Indefinite versus 2 years fixed duration of immune checkpoint inhibition in metastatic non–small cell lung cancer.

8590 Background: Clinical trials of immune checkpoint inhibitors (ICIs) in metastatic non-small cell lung cancer (mNSCLC) limited treatment duration to 2 years despite the absence of evidence defining the optimal time on therapy. In routine clinical practice, however, many patients receive ICIs for more than 2 years. We evaluated survival outcomes in patients treated with 2 years versus > 2 years of therapy. Methods: We conducted a global, retrospective cohort study of patients with mNSCLC treated with ICIs for at least 2 years. Patients were classified as receiving fixed-duration ICI (discontinued at 2 years) or indefinite ICI therapy. Outcomes included progression-free survival (PFS), and overall survival (OS) from ICI start. Multivariable Cox regression, propensity score matching, and 2-year landmark analyses with inverse probability weighting (IPW) were used to address time-dependent biases and adjust for relevant covariates. Results: Among 889 patients who received at least 24 months of ICI therapy, median age was 65.5 years; 45.6% were women; 92.8% had a smoking history; 80.2% had adenocarcinoma histology; 70% of patients received ICI as first-line therapy and median PD-L1 tumor proportion score was 60%. Overall, 58.8% received indefinite ICI and 41.2% discontinued at 2 years. Median PFS and OS for the overall cohort were 5.7 years and 8.1 years, respectively. Baseline clinicopathologic characteristics, including age, sex, histology, PD-L1 expression, ECOG performance status, and smoking history, were well balanced between groups. Indefinite ICI therapy was associated with significantly longer PFS (HR 0.75, p < 0.01) and OS (HR 0.62, p < 0.001) compared to 2 years of therapy. These findings were consistent in a propensity-matched analyses (PFS HR 0.62, p < 0.01; OS HR 0.60, p < 0.001) and multivariable models (adjusted PFS HR 0.75, p = 0.02; adjusted OS HR 0.57, p < 0.001). In 24-month landmark analyses with IPW, indefinite ICI remained associated with improved PFS (HR 0.74, p = 0.02) and OS (HR 0.56, p < 0.001). Benefit with indefinite therapy was observed across all predefined subgroups, including age, sex, histology, PD-L1 strata, ECOG performance status, smoking history. Among 98 patients who received ICI rechallenge at disease progression, the objective response rate was 45%, with a median PFS of 12.9 months and a median OS of 30.2 months. Conclusions: Continuation of ICI therapy beyond 2 years was consistently associated with superior PFS and OS compared with treatment limited to 2 years across subgroups and sensitivity analyses. These findings highlight the limitations of arbitrary treatment caps in clinical trial design, support individualized duration decisions, and underscore the need for prospective trials to define the optimal duration of ICI therapy in NSCLC.