Dr Xia on the Differences Between ctDNA Monitoring Strategies in MET Exon 14–Mutant NSCLC

"We found that MET-specific ctDNA [negativity] at week 4 was strongly associated with improved ORR and PFS. This suggests that ctDNA can identify nonresponders early, allowing for timely therapeutic changes before radiographic progression."

Yang Xia, MD, PhD, is an associate professor in the Department of Respiratory Medicine and vice chair of the Department of Pulmonary Medicine at the Second Affiliated Hospital Zhejiang University School of Medicine, discussed the utility of different circulating tumor DNA (ctDNA) monitoring approaches for detecting resistance and predicting outcomes in patients with advanced non–small cell lung cancer (NSCLC) with MET exon 14 skipping mutations receiving ensartinib (Ensacove).

Utilizing updated survival data from the phase 2 EMBRACE trial (ChiCTR2100048767), Xia and colleagues conducted a comparison of 3 distinct ctDNA monitoring paradigms in advanced NSCLC: MET-specific mutations, canonical mutations, and pan-mutations. MET-specific mutations encompassed all MET aberrations, canonical mutations included Tier 1 or Tier 2 mutations, and pan-mutations included any alterations from a broad panel of 229 cancer-related genes, Xia explained.

Findings presented at the 2025 IASLC World Conference on Lung Cancer showed that at baseline, MET/canonical mutations were detectable in ctDNA for 48.3% (n = 14/29) of patients, whereas pan-mutations were found in 75.9% (n = 22/29). Although the ctDNA-negative subgroup consistently showed superior outcomes across all efficacy end points, these differences did not reach statistical significance. Notably, patients harboring baseline ATRX/TP53 variants exhibited a significantly shorter median progression-free survival (PFS) of 2.9 months compared with 7.5 months for those without.

By week 4 of treatment, detection rates declined: MET-specific mutation detection decreased to 30% (n = 6/20), canonical decreased to 25% (n = 5/20), and pan-mutation decreased to 65% (n = 13/20). Xia explained that MET-specific negativity at week 4 was associated with a superior objective response rate and longer PFS, with canonical mutations showing a similar trend. In contrast, pan-mutation analysis failed to differentiate PFS outcomes.

Although pan-mutation analysis demonstrated higher sensitivity (85%) for predicting partial responses (PR) at baseline, its specificity was limited to 31%, Xia noted. MET-specific monitoring achieved a more balanced profile with 50% sensitivity, 90% specificity, and an 83% positive predictive value, making it more suitable for identifying true nonresponders. Based on these findings, Xia emphasized that ctDNA can effectively identify nonresponders early, enabling timely adjustments to therapy before radiographic progression becomes evident.