(051) Assessment of Risk-Benefit Balance of Immune Checkpoint Inhibitors in a Real-World Lung Cancer Population

Background: The benefits and harms of immune checkpoint inhibitor (ICI) therapy for lung cancer vary across groups, including those typically under-represented in randomized clinical trials.

Objectives: To quantify the harms and benefits of ICI-containing regimens in individuals with non-small-cell lung cancer (NSCLC) treated in their usual care settings and assess heterogeneity across priority subgroups.

Methods: Retrospective cohort study using the 2012-2019 Surveillance, Epidemiology and Endpoints Registries (SEER) Medicare data. Patients were followed up for up to one year. We included individuals aged ≥ 66 years with NSCLC exposed to either ICI + chemotherapy (chemo), single-ICI (reference group) from 2013-2019. Primary outcomes were severe immune-related adverse events (irAE; harm) and mortality (where delayed mortality was the benefit). Using severe irAE as a metric of harm and overall survival as a metric of benefit, we calculated the harm-benefit tradeoffs of ICI + chemotherapy vs. single-ICI therapy. Severe irAE was defined using validated diagnosis and medication codes. Mortality was ascertained from Medicare. We estimated adjusted hazard ratios (aHR) and 95% confidence interval (CI) by whether ICI was used as the first or second(+) systemic anticancer treatment (SACT) and by subgroup defined by pre-existing autoimmune disease; gender; and age.

Results: Relative to single ICI (n=14,249), individuals treated with ICI + chemo (n=3,432) had an elevated hazard of severe irAE in the first-SACT setting (aHR = 1.22, CI 1.09 – 1.37), but not in the second(+)-SACT setting (aHR = 1.07, CI 0.93 – 1.24); and a decreased hazard of mortality in the first-SACT setting (aHR = 0.66, CI 0.62 – 0.72) but not in the second(+)-SACT setting (aHR = 0.94, CI 0.68 – 1.03). Subgroup point estimates differed in magnitude of effect; in the first-SACT setting, patients with autoimmune disease at baseline had the highest hazard ratio for severe irAE and the lowest hazard ratio for mortality. There was a statistically significant tradeoff between harms and benefits overall (excess severe irAE / year of life gained [irAE/year] = 0.27 [CI 0.06 – 0.52]) as well as for patients with autoimmune disease at baseline (irAE/year = 0.48 [CI 0.05 – 0.95]) and males (irAE/year = 0.39 [CI 0.13 – 0.70]).

Conclusions: Given treatment-related benefits and harms, ICI + chemo use in the first-SACT setting should be accompanied by careful follow-up for mitigation of severe irAE, but potential benefits are significant for high-risk subgroups, such as people with pre-existing autoimmune disorders and male patients.