From Stanford University School of Medicine, Stanford Cancer Institute, Stanford, CA (H.W.); Centre Hospitalier de l'Université de Montréal (M.L.) and McGill University Health Centre (J.D.S.) - both in Montreal; Kanagawa Cancer Center, Yokohama (T.K.), and National Cancer Center Hospital East, Kashiwa (M.T.) - both in Japan; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (S.-H.L.); the National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (S.G.), and Beijing Cancer Hospital, Peking University (K.-N.C.) - both in Beijing; University Hospitals Leuven, Leuven, Belgium (C.D.); Hospital de la Santa Creu i Sant Pau, Barcelona (M.M.), and Hospital Universitario Insular de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas (D.R.-A.) - both in Spain; Zentralklinik Bad Berka, Bad Berka, Germany (E.E.); Sanatorio Parque, Cordoba, Argentina (G.L.M.); Hôpital d'Instruction des Armées Sainte-Anne, Toulon, France (O.B.); Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York (J.E.C.); the Department of Oncology, University of Turin, Azienda Ospedaliero-Universitaria San Luigi Gonzaga di Orbassano, Turin, Italy (S.N.); and Merck, Rahway, NJ (J.Y., S.M.K., A.S.).
N Engl J Med. 2023 Aug 10;389(6):491-503. doi: 10.1056/NEJMoa2302983. Epub 2023 Jun 3.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. (Funded by Merck Sharp and Dohme; KEYNOTE-671 ClinicalTrials.gov number, NCT03425643.).
背景：在可切除的早期非小细胞肺癌（NSCLC）患者中，包括新辅助和辅助免疫检查点抑制的围手术期方法可能提供的益处超过任何一种方法单独使用。
方法：我们进行了一项随机、双盲、III 期试验，以评估早期 NSCLC 患者的围手术期派姆单抗治疗。可切除的 II 期、III A 期或 IIIB（N2 期）NSCLC 患者以 1:1 的比例随机分配接受新辅助派姆单抗（200mg）或安慰剂，每 3 周一次，每 4 个周期接受顺铂为基础的化疗，随后进行手术和辅助派姆单抗（200mg）或安慰剂，每 3 周一次，最多 13 个周期。主要终点是无事件生存期（从随机分组到首次发生局部进展而无法进行计划手术、不可切除肿瘤、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反应、病理完全缓解和安全性。
结果：共有 397 名患者被分配到派姆单抗组，400 名患者被分配到安慰剂组。在预设的第一次中期分析中，中位随访时间为 25.2 个月。派姆单抗组 24 个月无事件生存率为 62.4%，安慰剂组为 40.6%（进展、复发或死亡的风险比，0.58；95%置信区间[CI]，0.46 至 0.72；P<0.001）。派姆单抗组 24 个月的总生存率为 80.9%，安慰剂组为 77.6%（P=0.02，未达到显著性标准）。派姆单抗组 30.2%的患者发生主要病理反应，安慰剂组为 11.0%（差异，19.2 个百分点；95%CI，13.9 至 24.7；P<0.0001；阈值，P=0.0001），18.1%和 4.0%的患者发生病理完全缓解（差异，14.2 个百分点；95%CI，10.1 至 18.7；P<0.0001；阈值，P=0.0001）。在所有治疗阶段，派姆单抗组 44.9%的患者和安慰剂组 37.3%的患者发生 3 级或以上的治疗相关不良事件，分别有 1.0%和 0.8%的患者发生 5 级事件。
结论：在可切除的早期 NSCLC 患者中，与单纯新辅助化疗后手术相比，新辅助派姆单抗加化疗后切除和辅助派姆单抗显著改善了无事件生存率、主要病理反应和病理完全缓解。在这项分析中，两组的总生存期无显著差异。（由默克公司资助；KEYNOTE-671 临床试验.gov 编号，NCT03425643。）
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