Neoadjuvant Pembrolizumab for Early Stage Non-Small Cell Lung Cancer

新辅助Pembrolizumab治疗早期非小细胞肺癌

Introduction
介绍

Neoadjuvant immune checkpoint inhibitor treatment is a promising approach for resectable cancer. The optimal treatment regimen has yet to be determined.

This study was initially reported at the ESMO annual meeting 2018 and at the ASCO 2019 annual meeting. We currently report the final analysis for safety, the primary endpoint of the study, and updated efficacy results.

新辅助免疫检查点抑制剂治疗是一种很有前景的可切除肿瘤的方法。最佳的治疗方案尚未确定。这项研究最初在2018年ESMO年会和2019年ASCO年会上进行了报道。我们目前报告了安全性的最终分析、研究的主要终点和最新的疗效结果。

Methods
研究方法

We have conducted a phase I, investigator-initiated single-center study, to examine the safety of neoadjuvant pembrolizumab for stage I-II (TNM v7) resectable NSCLC, to identify the recommended phase II dose/schedule (RP2D/S) and to evaluate efficacy by remaining viable cells (10% or less defined as a major pathologic response, MPR). The study cohorts differed in number of pembrolizumab doses, and in treatment initiation-to-surgery intervals. Exploratory analyses were done to evaluate factors possibly correlated with MPR.

我们已经进行了第一阶段,研究者发起的单中心研究中,检查安全的新辅助pembrolizumab阶段I II (TNM v7)可切除的非小细胞肺癌,确定推荐的二期剂量/时间表(RP2D / S)和评估疗效剩余可行的细胞(10%或更少定义为一个主要的病理反应,MPR)。研究队列在派姆单抗剂量数量和治疗开始至手术间隔上有所不同。探索性分析可能与MPR相关的因素。

Results
结果

26 patients initiated treatment on the study. Median age: 69 (range 51-79) years, 54% men, smoking status: 62%/31%/8% current/past/never. ECOG PS: 1/0 in 85%/15%. Histology: adenocarcinoma/squamous/adeno-squamous/NSCLC in 50%/42%/4%/4%. No DLT and no grade 5 TRAE occurred. Two patients (8%, 95% C.I 0-18%) had grade 3-4 TRAE; one patient had both grade 3 myositis and myocarditis (causing surgery deferral) and one patient had both grade 3 encephalitis and hepatitis (following surgery, 124 and 171 days respectively from pembrolizumab initiation). Median change in tumor diameter radiologically was -5% (range, -43% to 70%). By RECIST, one patient (4%; 95% C.I. 0-11%) had PR, 21 patients (81%; 95% C.I. 66-96%) had SD, two patients (8%; 95% C.I. 0-18%) had PD and two patients were non-evaluable. One patient refused surgery after treatment and one patient had a non-treatment-related myocardial infarct leading to surgery deferral. Pathologically, 7 patients (27%, 95% C.I 10-44%) achieved a MPR, 3 (12%, 95% C.I 1-24%) achieved pCR. Patients with MPR had longer treatment-surgery interval (Table). At a median follow up of 23 months (95% CI 13-32), 2 patients of the 26 treated patients (8%, 95% C.I 0-18) died, one of them with no evidence of disease. One of the 23 operated patients (4%, 95% C.I. 0-13%) had disease recurrence.

26例患者在研究中开始治疗。中位年龄:69岁(范围51-79)，54%男性，吸烟状况:62%/31%/8%目前/过去/从未吸烟。ECOG PS: 1/0在85%/15%。组织学:腺癌/鳞癌/腺鳞癌/非小细胞肺癌占50%/42%/4%/4%。未发生DLT和5级TRAE。2例患者(8%，95% C.I 0-18%)有3-4级TRAE;1例患者同时患有3级肌炎和心肌炎(导致手术延迟)，1例患者同时患有3级脑炎和肝炎(术后，派姆单抗启动124天和171天)。影像学上肿瘤直径的中位变化为-5%(范围为-43%至70%)。RECIST有1例患者(4%;95% C.I. 0-11%)有PR, 21例(81%;95% C.I. 66-96%)有SD, 2例(8%;95% C.I. 0-18%)有帕金森病，2例患者无法评估。1例患者在治疗后拒绝手术，1例患者出现与治疗无关的心肌梗死，导致手术延期。病理上，7例(27%，95% C.I 10-44%)达到MPR, 3例(12%，95% C.I 1-24%)达到pCR。MPR患者的治疗-手术间隔较长(表)。中位随访23个月(95% CI 13-32)， 26例治疗患者中有2例(8%，95% CI 0-18)死亡，其中1例无疾病迹象。23例手术患者中有1例(4%，95% C.I. 0-13%)有复发。

Conclusion
结论

Neoadjuvant pembrolizumab for early NSCLC achieved a 27% rate of MPR, a 12% rate of pCR, with 8% rate of grade 3-4 TRAE. Two doses of neoadjuvant pembrolizumab at a three week interval, followed by surgery two weeks later, is the RP2D/S. Longer interval from treatment to surgery was associated with higher rate of MPR. Correlative studies are ongoing.

早期NSCLC的新辅助派姆单抗达到27%的MPR率，12%的pCR率，8%的3-4级TRAE率。RP2D/S为每三周间隔两剂新辅助派姆单抗，两周后进行手术。从治疗到手术的较长时间间隔与较高的MPR率相关。相关研究正在进行中。