DAREONTM-9, a phase Ib study of obrixtamig plus topotecan in patients (pts) with advanced small cell lung cancer (SCLC): Interim analysis results.

8094 Background: Delta-like ligand 3 (DLL3) is highly expressed on SCLC cells and is a promising target for new therapeutic drugs. Obrixtamig (BI 764532) is a DLL3/CD3 IgG-like bispecific T-cell engager that binds simultaneously to DLL3 on tumor cells and CD3 on T-cells leading to tumor cell lysis. We report the first safety and preliminary efficacy data for the dose escalation part of the Dareon-9 trial, investigating the combination of obrixtamig and topotecan in pts with advanced SCLC (NCT05990738). Methods: Pts who progressed on or relapsed after ≥1 line of platinum-based treatment (Tx) ± anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) were eligible for the trial. Obrixtamig was given as step-up dosing followed by target dose (3 dose levels). Topotecan was given per label. Dose escalation of obrixtamig was guided by a Bayesian Logistic Regression Model with overdose control. Antitumor activity was assessed using RECIST 1.1. The ongoing dose confirmation part will assess obrixtamig at the dose selected at the end of dose escalation. Results: As of January 2, 2025, 25 pts had received ≥1 cycle of Tx. Median number of cycles for both obrixtamig and topotecan was 4 (range 1–13); median Tx exposure was 2.6 months (range ≤1–8.5). Median age was 65 years (range 38–78); ECOG PS was 0 in 13 pts (52%), 1 in 12 pts (48%); median number of prior lines of Tx was 1 (range 1–3), 92% had received prior anti-PD-1/PD-L1. Obrixtamig-related adverse events (AEs; any grade/grade ≥3) occurred in 23 (92%) and 7 (28%) pts, with no grade 5 AEs. Topotecan-related AEs (any grade/grade ≥3) occurred in 25 (100%) and 21 (84%) of pts, with no grade 5 AEs. No pts discontinued obrixtamig due to Tx-related AEs. No obrixtamig- or topotecan-related grade ≥2 neurologic events occurred. All cytokine release syndrome cases were low grade: grade 1 (44%) and grade 2 (4%). The most frequent (≥10%) Tx-emergent grade 3/4 AEs were: neutropenia and/or decreased neutrophil count in 15 pts (60%); thrombocytopenia and/or decreased platelet count in 13 pts (52%); decreased lymphocyte count in 8 pts (32%); anemia in 6 pts (24%); and fatigue in 4 pts (16%). Grade 3 febrile neutropenia was reported in 1 pt (4%). Preliminary efficacy data from evaluable pts (n=23) showed an unconfirmed ORR of 70% (95% CI 47–87); 1 pt (4%) had a CR and 15 (65%) pts had a PR. Disease control rate was 87% (95% CI 66–97). In the 13 pts with ≥2 post-baseline tumor assessments (follow-up >13 weeks), the confirmed ORR was 69%. Median duration of response was not reached. Conclusions: The obrixtamig plus topotecan combination was tolerable with no unexpected toxicities. AE frequency and severity reported for the combination were consistent with the expected safety findings for obrixtamig and topotecan as monotherapy. Preliminary efficacy data for the combination are encouraging and indicate an improvement on top of topotecan monotherapy. Clinical trial information: NCT05990738 .