Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial
Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial
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DOI：
10.1016/s1470-2045(21)00149-2
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发表时间：
2021-06-01
期刊：
影响因子：
51.1
通讯作者：
Formenti, Silvia C.
中科院分区：
文献类型：
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作者：
Altorki, Nasser K.;McGraw, Timothy E.;Formenti, Silvia C.
背景 先前针对早期非小细胞肺癌患者进行新辅助抗 PD-1 或抗 PD-L1 单药治疗的 2 期试验报告，主要病理缓解率为 15-45%。有证据表明，立体定向全身放疗可能是晚期非小细胞肺癌（NSCLC）的有效免疫调节剂。在这项试验中，我们旨在评估立体定向全身放疗在早期 NSCLC 患者中作为免疫调节剂的使用，以增强与抗 PD-L1 抗体 durvalumab 相关的抗肿瘤免疫反应。方法我们进行了一项单中心、开放标签、随机、对照、2 期试验，比较了早期 NSCLC 患者中单独使用新辅助 durvalumab 与新辅助 durvalumab 加立体定向放疗的效果。纽约长老会和威尔康奈尔医疗中心（美国纽约州纽约市）。我们招募了年龄为 18 岁或以上、东部肿瘤合作组表现状态为 0 或 1 的潜在可切除早期 NSCLC 患者（根据美国癌症联合委员会第七版临床分期为 I-IIIA）。符合条件的患者被随机分配 (1:1) 接受新辅助 durvalumab 单药治疗或新辅助 durvalumab 加立体定向全身放疗（8 Gy x 3 次），使用具有不同大小的排列块，并且没有临床或分子变量分层。在所有患者被随机分配后，患者、治疗医生和所有研究人员都被告知治疗分配情况。所有患者均接受两个周期的 durvalumab，间隔 3 周，剂量为 1.12 g，静脉输注时间超过 60 分钟。 durvalumab phis 放疗组中的患者还在 durvalumab 的第一个周期之前立即接受了连续 3 次每日 8 Gy 立体定向全身放疗，对原发肿瘤进行了放疗。没有全身性疾病进展的患者进行手术切除。主要终点是原发肿瘤的主要病理反应。所有分析都是在意向治疗的基础上进行的。该试验已在 ClinicalTrial.gov 注册，NCT02904954，正在进行中，但已接近应计阶段。结果 在 2017 年 1 月 25 日至 2020 年 9 月 15 日期间，筛选了 96 名患者，其中 60 名患者入组并随机分配到 durvalumab 单药治疗组 (n=30) 或 durvalumab 加放疗组 (n=30)。每组 30 名患者中有 26 名 (87%) 接受了肿瘤手术切除。在 durvalumab 单药治疗组的 30 名患者中，有 2 名患者 (6.7% [95% CI 0. 8-22-1]) 观察到了主要病理缓解，而在 durvalumab 加放疗组的 30 名患者中，有 16 名患者 (53.3% [34.3-71.7]) 观察到了主要病理缓解。两组之间主要病理缓解率差异显着（粗比值比 16.0 [95% CI 3-2-79-6]；p
Background Previous phase 2 trials of neoadjuvant anti-PD-1 or anti-PD-L1 monotherapy in patients with early-stage non-small-cell lung cancer have reported major pathological response rates in the range of 15-45%. Evidence suggests that stereotactic body radiotherapy might be a potent immunomodulator in advanced non-small-cell lung cancer (NSCLC). In this trial, we aimed to evaluate the use of stereotactic body radiotherapy in patients with early-stage NSCLC as an immunomodulator to enhance the anti-tumour immune response associated with the anti-PD-Ll antibody durvalumab.Methods We did a single-centre, open-label, randomised, controlled, phase 2 trial, comparing neoadjuvant durvalumab alone with neoadjuvant durvalumab plus stereotactic radiotherapy in patients with early-stage NSCLC, at NewYork-Presbyterian and Weill Cornell Medical Center (New York, NY, USA). We enrolled patients with potentially resectable early-stage NSCLC (clinical stages I-IIIA as per the 7th edition of the American joint Committee on Cancer) who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients were randomly assigned (1:1) to either neoadjuvant durvalumab monotherapy or neoadjuvant durvalumab plus stereotactic body radiotherapy (8 Gy x 3 fractions), using permuted blocks with varied sizes and no stratification for clinical or molecular variables. Patients, treating physicians, and all study personnel were unmasked to treatment assignment after all patients were randomly assigned. All patients received two cycles of durvalumab 3 weeks apart at a dose of 1.12 g by intravenous infusion over 60 min. Those in the durvalumab phis radiotherapy group also received three consecutive daily fractions of 8 Gy stereotactic body radiotherapy delivered to the primary tumour immediately before the first cycle of durvalumab. Patients without systemic disease progression proceeded to surgical resection. The primary endpoint was major pathological response in the primary tumour. All analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrial.gov, NCT02904954, and is ongoing but closed to accrual.Findings Between Jan 25, 2017, and Sept 15, 2020, 96 patients were screened and 60 were enrolled and randomly assigned to either the durvalumab monotherapy group (n=30) or the durvalumab plus radiotherapy group (n=30). 26 (87%) of 30 patients in each group had their tumours surgically resected. Major pathological response was observed in two (6.7% [95% CI 0. 8-22- 1]) of 30 patients in the durvalumab monotherapy group and 16 (53.3% [34.3-71.7]) of 30 patients in the durvalumab plus radiotherapy group. The difference in the major pathological response rates between both groups was significant (crude odds ratio 16.0 [95% CI 3- 2-79- 6]; p