Preclinical study and phase II trial of adapting low-dose radiotherapy to immunotherapy in small cell lung cancer

Hui Wang; Zhuoran Yao; Kai Kang; Lin Zhou; Weigang Xiu; Jianguo Sun; Conghua Xie; Min Yu; Yanying Li; Yan Zhang; Yue Zheng; Guo Lin; Xiangyu Pan; Yijun Wu; Ren Luo; Laduona Wang; Min Tang; Shuangsi Liao; Jiang Zhu; Xiaojuan Zhou; Xuanwei Zhang; Yong Xu; Yongmei Liu; Feng Peng; Jin Wang; Lisha Xiang; Limei Yin; Lei Deng; Meijuan Huang; Youling Gong; Bingwen Zou; Hui Wang; Lin Wu; Zhiyong Yuan; Nan Bi; Min Fan; Yaping Xu; Ruizhan Tong; Linglu Yi; Lu Gan; Jianxin Xue; Xianming Mo; Chong Chen; Feifei Na; You Lu

doi:10.1016/j.medj.2024.06.002

Preclinical study and phase II trial of adapting low-dose radiotherapy to immunotherapy in small cell lung cancer

Med. 2024 Oct 11;5(10):1237-1254.e9. doi: 10.1016/j.medj.2024.06.002. Epub 2024 Jul 3.

Authors

Hui Wang¹, Zhuoran Yao², Kai Kang², Lin Zhou², Weigang Xiu¹, Jianguo Sun³, Conghua Xie⁴, Min Yu¹, Yanying Li¹, Yan Zhang⁵, Yue Zheng¹, Guo Lin¹, Xiangyu Pan⁶, Yijun Wu², Ren Luo², Laduona Wang¹, Min Tang¹, Shuangsi Liao¹, Jiang Zhu¹, Xiaojuan Zhou², Xuanwei Zhang², Yong Xu², Yongmei Liu², Feng Peng¹, Jin Wang², Lisha Xiang¹, Limei Yin⁷, Lei Deng⁸, Meijuan Huang¹, Youling Gong², Bingwen Zou², Hui Wang⁹, Lin Wu¹⁰, Zhiyong Yuan¹¹, Nan Bi¹², Min Fan¹³, Yaping Xu¹⁴, Ruizhan Tong¹, Linglu Yi¹, Lu Gan¹⁵, Jianxin Xue², Xianming Mo¹⁶, Chong Chen⁶, Feifei Na¹⁷, You Lu¹⁸

Affiliations

¹ Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
² Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China; Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
³ Cancer Institute, Xinqiao Hospital, Army Medical University, Chongqing, China.
⁴ Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China.
⁵ Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China; Center of Lung Cancer, West China Hospital, Sichuan University, Chengdu, China.
⁶ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
⁷ Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China; Department of Health Management & Institute of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
⁸ University of Washington School of Medicine/Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁹ Department of Radiation Oncology, Hunan Cancer Hospital, Changsha, China.
¹⁰ Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha, China.
¹¹ Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
¹² Department of Radiation Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
¹³ Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
¹⁴ Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
¹⁵ Research Laboratory of Emergency Medicine, Department of Emergency Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
¹⁶ Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu, China.
¹⁷ Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China. Electronic address: nafeifei@scu.edu.cn.
¹⁸ Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China; Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China. Electronic address: radyoulu@hotmail.com.

PMID: 38964333
DOI: 10.1016/j.medj.2024.06.002

Abstract

Background: Immune checkpoint inhibitors (ICIs) provide modest but unsatisfactory benefits for extensive-stage small cell lung cancer (ES-SCLC). Developing strategies for treating ES-SCLC is critical.

Methods: We preliminarily explored the outcomes of salvage low-dose radiotherapy (LDRT) plus ICI on refractory SCLC patients. Next, we evaluated the combinational efficacy in murine SCLC. The tumor immune microenvironment (TIME) was analyzed for mechanistic study. Subsequently, we conducted a multicenter, prospective phase II trial that administered concurrent thoracic LDRT plus chemoimmunotherapy to treatment-naive ES-SCLC patients (MATCH trial, NCT04622228). The primary endpoint was confirmed objective response rate (ORR), and the key secondary endpoints included progression-free survival (PFS) and safety.

Findings: Fifteen refractory SCLC patients treated with LDRT plus ICI were retrospectively reviewed. The ORR was 73.3% (95% confidence interval [CI], 44.9-92.2). We identified a specific dose of LDRT (15 Gy/5 fractions) that exhibited growth retardation and improved survival in murine SCLC when combined with ICIs. This combination recruited a special T cell population, TCF1⁺ PD-1⁺ CD8⁺ stem-like T cells, from tumor-draining lymph nodes into the TIME. The MATCH trial showed a confirmed ORR of 87.5% (95% CI, 75.9-94.8). The median PFS was 6.9 months (95% CI, 5.4-9.3).

Conclusions: These findings verified that LDRT plus chemoimmunotherapy was safe, feasible, and effective for ES-SCLC, warranting further investigation.

Funding: This research was funded by West China Hospital (no. ZYJC21003), the National Natural Science Foundation of China (no. 82073336), and the MATCH trial was fully funded by Roche (China) Holding Ltd. (RCHL) and Shanghai Roche Pharmaceuticals Ltd. (SRPL).

Keywords: Translation to patients; extensive-stage small cell lung cancer; immune checkpoint inhibitor; low-dose radiotherapy; stem-like T cell; tumor-draining lymph node.

Publication types

Clinical Trial, Phase II
Multicenter Study

MeSH terms

Aged
Animals
Combined Modality Therapy
Female
Humans
Immune Checkpoint Inhibitors* / pharmacology
Immune Checkpoint Inhibitors* / therapeutic use
Immunotherapy* / methods
Lung Neoplasms* / immunology
Lung Neoplasms* / mortality
Lung Neoplasms* / pathology
Lung Neoplasms* / radiotherapy
Lung Neoplasms* / therapy
Male
Mice
Middle Aged
Progression-Free Survival
Prospective Studies
Radiotherapy Dosage
Small Cell Lung Carcinoma* / immunology
Small Cell Lung Carcinoma* / mortality
Small Cell Lung Carcinoma* / pathology
Small Cell Lung Carcinoma* / radiotherapy
Small Cell Lung Carcinoma* / therapy
Tumor Microenvironment / drug effects
Tumor Microenvironment / immunology

Substances

Immune Checkpoint Inhibitors