Background – Immunogenome characterization in early (eNSCLC; stage I-III) and metastatic (mNSCLC; stage IV) NSCLC is needed to improve ICI efficacy. We evaluated how CD8 T cell (CD8T) and PD-L1 proportions associate with real-world OS (rwOS) and driver alterations (dAlts) in pts with NSCLC treated with first-line (1L) ICI+chemotherapy (CT).

Methods – Using Lens Workspace (Tempus AI, Inc., Chicago, IL), de-identified samples collected prior to 1L and sequenced by the Tempus xT DNA and Tempus xR whole-transcriptome assays were selected (eNSCLC n=3,159; mNSCLC n=2,184, adenocarcinoma). dAlts were defined as classic (c; L858R or exon 19 del) or non-classic (nc) EGFR, KRAS G12C/non-G12C, or other guideline-defined alt (BRAF V600E, ERBB2, fusions in NTRK1-3, ALK, ROS1, RET or METex14 skipping). Immune cell proportions were estimated by quanTlseq (RNA). CD8T [High (H)/Low (L)], PD-L1 (TPS, IHC), and dAlt status were used for stratification with significance (p < 0.05) assessed using χ2 or Kruskal-Wallis tests. rwOS was defined as 1L start time to any cause of death (2 yr follow up). Median rwOS (mOS) and hazard ratio (HRs) were estimated using the Kaplan-Meier method and Cox proportional hazards (CoxPH) models.

Results – After 1L-ICI+CT, PD-L1 and CD8T were associated with improved mOS in mNSCLC; CD8T further stratified OS within PD-L1 groups and between 1L-ICI+CT (Table). In eNSCLC and mNSCLC, CD8T and PD-L1 were highest in cases with no dAlts and KRAS dAlts, and lowest in the c/ncEGFR dAlt cohorts (p<0.001). CD8T-H/PD-L1≥1 and CD8T-H/PD-L1≥50 were most frequent in the non-dAlt and KRAS groups (p<0.001), while CD8T-H/PDL1≥50% was least common and CD8T-L/PD-L1<1 was most frequent in the c/ncEGFR dAlt cohort (p<0.001).

Conclusions – OS following ICI+CT in mNSCLC was greatest when both CD8T and PD-L1 were high. The CD8T/PD-L1 immunophenotype analysis indicates these findings may apply across stage and dAlt status.

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