Obrixtamig Shows Activity in First-Line epNEC, Regardless of DLL3 Expression Level

Adding obrixtamig (BI 764532), an IgG-like T-cell engager that targets delta-like ligand 3 (DLL3), to first-line platinum and etoposide chemotherapy produced high and durable response rates with a manageable safety profile in patients with DLL3-positive extrapulmonary neuroendocrine carcinoma (epNEC), regardless of how strongly their tumors expressed DLL3.

Activity trended higher in tumors with high DLL3 expression, according to an analysis of the phase 1b DAREON-7 trial (NCT06132113) presented by Aman Chauhan, MD, associate professor of medicine at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, 2026 North American Neuroendocrine Tumor Society (NANETS) Symposium.¹

Responses to Obrixtamig Seen Across DLL3 Subgroups

Of 44 patients who received obrixtamig with standard-of-care chemotherapy, 24 (54.5%) had DLL3-high tumors, defined as moderate to strong staining in at least 50% of tumor cells, and 20 (45.5%) had DLL3-low tumors, with staining in fewer than 50% of tumor cells.

The objective response rate (ORR) was 77.3% in the overall population, 65.0% in the DLL3-low subgroup, and 87.5% in the DLL3-high subgroup. All responses were partial responses. Disease control was achieved in about 9 of every 10 patients overall, and only 1 patient in the DLL3-high group had progressive disease as best response.

“These are dream-come-true waterfall plots for any clinical trial, right?” Chauhan commented.

Responses also appeared durable. The median duration of response was 12.5 months in the overall population, and about half of responders remained in response at 12 months. In the DLL3-high subgroup, the median duration of response had not yet been reached. Chauhan noted that durability of this kind is well beyond what is historically seen with platinum doublet chemotherapy alone in this disease.

Progression-free survival (PFS) data are still maturing, with a median follow-up of 11.6 months. Median PFS was 7.7 months overall, 7.6 months in the DLL3-low subgroup, and 9.5 months in the DLL3-high subgroup. At 12 months, 35% of all patients and 47% of those with DLL3-high tumors were alive and free of progression.

Chauhan put that figure in historical context. Not long ago, clinicians counseled patients with metastatic epNEC to expect survival of around 1 year, and now roughly one-third of patients treated with the combination remain progression free at the 1-year mark. “It’s a huge advancement in [the] epNEC field,” Chauhan said.

A case study illustrated the depth of response possible. A 63-year-old woman with a DLL3-high epNEC of vaginal origin and multiple liver metastases achieved a partial response after 6 cycles of induction with obrixtamig plus carboplatin and etoposide. Her liver lesions continued to shrink on obrixtamig maintenance, and she reached a complete response that was later confirmed. At last follow-up she remained in complete response and had been on treatment for nearly 2 years.

Safety With Obrixtamig Was Consistent Regardless of DLL3 Expression

A key question was whether higher DLL3 expression would lead to more toxicity. It did not. “Fortunately, not,” Chauhan said, describing safety signals that were broadly similar across both subgroups.

Cytokine release syndrome (CRS), the hallmark toxicity of T-cell engagers, was the most common obrixtamig-related adverse event (AE), occurring in about three-quarters of patients overall and more often in the DLL3-high subgroup. All CRS events were grade 1 or 2, with no grade 3 or higher CRS reported in either group. Chauhan described these events as mostly fevers and chills that were well tolerated, and speculated that the combination with chemotherapy may help blunt CRS severity.

Obrixtamig-related immune effector cell-associated neurotoxicity syndrome (ICANS) was infrequent, occurring in 2 patients, and both events were grade 1.

Most grade 3 or higher AEs were attributed to the platinum doublet, consistent with the known profile of chemotherapy. Grade 3 or higher obrixtamig-related AEs occurred in fewer than 1 in 5 patients. One grade 5 AE, due to disease progression, was not related to obrixtamig.

“So, right off the bat, well tolerated in both DLL3-high and DLL3-low expressors,” Chauhan said.

DAREON-7 Trial Design

DAREON-7 is an international, open-label phase 1 dose-escalation and dose-expansion study. Eligible patients had locally advanced or metastatic, previously untreated epNEC, large cell neuroendocrine carcinoma of the lung, or neuroendocrine carcinoma of unknown primary site. All tumors had to be DLL3 positive by central testing, and patients could not have received prior DLL3-targeted T-cell engagers or cell therapies.

Part A explored obrixtamig doses of 10, 30, and 60 mg, and part B expanded at the recommended phase 2 dose of 60 mg. Because of the aggressive nature of the disease, patients received 1 cycle of chemotherapy alone, which also allowed time for DLL3 testing. They then received up to 5 cycles of obrixtamig plus chemotherapy, followed by obrixtamig maintenance every 3 weeks. The primary end point was occurrence of dose-limiting toxicities, and secondary end points included AEs, ORR, and duration of response. PFS was a further end point.

Of 83 patients screened, 72 underwent DLL3 testing and 57 (79.2%) were DLL3 positive. Baseline characteristics were similar between the DLL3-high and DLL3-low subgroups. The median age was 64.5 years, roughly three-quarters of patients had liver metastases, and the large majority had epNEC, most often of gastroenteropancreatic origin.

Phase 3 DAREON-NEC-1 trial Trial Now Enrolling

The investigators concluded that the findings provide a strong rationale for the ongoing phase 3 DAREON-NEC-1 trial (NCT07544654), which is comparing obrixtamig plus carboplatin and etoposide with standard chemotherapy as first-line treatment for patients with DLL3-positive epNEC.⁴ Longer follow-up of DAREON-7 is needed to further characterize duration of response in the DLL3-high subgroup.

Chauhan described DAREON-NEC-1 as likely the largest study ever conducted in epNEC and urged clinicians to refer eligible patients.

“I would encourage people, if they have a patient, to consider [enrolling them in] this important trial, because we have not had an FDA approval for this disease ever,” Chauhan said.

References

1. Chauhan A, Mishima S, Custodio A, et al. Outcomes with first-line obrixtamig plus standard of care in epNEC by DLL3 expression status: phase Ib DAREON-7 study. Presented at: 2026 North American Neuroendocrine Tumor Society (NANETS) Symposium; November 5-7, 2026; Las Vegas, NV. Abstract C-40.

2. Dasari A, Mehta K, Byers LA, Sorbye H, Yao JC. Comparative study of lung and extrapulmonary poorly differentiated neuroendocrine carcinomas: a SEER database analysis of 162,983 cases. Cancer. 2018;124(4):807-815. doi:10.1002/cncr.31124

3. Wermke M, Gambardella V, Kuboki Y, et al. 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. J Clin Oncol. 2025;43(27):3021-3031. doi:10.1200/JCO-25-00363

4. A study in people with advanced extrapulmonary neuroendocrine cancer (epNEC) to compare obrixtamig plus carboplatin/etoposide treatment with standard chemotherapy (DAREON-NEC-1). ClinicalTrials.gov identifier: NCT07544654. Accessed November 6, 2026. https://clinicaltrials.gov/study/NCT07544654