In a retrospective cohort study that evaluated the association between fixed 2-year versus indefinite-duration of front-line treatment with immune checkpoint inhibitor (ICI), there was no evidence of a difference in overall survival (OS) among patients with advanced non-small cell lung cancer (NSCLC). This finding remained robust in multivariable analyses adjusting for covariates such as smoking, PD-L1 status, and histologic type.

Approximately 1 in 5 patients who reached 2 years of ICI discontinued treatment in the absence of progression or death. The findings are reported by Dr. Lova Sun of the Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania in Philadelphia, PA, US, and colleagues on 4 June 2023 in the JAMA Oncology.

The authors wrote in the background that the optimal duration of ICI use is not known. Patients in key pivotal NSCLC studies informing the use of first-line ICI use were treated with ICI for up to 2 years, maximum of 35 cycles every 3 weeks. However, in clinical practice, many patients continue therapy beyond 2 years. Long-term follow-up of large randomised clinical studies has shown that durable responses can be maintained after fixed-duration treatment with ICI. Despite these encouraging results, there has been substantial hesitation around ICI discontinuation.

Compared with fixed-duration, indefinite-duration of ICI treatment has several disadvantages including the risk of additional medical and financial ttoxicities. Financial toxicity is also a major consideration with indefinite treatment. Many countries such as the UK have limited ICI to a maximum of 2 years treatment regardless of disease status.

The study team leveraged a nationwide US oncology database to investigate practice patterns and survival outcomes associated with 2-year ICI treatment discontinuation. They compared survival between long-term ICI responders whose therapy was discontinued at 2 years in the absence of death or progression (fixed-duration group) and those who continued ICI beyond 2 years (indefinite-duration group). The authors hypothesized that among patients in a clinical cohort who were progression-free at 2 years, there would be no difference in OS between fixed-duration and indefinite-duration of ICI treatment.

This retrospective, population-based cohort study included adult patients in a clinical database diagnosed with advanced NSCLC from 2016 to 2020, who received frontline ICI-based treatment. The data cut-off was 31 August 2022. Data analysis was conducted from October 2022 to January 2023. Overall survival from 760 days was analyzed using Kaplan-Meier methods. Multivariable Cox regression that adjusted for patient-specific and cancer-specific factors was used to compare survival beyond 760 days between the fixed-duration group and the indefinite-duration group.
Of 1091 patients in the analytic cohort who were still on ICI treatment at 2 years after exclusion criteria for death and progression were applied, 113 patients with median age of 69 years, of whom 62 female (54.9%), and 86 White (76.1%) were in the fixed-duration group, and 593 patients with median age 69 years, of whom 282 female (47.6%), 414 White (69.8%) were in the indefinite-duration group. Patients in the fixed-duration group were more likely to have a history of smoking (99% versus 93%; p = 0.01) and be treated at an academic centre (22% versus 11%; p = 0.001). 

Two-year OS from 760 days was 79% (95% confidence interval [CI] 66%-87%) in the fixed-duration group and 81% (95% CI 77%-85%) in the indefinite-duration group. There was no statistically significant difference in OS between patients in the fixed-duration and indefinite-duration groups, either on univariate (hazard ratio [HR] 1.26, 95% CI 0.77-2.08; p = 0.36) or multivariable (HR 1.33, 95% CI 0.78-2.25; p = 0.29) Cox regression. Approximately 1 in 5 patients discontinued immunotherapy at 2 years in the absence of progression.

The authors commented that the present study supports treatment discontinuation at 2 years as a valid approach that does not appear to compromise survival outcomes. Patients treated with fixed-duration therapy may benefit from rechallenge with ICI even if progression occurs after ICI cessation. In small cohort of patients who underwent ICI rechallenge, median progression-free survival after rechallenging was 8.1 months, with more than one-third of patients still on treatment at the data cut-off point. The authors expected to see a spike in discontinuation at 2 years aligned with the fixed 2-year ICI duration specified in the large pivotal studies; however, difference in probability of discontinuation of therapy was not substantially different at 2 years compared with other points in time. 

In an accompanied editor’s note, Dr. Howard (Jack) West of the City of Hope Comprehensive Cancer Center in Duarte, CA, US wrote that there are clear limitations in retrospective clinical data, but randomised clinical trial will be difficult to complete, and results will take many years to become available. In the meantime, these data may provide reassurance that discontinuing treatment at 2 years can confer the same OS as extended treatment with lower risk of side effects, less time in treatment for patients, and considerably lower healthcare costs.