柳叶刀-呼吸病学 | 首个针对中国人群的非小细胞肺癌一线免疫联合化疗的III期研究
《柳叶刀-呼吸病学》（The Lancet Respiratory Medicine）近日在线发表由同济大学附属上海市肺科医院周彩存教授牵头的一项随机、开放、多中心的III期临床试验，旨在评估卡瑞利珠单抗联合卡铂和培美曲塞对比化疗一线治疗晚期非鳞非小细胞肺癌（NSCLC）的抗肿瘤活性和安全性。研究结果显示，卡瑞利珠单抗组中位OS达27.9个月。这是全球首个针对中国人群的非小细胞肺癌一线免疫联合化疗的III期研究，也是第一个公布OS结果的中国自主研发免疫检查点抑制剂一线治疗晚期NSCLC的研究。我们邀请作者团队对文章进行解读。
作者介绍
周彩存
教授，同济大学附属上海肺科医院肿瘤科主任，同济大学医学院肿瘤研究所所长，中国临床肿瘤学会执行委员，中国临床肿瘤学会非小细胞专委会主任委员，国际肺癌研究学会董事会委员（IASLC BOD），擅长肺癌的早期诊断、靶向治疗、综合治疗及个体化治疗。
文章解读
一直以来，驱动基因阴性的晚期非鳞状非小细胞肺癌（NSCLC）的主要一线治疗方案为含铂双药化疗。直到2018年8月，贝伐珠单抗联合含铂双药化疗被批准用于治疗晚期非鳞状非小细胞肺癌。然而，这一方案的中位总生存期只有10.3至24.3个月，仍不令人满意，亟需更有效的一线治疗方案[1-3]。多项高质量的全球范围的临床试验表明，PD-1抑制剂（或PD-L1抑制剂）联合化疗与化疗相比可以显著改善晚期非鳞状非小细胞肺癌的无进展生存期和总生存期，并且与PD-L1表达水平无关[4-7]。然而，目前为止尚无针对中国患者的PD-1抑制剂（或PD-L1抑制剂）联合化疗用于一线治疗晚期NSCLC的研究。由于不同人种和民族之间的肿瘤生物学行为、疾病特征和基因组突变各不相同，导致了对同一种治疗的反应不同。PD-1抑制剂或PD-L1抑制剂联合化疗用于一线治疗晚期非鳞NSCLC对于中国人群的有效性仍有待验证。
卡瑞利珠单抗（SHR-1210）是一种人源化的抗PD-1单克隆抗体。数项I期、II期和III期研究已经报道了卡瑞利珠单抗在多种肿瘤中均具有抗肿瘤活性和良好的安全性[8-15]。在一项II期研究中，卡瑞利珠单抗治疗既往经过治疗的晚期NSCLC，客观缓解率达到18.5％，中位无进展生存期达到3.2个月，中位总生存期达到19.4个月，在数值上优于多西他赛二线治疗的历史数据。
基于卡瑞利珠单抗既往研究的成果，考虑到铂类药物联合培美曲塞具有提高抗肿瘤免疫反应的潜力，我们开展了一项随机、开放标签、多中心的III期临床试验，在中国患者人群中，比较卡瑞利珠单抗联合卡铂和培美曲塞对比化疗一线治疗EGFR和ALK突变阴性晚期非鳞非小细胞肺癌的疗效。纳入标准要求受试者年龄处于18-70岁，组织学或细胞学确诊的IIIB-IV期非鳞NSCLC，无EGFR和ALK基因突变，既往未接受过全身化疗，存在至少一个可测量病灶（RECIST 1.1标准），ECOG PS评分0或1分。（Table 1）
Table 1: Baseline characteristics
受试者以1:1的比例随机分配进入卡瑞利珠单抗联合化疗组和化疗组，性别和吸烟史作为分层因素。受试者接受卡瑞利珠单抗（200mg）联合卡铂（AUC=5）和培美曲塞（500mg/m2）或卡铂（AUC=5）联合培美曲塞（500mg/m2）治疗，每3周一次，治疗4-6个周期后，接受卡瑞利珠单抗加培美曲塞或培美曲塞单药维持治疗，直至出现疾病进展、不可耐受的毒性、死亡、受试者撤回知情同意、或研究者决定终止治疗。卡瑞利珠单抗治疗总时长不超过2年。化疗组的受试者在疾病进展后允许接受卡瑞利珠单抗单药治疗。研究的主要终点是BICR评估的PFS和PD-L1阳性患者的PFS。次要终点包括OS，研究者评估的PFS，ORR，DCR，DoR，TTR和安全性。
在2017年5月12日至2018年6月6日之间，我们对中国52所医院的845例患者进行了筛选。在符合纳入标准接受随机分配的419例受试者中，有7例（卡瑞利珠单抗联合化疗组4例，化疗组3例）未接受治疗，有412人接受了分配的治疗（205例接受卡瑞利珠单抗加化疗，207例接受了化疗）。两组之间的基线特征基本达到良好平衡。中期分析的中位随访时间为11.9个月（IQR 9.0–14.9）。卡瑞利珠单抗联合化疗组中的71例（35％）患者和化疗组中的32例（15％）患者仍在接受分配的治疗。在分配的治疗进展后，卡瑞利珠单抗联合化疗组中的75例（37％）患者和化疗组中的120例（58％）患者接受了至少一种后续的抗肿瘤治疗。在化疗组中，研究治疗结束后，有79例（38％）患者交叉接受卡瑞利珠单抗单药治疗，另外有9例（4％）患者接受了其他抗PD-1单抗的单药或与其他疗法联合的治疗。（Figure 1）
Figure 1: Trial profile
*12 patients did not complete screening within the scheduling window, two were excluded due to investigator's decision, one failed to complete pulmonary examinations due to pain, one had unknown status of EGFR and ALK mutations due to limited tumour tissue, one refused to participant in study, and one was excluded due to death. †In the camrelizumab plus chemotherapy group, four patients did not receive the assigned treatment after being randomly assigned due to consent withdrawal, misrandomisation, protocol violation, and detection of a squamous tumour (one for each reason). In the chemotherapy alone group, three patients did not receive the assigned treatment after being randomly assigned owing to consent withdrawal. ‡Seven patients (three in the camrelizumab plus chemotherapy group vs four in chemotherapy alone group) permanently discontinued assigned treatment due to the specified treatment being withheld longer than the protocol acceptable time limit (12 weeks for camrelizumab; 9 weeks for chemotherapy). No patients were lost to follow-up before treatment discontinuation.
