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<p>Selective RET inhibitors such as pralsetinib have become the standard of care for patients with <i>RET</i> 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 <i>RET</i> 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 <i>PIK3CA</i> co-mutations were associated with inferior progression-free survival (PFS; 3.0 vs. 12.4 months, <i>P</i> &lt; 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; <i>P</i> = 0.012), cfDNA quantity-normalized (HR = 0.20; 95% CI, 0.05–0.71; <i>P</i> = 0.006), and methylation-based (HR = 0.09; 95% CI, 0.01–0.85; <i>P</i> = 0.010). Early ctDNA clearance at the first radiographic assessment was also associated with prolonged PFS (median PFS not reached vs. 4.8 months; <i>P</i> = 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. <i>KRAS</i> 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 <i>RET</i> fusion-positive NSCLC. Early ctDNA clearance and dynamic profiles provide non-invasive biomarkers for early intervention, warranting further validation with ctDNA-guided strategies.</p>

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

  • 期刊论文

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  • 发表日期：

    2025年7月23日

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  • Chang Lu,
  • Chong-Rui Xu,
  • Yi-Chen Zhang,
  • E-E Ke,
  • Yue-Li Sun,
  • Xiao-Yan Bai,
  • Zhi-Hong Chen,
  • Jian Su,
  • Yu Deng,
  • Ting Hou,
  • Fei Zhao,
  • Min Li,
  • Bin-Chao Wang,
  • Hai-Yan Tu,
  • Zhen Wang,
  • Xu-Chao Zhang,
  • Hua-Jun Chen,
  • Jin-Ji Yang,
  • Wen-Zhao Zhong,
  • Qing Zhou,
  • Yi-Long Wu

摘要

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.