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WCLC 2026 | MTAP deletion and PRMT5 expression predict poor outcomes in NSCLC
Robert Hsu, MD, University of Southern California, Los Angeles, CA, discusses the clinical relevance of MTAP deletions in non-small cell lung cancer (NSCLC), highlighting that tumors with MTAP deletions have greater PRMT5 expression, which is associated with worse survival outcomes. The combination of high PRMT5 expression and MTAP deletion results in poor overall survival, and this pattern is consistent across various tumor mutations and in cases treated with immune checkpoint inhibitors. Tumor immune microenvironment analysis additionally revealed increased immune suppression in these tumors. This interview took place at the IASLC 2026 World Conference on Lung Cancer congress in Seoul, Republic of Korea.
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Transcript
Yeah, so, you know, MTAP deletions are found in about 10 to 15% of all tumors. And, you know, this is clinically relevant because there are PRMT5 inhibitors that are in development. So from this, we worked in collaboration with Keras Life Sciences using their kind of large database to look at the expression of PRMT5 along with MTAP deletions in non-small cell lung cancer...
Yeah, so, you know, MTAP deletions are found in about 10 to 15% of all tumors. And, you know, this is clinically relevant because there are PRMT5 inhibitors that are in development. So from this, we worked in collaboration with Keras Life Sciences using their kind of large database to look at the expression of PRMT5 along with MTAP deletions in non-small cell lung cancer. We looked at nearly 40,000 non-small cell lung cancer tumors, of which we found 17% of the tumors were MTAP-deleted. We were able to show that MTAP-deleted tumors had greater PRMT5 expression. And then we looked at survival data, which we showed that the combination of high PRMT5 expression and MTAP deletion had worse survival outcomes, particularly compared to PRMT5 not high expressors with MTAP not deleted. Overall, PRMT5 high expression with MTAP deletion had overall survival of 12 months, while PRMT5 not high with MTAP not deleted tumors had overall survival of 22 months. We also looked at this in TP53, EGFR, KRAS, STK11, KEAP1 mutated tumors, along with PD-L1 positivity and TMB high status that were TMB high tumors. And we showed that a consistent pattern of where PRMT5 high expressors with MTAP deletions had worse survival outcomes. We also looked at these tumors in cases that received immune checkpoint inhibitors of which we showed that PRMT5 high expressing tumors with MTAP deletions had a mean overall survival of about 13.8 months compared to 19 months in PRMT5 not high, MTAP not deleted tumors, showing a significant survival difference in those cases that received immune checkpoint inhibitors. And then we also did a tumor immune microenvironment analysis, which we were looking at immune cell fraction, and we showed that PRMT5 high expressors with MTAP deleted tumors had significantly more immune suppression. So we saw decreased CD8 T cells, regulatory T cells, B cells in these tumors compared to the PRMT5 not high and MTAP not deleted tumors. And so this, you know, this data is, you know, very, I think, hypothesis generating. And it does give credence to the fact that, you know, we should consider, you know, in addition to, you know, PRMT5 inhibitors that could be beneficial to consider other kind of more novel immunotherapy agents. There are bispecific, trispecific T-cell engagers that are out there, or even considering dual checkpoint inhibition in this patient population that has a kind of a tumor immune cold microenvironment.
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