例（11%）。这些5级事件均被视为与治疗不相关。在卡博替尼组中，有5名患者死于疾病进展或甲状腺癌。其他四名患者有以下5级不良事件导致死亡：动脉出血、心肺骤停、肺炎和肺栓塞（每个患者一名）。安慰剂组有四名患者死于疾病进展或甲状腺癌。其他三名患者有以下导致死亡的5级事件：心脏骤停、脑血管意外和一般身体健康恶化（每个患者一名）。

　　Adverse events of any causality and any grade occurred in 117 (94%) of 125 patients in the cabozantinib group and 58 (93%) of 62 in the placebo group, grade 3 or 4 adverse events occurred in 71 (57%) of 125 and 16 (26%) of 62, and grade 4 adverse events occurred in seven (6%) of 125 and two (3%) of 62 (table 3). The most common grade 3 or 4 adverse events included palmar-plantar erythrodysaesthesia (13 [10%] of 125 with cabozantinib vs 0% with placebo), hypertension (11 [9%] vs two [3%]), fatigue (ten [8%] vs 0%), diarrhoea (nine [7%] vs 0%), and hypocalcaemia (nine [7%] vs 1 [2%]). Serious treatment-related adverse events occurred in 20 (16%) patients in the cabozantinib group and one (2%) patients in the placebo group .

　　A total of 16 deaths occurred through to 30 days after the last dose: nine (7%) of 125 in the cabozantinib group and seven (11%) of 62 in the placebo group. None of these grade 5 events were considered treatment related. In the cabozantinib group, five patients died from disease progression or thyroid cancer. The other four patients had the following grade 5 adverse events leading to death: arterial haemorrhage, cardiorespiratory arrest, pneumonia, and pulmonary embolism (one patient for each). In the placebo group, four patients died from disease progression or thyroid cancer. The other three patients had the following grade 5 events leading to death: cardiac arrest, cerebrovascular accident, and general physical health deterioration (one patient for each).

　　总之，与安慰剂相比，卡博替尼治疗显著延长了先前接受VEGFR靶向治疗的进行性、放射性碘难治性DTC患者的无进展生存期。安全性分析是可管理的，并且与卡博替尼的已知安全性分析一致。这些发现支持卡博替尼作为一种新的治疗选择。

　　In conclusion, treatment with cabozantinib signifcantly prolonged progression-free survival compared with placebo in patients with progressive, radioiodinerefractory DTC previously treated with VEGFR-targeted therapy. The safety profile was manageable and consistent with the known safety profile of cabozantinib. These findings support cabozantinib as a new treatment option.

　　（余略）

　　中国医师协会核医学医师分会青年委员会

　　翻译者：南昌大学第一附属医院核医学科博士生刘少正

　　校译者：南昌大学第一附属医院核医学科张庆教授

　　审核者：山西医科大学第一医院刘海燕主任医师

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