Treviño, Santiago

Abstract Purpose: Homozygous deletion of the 9p21 locus, containing CDKN2A/B and MTAP [CDKN2A/MTAP deletion (CMdel)], underlies emerging therapeutic strategies, including PRMT5/MAT2A inhibition. The clinicogenomic context and treatment outcome associations of CMdel in non–small cell lung cancer (NSCLC) remain incompletely defined. Experimental Design: We analyzed Tempus Lens records with paired DNA (xT) and RNA (xR) sequencing. After quality filtering (purity ≥40%), 16,947 patients were included in the primary dataset, and 10,996 were included in the validation dataset and stratified by deletion status [CMdel vs. CM wild-type (CMwt)]. IFN status was defined by IFN-kappa (IFNK) expression [log2(TPM + 1)] using the 25th percentile of CMwt as the threshold. Immune composition was inferred by quanTIseq. First-line regimens were grouped as immune checkpoint inhibitor (ICI) monotherapy, ICI chemotherapy, chemotherapy, or tyrosine kinase inhibitors (TKI). Best response and time to next treatment (TTNT) with risk-set adjustment and 18-month truncation were assessed. Results: CMdel occurred in 11.7% (n = 1,991) and 15% (n = 1,676), respectively, and was enriched in mucinous histology, stage IV disease, and never smokers. CMdel was associated with EGFR, TERT, and SMARCA4 alterations, whereas CMwt was associated with RB1, SETD2, and ARID2. More than 50% of CMdel tumors harbored targetable coalterations, enriched in EGFR/ALK/RET and relatively depleted in KRAS. CMdel tumors exhibited lower PD-L1, mutation burden, and immune infiltration. TTNT did not differ by CM status for ICI monotherapy or TKI but was shorter in CMdel for ICI chemotherapy and chemotherapy. Discordant and broad deletions were less common and had weaker TTNT association. IFNK-low expression marked immune-excluded subgroups with worse treatment outcomes. Conclusions: CDKN2A/MTAP loss defines a prevalent, genomically distinct NSCLC subset enriched in actionable drivers. CMdel associates with worse outcomes to ICI/chemotherapy-containing regimens. These findings highlight convergent biology at 9p21 and support biomarker-guided development of PRMT5/MAT2A inhibitors in MTAP-deleted NSCLC.

Abstract 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. 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%, CMdel). Significantly more CMdelpatients had low IFNK expression compared to CDKN2A/B/MTAP intact (CMwt) patients (n=14, 956); of CMdel(n=1300), 65.3% had high IFNK expression (IFNKhi) and 34.7% had low IFNK expression (IFNKlo). Among CMdelpatients, IFNKhisamples were enriched in never smokers compared to IFNKlopatients (24% vs 18%, p=0.002). CMdel was enriched in samples with EGFR and ALK driver alterations, and depleted in samples with KRAS or TP53 alterations. In both CMdeland CMwtcontexts, KRAS, EGFR, and ALK alterations associated with IFNKhiexpression, whereas TP53, NFE2L2, STK11, KEAP1, SMARCA4, and KMT2D associated with IFNKloexpression. IFNKhiexpression within CMdelpatients 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 CMdeland IFNKlotrended toward higher rates of progressive disease (PD) (37%), whereas CMdel/IFNKhihad comparable rates of PD to CMwtl/IFNKhiand CMwtl/IFNKlo(28%, 27%, 30%, respectively). CMdel/IFNKlopatients treated with non-ICI/TKI therapies (mostly consisting of chemotherapy) had a non-significant trend toward increased rate of PD (63%). CMdelassociates with driver alterations in EGFR and ALK, along with worse ICI and chemotherapy outcomes in the context of IFNKlobut not IFNKhi expression. Further work to disentangle the impact of immune infiltrate and the co-mutation landscape will help clarify the underlying associated biology. Citation Format: Natalie Vokes, Jessica L. Symons, Brooke Rhead, Pooja A. Shah, Santiago Trevino, Konstantinos Levantakos, Stamatina Fragkogianni, Calvin Chao, Jordi A. Rodon. Low interferon expression coupled with 9p21 loss in non-small cell lung cancer (NSCLC) patients associated with distinct somatic landscape, altered immune population, and poorer response to immune checkpoint inhibitor (ICI) therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6620.