Abstract

Background: Deletions in MTAP occur in 10-15% of cancers and are associated with poor prognosis. MTAP deletion (MTAPdel) leads to accumulation of MTA which causes partial inhibition of PRMT5, creating a synthetic lethality approach with PRMT5 inhibitors. Multiple investigational MTA-cooperative PRMT5 inhibitors have demonstrated early clinical efficacy in MTAPdel NSCLC and other cancers. MTAPdel, PRMT5 expression, and clinical outcomes to standard of care immune checkpoint inhibitors (ICI) and chemotherapy (chemo) have not been well characterized.

Methods: The Tempus Lens Platform (Tempus AI, Inc., Chicago, IL) was used to query the Tempus multimodal de-identified database and establish and subsequently analyze a cohort of patients (pts)with NSCLC and DNA (Tempus xT) and RNA (Tempus xR) testing, treated with front-line (1L) ICI with or without chemo (N=3,676). PRMT5 expression was normalized as transcripts per million (TPM) and reported as log2(TPM + 1). Pts were classified into high vs low groups based on median PRMT5 expression and into MTAPdel vs intact (MTAPwt) based on MTAP biallelic loss. Immune infiltration was estimated using Quantiseq. Real-world overall survival (rwOS) was defined as the time from 1L start to death or last known follow-up. Real-world progression-free survival (rwPFS) was defined as the time from 1L start to death, progression or last known follow-up. Hazard ratios (HR) were calculated using Cox proportional hazards models and adjusted for age, sex, histology, smoking status and PDL1 status.

Results: PRMT5 expression was moderately increased in pts with MTAPdel (6.65 v 6.70, p=0.012). Alterations in MYC, SMARCA4 and KEAP1 were enriched in PRMT5-high tumors in both MTAPdel and MTAPwt pts (p<0.03). Pts with PRMT5-high tumors had decreased infiltrate of multiple immune cells, including B cells, macrophages (M1 and M2), NK cells, CD4 and CD8 T cells (p<0.001). Pts with MTAPdel/PRMT5-high expression had shorter rwOS compared to MTAPwt/PRMT5-low when treated with ICI alone (HR 1.58, 95% CI 1.11-2.24, p=0.011) or with ICI + chemo (HR 1.65, 95% CI 1.34-2.03, p<0.001). These associations persisted on multivariate analysis. Pts with MTAPdel/PRMT5-high expression were also associated with worse rwPFS when treated with ICI + chemo (HR 1.5, 95% CI 1.22-1.86, p<0.001) on univariate and multivariate analysis, but did not associate with rwPFS in pts treated with ICI alone (HR=0.97, 95% CI 0.66-1.42, p=0.9).

Conclusion: PRMT5 expression defines an immune suppressed subpopulation of pts with NSCLC. Pts with elevated PRMT5 expression and MTAPdel have poor outcomes with ICI+/- chemo, indicating PRMT5 RNA expression levels can be used to inform clinical trial designs, particularly those that are testing novel combinatorial strategies.

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