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Controlled Clinical Trial
. 2024 Jul 1;10(7):932-940.
doi: 10.1001/jamaoncol.2024.1779.

Circulating Tumor DNA-Guided De-Escalation Targeted Therapy for Advanced Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial

Song Dong  1 , Zhen Wang  1 , Jia-Tao Zhang  1 , Bingfa Yan  2 , Chao Zhang  1 , Xuan Gao  2 , Hao Sun  1 , Yang-Si Li  1 , Hong-Hong Yan  1 , Hai-Yan Tu  1 , Si-Yang Maggie Liu  3   4 , Yuhua Gong  2 , Wei Gao  2 , Jie Huang  1 , Ri-Qiang Liao  1 , Jun-Tao Lin  1 , E-E Ke  1 , Zelong Xu  2 , Xue Zhang  2 , Xuefeng Xia  2 , An-Na Li  1 , Si-Yang Liu  1 , Yi Pan  1 , Jin-Ji Yang  1 , Wen-Zhao Zhong  1 , Xin Yi  2 , Qing Zhou  1   4 , Xue-Ning Yang  1 , Yi-Long Wu  1   4
Affiliations
Controlled Clinical Trial

Circulating Tumor DNA-Guided De-Escalation Targeted Therapy for Advanced Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial

Song Dong et al. JAMA Oncol. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Wang reported a grant from Beijing CSCO Oncology Research Foundation (Y-2019AZMS-0034) during the conduct of the study. Dr Zhong reported grants from Guangdong Lung Cancer Institute during the conduct of the study. Dr Zhou reported personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, personal fees from Merck Sharp & Dohme, Pfizer, Roche, and Sanofi outside the submitted work. Dr Wu reported consulting, speaking, and/or personal fees from AstraZeneca, Lilly, Roche, Pfizer, Boehringer Ingelheim, Merck Sharp & Dohme Oncology, Bristol Myers Squibb, Hengrui, and Takeda, and grants from Boehringer Ingelheim, Roche, Pfizer, and Bristol Myers Squibb to the institution outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Summary of Participant Enrollment and Study Groups
Group A included patients who exhibited no positive molecular indicators and persisted in their treatment hiatus; group B, patients who initiated treatment following the indication of positive ctDNA and/or elevated CEA levels before RECIST PD; and group C, patients who, during their initial treatment intermission, registered confirmed RECIST PD, with or without the presence of positive molecular indicators. CEA indicates carcinoembryonic antigen; ctDNA, circulating tumor DNA; PD, progressive disease; and RESIST, Response Evaluation Criteria in Solid Tumors, version 1.1. aAll enrolled patients had a negative test result for both CEA and ctDNA before the treatment break, and no radiologically measurable lesions.
Figure 2.
Figure 2.. Timing and Duration of Tyrosine Kinase Inhibitor (TKI) Treatment, Breaks, and Retreatment
Blue bars represent prior TKI treatment durations, beige bars represent treatment breaks, and red bars represent retreatment durations. Arrows indicate that the treatment type is ongoing.
Figure 3.
Figure 3.. Progression-Free Survival (PFS) for All Participants and by Study Group
A, PFS of all patients. B, PFS for patients classified with the following indicators of retreatment: group A, no positive molecular indicators; group B, positive molecular indicators; and group C, radiographic progression.
Figure 4.
Figure 4.. Time to Next Treatment (TTNT) Failure and Duration of Discontinuation
See this image and copyright information in PMC

Comment in

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