Survival and safety of two year-fixed duration vs continuous immune checkpoint inhibitor therapy in advanced or metastatic NSCLC: A systematic review.

Abstract

8584 Background: The optimal duration of immune checkpoint inhibitor (ICI) therapy in advanced or metastatic non-small cell lung cancer (NSCLC) is unknown. While multiple randomized clinical trials (RCTs) have shown the benefit of ICI-based regimens over chemotherapy, they were not designed to test optimal duration of ICI. Most trials opted to continue ICI indefinitely or stopping at two years if no progressive disease or treatment limiting immune-related adverse events (irAEs) emerged. There is concern for increased cumulative risk of irAEs with indefinite treatment. Methods: A systematic review of randomized controlled trials (RCTs) and real-world evidence (RWE) studies was performed for adult patients with advanced/metastatic NSCLC treated with ICI therapy (alone or in combination) up to August 24, 2024. Studies were included if they specifically reported on patients who completed a minimum of 2 years of therapy. Databases, conference abstracts and clinical trials were queried. Patients were divided into two cohorts: a two year-fixed cohort where ICI therapy was discontinued after 2 years, and a continuous cohort where ICI therapy was continued beyond 2 years. Results: The database search identified 8741 records of which 174 articles were screened. The final qualitative analysis included 20 studies (11 RCTs and 9 RWE studies) and 5027 patients. There were 23 cohorts that belonged to the 2 year-fixed group (N=2051) and 7 that belonged to the continuous group (N=2976). Outcomes of patients in the 2 year-fixed arms from RCTs were excellent with 5-year overall survival (OS) rates in the range of 69-83%. This was supported by RWEs which showed similar OS rates. Continuous treatment with ICIs had similar OS rates in both RCTs and RWE and was comparable to the 2 year-fixed arms. Four RWE studies compared hazard ratios (HR) for survival outcomes among 2 year-fixed vs continuous arms and did not find any statistically significant difference. Patients that completed 2 years of therapy in RCTs tended to have greater rates of irAEs compared to the baseline population but lower rates of grade 3 or 4 events. Three out of four RWEs reported higher rates of irAEs in the continuous vs 2 year-fixed arms. These findings were likely associated with longer exposure to immunotherapy. A large proportion of patients that developed progressive disease after the 2 year-mark in both 2 year-fixed and continuous arms was alive at data cut-off. Many of these were re-challenged with ICI therapy. Data from RWEs showed that larger/academic centers tended to favor 2 year-fixed therapy whereas the reverse was true for community centers. Conclusions: Survival outcomes after ICI discontinuation at 2 years are comparable to continuous therapy in advanced/metastatic NSCLC. Immune-related adverse events tend to accumulate over time. Progressive disease is often localized and amenable to ICI re-challenge.