Background Immune checkpoint inhibitors (ICI), either as monotherapy or in combination with platinum-based chemotherapy, is standard of care in aNSCLC. However, most patients do not respond to ICI therapy, even when PD-L1≥50% (PD-L1 high). At BC Cancer, only those patients with PD-L1 high are eligible for first line (1L) ICI monotherapy, offering an opportunity to study potential new biomarkers in a relatively unbiased cohort of patients treated by ICI without chemotherapy. DetermaIO (IO score) is a 27-gene RT-qPCR immuno-oncology assay that classifies the tumor immune microenvironment (TIME) as IO+ or IO- and has been previously shown to associate with clinical benefit to ICI therapy in multiple tumor types.

Methods All available FFPE blocks were assembled for ECOG≤2 patients treated with at least one cycle of ICI monotherapy in the 1L (required to be PD-L1≥50%) or later line (2L+). DetermaIO was performed using a CAP/CLIA validated RT-qPCR assay for cases where sufficient tissue was available. IO score classification was analyzed for association with PFS and OS in patients treated in the 1L.

Results Considering the entire cohort of 147 patients, DetermaIO was significantly associated with OS (HR=0.68, 95%CI 0.47–0.89, p=0.042) and PFS (HR=0.62, 95%CI 0.43–0.88, p=0.0069). When examining the cohort by line of therapy, 78 (53%) were treated in 1L with ICI monotherapy and were all PD-L1 high. DetermaIO in this subgroup was significantly associated with PFS (HR=0.55, 95%CI 0.32–0.94, p=0.028) and demonstrated meaningful clinical benefit when measuring OS (HR=0.60, 95%CI 0.34–1.06, p=0.078). The objective response rate in the 1L subgroup was 53% for IO+ (2CR, 28PR out of 56 patients) and 23% for IO- (5PR out of 22 patients). The net reclassification rate of IO- amongst the PD-L1 high 1L group was 54.5% (12/22, p<0.01) for response.

Conclusions Retrospective analysis of outcomes of aNSCLC patients treated 1L with ICI monotherapy found that DetermaIO was significantly associated with PFS and trended towards significance for OS. First-line PD-L1 high patients who were IO- had significantly worse outcomes for PFS than PD-L1 high IO+ patients potentially informing the selection of combination therapy in PD-L1 high patients. These data confirm and expand previous studies of DetermaIO in advanced NSCLC and suggest IO score classification may offer significant incremental information for helping to make complex treatment decisions in aNSCLC.

Ethics Approval This study was approved by the Research Ethics Board (REB) of University of British Columbia (H20–02635). Individual consent for this retrospective analysis and the use of tumor samples for the IO score assay was required for live patients. Consent was waived by the REB for deceased patients.