Circulating Tumor DNA-Guided De-Escalation Targeted Therapy for Advanced Non-Small Cell Lung Cancer: A Nonrandomized
Song Dong1, Zhen Wang1, Jia-Tao Zhang1
1Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
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.
Insights
Adaptive de-escalation of tyrosine kinase inhibitors (TKIs) guided by circulating tumor DNA (ctDNA) is feasible for advanced non-small cell lung cancer (NSCLC) patients achieving remission after local consolidative therapy. This strategy may offer a new treatment approach for select NSCLC patients.
Area of Science:
- Oncology
- Genetics
- Clinical Trials
Background:
- Standard treatment for advanced non-small cell lung cancer (NSCLC) with driver mutations involves continuous targeted therapy until progression or toxicity.
- Drug resistance is an inevitable challenge in managing advanced NSCLC.
Purpose of the Study:
- To evaluate the clinical feasibility of an adaptive de-escalation strategy for tyrosine kinase inhibitor (TKI) treatment in advanced NSCLC patients.
- To assess if circulating tumor DNA (ctDNA) can guide TKI treatment de-escalation after local consolidative therapy (LCT) to achieve complete remission.
Main Methods:
- A prospective, nonrandomized controlled trial involving 60 advanced NSCLC patients with driver mutations who achieved remission post-TKI and LCT.
- The intervention involved TKI cessation with monitoring via ctDNA and CEA; TKI retreatment was initiated upon disease progression or biomarker elevation.
- Progression-free survival (PFS) was the primary endpoint, with response rate, time to next treatment, and overall survival as secondary endpoints.
Main Results:
- The median PFS was 18.4 months, with a median treatment break duration of 9.1 months.
- Patients who remained off TKIs had a longer treatment break (20.3 months).
- Patients retreated due to ctDNA/CEA elevation had a median PFS of 20.2 months, while those retreated due to progressive disease had a median PFS of 5.5 months. The overall TKI retreatment response rate was 96%.
Conclusions:
- Adaptive de-escalation of TKIs guided by ctDNA is a feasible strategy for advanced NSCLC patients in remission after LCT.
- This approach may provide a valuable de-escalation treatment option for a subset of advanced NSCLC patients.
- Further research can explore optimizing this strategy for improved patient outcomes.
