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TNG462 + pembrolizumab is a combination therapy under investigation for advanced or metastatic solid tumors characterized by homozygous MTAP deletion. TNG462 is a selective, orally administered MTA-cooperative PRMT5 inhibitor that induces synthetic lethality in cancer cells lacking MTAP, resulting in preferential cytotoxicity against tumor cells while sparing normal tissue. Pembrolizumab is an immune checkpoint inhibitor targeting PD-1, used to enhance anti-tumor T cell responses. The combination aims to exploit the dependence of MTAP-deleted tumors on PRMT5 activity while also leveraging the immunotherapeutic effects of PD-1 blockade. This combination is being evaluated in a Phase 1/2 multi-center, open-label clinical trial for efficacy, safety, tolerability, and anti-neoplastic activity across multiple MTAP-deleted cancer types, including non-small cell lung cancer (NSCLC), mesothelioma, pancreatic ductal adenocarcinoma, sarcoma, and other solid tumors[1][2][3].
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