Background: 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. 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.Methods: Electronic 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.Results: A 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.Conclusion: Early 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.

Background: Bone metastasis (BoM) is common in patients with advanced non‐small cell lung cancer (NSCLC) and considered as one of the negative prognostic factors. However, the impact of BoM on clinical outcomes of patients with advanced NSCLC treated with immune checkpoint inhibitors (ICIs) remains unclear.Methods: A total of 103 patients treated with ICI monotherapy and 101 patients treated with ICIs combined with chemotherapy or antiangiogenesis therapy were retrospectively analyzed. The differences in progression‐free survival (PFS), overall survival (OS) and objective response rate (ORR) between BoM+ and BoM− were investigated.Results: Of those 101 patients who received combination therapy, no significant difference between BoM− and BoM+ in terms of both median PFS and median OS (median PFS, 10.1 vs. 12.1 months, P = 0.6; median OS, NR vs. 24.6 months, P = 0.713) was determined. In contrast, of the 103 patients who received ICI monotherapy, BoM+ patients had an inferior PFS (4.2 vs. 6.7 months, P = 0.0484) and OS (12.5 vs. 23.9 months, P = 0.0036) compared with BoM− patients. The univariate and multivariate analysis in the ICI monotherapy group also identified BoM as an independent factor attenuating the efficacy of ICI monotherapy. Of all BoM+ patients who received ICI monotherapy, neither palliative radiotherapy nor bisphosphonate drugs improved OS (palliative radiotherapy: 12.5 vs. 16.7 months, P = 0.487; bisphosphonate drugs: 12.5 vs. 9.7 months, P = 0.568).Conclusions: BoM attenuated the efficacy of ICI monotherapy in patients with advanced NSCLC. Of BoM+ patients who received ICI monotherapy, neither palliative radiotherapy nor bisphosphonate drugs improved OS. Other therapeutic strategies are needed for patients with BoM.