Phase 1 Trial of Pembrolizumab Administered Concurrently With Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer A Nonrandomized Controlled Trial
Phase 1 Trial of Pembrolizumab Administered Concurrently With Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer A Nonrandomized Controlled Trial
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DOI：
10.1001/jamaoncol.2019.6731
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发表时间：
2020-06-01
期刊：
影响因子：
28.4
通讯作者：
Malhotra, Jyoti
中科院分区：
文献类型：
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作者：
Jabbour, Salma K.;Berman, Abigail T.;Malhotra, Jyoti
问题：对于III期非小细胞肺癌，程序性细胞死亡1抑制剂与确定性放化疗同时使用的安全性和耐受性的初步证据是什么？结果：在这项同步程序性细胞死亡1阻断的放化疗的1期非随机对照试验中，4级肺炎是用于定义安全性的预定剂量限制性毒性作用。III期非小细胞肺癌的程序性细胞死亡1抑制和放化疗是可耐受的，显示3级或以上免疫相关不良事件的发生率为18%，包括3级和5级肺炎、3级间质性肾炎和1型糖尿病。意义程序性死亡配体1（PD-L）抑制剂联合放化疗一线治疗III期非小细胞肺癌似乎是可耐受的，应继续在II期和III期临床试验中进行评估。重要意义放化疗后巩固性程序性死亡配体1（PD-L）抑制剂可改善III期非小细胞肺癌（NSCLC）的总生存期和无进展生存期（PFS）并且需要对在放化疗开始时加入程序性细胞死亡1（PD-1）抑制剂进行安全性评价。目的确定PD-1抑制剂与确定性放化疗同时用于NSCLC的安全性和耐受性。2016年至2018年10月24日，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例受试者经多学科审查确定为局部晚期、不可切除、III期NSCLC，东部肿瘤协作组体能状态为0或1，血液学、肾功能和肝功能良好。数据分析时间为2016年10月17日至2019年7月19日。干预Pembrolizumab联合同步放化疗（卡铂和紫杉醇每周一次，放疗60戈伊，2戈伊/d）。评价的剂量队列包括全剂量派姆单抗（200 mg静脉注射，每3周一次）放化疗后2 - 6周（队列1）;帕博利珠单抗减量（100 mg静脉注射，每3周一次），从放化疗第29天开始（队列2）;从放化疗第29天开始接受全剂量派姆单抗第一组（队列3）;第二组（队列4）;第三组（队列3）;第四组（队列4）;第五组（队列5）。基于帕博利珠单抗的最大耐受剂量，计划了6例患者的安全性扩展队列。剂量限制性毒性作用定义为Pembrolizumab治疗第1周期内至少4级的肺炎。主要结局和指标：PD-1抑制联合放化疗治疗NSCLC的安全性和耐受性。结果在纳入分析的21例患者中（11例女性[52%];中位年龄，69.5 [范围，53.0-85.0]岁），在任何队列中均未观察到剂量限制性毒性作用。队列5方案的安全性扩展队列中发生了1例5级肺炎。4例患者（18%）发生了至少3级的免疫相关不良事件。接受至少1剂帕博利珠单抗治疗的患者（n = 21）的中位PFS为18.7（95% CI，11.8-29.4）个月，6个月和12个月PFS分别为81.0%（95% CI，64.1%-97.7%）和69.7%（95% CI，49.3%-90.2%）。接受至少2剂帕博利珠单抗的患者（n = 19）的中位PFS为21.0结论和相关性这些发现表明，PD-1抑制剂和放化疗联合治疗III期NSCLC是可耐受的，12个月时有希望的PFS为69.7%，这项1期非随机对照试验评估了在非小细胞肺癌患者中，程序性细胞死亡1抑制剂与确定性放化疗同时使用与程序性细胞死亡1抑制剂和放疗相比的安全性和耐受性。(c)2020年美国医学会All rights reserved.
Question What is the preliminary evidence of safety and tolerability of programmed cell death 1 inhibition concurrently with definitive chemoradiotherapy for stage III non-small cell lung cancer? Findings In this phase 1 nonrandomized controlled trial of chemoradiotherapy with concurrent programmed cell death 1 blockade, grade 4 pneumonitis was the predetermined dose-limiting toxic effect used to define safety. Programmed cell death 1 inhibition and chemoradiotherapy for stage III non-small cell lung cancer was tolerable and showed an 18% rate of grade 3 or greater immune-related adverse events, including grades 3 and 5 pneumonitis, grade 3 interstitial nephritis, and type 1 diabetes. Meaning First-line therapy with programmed cell death 1 inhibition and chemoradiotherapy for stage III non-small cell lung cancer appears to be tolerable and should continue to be evaluated in phase 2 and 3 clinical trials.IMPORTANCE 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.OBJECTIVE 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.INTERVENTIONS 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.MAIN OUTCOMES AND MEASURES Safety and tolerability of PD-1 inhibition with chemoradiotherapy for NSCLC. Secondary outcomes included PFS and pneumonitis rates.RESULTS 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.CONCLUSIONS AND RELEVANCE 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.This phase 1 nonrandomized controlled trial assesses the safety and tolerability of programmed cell death 1 inhibition concurrently with definitive chemoradiotherapy compared with programmed cell death 1 inhibition and radiotherapy in patients with non-small cell lung cancer. (c) 2020 American Medical Association. All rights reserved.