再看Keynote671研究，新辅助治疗将何去何从？

点击上方“知识城邦”关注我们吧！

Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial

Jonathan D Spicer*, Marina C Garassino*, Heather Wakelee, Moishe Liberman, Terufumi Kato, Masahiro Tsuboi, Se-Hoon Lee, Ke-Neng Chen, Christophe Dooms, Margarita Majem, Ekkehard Eigendorff, Gastón L Martinengo, Olivier Bylicki, Delvys Rodríguez-Abreu, Jamie E Chaft, Silvia Novello, Jing Yang, Ashwini Arunachalam, Steven M Keller, Ayman Samkari, Shugeng Gao, on behalf of the KEYNOTE-671 Investigators†

Lancet 14 September 2024

Background: At the first interim analysis of the KEYNOTE-671 trial, adding perioperative pembrolizumab to neoadjuvant chemotherapy significantly improved event-free survival in participants with early-stage non-small-cell lung cancer (NSCLC). We report overall survival and health-related quality of life outcomes from the second interim analysis.

背景：在KEYNOTE-671试验的第一次中期分析中，在新辅助化疗中添加围手术期帕博利珠单抗显著改善了早期非小细胞肺癌（SOC）参与者的无事件生存期。我们报告了第二次中期分析的总体生存率和与健康相关的生活质量结果。

Methods: KEYNOTE-671 was a global phase 3 trial done at 189 medical centres. Eligible participants (aged ≥18 years) with resectable stage II, IIIA, or IIIB (N2) NSCLC were randomly assigned (1:1) to four cycles of neoadjuvant pembrolizumab (200 mg administered intravenously every 3 weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant pembrolizumab (200 mg administered intravenously every 3 weeks) or to four cycles of neoadjuvant placebo (administered intravenously every 3 weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant placebo (administered intravenously every 3 weeks). Randomisation was done centrally using an interactive response technology system and was stratified by disease stage, PD-L1 expression, histology, and geographical region in blocks of four. Participants, investigators, and sponsor personnel were masked to treatment assignments; local pharmacists were unmasked to support treatment preparation. The dual primary endpoints were overall survival and event-free survival evaluated in the intention-to-treat population. This study is registered at ClinicalTrials.gov, NCT03425643, and is ongoing but closed to enrolment.

方法：KEYNOTE-671是一项在189个医疗中心进行的全球3期试验。符合条件的可切除II、LGA或IIIB期（N2）非小细胞肺癌参与者（年龄大于18岁）被随机分配（1：1）接受4个周期的新辅助帕博利珠单抗（每3周静脉注射200毫克）加基于顺铂的化疗，然后进行手术和13个周期的辅助帕博利珠单抗（每3周静脉注射200毫克）或接受4个周期的新辅助安慰剂（每3周静脉注射）加基于顺铂的化疗，然后进行手术和13个周期的辅助安慰剂（每3周静脉注射）。随机化是使用交互式反应技术系统集中进行的，并按疾病分期、PD-L1表达、组织学和地理区域进行分层，每四个区块。参与者、研究人员和申办者人员对治疗任务不设盲;当地药剂师不设盲，以支持治疗准备。双重主要终点是在意向治疗人群中评估的总生存期和无事件生存期。本研究在ClinicalTrials.gov（NCT 03425643）注册，正在进行中，但已关闭入组。

Results: Between May 11, 2018, and Dec 15, 2021, 797 participants were randomly assigned to the pembrolizumab group (n=397) or the placebo group (n=400). Median study follow-up at the second interim analysis was 36·6 months (IQR 27·6–47·8). 36-month overall survival estimates were 71% (95% CI 66–76) in the pembrolizumab group and 64% (58–69) in the placebo group (hazard ratio 0·72 [95% CI 0·56–0·93]; one-sided p=0·0052; threshold, one-sided p=0·0054). Median event-free survival was 47·2 months (95% CI 32·9 to not reached) in the pembrolizumab group and 18·3 months (14·8–22·1) in the placebo group (hazard ratio 0·59 [95% CI 0·48–0·72]). In the as-treated population, grade 3–5 treatment-related adverse events occurred in 179 (45%) of 396 participants in the pembrolizumab group and in 151 (38%) of 399 participants in the placebo group. Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group and three (1%) participants in the placebo group.

