Dynamic Changes of Circulating Tumor DNA Predict Clinical Outcome in Patients With Advanced Non-Small-Cell Lung
Sabrina Weber1,2, Paul van der Leest3, Hylke C Donker4
1Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria.
Purpose:
Immune checkpoint inhibitors (ICIs) are increasingly being used in non-small-cell lung cancer (NSCLC), yet biomarkers predicting their benefit are lacking. We evaluated if on-treatment changes of circulating tumor DNA (ctDNA) from ICI start (t0) to after two cycles (t1) assessed with a commercial panel could identify patients with NSCLC who would benefit from ICI.
Patients And Methods:
The molecular ctDNA response was evaluated as a predictor of radiographic tumor response and long-term survival benefit of ICI. To maximize the yield of ctDNA detection, de novo mutation calling was performed. Furthermore, the impact of clonal hematopoiesis (CH)-related variants as a source of biologic noise was investigated.
Results:
After correction for CH-related variants, which were detected in 75 patients (44.9%), ctDNA was detected in 152 of 167 (91.0%) patients. We observed only a fair agreement of the molecular and radiographic response, which was even more impaired by the inclusion of CH-related variants. After exclusion of those, a ≥ 50% molecular response improved progression-free survival (10 v 2 months; hazard ratio [HR], 0.55; 95% CI, 0.39 to 0.77; P = .0011) and overall survival (18.4 v 5.9 months; HR, 0.44; 95% CI, 0.31 to 0.62; P < .0001) compared with patients not achieving this end point. After adjusting for clinical variables, ctDNA response and STK11/KEAP1 mutations (HR, 2.08; 95% CI, 1.4 to 3.0; P < .001) remained independent predictors for overall survival, irrespective of programmed death ligand-1 expression. A landmark survival analysis at 2 months (n = 129) provided similar results.
Conclusion:
On-treatment changes of ctDNA in plasma reveal predictive information for long-term clinical benefit in ICI-treated patients with NSCLC. A broader NSCLC patient coverage through de novo mutation calling and the use of a variant call set excluding CH-related variants improved the classification of molecular responders, but had no significant impact on survival.
Insights
Tracking changes in circulating tumor DNA (ctDNA) during treatment can predict long-term benefits for non-small-cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs). This method helps identify patients likely to respond to ICI therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Immune checkpoint inhibitors (ICIs) are a key treatment for non-small-cell lung cancer (NSCLC).
- Predictive biomarkers for ICI efficacy in NSCLC are currently lacking.
- Circulating tumor DNA (ctDNA) analysis offers a potential non-invasive method for monitoring treatment response.
Purpose of the Study:
- To evaluate on-treatment changes in ctDNA as a predictor of clinical benefit in NSCLC patients treated with ICIs.
- To assess the utility of ctDNA response, assessed via a commercial panel, in identifying patients who will benefit from ICI therapy.
- To investigate the impact of clonal hematopoiesis (CH)-related variants on ctDNA analysis and its predictive value.
Main Methods:
- Blood samples were collected from NSCLC patients at the start of ICI treatment (t0) and after two cycles (t1).
- ctDNA levels were analyzed using a commercial panel, with de novo mutation calling to maximize detection sensitivity.
- CH-related variants were identified and excluded to minimize biological noise and improve the accuracy of molecular response assessment.
Main Results:
- After correcting for CH-related variants (present in 44.9% of patients), ctDNA was detected in 91.0% of patients.
- A molecular response of ≥50% in ctDNA levels was associated with significantly improved progression-free survival (10 vs. 2 months) and overall survival (18.4 vs. 5.9 months) compared to non-responders.
- ctDNA response and STK11/KEAP1 mutations were independent predictors of overall survival, regardless of PD-L1 expression.
Conclusions:
- On-treatment changes in plasma ctDNA provide valuable predictive information for long-term clinical benefit in NSCLC patients receiving ICIs.
- Excluding CH-related variants enhances the classification of molecular responders.
- ctDNA monitoring represents a promising tool for personalizing ICI therapy in NSCLC.
