Phase I Dose-Escalation Results for the Delta-Like Ligand 3/CD3 IgG-Like T-Cell Engager Obrixtamig (BI 764532) in Patients With Delta-Like Ligand 3+ Small Cell Lung Cancer or Neuroendocrine Carcinomas.

PURPOSE We report phase I results for obrixtamig (BI 764532), a delta-like ligand 3 (DLL3)/CD3 IgG-like T-cell engager, in patients with previously treated DLL3-positive small cell lung cancer (SCLC), extrapulmonary neuroendocrine carcinomas (epNECs), or large cell neuroendocrine carcinoma of the lung (LCNEC-L). METHODS Patients received escalating intravenous obrixtamig doses using four regimens: a fixed dose once every 3 weeks (A); a fixed dose once weekly (B1); a step-up dose once weekly for two weeks and target dose once weekly (B2); and a step-up dose once weekly for 3 weeks, target dose once weekly for 3 weeks, and once every 3 weeks thereafter (B3). The primary objective was maximum tolerated dose (MTD). Secondary objectives included safety, pharmacokinetics, and tumor response (RECIST v1.1). RESULTS As of February 21, 2024, 168 patients received obrixtamig, 72% received ≥2 lines of previous anticancer therapy, and 51% received previous anti-PD-1/PD-L1 therapy. Seven dose-limiting toxicities occurred during MTD evaluation (Regimen A, n = 1; Regimen B2, n = 6). MTD was not reached. The most common treatment-related adverse event was cytokine release syndrome (any grade: 57%; grade ≥3: 3%); most cases occurred early and were reversible. Across all doses, regimens, and tumor types, the overall response rate (ORR) was 23% (95% CI, 17.4% to 30.2%), the median duration of response (DoR) was 8.5 months (95% CI, 6.2 to not reached), and the 6-month DoR rate was 70% (95% CI, 53% to 88%). All patients in Regimens B2/B3 received the minimum effective dose (≥90 μg/kg once weekly or once every 3 weeks), achieving an ORR of 28% (95% CI, 20.7% to 35.9%). With Regimens B2/B3, ORRs were 21% (95% CI, 12.9% to 33.1%), 27% (95% CI, 17.4% to 39.6%), and 70% (95% CI, 39.7% to 89.2%) for SCLC, epNECs, and LCNEC-L, respectively. CONCLUSION The demonstrated tolerability and efficacy of obrixtamig regimens, administered as step-up followed by target doses of 90-1,080 μg/kg (once weekly or once every 3 weeks), in patients with heavily pretreated DLL3-positive tumors support further exploration in SCLC, epNEC, and LCNEC-L.