结果：2018年5月11日至2021年12月15日期间，797名参与者被随机分配到帕博利珠单抗组（n=397）或安慰剂组（n=400）。第二次中期分析时的中位研究随访时间为36·6个月（IQR 27·6-47·8）。36-帕博利珠单抗组的月总生存期估计为71%（95%CI 66-76），安慰剂组为64%（58-69）（风险比0.72 [95%CI 0.56 - 0.93];一侧p= 0.0052;阈值，一侧p= 0.0054）。帕博利珠单抗组的中位无事件生存期为47.2个月（95%CI 32.9至未达到），安慰剂组为18.3个月（14.8 - 22.1）（风险比0.59 [95%CI 0.48 - 0.72]）。在接受治疗的人群中，帕博利珠单抗组396名参与者中有179名（45%）发生了3-5级治疗相关不良事件，安慰剂组399名参与者中有151名（38%）发生了3-5级治疗相关不良事件。与治疗相关的不良事件导致帕博利珠单抗组中有四名（1%）参与者和安慰剂组中有三名（1%）参与者死亡。

Conclusions: The significant overall survival benefit of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone coupled with a manageable safety profile support the use of perioperative pembrolizumab in patients with resectable, early-stage NSCLC.

结论：与单独新辅助化疗相比，新辅助帕博利珠单抗加化疗，随后辅助帕博利珠单抗具有显著的总体生存益处，再加上可管理的安全性特征，支持在可切除的早期非小细胞肺癌患者中使用围手术期帕博利珠单抗。

目录

1. INTRODUCTION

2. Methods

    2.1 Study design and participants

    2.2 Randomisation and masking

    2.3 Procedures

    2.4 Outcomes

    2.5 Statistical analysis

3. Results (Figure 1)(Table 1)(Figure 2-4)(Table 2)

4. Discussion

— 图表汇总—

    2.3 Procedures

Table S1: Summary of the planned hypothesis testing at the interim and final analyses

EFS=event-free survival. mPR=major pathologic response. OS=overall survival. pCR=pathologic complete response. 

3. Results

Figure 1. Trial profile

The pembrolizumab group included neoadjuvant therapy with pembrolizumab plus platinum-based chemotherapy followed by surgery or radiotherapy (or both) and adjuvant pembrolizumab.

The placebo group included neoadjuvant therapy with placebo plus platinum-based chemotherapy followed by surgery or radiotherapy (or both) and adjuvant placebo.

*In the pembrolizumab group, 307 participants underwent in-study surgery alone and 18 participants underwent both in-study surgery and in-study radiotherapy; an additional 8 participants underwent off-study surgery.

†In the placebo group, 282 participants underwent in-study surgery alone and 35 participants underwent both in-study surgery and in-study radiotherapy; an additional 7 participants underwent off-study surgery.

‡Includes 4 participants who underwent exploratory thoracotomy and 1 participant who underwent lobectomy but was found to have metastatic disease at the time of surgery.

§Includes 13 participants who underwent exploratory thoracotomy and 2 participants who underwent lobectomy but were found to have metastatic disease at the time of surgery.

Table 1. Baseline demographic and disease characteristics in the intention-to-treat population

appendix p 28 Table S2: Summary of exposure to trial treatment or placebo in the combined treatment phases in the as-treated population

Data are median (IQR). 

*Treatment includes all trial drugs, in-study surgery, and in-study radiotherapy (if administered). 

appendix p 29 Table S3: Subsequent anticancer therapy in participants who experienced disease progression or recurrence

Data are n (%).  

*Excludes participants who received chemotherapy in combination with a PD-1 inhibitor, a PD-L1 inhibitor, or a tyrosine kinase inhibitor. 

appendix p 30 Table S4: Baseline demographic and disease characteristics in participants who died within the first 16 months

Data are median (IQR) or n (%). Some proportions may not total 100% due to rounding. ECOG=Eastern Cooperative Oncology Group. PD-L1=programmed death ligand 1. 

Figure 2. Overall survival in the intention-to-treat population

(A) Kaplan–Meier estimates of overall survival in the overall population; tick marks indicate censored data.

(B) Overall survival in subgroups of the overall population, with the vertical grey shaded band indicating the 95% CI for the overall population.

