PD-1 抑制剂（拓益）联合化疗新辅助治疗 II-III 期 NSCLC 的安全性和有效性（LungMate 002）：一项开放标签、单臂、Ⅱ期临床试验。
Safety and effectiveness of neoadjuvant PD-1 inhibitor (toripalimab) plus chemotherapy in stage II-III NSCLC (LungMate 002): an open-label, single-arm, phase 2 trial.
机构信息
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
出版信息
BMC Med. 2022 Dec 30;20(1):493. doi: 10.1186/s12916-022-02696-4.
BACKGROUND
This trial aimed to analyse the safety, effectiveness and transcriptomic characteristics of neoadjuvant toripalimab plus chemotherapy in II-III non-small-cell lung cancer (NSCLC).
METHODS
Patient eligibility mainly involved treatment-naive, clinical stage II-III and wild-type EGFR/ALK NSCLC. The patients received 2-4 cycles of toripalimab (240 mg q3w) plus carboplatin-based chemotherapy. After the second treatment cycle, all patients were re-evaluated by a multidisciplinary team. Candidates eligible for surgery underwent surgery; otherwise, patients received the remaining treatment cycles. The primary endpoints were safety and major pathological response (MPR). Secondary endpoints were R0 resection rate, progression-free survival (PFS) and overall survival (OS). RNA sequencing of baseline and post-treatment samples was conducted to explore the transcriptomic characteristics of the therapeutic response.
RESULTS
In total, 50 eligible patients were enrolled, including 12 (24.0%) with resectable disease (RD) and 38 (76.0%) with potentially resectable disease (PRD). Treatment-related adverse events (TRAEs) were recorded in 48 cases (96.0%). Severe TRAEs occurred in 3 (6.0%) cases, including myelosuppression, drug-induced liver injury and death related to haemoptysis. The objective response rate (ORR) was 76.0%, with 8 (16.0%) patients having a complete response (CR), 30 (60.0%) partial response (PR), 10 (20.0%) stable disease (SD) and 2 (4.0%) progressive disease (PD). Surgery could be achieved in 12 (100%) patients with RD and 25 (65.8%) with PRD; 1 (2.0%) with PRD refused surgery. Therefore, R0 resection was performed for all 36 (100%) patients who underwent surgery; 20 (55.6%) achieved MPR, including 10 (27.8%) with a complete pathological response (pCR). The CHI3L1 (chitinase-3-like protein 1) immunohistochemistry (IHC) expression of baseline tumour samples could predict the therapeutic response (AUC=0.732), OS (P=0.017) and PFS (P=0.001). Increased PD-1 expression, T cell abundance and immune-related pathway enrichment were observed in post-treatment samples compared to baseline in the response group (CR+PR) but not in the non-response group (SD+PD).
CONCLUSIONS
Neoadjuvant toripalimab plus chemotherapy was safe and effective, with a high MPR and manageable TRAEs for II-III NSCLC, even converting initially PRD to RD. Disparate transcriptomic characteristics of therapeutic efficiency were observed, and CHI3L1 expression predicted therapeutic response and survival.
TRIAL REGISTRATION
ChiCTR1900024014, June 22, 2019.
背景
本研究旨在分析新辅助替雷利珠单抗联合化疗治疗 II-III 期非小细胞肺癌（NSCLC）的安全性、有效性和转录组学特征。
方法
患者纳入标准为未经治疗、临床分期为 II-III 期且 EGFR/ALK 野生型的 NSCLC 患者。患者接受 2-4 个周期的替雷利珠单抗（240mg，q3w）联合基于卡铂的化疗。在第二个治疗周期后，所有患者均由多学科团队进行重新评估。有手术条件的患者进行手术；否则，患者接受剩余的治疗周期。主要终点为安全性和主要病理缓解（MPR）。次要终点为 R0 切除率、无进展生存期（PFS）和总生存期（OS）。对基线和治疗后样本进行 RNA 测序，以探讨治疗反应的转录组学特征。
结果
共纳入 50 例符合条件的患者，其中 12 例（24.0%）为可切除疾病（RD），38 例（76.0%）为潜在可切除疾病（PRD）。48 例（96.0%）患者发生了治疗相关不良事件（TRAEs）。3 例（6.0%）发生严重 TRAEs，包括骨髓抑制、药物性肝损伤和与咯血相关的死亡。客观缓解率（ORR）为 76.0%，8 例（16.0%）患者完全缓解（CR），30 例（60.0%）部分缓解（PR），10 例（20.0%）疾病稳定（SD），2 例（4.0%）疾病进展（PD）。RD 患者中有 12 例（100%）和 PRD 患者中有 25 例（65.8%）接受了手术；1 例（2.0%）PRD 患者拒绝手术。因此，所有接受手术的 36 例（100%）患者均达到 R0 切除；20 例（55.6%）达到 MPR，其中 10 例（27.8%）达到完全病理缓解（pCR）。基线肿瘤样本的 CHI3L1（几丁质酶-3 样蛋白 1）免疫组化（IHC）表达可预测治疗反应（AUC=0.732）、OS（P=0.017）和 PFS（P=0.001）。与非缓解组（SD+PD）相比，缓解组（CR+PR）的治疗后样本中观察到 PD-1 表达增加、T 细胞丰度增加和免疫相关途径富集。
结论
新辅助替雷利珠单抗联合化疗治疗 II-III 期 NSCLC 安全有效，MPR 高，TRAEs 可管理，甚至可将初始 PRD 转化为 RD。观察到治疗效果的转录组学特征存在差异，CHI3L1 表达可预测治疗反应和生存。
临床试验注册
ChiCTR1900024014，2019 年 6 月 22 日。
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