The combination of obrixtamig and standard-of-care platinum-doublet chemotherapy proved to be efficacious and tolerable when used as first-line treatment in patients with DLL3-positive neuroendocrine carcinomas, according to data from the phase 1 DAREON-7 study (NCT06132113).1
The findings, which were shared during the 2025 NANETS Symposium indicated that no dose-limiting toxicities (DLTs) were reported during the maximum tolerated dose (MTD) evaluation period. Grade 3 or higher treatment-emergent adverse effects (TEAEs) were reported in 92% of patients (n = 25); grade 3 or higher treatment-related adverse effects (TRAEs) attributed to chemotherapy were observed in 88% of patients.
The most common grade 3 or higher TEAE was neutropenia (80%), followed by anemia (40%), thrombocytopenia (28%), decreased white blood cell (WBC) count (16%), asthenia (12%), and hypokalemia (12%). Grade 3 or higher TRAEs attributed to chemotherapy also included neutropenia, anemia, thrombocytopenia, decreased WBC count, asthenia, and hypokalemia, and were experienced by 72%, 40%, 28%, 16%, 4%, and 4% of patients, respectively.
DLL3-Targeted Therapy Shows Early Promise in Frontline NEC
- Obrixtamig combined with platinum-doublet chemotherapy demonstrated encouraging first-line activity in DLL3-positive neuroendocrine carcinomas, with a 72% objective response rate.
- No dose-limiting toxicities were observed, and the safety profile was consistent with expectations for platinum-based chemotherapy and T-cell–engaging therapies.
- Responses were durable, with meaningful tumor shrinkage in most patients and ongoing benefit in nearly half at the time of data cutoff.
In terms of efficacy, the regimen elicited an objective response rate (ORR) of 72% (95% CI, 52%-86%), which was comprised entirely of partial responses (PRs). As of August 28, 2025, a total of 18 patients had a confirmed PR. The disease control rate achieved with the combination was 88% (95% CI, 70%-96%). Sixteen percent of patients had stable disease, and 12% experienced disease progression. As of the data cutoff date, 11 patients were still receiving treatment.
The median duration of response (DOR) was 8.8 months (95% CI, 5.4-not calculable), and the DOR rate at 6 months was 62% (95% CI, 35%-89%). Moreover, the median progression-free survival (PFS) with the combination was 7.6 months (95% CI, 5.8-9.5); the 6-month PFS rate was 64% (95% CI, 44%-84%). Out of 25 evaluable patients, 23 had observable tumor shrinkage in target lesions.
“In patients with epNEC [extrapulmonary neuroendocrine carcinoma] and LCNEC [large cell neuroendocrine carcinoma], encouraging efficacy was observed in the [first-line] setting, warranting prioritized development of obrixtamig in combination with platinum-doublet chemotherapy regimens in these settings of high unmet need,” Aman Chauhan, MD, leader of the Neuroendocrine Tumor Program in the Department of Internal Medicine at Sylvester Comprehensive Cancer Center, University of Miami, in Miami, Florida, and colleagues, wrote in a poster on the data.
What was the design of the DAREON-7 trial?
The open-label, dose-escalation/-expansion study enrolled patients with locally advanced or metastatic DLL3-positive epNEC, LCNEC of the lung (LCNEC-L), or NEC of unknown primary site. Patients needed to be eligible to continue carboplatin plus etoposide as frontline treatment, and they were required to have acceptable liver, bone marrow, and renal function. If they previously received DLL3-targeting T-cell engagers and cell therapies; had Merkel cell carcinoma, medullary thyroid carcinoma, or grade 3 NEC; or immunodeficiency that called for systemic steroids or immunosuppressive therapy, they were excluded.
