Early Circulating Tumor DNA Dynamics and Efficacy of Lorlatinib in Patients With Treatment-Naive, Advanced, ALK-Positive NSCLC
- Author(s)
- Soo, RA; Martini, JF; van der Wekken, AJ; Teraoka, S; Ferrara, R; Shaw, AT; Shepard, D; Calella, AM; Polli, A; Toffalorio, F; Tomasini, P; Chiu, CH; Kowalski, DM; Kim, HR; Solomon, BJ;
- Details
- Publication Year 2023-11,Volume 18,Issue #11,Page 1568-1580
- Journal Title
- Journal of Thoracic Oncology
- Publication Type
- Research article
- Abstract
- INTRODUCTION: Circulating tumor DNA (ctDNA) has been used as a biomarker for prognostication and response to treatment. Here, we evaluate ctDNA as a potential biomarker for response to lorlatinib, a third-generation ALK tyrosine kinase inhibitor in patients with treatment-naive, advanced, ALK-positive NSCLC in the ongoing phase 3 CROWN study (NCT03052608). METHODS: Molecular responses were calculated using mean variant allele frequency (VAF), longitudinal mean change in VAF (dVAF), and ratio to baseline. Efficacy assessments (progression-free survival [PFS] and objective response rate) were paired with individual patient ctDNA and analyzed for association. RESULTS: Compared with baseline, mean VAF at week 4 was decreased in both treatment arms. Considering all detected somatic variants, a reduction in dVAF (</=0) was associated with a longer PFS in the lorlatinib arm. The hazard ratio (HR) for a dVAF less than or equal to 0 versus more than 0 was 0.50 (95% confidence interval [CI]: 0.23-1.12) in the lorlatinib arm. A similar association was not observed for crizotinib (HR = 1.00, 95% CI: 0.49-2.03). Comparing molecular responders with nonresponders, patients treated with lorlatinib who had a molecular response had longer PFS (HR = 0.37, 95% CI: 0.16-0.85); patients treated with crizotinib who had a molecular response had similar PFS as those without a molecular response (HR = 1.48, 95% CI: 0.67-3.30). CONCLUSIONS: In patients with treatment-naive, advanced, ALK-positive NSCLC, early ctDNA dynamics predicted better outcome with lorlatinib but not with crizotinib. These results suggest that ctDNA may be used to monitor and potentially predict efficacy of lorlatinib treatment.
- Keywords
- Humans; Crizotinib; *Lung Neoplasms/drug therapy/genetics; *Circulating Tumor DNA; Anaplastic Lymphoma Kinase/genetics; *Carcinoma, Non-Small-Cell Lung/genetics; Lactams, Macrocyclic/therapeutic use; Protein Kinase Inhibitors/adverse effects; Biomarkers; Alk; Circulating tumor DNA; Lorlatinib; Non-small cell lung cancer; Tyrosine kinase inhibitor
- Department(s)
- Medical Oncology
- PubMed ID
- 37295609
- Publisher's Version
- https://doi.org/10.1016/j.jtho.2023.05.021
- Open Access at Publisher's Site
https://doi.org/10.1016/j.jtho.2023.05.021- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-01-03 06:51:02
Last Modified: 2024-01-03 06:51:52