All subgroups were prespecified except for the subgroups of clinical nodal status, clinical disease stage (IIA vs IIB vs IIIA vs IIIB), and clinical disease and nodal status, which were post hoc. Per protocol, the subgroup of participants with ALK translocation is not shown because it included <30 participants. The analysis of the overall population was stratified by the randomisation stratification factors, whereas the analyses of the subgroups were not stratified in accordance with the protocol. HR=hazard ratio. TPS=tumour proportion score.

appendix p 13-18

Figure S1: Kaplan-Meier estimates of overall survival in subgroups based on PD-L1 expression

Figure S2: Kaplan-Meier estimates of overall survival in subgroups based on tumour histology

Figure S3: Kaplan-Meier estimates of overall survival in subgroups based on  clinical disease stage at baseline

Figure S4: Kaplan-Meier estimates of overall survival in subgroups based on clinical  nodal status at baseline

Figure S5: Kaplan-Meier estimates of overall survival in subgroups based on combined  clinical stage III and N2 status

Figure S6: Kaplan-Meier estimates of overall survival from the time of in-study surgery in subgroups based on receipt of adjuvant therapy

appendix p 31 Table S5: Categorization of events that contributed to event-free survival in the intention-to-treat population

Data are n (%). 

*Includes participants who had distant metastasis only and participants who had both distant metastasis and locoregional progression or recurrence. 

†Unknown denotes participants for whom data on locoregional progression or recurrence versus distant metastasis was unavailable. 

Figure 3. Event-free survival in the intention-to-treat population

(A) Kaplan–Meier estimates of event-free survival in the overall population; tick marks indicate censored data.

(B) Event-free survival in subgroups of the overall population, with the vertical grey shaded band indicating the 95% CI for the overall population.

All subgroups were prespecified except for the subgroups of clinical nodal status, clinical disease stage (IIA vs IIB vs IIIA vs IIIB), and clinical disease and nodal status, which were exploratory. Per protocol, the subgroup of participants with ALK translocation is not shown because it included <30 participants. The analysis of the overall population was stratified by the randomisation stratification factors, whereas the analyses of the subgroups were not stratified in accordance with the protocol. HR=hazard ratio. TPS=tumour proportion score.

Figure S7: Kaplan-Meier estimates of event-free survival in subgroups based on PD-L1 expression

Figure S8: Kaplan-Meier estimates of event-free survival in subgroups based on tumour histology

Figure S9: Kaplan-Meier estimates of event-free survival in subgroups based on clinical disease stage at baseline

Figure S10: Kaplan-Meier estimates of event-free survival in subgroups based on clinical nodal status at baseline

Figure S11: Kaplan-Meier estimates of event-free survival in subgroups based on combined clinical stage III and N2 status

Figure S12: Kaplan-Meier estimates of event-free survival from the time of in-study surgery in subgroups based on receipt of adjuvant therapy

Figure S13: Kaplan-Meier estimates of event-free survival from the time of in-study surgery in subgroups based on pathologic response

Table S6: Completion and compliance percentages for the EORTC QLQ-C30 and LC-13  in the patient-reported outcomes population

Table S7: Analysis of change from baseline in health-related quality of life at  neoadjuvant week 11 in the patient-reported outcomes population

Table S8: Analysis of change from baseline in health-related quality of life at adjuvant week 10 in the patient-reported outcomes population

Figure 4. Empirical mean change from baseline in the EORTC Core Quality of Life Questionnaire global health status/quality of life score over time in the patient-reported outcomes population

All values are accompanied by their associated 95% CI. Per protocol, week 37 was considered the end of the adjuvant therapy phase for health-related quality of life analyses. EORTC=European Organisation for Research and Treatment of Cancer.

Figure S14: Empirical mean change from baseline in health-related quality of life in the patient-reported outcomes population

Table S9: Summary of improvement and stability in the EORTC QLQ-C30 global health status/quality of life score in the patient-reported outcomes population

Table 2

Table S10: Treatment-related adverse events that occurred during the neoadjuvant/surgery treatment phase of the as-treated population 

Table S11: Treatment-related adverse events that occurred during the adjuvant treatment phase in the as-treated population

Table S12: Summary of adverse events that occurred during the surgical treatment phase in participants who underwent in-study surgery 

Table S13: Immune-mediated adverse events and infusion reactions that occurred in any trial phase in the as-treated population

大展宏兔~！