Abstract
BackgroundThe use of circulating tumor DNA (ctDNA) to reflect clinical benefits of advanced non-small cell lung cancer (NSCLC) patients during immune checkpoint inhibitor (ICI) therapy remains controversial. This study aimed to determine the association of pre-treatment and early dynamic changes of ctDNA with clinical outcomes in advanced NSCLC patients treated with ICIs.MethodsElectronic databases (PubMed, Embase, Web of Science, and Cochrane) were systematically searched to include relevant studies published in English up to November 2020. The primary outcomes were overall survival (OS) and progression-free survival (PFS) and the secondary outcome was objective response rate (ORR) with RECIST criteria.ResultsA total of 1017 patients from 10 studies were identified. The baseline ctDNA levels (detected versus not detected) showed no significant association with clinical outcomes regarding OS (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.93-1.51), PFS (HR, 0.98; 95% CI, 0.80-1.21), and ORR (odds ratio [OR], 0.89; 95% CI, 0.54-1.46). Interestingly, when taken early longitudinal assessment of ctDNA into consideration, the early reduction of the concentration of ctDNA was associated with significant improvements of OS (HR, 0.19; 95% CI, 0.10-0.35), PFS (HR, 0.30; 95% CI, 0.22-0.41) and ORR (OR, 0.07; 95% CI, 0.03-0.18). Further subgroup analyses revealed that the reduction magnitude did not significantly impact the association between ctDNA and clinical outcomes, suggesting that both patients with decreased ctDNA or a ≥50% reduction of ctDNA was associated with improved OS, PFS and ORR.ConclusionEarly reduction of ctDNA was associated with improved OS, PFS and ORR in advanced NSCLC patients treated with ICIs.Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO, CRD42021226255.
Highlights
Over the past decade, immunotherapy, targeting immune checkpoint molecules, programmed-death-1(PD-1)/PD ligand1 (PD-L1) axis, has turned into one of the most important breakthroughs in cancer treatment, including non-small cell lung cancer (NSCLC) [1]
The baseline circulating tumor DNA (ctDNA) levels showed no significant association with clinical outcomes regarding overall survival (OS), progression-free survival (PFS) (HR, 0.98; 95% CI, 0.80-1.21), and objective response rate (ORR)
Further subgroup analyses revealed that the reduction magnitude did not significantly impact the association between ctDNA and clinical outcomes, suggesting that both patients with decreased ctDNA or a ≥50% reduction of ctDNA was associated with improved OS, PFS and ORR
Summary
Immunotherapy, targeting immune checkpoint molecules, programmed-death-1(PD-1)/PD ligand (PD-L1) axis, has turned into one of the most important breakthroughs in cancer treatment, including non-small cell lung cancer (NSCLC) [1]. Several promising biomarkers for ICI therapy have been widely investigated, such as tumor mutation burden (TMB), PD-L1 expression, germline genotype of HLA-I, the molecular profiling of the tumor microenvironment, mutations in DNA mismatch repair and replication genes [1, 5, 6]. Most of these biomarkers are far from perfect biomarkers owing to being invasive, not always feasible, and its spatial and temporal heterogeneity [6, 7]. The use of circulating tumor DNA (ctDNA) to reflect clinical benefits of advanced non-small cell lung cancer (NSCLC) patients during immune checkpoint inhibitor (ICI) therapy remains controversial.
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