Phase 1/2 navlimetostat PRMT5 inhibitor + pumitamig PD-L1×VEGF-A bispecific in MTAP-loss NSCLC.

This MD Anderson–sponsored Phase 1/2 study tests navlimetostat (aka MRTX1719/BMS-986504), an MTA-cooperative PRMT5 inhibitor designed to preferentially suppress PRMT5 activity in MTAP-deleted tumors, combined with pumitamig, a PD-L1 and VEGF-A–directed bispecific fusion protein intended to pair checkpoint blockade with anti-angiogenic/TME remodeling. Phase 1 is a safety lead-in to define a tolerable combination dose; Phase 2 evaluates anti-tumor activity with endpoints including disease control, PFS, OS, and duration of response, and includes planned comparisons by prior immune checkpoint inhibitor exposure. The regimen is oral navlimetostat once daily plus IV pumitamig every 3 weeks in 21-day cycles until progression or intolerance. The scientific angle is a biomarker-selected “synthetic lethality” backbone (MTAP loss, which is a meaningful minority of NSCLC and often co-deleted with CDKN2A) layered with PD-(L)1+VEGF dual biology that has precedent as an immuno-angiogenic strategy. Today’s second-line+ care for advanced NSCLC is guided by driver status and prior PD-(L)1 therapy, typically moving through docetaxel ± ramucirumab, single-agent chemo, or targeted agents if an actionable alteration is present, so this explores a genotype-directed alternative for a hard-to-treat subset.