ATM-mutant tumors: 4Gy×2 palliative RT delivers 83% 6‑mo local control with near-zero toxicity

This is a single-arm Phase II basket trial testing genomically guided RT dose de-escalation in metastatic solid tumors with pathogenic ATM mutations (NCT05010031): all patients received 4Gy×2 (8Gy total) to a progressing lesion, vs a historical benchmark of ~82% local control at 6 months with conventional 4Gy×5 (20Gy). Among 21 enrolled across 9 histologies (3 germline, 18 somatic), 12 were evaluable at 6 months; 10/12 (83.3%) achieved local control (including a complete response in a 4.4cm angiosarcoma), while 2/12 (16.7%) failed locally—both retained ATM protein by IHC and had concurrent pathogenic TP53 mutations; molecular profiling suggested deeper (biallelic) ATM loss in the strongest responders. No Grade ≥2 RT-related toxicities were reported, and the regimen’s 8Gy total dose is in the same “single/few-fraction palliation” neighborhood commonly used in practice (e.g., 8Gy×1 or 20Gy/5) but here is being positioned as biomarker-selected dose minimization rather than convenience.