Determination of clinical benefit among patients with radiological stable disease to immune checkpoint inhibitors.

9041 Background: SD is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs) and likely represents a heterogenous mix of responders and non-responders. This study aimed to characterize SD and identify the subset of patients with SD who are benefiting from treatment. The ability to distinguish whom among patients with SD is actually benefiting from treatment would facilitate drug development and improve precision in correlative research. Methods: A systematic review was performed to characterize SD in ICI trials. SD and objective response was compared to proliferation index using TCGA gene expression data. To identify a subgroup of SD with outcomes mirroring responders, we examined a discovery cohort of NSCLC treated with ICIs and had RECIST assessment. In patients with best overall response (BOR) of SD, serial cutpoints of two variables, % BOR and PFS, were tested to define a subgroup with similar survival as PR-minor (patients with partial response [PR] and % shrinkage < median among responders). Results were then tested in two external validation cohorts (n = 326, n = 381). Results: Among trials of ICIs (59 studies, 14,280 patients), SD ranged from 16-42% in different tumor types and was associated with disease-specific proliferation index (Spearman rho = -0.75, p = 0.03), a proxy of tumor kinetics, rather than relative response to ICIs. In a discovery cohort of 1220 patients with NSCLC who were treated with ICIs, 26% had SD, 19% had PR/CR, and 55% had PD. Outcomes among those with SD ranged widely (OS range 0.5-76 months, PFS range 0.2-49 months). The subset of SD with PFS > 6 months and no tumor growth mirrored PR-minor (OS HR 1.0) and was proposed as the definition of “SD-responder”. SD-responders (n = 87) represented 7% (95% CI 6-9%) of the overall population and 28% (95% CI 23-33%) of the SD population. This definition was confirmed in two validation cohorts from trials of NSCLC treated with durvalumab. Conclusions: RECIST-defined SD to immunotherapy is common, heterogenous, and may largely reflect tumor growth rate rather than ICI response. In patients with NSCLC and SD to ICIs, PFS > 6 months and no tumor growth (̃1/3 of SD) may be considered “SD responders.” This definition may improve the efficiency of and insight derivable from clinical and translational research.