# Multiple ctDNA- based biomarkers predict benefit from selective RET Inhibition in non-small cell lung cancer patients: exploratory analysis of a prospective study

## TL;DR

This study shows that measuring ctDNA in patients with RET fusion-positive lung cancer can predict treatment response and disease progression, offering non-invasive biomarkers for early intervention.

## Contribution

The study introduces multiple ctDNA-based biomarkers that predict benefit from RET inhibition in RET fusion-positive NSCLC patients.

## Key findings

- Baseline PIK3CA co-mutations were linked to worse progression-free survival in RET fusion-positive NSCLC patients.
- Lower baseline ctDNA levels were associated with better progression-free survival across multiple metrics.
- Early ctDNA clearance correlated with prolonged PFS and better disease control.

## Abstract

Selective RET inhibitors such as pralsetinib have become the standard of care for patients with RET fusion-positive non-small cell lung cancer (NSCLC). Serial analysis of circulating tumor DNA (ctDNA) has proven effective in monitoring disease control/progression and therapeutic response in NSCLC. In this prospective study, we analyzed longitudinal ctDNA profiles (at baseline, week 8, and at progression) in Chinese patients with advanced RET fusion-positive NSCLC treated with pralsetinib (NCT03037385), utilizing allele frequency-based, cfDNA quantity-normalized, and methylation-based metrics. Associations between ctDNA dynamics, tumor response, and genomic alterations were assessed. A total of 21 patients were enrolled. Baseline PIK3CA co-mutations were associated with inferior progression-free survival (PFS; 3.0 vs. 12.4 months, P < 0.001). Superior PFS was observed in patients with lower baseline ctDNA levels across all metrics: allele frequency-based (HR = 0.24; 95% confidence interval [CI], 0.07–0.80; P = 0.012), cfDNA quantity-normalized (HR = 0.20; 95% CI, 0.05–0.71; P = 0.006), and methylation-based (HR = 0.09; 95% CI, 0.01–0.85; P = 0.010). Early ctDNA clearance at the first radiographic assessment was also associated with prolonged PFS (median PFS not reached vs. 4.8 months; P = 0.002) and enhanced disease control (71.4% vs. 0%). Moreover, three distinct ctDNA dynamic profiles—clearance-rebound, reduction-rebound, and sustained clearance—were associated with different progression patterns (systemic progression, new extrathoracic lesions, new intracranial/intrathoracic lesions). No evidence of histologic transformation was identified at the time of progression. KRAS G12R and other non-canonical alterations emerged in ctDNA-rebound samples. Molecular progression preceded radiographic progression by a mean interval of 2.2 months. These findings suggest that ctDNA-based surveillance using multiple metrics, enables early forecasting of tumor response and progression in RET fusion-positive NSCLC. Early ctDNA clearance and dynamic profiles provide non-invasive biomarkers for early intervention, warranting further validation with ctDNA-guided strategies.

The online version contains supplementary material available at 10.1186/s40364-025-00809-8.