Next-generation tumor-agnostic targets on the horizon

Tumor-agnostic drug development reframes oncology around shared molecular dependencies rather than tissue origin, enabling efficient development for rare, actionable drivers across tumors. Since the first tumor-agnostic approval in 2017 for immunotherapy in microsatellite instability-high or mismatch repair-deficient tumors, the regulatory paradigm has expanded to high tumor mutation burden (TMB-H) cancers, oncogene-directed kinase inhibitors, such as NTRK, rearranged during transfection (RET), BRAF valine-to-glutamic acid substitution at codon 600 (BRAF V600E), and antibody-drug conjugate targeting Her2 overexpression, establishing proof of principle across modalities. In this review, we examine current tumor-agnostic approvals and emerging targets with pan-cancer potential: Kirsten rat sarcoma viral oncogene homolog (KRAS) variants [glycine-to-cysteine substitution at codon 12 (G12C), glycine-to-aspartic acid substitution at codon 12 (G12D), and active GTP-bound RAS (RAS(ON)) inhibitors; degraders; and chimeric antigen receptor T-cell (CAR-T)], methylthioadenosine phosphorylase (MTAP) loss (methylthioadenosine (MTA)-cooperative protein arginine methyltransferase 5 (PRMT5) and methionine adenosyltransferase 2A (MAT2A) inhibition), tumor protein p53 (TP53) tyrosine-to-cysteine substitution at codon 220 (Y220C) allele-specific reactivation, and fibroblast growth factor receptor 2 (FGFR2) and neuregulin (NRG) fusions. We explore critical challenges including standardized assays, endpoints, infrastructure, and access limitations. Finally, we outline features shaping next-generation programs: novel basket-trial designs, real-world evidence integration, and international collaborative frameworks. With molecules, infrastructure, and trial designs advancing in parallel, tumor-agnostic strategies are poised to deliver equitable benefit across cancers, realizing precision medicine without borders.