Peposertib (M3814) + DNA-PK Inhibition Sensitizes Lu-177 DOTATATE, Driving 21% ORR in Pre-treated SSTR+ GEP-NETs

Peposertib is an oral DNA-dependent protein kinase (DNA-PK) inhibitor designed to radiosensitize tumors by blocking nonhomologous end-joining DNA repair; here it was combined with Lu-177 DOTATATE peptide receptor radionuclide therapy (PRRT) in an investigator-initiated, NCI-sponsored ETCTN multicenter Phase 1 dose-escalation/expansion trial (LAO-OH-007; NCT04750954) in metastatic, well-differentiated SSTR+ GEP-NETs after progression on ≥1 prior systemic line (27 enrolled; 24 efficacy-evaluable). Across evaluable patients, ORR was 20.83% (5/24 PR), with 16/24 stable disease and median PFS not reached at a median follow-up of 23.9 months—numerically in the same ballpark as historic Lu-177 DOTATATE monotherapy ORR (~18% in NETTER-1, albeit a different midgut-only population) and without a clear PFS delta yet given the immature follow-up. Safety was dominated by hematologic toxicity (grade ≥3 lymphopenia n=12; anemia n=2); grade 3 treatment-related anaphylaxis occurred in 2 patients at dose level 3, prompting discontinuation of that dose level, while no DLTs were reported at dose level 2 (selected for RP2D development).