根据BICR评估的结果，卡瑞利珠单抗联合化疗组的中位无进展生存期（PFS）为11.3个月[95% CI 9.6–15.4]，化疗组的中位PFS为8.3个月[95% CI 6.0–9.7]（HR 0.60 [0.45–0.79]; p=0.0001）。卡瑞利珠单抗联合化疗组的12个月PFS率为49.6%（41.7%–57.1%），化疗组为35.1% （27.0%–43.2%）。对于PD-L1表达水平≥1%的患者，卡瑞利珠单抗联合化疗组的中位PFS为15.4个月（11.0–未达到），化疗组的中位PFS为9.9个月（5.7–12.4）（HR 0.56 [0.39–0.82]; p=0.0011）。（Figure 2）
Figure 2: Kaplan-Meier estimates for progression-free survival per blinded independent central review
(A) Kaplan-Meier curves of progression-free survival. The hazard ratio was estimated from a stratified Cox proportional hazards model. Comparisons between groups were analysed using stratified one-sided log-rank test. Stratified factors included sex (male versus female) and smoking history (≥20 pack-years vs <20 pack years or never). (B) Subgroup analysis of progression-free survival. For sex and smoking history, the hazard ratio was estimated from an unstratified Cox proportional hazards model with treatment as the fixed effect. For other variables, the hazard ratio was estimated from a Cox proportional hazards model stratified by sex (male versus female) and smoking history (≥20 pack-years vs <20 pack-years or never), with treatment as the fixed effect. *Assessed by blinded independent central review.
截至2020年2月25日，我们对总生存期OS进行了进一步分析。中位随访时间为19.3个月（IQR 9.8-23.7），其中卡瑞利珠单抗联合化疗组有92例（45％）死亡，化疗组113例（55％）死亡。化疗组的中位OS为20.5个月（95％CI 15.9-24.4），而卡瑞利珠单抗联合化疗组的中位OS达到27.9个月（95％CI，21.9-未达到）。
根据BICR评估的结果，卡瑞利珠单抗联合化疗组205例受试者中有124例达到客观缓解，客观缓解率（ORR）达到60.5%（95% CI 53.4–67.2%），化疗组207例受试者中有80例达到客观缓解，ORR为38.6%（95% CI 32.0%–45.7%）。卡瑞利珠单抗联合化疗组中的180例受试者达到疾病控制（87.8% [95% CI 82.5–92.0]），化疗组中的154例达到疾病控制（74.4% [95% CI 67.9–80.2%]）。中位缓解持续时间(DoR)为17.6（95% CI 11.6–未到达）对9.9个月（95% CI 8.4–13.8）；中位起效时间（TTR）为1.5 （IQR 1.4–2.8）对2.7个月（IQR 1.4–3.0）。
安全性方面，卡瑞利珠单抗联合化疗组和化疗组的≥3级治疗相关不良事件发生率分别为69%和47%。最常见的免疫相关不良事件包括反应性皮肤毛细血管增生症（159 [78％]），丙氨酸转氨酶升高（25 [12％]），天冬氨酸转氨酶升高（23[11%]）和甲状腺功能减退（21[10%]）。157例（77％）患者发生1或2级反应性皮肤毛细血管增生症，仅有2例（<1％）患者发生3级反应性皮肤毛细血管增生症。(Table 2)
Table 2: Treatment-related adverse events and serious treatment-related adverse events in each group
在这项III期临床试验中，卡瑞利珠单抗联合化疗显著延长了EGFR/ALK突变阴性晚期非鳞NSCLC患者的无进展生存期，这是第一个免疫检查点抑制剂联合化疗治疗后中位PFS超过10个月的临床试验。虽然OS仍在继续随访中，但是卡瑞利珠单抗联合化疗对比化疗能够显著延长总生存期的趋势已经显而易见。该研究是第一个针对中国患者人群的免疫治疗联合化疗作为非鳞NSCLC一线治疗的III期临床试验，为中国晚期非鳞状非小细胞肺癌患者提供了新的一线治疗选择。END
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