3004 Background: Delta-like ligand 3 (DLL3) is highly expressed in neuroendocrine carcinomas (NEC). Obrixtamig (BI 764532) is a DLL3/CD3 IgG-like T-cell engager that targets DLL3-positive (DLL3+) tumors. NCT04429087 is an ongoing, Phase (Ph) I dose-escalation trial of obrixtamig in patients (pts) with DLL3+ pulmonary and extrapulmonary NEC (epNEC), who had failed to respond to standard treatment (Tx). This analysis examined the efficacy and safety of obrixtamig in pts with epNEC with high vs low DLL3 expression. Methods: Obrixtamig was given IV in 4 dose-escalation regimens (R): RA (fixed dose q3w); RB1 (fixed dose qw); RB2 (step-up dose, then qw) and RB3 (step-up dose, then qw for 3 weeks, then q3w), until disease progression or unacceptable toxicity. Efficacy was assessed through objective response rate (ORR) and disease control rate (DCR) using RECIST v1.1. Results are reported for pts who received obrixtamig RB2 or RB3, categorized as having high vs low DLL3, using a threshold of ≥50% of tumor cells stained with an investigational antibody for DLL3 (SP347, Roche Diagnostics). Results: As of June 21, 2024, 60 pts with epNEC were included (gastroenteropancreatic [GEP]: 45.0%, genitourinary [GU]: 30.0%, other/unknown primary site: 25.0%); 30 each DLL3-high and DLL3-low. Mean age: 63.9 years in DLL3-high; 59.1 in DLL3-low pts. Baseline characteristics were well-balanced across DLL3 groups. All pts had received prior systemic therapy; 30.0% of DLL3-high and 50.0% of DLL3-low pts had received > 2 lines of prior Tx. Efficacy data are shown in the Table. After obrixtamig Tx, pts with high DLL3 expression had greater ORR, DCR, and duration of response (DoR) than DLL3-low pts. Responses were seen most frequently amongst pts with DLL3-high GEP (50.0%) or GU (60.0%) epNECs. Seven DLL3-high pts are still receiving Tx. Most treatment-related AEs (TRAEs) were mild to moderate for both groups (Table). Conclusions: Analyses from this ongoing Ph I study show greater obrixtamig efficacy in patients with epNEC with high DLL3 expression compared with low DLL3 expression, with a manageable safety profile that is comparable across both groups. The ORR of 40.0% and median DoR of 7.9 months in heavily pretreated epNEC tumors with DLL3 high expression are encouraging, and support further development of obrixtamig for this subgroup. Clinical trial information: NCT04429087 . Efficacy/safety parameter DLL3-high (n=30) DLL3-low (n=30) ORR, % (95% CI) 40.0 (24.6–57.7) 3.3 (0.6–16.7) DCR, % (95% CI) 66.7 (48.8–80.8) 26.7 (14.2–44.4) Median DoR (95% CI), months 7.9 (6.2–NC) 2.8 (NC–NC) TRAEs, all G/G ≥3, (%) 100.0/23.3 90.0/20.0 Cytokine release syndrome, all G/G ≥3, (%) 70.0/3.3 60.0/3.3 Neurotoxicity, including immune effector cell-associated neurotoxicity syndrome*, all G/G ≥3, (%) 16.7/6.7 10.0/3.3 *Evaluated with a customised MedDRA query. CI, confidence interval; NC, not calculable.

