Background – Deletions in 9p21 are common across multiple cancer types including NSCLC. Notably, 9p21 deletions have been implicated in an immune-excluded tumor immune phenotype and worse outcomes following ICIs. Whether this effect is due to CDKN2A loss, collateral loss of MTAP, or loss of type I interferon genes (IFNK, IFNA) has not been fully adjudicated.

Methods – The Tempus Database (Tempus AI, Inc., Chicago, IL) was queried for de-identified records of patients with NSCLC and DNA (Tempus xT) and RNA (Tempus xR) molecular profiling. CDKN2A/MTAP deleted samples were defined as those containing biallelic loss of CDKN2A/B and MTAP. As IFNK is not included in the DNA sequencing bait set, IFNK status was defined as low in any sample with expression ≤ the first quartile of IFNK expression from samples with intact CDKN2A/B and MTAP. Samples with tumor purity < 40% or mixed loss of CDKN2A/B and MTAP were excluded. Association analysis of CDKN2A/MTAP/IFNK status with other genomic events and clinical outcomes was performed. N=16,947 patients were included in the overall analysis, of whom n=1,991 had CDKN2A/B/MTAP deletion (11.7%, CM^del).

Results – Significantly more CM^del patients had low IFNK expression compared to CDKN2A/B/MTAP intact (CM^wt) patients (n=14,956); of CM^del (n=1300), 65.3% had high IFNK expression (IFNK^hi) and 34.7% had low IFNK expression (IFNK^lo). Among CM^del patients, IFNK^hi samples were enriched in never smokers compared to IFNK^lo patients (24% vs 18%, p=0.002). CM^del was enriched in samples with EGFR and ALK driver alterations, and depleted in samples with KRAS or TP53 alterations. In both CM^del and CM^wt contexts, KRAS, EGFR, and ALK alterations associated with IFNK^hi expression, whereas TP53, NFE2L2, STK11, KEAP1, SMARCA4, and KMT2D associated with IFNK^lo expression. IFNK^hi expression within CM^del patients was associated with an increase in the estimated proportion of immune cell subpopulations, including CD8 T cells and macrophages (M1 and M2), and a decrease in neutrophils and NK cells. In metastatic/unresectable stage III patients with recorded ICI-containing 1L therapies (n=1,795), patients with CM^del and IFNK^lo trended toward higher rates of progressive disease (PD) (37%), whereas CM^del/IFNK^hi had comparable rates of PD to CM^wtl/IFNK^hi and CM^wtl/IFNK^lo (28%, 27%, 30%, respectively). CM^del/IFNK^lo patients treated with non-ICI/TKI therapies (mostly consisting of chemotherapy) had a non-significant trend toward increased rate of PD (63%).

Conclusions – CM^del associates with driver alterations in EGFR and ALK, along with worse ICI and chemotherapy outcomes in the context of IFNK^lo but not IFNK^hi expression. Further work to disentangle the impact of immune infiltrate and the co-mutation landscape will help clarify the underlying associated biology.

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