Circulating Tumor DNA-Guided De-Escalation Targeted Therapy for Advanced Non−Small Cell Lung Cancer

Author:

Dong Song1,Wang Zhen1,Zhang Jia-Tao1,Yan Bingfa2,Zhang Chao1,Gao Xuan2,Sun Hao1,Li Yang-Si1,Yan Hong-Hong1,Tu Hai-Yan1,Liu Si-Yang Maggie34,Gong Yuhua2,Gao Wei2,Huang Jie1,Liao Ri-Qiang1,Lin Jun-Tao1,Ke E-E.1,Xu Zelong2,Zhang Xue2,Xia Xuefeng2,Li An-Na1,Liu Si-Yang1,Pan Yi1,Yang Jin-Ji1,Zhong Wen-Zhao1,Yi Xin2,Zhou Qing14,Yang Xue-Ning1,Wu Yi-Long14

Affiliation:

1. Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China

2. Geneplus-Beijing Institute, Beijing, China

3. Department of Hematology, First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China

4. Chinese Thoracic Oncology Group, Guangzhou, Guangdong, China

Abstract

ImportanceUninterrupted targeted therapy until disease progression or intolerable toxic effects is currently the routine therapy for advanced non−small cell lung cancer (NSCLC) involving driver gene variations. However, drug resistance is inevitable.ObjectiveTo assess the clinical feasibility of adaptive de-escalation tyrosine kinase inhibitor (TKI) treatment guided by circulating tumor DNA (ctDNA) for achieving complete remission after local consolidative therapy (LCT) in patients with advanced NSCLC.Design, Setting, and ParticipantsThis prospective nonrandomized controlled trial was conducted at a single center from June 3, 2020, to July 19, 2022, and included 60 patients with advanced NSCLC with driver variations without radiologically detectable disease after TKI and LCT. The median (range) follow-up time was 19.2 (3.8-29.7) months. Data analysis was conducted from December 15, 2022, to May 10, 2023.InterventionCessation of TKI treatment and follow-up every 3 months. Treatment was restarted in patients with progressive disease (defined by the Response Evaluation Criteria in Solid Tumors 1.1 criteria), detectable ctDNA, or elevated carcinoembryonic antigen (CEA) levels, whichever manifested first, and treatment ceased if all indicators were negative during follow-up surveillance.Main Outcomes and MeasuresProgression-free survival (PFS). Secondary end points were objective response rate, time to next treatment, and overall survival.ResultsAmong the total study sample of 60 participants (median [range] age, 55 [21-75] years; 33 [55%] were female), the median PFS was 18.4 (95% CI, 12.6-24.2) months and the median (range) total treatment break duration was 9.1 (1.5-28.1) months. Fourteen patients (group A) remained in TKI cessation with a median (range) treatment break duration of 20.3 (6.8-28.1) months; 31 patients (group B) received retreatment owing to detectable ctDNA and/or CEA and had a median PFS of 20.2 (95% CI, 12.9-27.4) months with a median (range) total treatment break duration of 8.8 (1.5-20.6) months; and 15 patients (group C) who underwent retreatment with TKIs due to progressive disease had a median PFS of 5.5 (95% CI, 1.5-7.2) months. For all participants, the TKI retreatment response rate was 96%, the median time to next treatment was 29.3 (95% CI, 25.3-35.2) months, and the data for overall survival were immature.Conclusions and RelevanceThe findings of this nonrandomized controlled trial suggest that this adaptive de-escalation TKI strategy for patients with NSCLC is feasible in those with no lesions after LCT and a negative ctDNA test result. This might provide a de-escalation treatment strategy guided by ctDNA for the subset of patients with advanced NSCLC.Trial RegistrationClinicalTrials.gov Identifier: NCT03046316

Publisher

American Medical Association (AMA)

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