DAREON-8: Updated efficacy and safety from a phase I dose-escalation/expansion trial of first-line (1L) obrixtamig plus chemotherapy and atezolizumab in extensive-stage small cell lung carcinoma (ES-SCLC).

Abstract

8089 Background: Obrixtamig (BI 764532) is a DLL3/CD3 IgG-like T-cell engager that has shown promising efficacy in ES-SCLC, as monotherapy and in combination with other agents. Due to the aggressiveness of ES-SCLC, early initiation of optimal 1L induction therapy is critical, as many patients (pts) may not reach treatment maintenance. We report updated efficacy and safety data from the ongoing Phase I DAREON-8 (NCT06077500) dose-escalation/expansion trial investigating 1L obrixtamig + induction SoC (carboplatin + etoposide + atezolizumab) and maintenance obrixtamig + atezolizumab in pts with ES-SCLC. Methods: Obrixtamig was given IV as step-up dosing followed by target dose (Part A: 3 dose levels [10, 30, 60 mg] guided by a BLRM with overdose control; Part B: selected target dose) + SoC (given per label). After 4 cycles of obrixtamig + SoC, obrixtamig + atezolizumab was continued until disease progression or another reason requiring discontinuation. Primary endpoint: DLTs; secondary endpoints included PFS, DoR, and ORR (RECIST v1.1; investigator assessed). Results: As of Dec 17, 2025, 46 pts were treated (Part A/B: n=28/18); 44 pts received ≥1 dose of obrixtamig. Median cycles of obrixtamig: 10 (range: 1–21); median age: 69 yrs (range: 34–76); ECOG PS 0/1: 27%/73%; brain metastasis: 16%. MTD was not reached in Part A; the study continued in Part B with the highest dose level (60 mg). Key efficacy data are in the table. Confirmed ORR: 73% (95% CI: 58–84); DCR: 91% (95% CI: 79–96). mDoR: NC; mPFS: NC; 6- and 9-month PFS rates (95% CI): 76% (62–90), and 61% (44–79), respectively. In the 60 mg cohort, confirmed ORR: 76% (95% CI: 58–88); mDoR and mPFS: NC. Most common G≥3 AEs were cytopenias and were almost wholly related to chemotherapy. Most common obrixtamig-related AE: cytokine release syndrome (52%). SoC discontinuations due to TRAEs: n=2 (G2 asthenia, G2 decreased platelets, G3 anemia). Obrixtamig discontinuations due to TRAEs: n=1 (G2 asthenia). Conclusions: Obrixtamig + SoC demonstrated encouraging efficacy, supporting obrixtamig as a combination partner for 1L SoC. The combination showed a safety profile consistent with individual agents, supporting the favorable tolerability of obrixtamig in combination regimens. Updated safety data are consistent with previous findings (Peters S et al, Ann Oncol 2025;36: S1466–7), and results warrant further development in Phase III trials. Clinical trial information: NCT06077500 . Best confirmed response, n (%) Obrixtamig 60 mg, n=29* Total (obrixtamig 10‒60 mg), N=44* CR / PR 4 (14) / 18 (62) 4 (9) / 28 (64) SD 4 (14) 8 (18) PD 0 (0) 1 (2) NE/missing 3 (10) 3 (7) ORR, % (95% CI) 76 (58–88) 73 (58–84) DCR, % (95% CI) 90 (74–96) 91 (79–96) Median PFS, months (95% CI) NC (NC–NC) NC (7.2–NC) 6-/9-month PFS rate, % (95% CI) 84 (69–98) / 78 (60–95) 76 (62–90) / 61 (44–79) *Efficacy-evaluable population.