Circulating Tumor DNA-Guided De-Escalation Targeted Therapy for Advanced Non−Small Cell Lung Cancer
Authors: Dong Song , Wang Zhen , Zhang Jia-Tao , Yan Bingfa , Zhang Chao , Gao Xuan , Sun Hao , Li Yang-Si , Yan Hong-Hong , Tu Hai-Yan , Liu Si-Yang Maggie , Gong Yuhua , Gao Wei , Huang Jie , Liao Ri-Qiang , Lin Jun-Tao , Ke E-E. , Xu Zelong , Zhang Xue , Xia Xuefeng , Li An-Na , Liu Si-Yang , Pan Yi , Yang Jin-Ji , Zhong Wen-Zhao , Yi Xin , Zhou Qing , Yang Xue-Ning , Wu Yi-Long 
Published: June 2024

Importance

Uninterrupted 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.

Objective

To 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 Participants

This 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.

Intervention

Cessation 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 Measures

Progression-free survival (PFS). Secondary end points were objective response rate, time to next treatment, and overall survival.

Results

Among 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 Relevance

The 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 Registration

ClinicalTrials.gov Identifier: NCT03046316