Factors associated with clinical trial failure and termination in non–small cell lung cancer immunotherapy: A ten-year review.

Abstract

11116 Background: Immunotherapy (IO) has transformed NSCLC management, yet trial efficiency and strategy-level success patterns across settings remain incompletely described. We evaluated NSCLC IO trials for termination trends, outcome accessibility, shifts in strategies over time, and factors associated with endpoint success and failure to inform future trial designs. Methods: We identified interventional NSCLC IO trials from ClinicalTrials.gov from 2015–2024 with completed/terminated status. Trials were categorized by setting (metastatic 1L and beyond 1L; perioperative; other/mixed), intervention strategy (PD-(L)1 monotherapy; PD-(L)1+chemotherapy; PD-(L)1+CTLA-4; PD-(L)1+targeted/VEGF/ADC; RT/CRT+ICI; other IO), phase group, sponsor type (industry vs non-industry), and disease stage. Statistic analysis was done using chi-square/Fisher tests and multivariable logistic regression. Among completed trials, success/failure was defined as meeting/not meeting the primary endpoint when outcomes were assessable. Results: Among 198 NSCLC IO trials, 67 (33.8%) were terminated, 131 (66.2%) completed. Termination increased over time (24.0% 2015–2017, 48.1% 2018–2019, 57.1% 2020–2022; p = 0.0005) and persisted after accounting for setting, phase, sponsor type (2018-2019 vs 2015-2017: OR 2.87, p = 0.0037; 2020-2022 vs 2015-2017: OR 3.22, p = 0.0277). Metastatic disease trials shifted from late (56.0%, 2015–2017;42.9%, 2020–2022) to 1L (28.8% - 47.6%). Endpoint outcomes were assessable in 72/131 (55.0%) completed trials - more in metastatic 1L vs later-line (75.0% vs 42.3%, p = 0.0086; OR 0.30, p = 0.013) and in industry vs non-industry trials (71.9% vs 41.9%; p = 0.0012, OR 0.38, p = 0.030). Among these, 47 (65.3%) met primary endpoints. Success varied by strategy: PD-(L)1+chemo 73.1%, PD-(L)1 mono 60.9%, PD-(L)1+CTLA-4 50.0%, PD-(L)1+targeted 20.0%, RT+ICI 85.7%; PD-(L)1+chemo outperformed PD-(L)1+targeted (Fisher p = 0.0416). Strategy shifted over time (p = 0.034), with decreased PD-(L)1 mono and increased RT+ICI and PD-(L)1+targeted combinations in later years. Proportion of PD-(L)1 monotherapy was higher for perioperative trials (47.4%) vs metastatic 1L (16.7%) and later-line settings (26.7%). Cell-(n = 8) and vaccine/virus-based (n = 12) approaches were uncommon (term. 25% and 50%) with limited assessable outcomes. Conclusions: Treatment strategies shifted away from PD-(L)1 monotherapy toward combination approaches and, in metastatic disease, from late-line to 1st line settings. PD-(L)1+chemotherapy and RT+ICI showed higher success rates than PD-(L)1+targeted combinations, though some subgroups were small. Other IO agents are rarely used in NSCLC and have insufficient reporting. Incorporating predictive risk models into trial planning may reduce low-yield studies and accelerate identification of effective treatments.