早期非小细胞肺癌的围手术期帕博利珠单抗治疗

SCI

12 June 2023

Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer

(N Engl J Med ; IF:176.079)

Wakelee H, Liberman M, Kato T, et al. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med. Jun 3 2023.

Correspondence to: Dr. Wakelee. hwakelee@ stanford.edu

Division of Oncology, Stanford University School of Medicine, Stanford Cancer Institute, 269 Campus Dr., CCSR 1115, MC 5151, Stanford, CA 94305

BACKGROUND 背景

Among patients with resectable early-stage non–small-cell lung cancer (NSCLC), a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone.

在可切除的早期非小细胞肺癌(NSCLC)患者中，包括免疫检查点抑制剂新辅助治疗和辅助治疗的围手术期方法可能带来超过其中任何一种方法的益处。

METHODS 方法

We conducted a randomized, double-blind, phase 3 trial to evaluate perioperative pembrolizumab in patients with early-stage NSCLC. Participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1 ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3 weeks for up to 13 cycles. The dual primary end points were event-free survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death) and overall survival. Secondary end points included major pathological response, pathological complete response, and safety.

我们开展了一项随机、双盲、3期试验，在早期NSCLC患者中评估了围手术期帕博利珠单抗治疗。我们以1∶1的比例将可切除II, IIIa或IIIb期(N2期)NSCLC参与者分组，两组分别接受每3周1次的帕博利珠单抗(200 mg)或安慰剂新辅助治疗，两组均接受4个周期的顺铂化疗，之后接受手术和帕博利珠单抗(200 mg)或安慰剂辅助治疗（每3周1次），最多13个周期。主要终点是无事件生存期(从随机分组至首次发生导致无法进行计划的手术的局部进展、不可切除的肿瘤、进展或复发或死亡的时间)和总生存期。次要终点包括主要病理学缓解、病理学完全缓解和安全性。

RESULTS 结果

A total of 397 participants were assigned to the pembrolizumab group, and 400 to the placebo group. At the prespecified first interim analysis, the median follow-up was 25.2 months. Event-free survival at 24 months was 62.4% in the pembrolizumab group and 40.6% in the placebo group (hazard ratio for progression, recurrence, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72; P<0.001). The estimated 24-month overall survival was 80.9% in the pembrolizumab group and 77.6% in the placebo group (P = 0.02, which did not meet the significance criterion). A major pathological response occurred in 30.2% of the participants in the pembrolizumab group and in 11.0% of those in the placebo group (difference, 19.2 percentage points; 95% CI, 13.9 to 24.7; P<0.0001; threshold, P = 0.0001), and a pathological complete response occurred in 18.1% and 4.0%, respectively (difference, 14.2 percentage points; 95% CI, 10.1 to 18.7; P<0.0001; threshold, P = 0.0001). Across all treatment phases, 44.9% of the participants in the pembrolizumab group and 37.3% of those in the placebo group had treatment-related adverse events of grade 3 or higher, including 1.0% and 0.8%, respectively, who had grade 5 events.

共计397例参与者被分配至帕博利珠单抗组，400例被分配至安慰剂组。在预定的第一次中期分析时，中位随访时间为25.2个月。在帕博利珠单抗组和安慰剂组中，24个月时的无事件生存率分别为62.4%和40.6%(进展、复发或死亡的风险比，0.58;95%置信区间CI， 0.46 ~ 0.72;P < 0.001)。帕博利珠单抗组和安慰剂组的24个月总生存率分别为80.9%和77.6% (P = 0.02，未达到显著性标准)。帕博利珠单抗组30.2%的参与者和安慰剂组11.0%的参与者出现了主要病理学缓解(差异值，19.2%;95% CI: 13.9 ~ 24.7;P < 0.0001;阈值，P = 0.0001)，病理完全缓解率分别为18.1%和4.0%(差异值，14.2%;95% CI: 10.1 ~ 18.7;P < 0.0001;阈值，P = 0.0001)。在所有治疗阶段，帕博利珠单抗组44.9%的参与者和安慰剂组37.3%的参与者发生了3级或更高级别的治疗相关不良事件，其中分别有1.0%和0.8%的参与者发生了5级事件。

CONCLUSIONS 结论

Among patients with resectable, early-stage NSCLC, neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved event-free survival, major pathological response, and pathological complete response as compared with neoadjuvant chemotherapy alone followed by surgery. Overall survival did not differ significantly between the groups in this analysis.

在可切除的早期NSCLC患者中，与单独新辅助化疗后手术相比，帕博利珠单抗新辅助治疗+手术+帕博利珠单抗辅助化疗显著改善了无事件生存期、显著病理学缓解和病理学完全缓解。在这项分析中，两组的总生存期无显著差异。

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