Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey.
Department of Radiation Oncology, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
JAMA Oncol. 2020 Jun 1;6(6):848-855. doi: 10.1001/jamaoncol.2019.6731.
Consolidative programmed death ligand-1 (PD-L) inhibition after chemoradiotherapy improves overall survival and progression-free survival (PFS) for stage III non-small cell lung cancer (NSCLC) and requires safety evaluation for incorporation of programmed cell death 1 (PD-1) inhibition at the onset of chemoradiotherapy.
To determine the safety and tolerability of PD-1 inhibition concurrently with definitive chemoradiotherapy for NSCLC.
DESIGN, SETTING, AND PARTICIPANTS: This phase 1 prospective multicenter nonrandomized controlled trial using a 3 plus 3 design was performed from August 30, 2016, to October 24, 2018, with a median follow-up of 16.0 (95% CI, 12.0-22.6) months and data locked on July 25, 2019. Twenty-one participants had locally advanced, unresectable, stage III NSCLC as determined by multidisciplinary review, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate hematologic, renal, and hepatic function. Data were analyzed from October 17, 2016, to July 19, 2019.
Pembrolizumab was combined with concurrent chemoradiotherapy (weekly carboplatin and paclitaxel with 60 Gy of radiation in 2 Gy per d). Dose cohorts evaluated included full-dose pembrolizumab (200 mg intravenously every 3 weeks) 2 to 6 weeks after chemoradiotherapy (cohort 1); reduced-dose pembrolizumab (100 mg intravenously every 3 weeks) starting day 29 of chemoradiotherapy (cohort 2); full-dose pembrolizumab starting day 29 of chemoradiotherapy (cohort 3); reduced-dose pembrolizumab starting day 1 of chemoradiotherapy (cohort 4); and full-dose pembrolizumab starting day 1 of chemoradiotherapy (cohort 5). A safety expansion cohort of 6 patients was planned based on the maximum tolerated dose of pembrolizumab. Dose-limiting toxic effects were defined as pneumonitis of at least grade 4 within cycle 1 of pembrolizumab treatment.
Safety and tolerability of PD-1 inhibition with chemoradiotherapy for NSCLC. Secondary outcomes included PFS and pneumonitis rates.
Among the 21 patients included in the analysis (11 female [52%]; median age, 69.5 [range, 53.0-85.0] years), no dose-limiting toxic effects in any cohort were observed. One case of grade 5 pneumonitis occurred in the safety expansion cohort with the cohort 5 regimen. Immune-related adverse events of at least grade 3 occurred in 4 patients (18%). Median PFS for patients who received at least 1 dose of pembrolizumab (n = 21) was 18.7 (95% CI, 11.8-29.4) months, and 6- and 12-month PFS were 81.0% (95% CI, 64.1%-97.7%) and 69.7% (95% CI, 49.3%-90.2%), respectively. Median PFS for patients who received at least 2 doses of pembrolizumab (n = 19) was 21.0 (95% CI, 15.3 to infinity) months.
These findings suggest that combined treatment with PD-1 inhibitors and chemoradiotherapy for stage III NSCLC is tolerable, with promising PFS of 69.7% at 12 months, and requires further study.
ClinicalTrials.gov Identifier: NCT02621398.
重要性：在放化疗后进行联合程序性死亡配体 1（PD-L）抑制可改善 III 期非小细胞肺癌（NSCLC）的总生存率和无进展生存率（PFS），并且需要对 PD-1 抑制在放化疗开始时的纳入进行安全性评估。
目的：确定 PD-1 抑制与 NSCLC 根治性放化疗同时使用的安全性和耐受性。
设计、地点和参与者：这是一项前瞻性多中心非随机对照的 3+3 设计的 I 期临床试验，于 2016 年 8 月 30 日至 2018 年 10 月 24 日进行，中位随访时间为 16.0（95%CI，12.0-22.6）个月，数据锁定于 2019 年 7 月 25 日。21 名参与者为经多学科审查确定的局部晚期、不可切除的 III 期 NSCLC，Eastern Cooperative Oncology Group 表现状态 0 或 1，且血液学、肾脏和肝功能足够。数据分析于 2016 年 10 月 17 日至 2019 年 7 月 19 日进行。
干预措施：派姆单抗联合同期放化疗（每周卡铂和紫杉醇，60 Gy 分 2 Gy/d）。评估的剂量组包括放化疗后 2 至 6 周内全剂量派姆单抗（每 3 周静脉注射 200 mg）（队列 1）；放化疗开始第 29 天开始的低剂量派姆单抗（每 3 周静脉注射 100 mg）（队列 2）；放化疗开始第 29 天开始的全剂量派姆单抗（队列 3）；放化疗开始第 1 天开始的低剂量派姆单抗（队列 4）；以及放化疗开始第 1 天开始的全剂量派姆单抗（队列 5）。根据派姆单抗的最大耐受剂量，计划了一个包含 6 名患者的安全扩展队列。剂量限制毒性定义为派姆单抗治疗第 1 周期内至少 4 级的肺炎。
主要结果和测量：NSCLC 放化疗联合 PD-1 抑制的安全性和耐受性。次要结果包括 PFS 和肺炎发生率。
结果：在纳入分析的 21 名患者中（11 名女性[52%]；中位年龄 69.5[范围 53.0-85.0]岁），任何队列均未观察到剂量限制毒性。在队列 5 方案中，1 例安全扩展队列中发生 5 级肺炎。4 名患者（18%）出现至少 3 级的免疫相关不良事件。至少接受 1 剂派姆单抗的患者（n=21）的中位 PFS 为 18.7（95%CI，11.8-29.4）个月，6 个月和 12 个月的 PFS 分别为 81.0%（95%CI，64.1%-97.7%）和 69.7%（95%CI，49.3%-90.2%）。至少接受 2 剂派姆单抗的患者（n=19）的中位 PFS 为 21.0（95%CI，15.3 至无限）个月。
结论和相关性：这些发现表明，PD-1 抑制剂联合放化疗治疗 III 期 NSCLC 是可以耐受的，12 个月的 PFS 有希望达到 69.7%，需要进一步研究。
试验注册：ClinicalTrials.gov 标识符：NCT02621398。
