A phase 1 trial of M3814 (peposertib) in combination with lutetium 177 DOTATATE for metastatic well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs)

Background: Radiolabeled SSA, Lu-177 DOTATATE is a beta-emitting radionuclide, currently used for SSTR positive GEP-NETS. Despite favorable progression free survival (PFS) and safety profile, next generation of radioligand therapy trials must seek improvement in PFS and objective response rates (ORR). We hypothesize that addition of an effective radiation sensitizer could help improve antitumor activity of Lu-177 DOTATATE. Radiation is a potent inducer of DNA breaks. The primary repair mechanism for DNA is nonhomologous end-joining (NHEJ) pathway, in which the DNA-PK (Deoxyribonucleic acid protein kinase) complex plays a pivotal role. Upregulation of DNA-PK promotes repair of DNA leading to tumor radio-resistance preclinically and clinically. Thus, DNA-PK is an important molecular target for inhibiting DNA repair and enhancing the cytotoxicity of radiation. In this study, we evaluate Peposertib's safety and efficacy in combination with Lu-177 DOTATATE in NET patients. Material and Methods: This study is an investigator initiated, NCI sponsored, ETCTN (LAO-OH-007), multicenter phase 1 trial of Peposertib and Lu-177 DOTATATE in well-differentiated SSTR positive GEP-NETs after progression on at least one line of prior systemic treatment. Peposertib was administered orally from Day 1-Day 21, and Lu-177 DOTATATE [200 mCi] on Day 1 of every 8-week cycle for a total of 4 doses. Bayesian optimal interval design (BOIN) was used for dose escalation. NCT04750954. The primary endpoint was to evaluate safety and recommended phase II dose (RP2D) of Peposertib when used in combination with Lu-177 DOTATATE. Secondary endpoints included assessment of pharmacokinetics, ORR and median PFS. Results: Of the 27 enrolled patients across 5 cancer centers in the US, 13 were treated in the dose escalation and additional 14 in the dose expansion cohort. All patients were evaluated for safety analysis based on CTCAE version 5.0; the most common treatment related Grade ≥3 adverse events (TEAEs) were anemia (n=2) and lymphopenia (n=12). Grade 3 treatment related anaphylaxis was reported in two patients at dose level 3 (DL3) following which DL3 was discontinued. No dose limiting toxicities (DLTs) were reported at dose level 2. Of the 24 evaluable patients for efficacy analysis, 5 had a partial response, 16 had stable disease and 1 had progressive disease (median follow-up period: 23.9 months); the ORR was 20.83%. At two years, the median PFS has not yet reached. Conclusions: Combination of oral peposertib with Lu-177 dotatate is a safe and promising radiation sensitizer in NET patients. This combination is suitable for investigation in a larger randomized clinical trial.