Hypothetical target trial to compare the effectiveness of atezolizumab, pembrolizumab and nivolumab in second line treatment of advanced non-small cell lung cancer

Background: Non-Small Cell Lung Cancer (NSCLC) is the predominant lung cancer subtype, often diagnosed at advanced stage of disease (de novo stage III or IV). In recent years, immunotherapy (IO) has emerged as a promising treatment modality for advanced NSCLC, first proven effective as second line treatment following a failure of first-line therapies. Notably, there is no comparative evidence from randomized clinical trials (RCTs) between different IOs in the second line setting.

Objectives: This observational study aimed to assess the comparative effectiveness of IO therapy in the second-line setting.

Methods: Population-based data was obtained from the Cancer Registry of Norway and linked with the hospital data from the Norwegian Patient Registry and treatment data from the Norwegian Prescribed Drug Registry. Adult patients with aNSCLC diagnosed in Norway in 2015-2021 were included. The final cohort included patients using IO in the second line setting after failure of first-line with chemotherapy. We performed a hypothetical target trial emulating key eligibility criterion commonly used in RCTs and constructed three pair-wise 1:1 Propensity score (PS) matched comparison cohorts: atezolizumab versus pembrolizumab, atezolizumab versus nivolumab and nivolumab versus pembrolizumab. Age, sex, morphology, ECOG performance status, PDL1 expression, peripheral vascular disease, chronic lung disease, diabetes without complications, heart failure, moderate to severe kidney disease, cerebrovascular disease, number of comorbidities per patients and etoposide were included in the PS. The primary outcome was overall survival (OS). Patients were followed until experiencing death, lost-to-follow-up or end of study. A Cox proportional hazards regression model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: Analyses included a total of 466 patients, 217 users of atezolizumab, 72 nivolumab and 177 pembrolizumab. The median follow-up time was 3 (IQR 2—4) years. We found no significant difference in OS in any of the three pair-wise comparisons; atezolizumab vs. pembrolizumab (HR 0.89; 95% CI: 0.69—1.16), atezolizumab vs. nivolumab (HR 1.12; 95% CI: 0.8—1.61) and nivolumab vs. pembrolizumab (HR 1.07; 95% CI: 0.73—1.62).

Conclusions: The study indicates that the three IO drugs atezolizumab, nivolumab and pembrolizumab, when used in second line advanced NSCLC, demonstrate a similar level of effectiveness. To substantiate these results, further investigation with larger-scale studies is required.