In the dose-escalation portion of the research, patients received step-up dosing of obrixtamig followed by the target dose at the following levels: 10 mg, 30 mg, or 60 mg; they also received carboplatin plus etoposide in accordance with the label. The induction period consisted of cycles 1 to 6; in this period, patients received obrixtamig plus chemotherapy. One cycle of platinum-doublet chemotherapy was completed before the treatment period. In the maintenance period, which consisted of cycle 7 and beyond, patients were given single-agent obrixtamig every 3 weeks. Treatment continued until progressive disease or other termination criteria were met.
The primary end point of the study was the occurrence of DLTs, and a key secondary end point was the occurrence of DLTs and adverse effects (AEs) during the on-treatment period. Additional end points of interest included investigator-assessed efficacy of obrixtamig plus chemotherapy in the form of ORR, DOR, and PFS by RECIST 1.1 criteria.
What did the patient population look like in the DAREON-7 trial of obrixtamig?
As of the data cutoff date, a total of 25 patients were enrolled in the dose-escalation portion of the research, and all received at least 1 dose of obrixtamig. The median patient age was 67 years (range, 42-79), and 44.0% of patients were male. Moreover, 32% patients were Asian, 4% were Black, and 48% were White; this information was missing for 16% of patients. In terms of ECOG performance status, 76% had a status of 0, and 24% had a status of 1.
Most patients had epNEC (88%); this was gastrointestinal for 80% of patients, genitourinary for 4% of patients, and other for 4% of patients. Moreover, 4% of patients had LCNEC-L and 8% had NEC of unknown primary site. Lastly, the median number of obrixtamig cycles received was 8, with a range of 2 to 17 cycles; median time of exposure to the drug was 6.9 months (range, 1.4-12.0).
What other safety data were presented with regard to obrixtamig plus chemotherapy in this population?
AEs related to obrixtamig of any grade occurred in 92% of patients; these effects were grade 3 or higher for 12% of patients. The most common obrixtamig-related AEs included asthenia (any grade, 32%; grade ≥ 3, 8%), neutropenia (12%; 8%), increased alanine aminotransferase levels (8%; 4%), increased aspartate aminotransferase (AST) levels (4%; 4%), and thrombocytopenia (4%; 4%).
Cytokine release syndrome was reported as an obrixtamig-related toxicity of special interest. Most events were grade 1 (56%; n = 14); 16% of events (n = 4) were grade 2, and no grade 3 or higher events were observed. “Obrixtamig-related neurologic toxicity was rare,” the authors wrote. Only 1 patient experienced this. Other AEs of special interest that were related to obrixtamig were increased AST levels (n = 1; grade 3) and infusion-related reaction (n = 1; grade 1).
What is the significance of these early data from DAREON-7?
The authors concluded that the safety data for the regimen were aligned with expectations, and no new AEswere reported. “Significant tumor shrinkage was seen in nearly three-quarters of patients, and most of these patients are still benefiting,” they wrote. “These results are promising and warrant further research.”
Disclosures: Chauhan reported advisory board work for Boehringer Ingelheim, Crinetics Pharmaceuticals, Curium Pharma, Exelixis, and Novartis. He also disclosed receipt of institutional funding from Bristol Myers Squibb, Clovis Oncology, Merck KGaA, Nano Therapeutics, and TerSera. Speaker, consultant, or advisor fees were received from Advanced Accelerator Applications/Novartis, Crinetics Pharmaceuticals, Curium Pharma, Exelixis, and TerSera. He also disclosed stocks or ownership in Elicio Therapeutics and Revolution Medicine, and having received travel, accommodations, or expense support from Entrinsic Health Solutions.
Reference
Chauhan A, Mishima S, Custodio A, et al. DAREON-7: Phase I open-label dose-escalation/-expansion study of first-line obrixtamig (BI 764532) plus platinum-doublet chemotherapy in patients with DLL3-positive neuroendocrine carcinomas. Presented at: 2025 NANETS Symposium; October 23-25, 2025; Austin, TX. Poster #C-8. https://pro.boehringer-ingelheim.com/events/inoncology-congresses/bipdf/obrixtamig-dareon7-poster-nanets-congress