2642 Background: Specific DLL3 expression on the surface of epNEC tumor cells makes it a promising therapeutic target, but there is a lack of prospective data on DLL3 expression patterns in pts with epNEC. Obrixtamig (BI 764532) is a DLL3/CD3 IgG-like T-cell engager. The first-in-human phase I trial (NCT04429087) showed obrixtamig activity in pts with DLL3-positive epNEC, especially pts with DLL3-high tumors (Capdevila et al, ASCO 2025, #3004). We report updated DLL3 expression data and pt/tumor characteristics in pts with epNEC from NCT04429087. Methods: DLL3 IHC was performed with an investigational DLL3 antibody (SP347) at the Roche CDx CAP/CLIA Laboratory. DLL3 expression was categorized as: negative (absent or weak tumor cell [TC] membrane/cytoplasm staining), positive (moderate-to-strong staining in any TCs), high (≥50% moderate-to-strong TC staining), or low (<50% moderate-to-strong TC staining). Results: As of Sept 4, 2025, 282 of 365 screened pts with epNEC were DLL3-evaluable, of whom 235 (83.3%) had DLL3-positive tumors (DLL3-high: n=120 [42.6%], DLL3-low: n=115 [40.8%]); 47 (16.7%) were DLL3-negative. In the DLL3-positive treated set (n=93), 51 pts (54.8%) had DLL3-high and 42 (45.2%) had DLL3-low tumors. The prevalence of DLL3-high tumors in male/female pts was 47.5%/68.8%, and prevalence in pts with liver/brain metastases was 57.1%/70.0%. DLL3-high prevalence by primary tumor site, GI/GU/cancer of unknown primary site (CUP), was 44.9%/67.7%/60.0%. Pt characteristics in obrixtamig-treated DLL3-high and -low epNEC subgroups are in Table 1. Conclusions: In the largest prospectively screened cohort of pts with epNEC, high (83.3%) prevalence of DLL3 expression was seen, underscoring DLL3 as a promising target for clinical development of DLL3-targeted therapies such as obrixtamig. Obrixtamig safety and efficacy in pts with DLL3-positive epNEC are being assessed in several ongoing trials, including DAREON-5 (NCT05882058), with the data expected to inform and support Phase III development. Clinical trial information: NCT04429087 . DLL3-high (n=51) DLL3-low (n=42) Male / female, n (%) 29 (56.9) / 22 (43.1) 32 (76.2) / 10 (23.8) Primary tumor site: GI / GU / CUP, n (%) 22 (43.1) / 21 (41.2) / 6 (11.8) 27 (64.3) / 10 (23.8) / 4 (9.5) Lactate dehydrogenase ≤ULN / >ULN, n (%) 22 (43.1) / 29 (56.9) 16 (38.1) / 26 (61.9) Prior lines of therapy: 1 / 2 / 3 / >3 12 (23.5) / 17 (33.3) / 9 (17.6) / 13 (25.5) 11 (26.2) / 12 (28.6) / 10 (23.8) / 9 (21.4) Median duration of prior anticancer treatment, weeks (range) 22 (5–349) 22 (8–148) Prior radiotherapy / surgery / anti PD-(L)1, n (%) 22 (43.1) / 28 (54.9) / 14 (27.5) 11 (26.2) / 24 (57.1) / 9 (21.4) Liver / brain metastases, n (%) 40 (78.4) / 7 (13.7) 30 (71.4) / 3 (7.1) Median sum of diameters of target lesions, mm (IQR) 87.5 (64.0–123.0) 117.3 (66.2–176.0)

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.

