Elevated antidrug antibodies against atezolizumab and associated clinical outcomes in advanced non-small-cell lung cancer

Background: Although atezolizumab has demonstrated efficacy in advanced non-small-cell lung cancer (NSCLC), antidrug antibody (ADA) may reduce its effectiveness by lowering drug exposure. We explored the association between ADA levels and clinical outcomes. Methods: We retrospectively analyzed 86 patients with advanced NSCLC who received atezolizumab monotherapy (1200 mg every 3 weeks) between August 2018 and September 2022 at Samsung Medical Center, Seoul, Korea. Blood samples were collected prior to the first and second doses (baseline and week 3). ADA levels were measured by ELISA and correlated with plasma atezolizumab concentrations and clinical outcomes using Kaplan–Meier estimates and Cox proportional hazards models. Results: All 86 patients received atezolizumab as a second-line or later treatment (second-line, n = 65; third-line, n = 12; ≥ fourth-line, n = 9). Patients (median age [IQR], 67 [61–73] years; 73 [84.9%] male) showed significantly elevated ADA levels three weeks after treatment (median [IQR] 0 [0–0] vs. 530.3 [146.9–3050.5] ng/mL; p < 0.001). Strong ADA levels (≥ 1000 ng/mL) were observed in 32 (37.2%) patients and were associated with shorter PFS (HR = 1.86, 95% CI: 1.15–3.02, p = 0.010) and OS (HR = 1.92, 95% CI: 1.14–3.23, p = 0.013). Furthermore, patients with high ADA levels exhibited lower atezolizumab concentrations and reduced response rates compared to those with low ADA levels. Importantly, high ADA levels independently predicted poor prognosis in a multivariable analysis adjusted for clinical variables. Conclusions: High ADA levels were linked to lower atezolizumab exposure and worse outcomes. ADA monitoring may help predict prognosis and guide immunotherapy strategies.