Circulating tumor DNA as a biomarker for monitoring early treatment responses of patients with advanced lung adenocarcinoma receiving immune checkpoint inhibitors
Paul van der Leest, Birgitta I. Hiddinga, Anneke Miedema, Maria L. Aguirre Azpurua, Naomi Rifaela, Arja ter Elst et al. · 2021 · 54 citationsRead the paper
Immunotherapy for metastasized non‐small‐cell lung cancer (NSCLC) can show long‐lasting clinical responses. Selection of patients based on programmed death‐ligand 1 (PD‐L1) expression shows limited predictive value for durable clinical benefit (DCB). We investigated whether early treatment effects as measured by a change in circulating tumor DNA (ctDNA) level is a proxy of early tumor response to immunotherapy according to response evaluation criteria in solid tumors v1.1 criteria, progression‐free survival (PFS), DCB, and overall survival (OS). To this aim, blood tubes were collected from advanced‐stage lung adenocarcinoma patients ( n = 100) receiving immune checkpoint inhibitors (ICI) at baseline (t 0 ) and prior to first treatment evaluation (4–6 weeks; t 1 ). Nontargetable (driver) mutations detected in the pretreatment tumor biopsy were used to quantify tumor‐specific ctDNA levels using droplet digital PCR. We found that changes in ctDNA levels were strongly associated with tumor response. A > 30% decrease in ctDNA at t 1 correlated with a longer PFS and OS. In total, 80% of patients with a DCB of ≥ 26 weeks displayed a > 30% decrease in ctDNA levels. For patients with a PD‐L1 tumor proportion score of ≥ 1%, decreasing ctDNA levels were associated with a higher frequency a DCB (80%) and a prolonged median PFS (85 weeks) and OS (101 weeks) compared with patients with no decrease in ctDNA (34%; 11 and 39 weeks, respectively). This study shows that monitoring of ctDNA dynamics is an easy‐to‐use and promising tool for assessing PFS, DCB, and OS for ICI‐treated NSCLC patients.
What the full text shows
Working prototype- A decrease in ctDNA levels at 4-6 weeks (t1) is associated with significantly longer PFS and OS compared to stable or increasing levels. — Median PFS 43 vs 6 weeks; Median OS 125 vs 29 weeks (Advanced lung adenocarcinoma patients receiving ICI monotherapy (excluding ctDNA-negative patients))
- A specific threshold of ctDNA decrease at t1 correlates with durable clinical benefit (DCB). — > 30% decrease in ctDNA observed in 80% of patients with DCB ≥ 26 weeks (Advanced lung adenocarcinoma patients receiving ICI monotherapy)
- Combining PD-L1 expression (TPS ≥ 1%) with decreasing ctDNA levels further improves survival outcomes. — Median PFS 85 vs 11 weeks; Median OS 101 vs 39 weeks (vs no ctDNA decrease) (Patients with PD-L1 TPS ≥ 1% receiving ICI monotherapy)
- An initial transient spike in ctDNA levels occurs shortly after treatment initiation. — Observed in 61% of all patients with baseline ctDNA and 70% of eventual responders (First 2 weeks of ICI treatment)
- High mutant ctDNA levels at baseline (t0) correlate with poorer survival. — P < 0.001 for PFS; P < 0.0001 for OS (Advanced lung adenocarcinoma patients receiving ICI monotherapy)
- Setup
- 100 patients with advanced-stage lung adenocarcinoma receiving immune checkpoint inhibitors (ICI).
- How
- Tumor-informed ddPCR was used to quantify specific non-targetable mutations in plasma ctDNA at baseline (t0) and 4-6 weeks (t1). Results were compared against RECIST v1.1 radiological evaluations and PD-L1 expression levels.
- Limitations
- 31% of patients were ctDNA-negative at baseline, limiting the ability to monitor dynamics. · Technical variance of ddPCR (30%) required a minimum threshold for defining 'true' change. · Small subset (n=27) used to determine the optimal timepoint for follow-up.
Summarized by Gemma 4 from the open-access full text · 8 Oct 2026. Read it