Abstract BACKGROUND Patients with progressive diffuse gliomas have limited treatment options. DLL3, a Notch ligand, is expressed on most diffuse gliomas. BI 764532, a humanized IgG-like T cell engager, binds selectively to DLL3-positive cells and promotes T cell-mediated cytotoxicity. Preclinical data showed activity of BI 764532 against intracranial tumors. In an ongoing first-in-human trial in patients with DLL3-positive small-cell lung carcinoma and other neuroendocrine carcinomas (NECs) including extrapulmonary NECs and large-cell NECs of the lung (NCT04429087), BI 764532 exhibited promising efficacy and manageable tolerability. Here we describe a planned Phase Ib dose-escalation/expansion trial of BI 764532 monotherapy in patients with DLL3-positive refractory/relapsed diffuse glioma. METHODS The dose-escalation part will include ~12–20 patients (≥3 patients per dose level) from 12 sites across Europe/USA. Dose escalation will be guided by Bayesian logistic regression model with overdose control. BI 764532 will be administered intravenously. Treatment will continue until disease progression, undue toxicity, informed consent withdrawn, or other reasons requiring treatment discontinuation. Once a recommended dose for expansion is established, ~15 patients from Europe will be treated in a dose-expansion phase. Key inclusion criteria: ≥18 years old; histologically confirmed primary progressive diffuse glioma who have failed on standard-of-care therapies; DLL3-positivity by IHC on archived tumor tissue by central pathology review. Key exclusion criteria: extracranial metastatic or leptomeningeal disease; previous treatment with DLL3-targeting therapies; prior treatment with bevacizumab/other anti-VEGF/anti-angiogenic treatment ≤6 months prior to first administration of BI 764532; persistent toxicity from previous treatments that has not resolved to ≤CTCAE Grade 1; diagnosis of immunodeficiency, or intake of immunosuppressive therapy ≤7 days prior to first administration of BI 764532. Primary endpoints: dose-limiting toxicities (DLTs) during the maximum tolerated dose evaluation period (escalation phase); DLTs during the entire treatment period (expansion phase). Other objectives include pharmacokinetics, pharmacodynamics, preliminary efficacy and evaluation of DLL3 as a potential biomarker.

8502 Background: The inhibitory Notch ligand, DLL3, is highly expressed on the cell surface of SCLC and NEC tumors and is a promising drug target. BI 764532 is a DLL3/CD3 T cell engaging bispecific antibody that has shown potent preclinical anti-tumor activity in DLL3+ cells and xenograft models. NCT04429087 is an ongoing phase I first-in-human, open-label, dose-escalation trial of BI 764532 in adults with locally advanced/metastatic DLL3+ (confirmed centrally) SCLC, NEC or small cell carcinoma of any other origin (grouped as NEC), or large cell NEC (LCNEC). Methods: BI 764532 was administered intravenously using three different regimens: Regimen (R) A (fixed iv dose q3w); RB1 (fixed iv dose qw); RB2 (step-in doses followed by a fixed dose). Treatment (Tx) continued until progressive disease (PD), unacceptable toxicity, other withdrawal criteria, or maximum Tx duration (36 mos). The main objective was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion of BI 764532, based on dose-limiting toxicities (DLTs) during the MTD evaluation period. Further objectives were safety, tolerability, PK/PD and preliminary efficacy based on investigator review (RECIST v1.1). Results: As of 28th Dec 2022, 90 pts received ≥1 dose of BI 764532 (RA: n = 24, 8 dose levels; RB1: n = 10, 3 dose levels; RB2: n = 56, 6 dose levels; starting dose: 0.03 µg/kg). Median age: 60 years (32–78); ECOG PS 0/1: 24/74%; prior PD1/PD-L1 Tx: 40%; ≥2 prior lines of Tx: 69%. SCLC/NEC/LCNEC: 52/41/4%. Median Tx duration: 43 days (range 1–443); 25 pts are ongoing. DLTs were seen in 1 pt on RA (Grade 3 confusion) and 4 pts on RB2 (Grade 4 cytokine release syndrome [CRS]; Grade 3 CRS, Grade 3 nervous system disorder, Grade 2 infusion-related reaction). MTD has not been reached and dose escalation is ongoing. Overall, the most common treatment-related AEs were (any/Grade 3+): CRS (58/2%); pyrexia (19/0%); decreased lymphocytes (18/14%); asthenia (17/1%); dysgeusia (14/0%). CRS was managed with supportive care, corticosteroids, and/or anti-IL-6R antibodies. With RB2, most CRS and neurological events occurred early, and were reversable. Tumor response data were available for 70 pts (RA/RB1/RB2: n = 19/8/43). In pts with SCLC (n = 24) or NEC (n = 23) who received ≥ target dose of BI 764532, ORR was 33% and 22% across all regimens, respectively. One pt with LCNEC was also evaluable for response and achieved PR. Conclusions: BI 764532 showed clinically manageable tolerability and MTD has not been reached at the doses administered to date. Promising efficacy has been observed, not only in SCLC but also in difficult to treat entities such as NEC and LCNEC. The study is ongoing; updated data will be presented. Clinical trial information: NCT04429087 .

