度伐利尤单抗联合同步放疗治疗局部晚期非小细胞肺癌-DOLPHIN 2期非随机对照试验

SCI

16 September 2023

Durvalumab Plus Concurrent Radiotherapy for Treatment of Locally Advanced Non–Small Cell Lung Cancer The DOLPHIN Phase 2 Nonrandomized Controlled Trial

(JAMA Oncology, IF: 28.4)

Motoko Tachihara, MD, PhD; Kayoko Tsujino, MD, PhD; Takeaki Ishihara, MD, PhD; Hidetoshi Hayashi, MD, PhD; Yuki Sato, MD; Takayasu Kurata, MD, PhD; Shunichi Sugawara,MD, PhD; Yoshimasa Shiraishi, MD; Shunsuke Teraoka, MD; Koichi Azuma, MD, PhD; Haruko Daga, MD, PhD; Masafumi Yamaguchi, MD, PhD; Takeshi Kodaira, MD, PhD; Miyako Satouchi, MD, PhD; Mototsugu Shimokawa, PhD; Nobuyuki Yamamoto,MD, PhD; Kazuhiko Nakagawa, MD, PhD; for the West Japan Oncology Group (WJOG)

CORRESPONDENCE TO: mt0318@med.kobe-u.ac.jp

IMPORTANCE 重要性

Administration of durvalumab after concurrent chemoradiotherapy is the standard treatment of unresectable, locally advanced non–small cell lung cancer (NSCLC); however, 20% to 30% of patients do not receive durvalumab because of adverse events (AEs) during concurrent chemoradiotherapy. In addition, radiotherapy and immunotherapy have a synergistic effect.

同步放化疗后给予度伐利尤单抗是不可切除的局部晚期非小细胞肺癌（NSCLC）的标准治疗方法；然而，20%至30%的患者在同步放化疗期间因不良事件（AE）而不接受度伐利尤单抗治疗。此外，放疗和免疫疗法具有协同作用。

OBJECTIVE 目标

To investigate the efficacy and safety of durvalumab immunotherapy plus concurrent radiotherapy followed by maintenance with durvalumab therapy for treatment of locally advanced NSCLC without chemotherapy.

研究度伐利尤单抗免疫治疗加同步放疗后维持度伐利尤单抗治疗局部晚期非小细胞肺癌的疗效和安全性。

DESIGN, SETTING, AND PARTICIPANTS 设计、设置和参与者

The multicenter, single-arm DOLPHIN (Phase II Study of Durvalumab [MEDI4736] Plus Concurrent Radiation Therapy in Advanced Localized NSCLC Patients) nonrandomized controlled trial was performed by 12 institutions in Japan from September 13, 2019, to May 31, 2022. Participants in the primary registration phase included 74 patients with programmed cell death ligand 1 (PD-L1)-positive, unresectable, locally advanced NSCLC. The current analyses were conducted from June 1, 2022, to October 31, 2022.

2019年9月13日至2022年5月31日，日本12家机构进行了多中心、单臂DOLPHIN（度伐利尤单抗[MEDI4736]联合同步放疗治疗局部晚期NSCLC患者的II期研究）非随机对照试验。初次登记阶段的参与者包括74名程序性细胞死亡配体 1（PD-L1）阳性、不可切除、局部晚期NSCLC患者。目前的分析是在2022年6月1日至2022年10月31日期间进行的。

INTERVENTIONS 干预措施

Patients received radiotherapy (60 Gy) in combination with concurrent and maintenance durvalumab immunotherapy, 10mg/kg every 2 weeks, for up to 1 year.

患者接受放射治疗（60 Gy），同时接受同步度伐利尤单抗治疗和维持性度伐利尤单抗免疫治疗，每2周10mg/kg，持续1年。

MAIN OUTCOMES AND MEASURES 主要成果和措施

The primary end point of the rate of 12-month progression-free survival (PFS), as assessed by an independent central review, was estimated using the Kaplan-Meier method and evaluated with 90% CIs calculated using the Greenwood formula. The key secondary end points were PFS, objective response rate, treatment completion rate, and AEs.

通过一项独立的中央审查评估的12个月无进展生存率（PFS）的主要终点使用Kaplan-Meier方法进行估计，并使用Greenwood公式计算的90%CI进行评估。次要终点是PFS、客观缓解率、治疗完成率和AE。

RESULTS 结果

Data from 35 patients (median [range] age, 72 [44–83] years; 31 [88.6%] men) were included in the full analysis set of the evaluable population. The 12-month PFS rate was 72.1% (90% CI, 59.1%-85.1%), and the median PFS was 25.6 months (95%CI, 13.1 months to not estimable) at a median follow-up of 22.8 months (range, 4.3-31.8 months). Scheduled radiation therapy was completed in 97.1%of patients. The confirmed objective response rate was 90.9% (95%CI, 75.7%-98.1%), and the treatment completion rate was 57.6% (95%CI, 39.2%-74.5%). Among 34 patients evaluated in the safety analysis set, AEs of grade 3 or 4 occurred in 18 patients (52.9%), and of grade 5 in 2 patients (5.9%). Pneumonitis or radiation pneumonitis of any grade occurred in 23 patients (67.6%), and of grades 3 or 4 in 4 patients (11.8%).

来自35名患者（中位[范围]年龄，72[44-83]岁；31[88.6%]男性）的数据包括在可评估人群的完整分析数据集。12个月的PFS率为72.1%（90%CI，59.1%-85.1%），中位PFS为25.6个月（95%CI，13.1个月至不可估计），随访时间为22.8个月（范围4.3-31.8个月）。97.1%的患者完成了预定的放疗。经证实的客观有效率为90.9%（95%CI，75.7%-98.1%），治疗完成率为57.6%（95%CI，39.2%-74.5%）。在安全性分析数据集评估的34名患者中，3级或4级AE发生在18名患者中（52.9%），5级AE出现在2名患者中（5.9%）。23名患者（67.6%）发生任何级别的肺炎或放射性肺炎，4名患者（11.8%）发生3级或4级肺炎。

CONCLUSIONS AND RELEVANCE 结论和相关性

Findings from this phase 2 nonrandomized controlled trial indicate that durvalumab immunotherapy combined with curative radiotherapy for patients with PD-L1–positive, unresectable, locally advanced NSCLC is a promising treatment with tolerable AEs and is appropriate as a study treatment for phase 3 clinical trials. 

这项2期非随机对照试验的结果表明，对于PD-L1阳性、不可切除、局部晚期NSCLC患者，度伐利尤单抗免疫疗法联合治疗性放疗是一种有前景的治疗方法，可耐受AE，适合作为3期临床试验的研究治疗。

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