Early Liquid Biopsy in Advanced Lung Cancer: Real-World Data Suggest Targeted Gains

As molecular profiling becomes integral to first-line treatment in non–small cell lung cancer, so does the question of timing—how early should clinicians pursue comprehensive genomic testing? The LIBELULE trial, a multicenter randomized phase III study published in Journal of Thoracic Oncology, provides timely insights into the clinical utility of liquid biopsy (LB) at the point of suspicion for metastatic disease.

LIBELULE randomized 319 patients across 15 French centers with radiologic suspicion of advanced lung cancer to receive either standard diagnostic procedures or immediate LB via the InVisionFirst-Lung assay, a 37-gene NGS panel. Notably, this real-world study encompassed academic, community, and private practice settings, mirroring the diversity of lung cancer management.

The primary endpoint was time to initiation of appropriate treatment (TTI), defined as treatment started with informative pathological and genomic data in line with ESMO guidelines. Secondary endpoints included time to contributory genomic results, appropriateness of initiated therapy, and progression-free survival (PFS).

Overall TTI Impact

Across the full intention-to-treat (ITT) population, early LB did not significantly reduce TTI (29.0 vs 34.0 days; p=0.26). However, targeted analyses revealed clinically meaningful differences in patients with actionable molecular alterations:

• Among patients receiving first-line systemic therapy, mean TTI was 29.1 days in the LB arm vs 38.9 days in control (p=0.01).
• In patients with advanced non-squamous NSCLC, LB reduced TTI by over 10 days (29.5 vs 40.3 days; p=0.01).
• For those with category 1 alterations (EGFR, ALK, ROS1, BRAF V600E), LB enabled treatment nearly 17 days sooner (21.0 vs 37.6 days; p=0.003).

Importantly, time to contributory genomic results—irrespective of tissue or blood—was significantly shorter in the LB group (17.9 vs 25.6 days; p<0.001).

ctDNA was detectable in 81 percent of LB patients, and when combined with tissue analysis, led to a higher detection rate of category 1 alterations compared to tissue alone (42.7 percent vs 36.5 percent in non-squamous NSCLC). In 13.6 percent of LB patients, clinically actionable alterations were found in ctDNA but not in tissue, often due to insufficient tissue quality.

Treatment appropriateness also favored early LB: 90 percent of treated patients in the LB arm initiated guideline-recommended therapy based on available data, compared with 79.8 percent in control. Notably, two control patients with EGFR mutations received inappropriate chemo-immunotherapy—highlighting a critical safety risk when genomic data are missing at initiation.

Despite earlier result availability, 30 percent of patients in the LB arm began treatment more than 15 days after receiving informative genomic results, suggesting delays unrelated to testing logistics. Hesitancy to act on ctDNA alone, particularly without confirmatory tissue data, may reflect persistent skepticism or unfamiliarity with ctDNA's predictive value.

The trial’s real-world nature also introduced practice variability. Molecular testing strategies were not standardized across centers, and 15 percent of control patients received out-of-protocol LB. These factors may have narrowed observed differences.

No significant differences in PFS were observed between arms. However, the trial confirmed the safety of early LB and its utility in identifying patients who might otherwise remain molecularly uncharacterized. The platform’s sensitivity in low-shedding settings (e.g., brain-only or thoracic metastases) supports its reliability, though false negatives remain a limitation.

Key Clinical Takeaways

While early liquid biopsy did not broadly shorten time to treatment in unselected patients with suspected metastatic lung cancer, it provided clear diagnostic and workflow benefits in those who ultimately required systemic therapy—especially patients with targetable alterations. In real-world practice, timely ctDNA profiling can improve access to appropriate, guideline-based therapy and reduce inappropriate treatment risks, provided clinicians are prepared to act on the results.

Wider adoption will require not only assay sensitivity but also education and process integration to ensure that earlier results translate into earlier—and better—treatment decisions.

Reference

Swalduz A, Schiffler C, Curcio H, et al. LIBELULE: a randomized phase III study to evaluate the clinical relevance of early liquid biopsy in patients with suspicious metastatic lung cancer. J Thorac Oncol. 2025;20(4):437-450. doi:10.1016/j.jtho.2024.12.011