DLL3 is highly expressed on small-cell lung cancer (SCLC) tumours and neuroendocrine carcinomas (NECs). BI 764532 is a DLL3/CD3 IgG-like T cell engager with potent preclinical activity. NCT04429087 is an ongoing phase I dose-escalation trial of BI 764532 in adults with locally advanced/metastatic DLL3+ (confirmed centrally) SCLC, extrapulmonary (ep) NEC or large cell neuroendocrine lung carcinoma. Here we focus on pts with epNEC. BI 764532 was given intravenously in 4 regimens: Regimen A (RA; fixed dose q3w); RB1 (fixed dose qw); RB2 (step-in doses, then fixed dose); RB3 (step-in, followed by target dose). Treatment (Tx) continued until progressive disease, unacceptable toxicity, other withdrawal criteria or maximum Tx duration (36 months). Main objective: maximum tolerated dose (MTD) and/or recommended dose for expansion of BI 764532. Other objectives: safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy based on investigator review (RECIST v1.1). As of 26 July 2023, 129 pts received ≥1 dose (≥ 0.03 μg/kg) of BI 764532 (RA: n=24; RB1: n=10; RB2: n=79; RB3: n=16). Male: 59%; median age: 60 (range 32–81); ECOG PS 0/1: 28/71%; prior PD1/PD-L1 Tx: 49%; ≥2 prior lines of Tx: 70%. Dose limiting toxicities: 1 pt on RA (Grade [G]3 confusion) and 6 pts on RB2 (G5 immune effector cell-associated neurotoxicity syndrome [ICANS]; G4 cytokine release syndrome [CRS]; G3 CRS; G3 ICANS; G3 nervous system disorder and G2 infusion-related reaction). MTD has not been reached; dose escalation is ongoing. 53 pts with epNEC have been treated (ongoing in 14). TRAEs (any/G≥3): 92/17%. The most common TRAEs (any/G≥3) were: CRS (72/4%); pyrexia (26/0%); dysgeusia (19/0%) and fatigue (17/0%); there were no Tx discontinuations due to TRAEs. In the efficacy population, there were 46 pts with epNEC (gastrointestinal: n=23; genitourinary: n=16; unknown origin: n=7). ORR/DCR was 22/41%. In pts who received clinically active doses of BI 764532 (n=36), ORR/DCR was 28/47%. BI 764532 showed clinically manageable tolerability; MTD has not been reached. Promising efficacy was observed in pts with epNEC. The study is ongoing.

