Medical Oncology, Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
Oncology, Sanford Health, Sioux Falls, USA.
Ann Oncol. 2021 Jul;32(7):881-895. doi: 10.1016/j.annonc.2021.04.008. Epub 2021 Apr 22.
BACKGROUND: In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed-platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed-platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed-platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab. PATIENTS AND METHODS: Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m) and investigators' choice of cisplatin (75 mg/m) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed-platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS. RESULTS: After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed-platinum continued to improve OS [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69] and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed-platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed-platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed-platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed-platinum and 66.8% of patients receiving placebo plus pemetrexed-platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off. CONCLUSIONS: Pembrolizumab plus pemetrexed-platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed-platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous NSCLC.
背景：在 III 期 KEYNOTE-189 研究（NCT02578680）中，与安慰剂加培美曲塞-铂相比，帕博利珠单抗联合培美曲塞和铂类化疗（培美曲塞-铂）显著改善了未经治疗的转移性非鳞状非小细胞肺癌（NSCLC）患者的总生存期（OS）和无进展生存期（PFS）。我们报告了协议规定的最终分析中更新的疗效结果，包括接受培美曲塞-铂治疗后交叉至帕博利珠单抗的患者和完成 35 个周期（约 2 年）帕博利珠单抗治疗的患者的结果。 患者和方法：符合条件的患者以 2:1 的比例随机分配接受帕博利珠单抗 200mg（n=410）或安慰剂（n=206），每 3 周（最多 35 个周期，约 2 年），加培美曲塞（500mg/m）和研究者选择顺铂（75mg/m）或卡铂（曲线下面积 5mg·min/ml）每 3 周一次，随后培美曲塞直至疾病进展。如果符合入组标准，接受安慰剂加培美曲塞-铂的患者在疾病进展后可以交叉至帕博利珠单抗治疗。主要终点是 OS 和 PFS。 结果：中位随访 31.0 个月后，与安慰剂加培美曲塞-铂相比，帕博利珠单抗联合培美曲塞-铂继续改善 OS[风险比（HR），0.56；95%置信区间（CI），0.46-0.69]和 PFS（HR，0.49；95%CI，0.41-0.59），无论程序性死亡配体 1 表达如何。与安慰剂加培美曲塞-铂相比，接受帕博利珠单抗联合培美曲塞-铂治疗的患者客观缓解率（ORR）（48.3%比 19.9%）和二线治疗后第二次/随后肿瘤进展的时间（PFS2；HR，0.50；95%CI，0.41-0.61）得到改善。安慰剂加培美曲塞-铂组有 84 例（40.8%）患者交叉至帕博利珠单抗治疗组。接受帕博利珠单抗联合培美曲塞-铂治疗的患者中有 72.1%发生 3-5 级不良事件，接受安慰剂加培美曲塞-铂治疗的患者中有 66.8%发生 3-5 级不良事件。56 例患者完成了 35 个周期（约 2 年）的帕博利珠单抗治疗；ORR 为 85.7%，数据截止时 53 例（94.6%）存活。 结论：与安慰剂加培美曲塞-铂相比，帕博利珠单抗联合培美曲塞-铂继续显示出改善的疗效，且毒性可管理。这些发现支持将帕博利珠单抗联合培美曲塞-铂作为未经治疗的转移性非鳞状 NSCLC 的一线治疗药物。
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