Circulating Tumor DNA-Guided De-Escalation Targeted Therapy for Advanced NSCLC

1. Patients with no biochemical or radiographic evidence of progressive disease had a median treatment break of 20.3 months.

2. 96% of patients with biochemical but not radiographic evidence of progressive disease had a further biochemical response to prior TKI retreatment.

Evidence Rating Level: 2 (Good)

Study Rundown: Treatment discontinuation for targeted therapies in NSCLC can improve quality of life but may cause rapid progression, requiring adaptive or intermittent strategies. This study looked at the use of plasma ctDNA as a biomarker to guide adaptive de-escalation of targeted TKI treatment in NSCLC. The primary endpoint was progression-free survival (PFS), and secondary endpoints included objective response rate (ORR), time to next treatment (TTNT), and overall survival (OS). Patients who received local consolidative therapy (LCT) for oligometastatic diseases after TKI treatment were analyzed in three groups; group A (no positive indicators and continued treatment break, group B (positive ctDNA and/or elevated CEA levels before RECIST-based progressive disease, initiated retreatment); and group C (confirmed RECIST-based progressive disease with or without positive molecular indicators, initiated retreatment). The median PFS in all groups was 18.4 months, and the 12- and 24-month PFS rates were 67.7% and 40.2%, respectively. Group A had a median treatment break of 20.3 months. Group B had a median treatment break of 8.8 months with a median PFS of 20.2 months. Group C had a median PFS of 5.5 months, with 9 patients who had undetectable ctDNA. The median TTNT from the first treatment break was 29.3 months, with 12- and 24-month TTNT of 92.2% and 74.1%, respectively. Median OS data was immature. With regards to retreatment efficacy, 96% of patients in group B had undetectable ctDNA after 3 months of retreatment with prior TKI. Among 24 patients (9 in group B and 15 in group C) who had disease progression during the treatment break and had restarted treatment, the ORR was 96% with 12 patients achieving CR. For patients who received TKI retreatment, there were no grade 3 or worse adverse events. The strength of this study included its novel approach, and the limitations of the study included the methodology, the small sample size, and the limited follow-up time. Overall, this study found that ctDNA could be a useful tool used for monitoring patients after systemic therapy and LCT.

Click to read the study in JAMA Oncology

Relevant Reading: Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling.

In-Depth [prospective cohort]: This nonrandomized trial enrolled adults (n=60) with NSCLC stage IIIA-IV with driver gene mutations who received LCT for oligometastatic diseases after TKI treatment. The patients must have had no residual lesions, undetectable ctDNA and normal CEA levels after TKI and LCT. Group A had 14 patients (23%), group B had 31 patients (52%), and group C had 15 patients (25%). The median follow-up time after initial TKI treatment cessation was 19.2 months (3.8-29.7). The median PFS in all groups was 18.4 months (95%CI, 12.6-24.2), and the 12- and 24-month PFS rates were 67.7% (95%CI, 53.5%-78.5%) and 40.2% (95%CI, 24.3%-55.6%), respectively. Group A had a median treatment break of 20.3 months (6.8-28.1). Group B had a median treatment break of 8.8 months (1.5-20.6) with a median PFS of 20.2 months (95%CI, 12.9-27.4). Group C had a median PFS of 5.5 months (95%CI, 1.5-7.2), with 9 patients who had undetectable ctDNA. The median TTNT from the first treatment break was 29.3 months (95%CI, 25.3-35.2), with 12- and 24-month TTNT of 92.2% (95%CI, 80.2%-97.0%) and 74.1% (95%CI, 56.2%-85.5%), respectively. Median OS data was immature. With regards to retreatment efficacy, 96% of patients in group B had undetectable ctDNA after 3 months of retreatment with prior TKI. Among 24 patients (9 in group B and 15 in group C) who had disease progression during the treatment break and had restarted treatment, the ORR was 96% (95%CI, 87.7%-100%) with 12 patients achieving CR. For patients who received TKI retreatment, there were no grade 3 or worse adverse events. Overall, this study found that ctDNA could be a useful tool used for monitoring patients after systemic therapy and LCT.

Image: PD

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