DLL3 is expressed on small-cell lung cancer (SCLC) tumors and neuroendocrine carcinomas (NECs). NCT04429087 is an ongoing phase I dose-escalation trial of BI 764532, a DLL3/CD3 IgG-like T-cell engager, in pts with locally advanced/metastatic DLL3+ SCLC, extrapulmonary (ep) NEC or large cell NEC of the lung (LCNEC). Here we focus on Asian pts. BI 764532 was given iv in 3 regimens: Regimen A (RA; fixed dose q3w); RB1 (fixed dose qw); RB2 (step-in doses followed by a fixed dose). Treatment (Tx) continued until progressive disease, unacceptable toxicity, other withdrawal criteria or max Tx duration (36 mo). Main objective: MTD and/or recommended dose for expansion. Other objectives: safety, tolerability, PK, PD, and preliminary efficacy (RECIST v1.1). As of 26 March 2023, 107 pts received ≥1 dose (≥ 0.03 μg/kg) of BI 764532 (RA n=24; RB1 n=10; RB2 n=73). 20 pts were Asian (Japanese n=18). Baseline characteristics (all/Asian): male: 57/60%; median age. years (range): 60 (32–79)/65.5 (35–77); ECOG PS 0: 26/60%; ≥2 prior lines of Tx: 68/45%. Tumor type (all/Asian): SCLC 53/5%, epNEC 38/95%, LCNEC 8/0%. Overall DLTs: 1 pt on RA (G3 confusion) and 4 pts on RB2 (G4 cytokine release syndrome [CRS]; G3 CRS; G3 nervous system disorder and G2 infusion-related reaction). MTD has not been reached. Dose escalation is ongoing. One DLT occurred in an Asian pt (G3 CRS). TRAEs were similar in all pts and Asian pts (Table). Tx discontinuations due to TRAEs (all/Asian): 4/0%. Overall, ORR in pts who received clinically active doses of BI 764532 (n=71) was 25% (SCLC 26%; epNEC 19%; LCNEC 60%). In Asian pts who received clinically active doses (n=13), ORR was 23%. As of 21 April 2023, all 3 responding Asian pts were ongoing Tx (duration: 392, 121, 35 days).Table: 75MOAll pts (N=107)Asian pts (n=20)SafetyAny gradeGrade ≥3Any gradeGrade ≥3≥1 TRAE, n (%)92 (86)29 (27)19 (95)2 (10)CRS63 (59)2 (2)17 (85)1 (5)Decreased lymphocytes21 (20)17 (16)――Dysgeusia21 (20)0 (0)3 (15)0 (0)Asthenia20 (19)1 (<1)――Pyrexia19 (18)0 (0)4 (20)0 (0)Efficacy (clinically active doses)All pts (n=71)*Asian pts (n=13)*PR, n (%)18 (25)3 (23)SD, n (%)19 (27)5 (38)PD, n (%)25 (35)4 (31)DCR, n (%)37 (52)8 (62)Not evaluable†, n (%)9 (13)1 (8)*Efficacy population: ≥1 post-baseline tumor assessment (P-BTA) or permanently discontinued before first P-BTA; responses evaluated per RECIST v1.1 criteria; †Discontinued before first P-BTATRAEs occurring in ≥15% of pts are listed Open table in a new tab *Efficacy population: ≥1 post-baseline tumor assessment (P-BTA) or permanently discontinued before first P-BTA; responses evaluated per RECIST v1.1 criteria; †Discontinued before first P-BTA TRAEs occurring in ≥15% of pts are listed BI 764532 showed manageable tolerability; MTD has not been reached. Promising efficacy was observed in SCLC, epNEC and LCNEC. The tolerability and efficacy of BI 764532 was similar in Asian pts and the overall population.

The inhibitory Notch ligand, DLL3, is highly expressed on the cell surface of small cell lung cancer (SCLC) and neuroendocrine carcinomas (NECs) and is a promising drug target. BI 764532 is a DLL3/CD3 IgG-like T cell engager that has shown potent preclinical anti-tumor activity in DLL3+ cells and xenograft models. NCT04429087 is an ongoing phase I, first-in-human, open-label, dose-escalation trial of BI 764532 in adults with locally advanced/metastatic DLL3+ (confirmed centrally) SCLC, NEC or small cell carcinoma of any other origin (grouped as NEC), or large cell NEC.

Poorly differentiated neuroendocrine carcinomas such as small-cell lung cancer (SCLC) have poor survival and high relapse rates. DLL3 is found on these carcinomas and has become a target of increasing interest in recent years. The bispecific DLL3/CD3 T-cell engager BI 764532 has been shown to induce complete tumor regression in a human T cell-engrafted mouse model. Here, we describe the study design of a first-in-human, phase I, multicenter, open-label, non-randomized, dose-escalation study in patients with SCLC or other DLL3-positive neuroendocrine carcinomas. The study will determine the maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics and preliminary efficacy of BI 764532 monotherapy.