ASCO 2025: Novel Bispecific T-Cell Engager Targeting DLL3 Offers Hope for Refractory Neuroendocrine Carcinomas

In a presentation at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, Jaume Capdevila, MD, PhD, senior medical oncologist at Vall d'Hebron University Hospital in Barcelona, Spain, shared data on obrixtamig (BI 764532; Boehringer Ingelheim International), a DLL3/CD3 bispecific T-cell engager, for the treatment of extrapulmonary neuroendocrine carcinomas (epNECs)—a rare and aggressive tumor type with limited treatment options and historically poor outcomes.

During the oral session, Capdevila highlighted results from a phase 1 study demonstrating obrixtamig’s marked efficacy in patients with high DLL3 expression, with an objective response rate (ORR) of 40% and a disease control rate (DCR) of nearly 67%, compared to significantly lower rates in patients with low DLL3 expression. These findings support DLL3 as a clinically meaningful biomarker and position obrixtamig as a potential precision medicine approach for patients with R/R epNECs.

In this interview with Pharmacy Times^®, Capdevila discusses the clinical implications of these study findings, safety considerations, and ongoing trials exploring obrixtamig as both a monotherapy and in combination regimens.

Pharmacy Times: Could you summarize the key findings from the data you are presenting at ASCO on obrixtamig for the treatment of epNECs with high DLL3 expression?

Jaume Capdevila, MD, PhD, is a senior medical oncologist at Vall d'Hebron University Hospital in Barcelona, Spain.

Jaume Capdevila, MD, PhD: In our phase 1 dose-escalation study (NCT04429087), obrixtamig, a DLL3/CD3 IgG-like T-cell engager, demonstrated promising efficacy in patients with previously treated epNECs with high DLL3 expression. The ORR was 40% (95% CI: 24.6-57.7) in patients with high DLL3 expression compared to 3.3% (95% CI: 0.6-16.7) in those with low DLL3 expression. The median duration of response (DOR) was 7.9 months (95% CI: 6.2-not calculable) for high DLL3 expressors vs 2.8 months for low expressors. The DCR was 66.7% (95% CI: 48.8-80.8) in high DLL3 expressors compared to 26.7% (95% CI: 14.2-44.4) in low expressors. This is the first time that a cut-off for DLL3 expression has been defined in epNECs and correlated with higher efficacy. The 40% ORR in high DLL3 expressors underscores obrixtamig’s potential to produce effective and durable responses in a population with limited treatment options and poor prognosis due to the aggressive nature of epNECs.

The ongoing phase 2 DAREON-5 trial (NCT05882058) is further evaluating obrixtamig monotherapy in patients with relapsed/refractory (R/R) DLL3-high epNECs, as well as small-cell lung cancer and large-cell neuroendocrine carcinoma of the lung. This trial includes patients with epNECs who have received at least one prior platinum-based regimen, with high DLL3 expression confirmed via central assessment in part 2 of the study. The primary end point is ORR, with secondary end points including DOR, progression-free survival, DCR, overall survival (OS), and health-related quality of life.

Pharmacy Times: How does DLL3 expression influence patient selection and treatment response in epNECs?

Photomicrograph of histological slide showing neuroendocrine tumor. Image Credit: © Saiful52 - stock.adobe.com

Capdevila: DLL3 is a protein highly expressed in up to 77% of neuroendocrine carcinomas, including epNECs, but minimally expressed in normal tissues, making it an ideal therapeutic target for precision medicine. High DLL3 expression is a critical biomarker for identifying patients likely to respond to obrixtamig. Our phase 1 data showed a stark contrast in efficacy based on DLL3 expression levels, with a 40% ORR and 66.7% DCR in high DLL3 expressors vs 3.3% ORR and 26.7% DCR in low expressors. The prolonged DOR (7.9 months) in high DLL3 expressors further supports the importance of DLL3 as a determinant of treatment success.

Pharmacy Times: What are the most important safety considerations when managing patients on obrixtamig?

Capdevila: One of the primary safety concerns with obrixtamig is cytokine release syndrome (CRS), which occurred in 63% of patients, although grade 3 or higher CRS was seen in only 3%. Notably, most CRS events occurred after the first dose. Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 7% of patients, all of which were grade 1 or 2. Other common adverse events (AEs) included fatigue (37%), dysgeusia (36%), nausea (23%), and vomiting (21%). Despite these events, only 4% of patients discontinued treatment due to AEs.

Clinicians should closely monitor for CRS and ICANS, particularly following the initial dose, and should be prepared to manage these events using standardized protocols, such as tocilizumab (Actemra; Genentech) for CRS. Supportive care measures are important for managing fatigue and gastrointestinal symptoms. Additionally, regular monitoring for rare but serious complications—such as respiratory failure or pneumonitis—is recommended, especially in patients with existing comorbidities.

Pharmacy Times: How do the toxicity profiles observed with obrixtamig compare to other treatments for epNECs, and what monitoring strategies are recommended?

Capdevila: Second-line regimens after progression to platinum-etoposide (eg, folinic acid, fluorouracil, and irinotecan hydrochloride [FOLFIRI] and folinic acid, fluorouracil, and oxaliplatin [FOLFOX]): are commonly used for epNECs and are associated with significant toxicities, including neutropenia, thrombocytopenia, nausea, vomiting, and neuropathy. FOLFIRI, a preferred second-line therapy for platinum-refractory epNECs, has a lower ORR (around 10-15% in real-world data) compared to obrixtamig’s 40% in high DLL3 expressors, and its toxicity profile may includes hematologic and gastrointestinal effects. Obrixtamig’s CRS and ICANS are unique to T-cell engagers but appear manageable with early intervention.

Immunotherapy (eg, ipilimumab/nivolumab) have shown modest activity (ORR, 10-15% in real-world datasets), with toxicities including immune-related AEs (irAEs) such as colitis, hepatitis, and pneumonitis. Obrixtamig’s CRS and ICANS differ from irAEs but require similar vigilant monitoring.

Recommended Monitoring Strategies:

• CRS monitoring: Assess patients for fever, hypotension, and hypoxia within the first 24 to 48 hours post-infusion, especially after the initial dose. Have tocilizumab and corticosteroids readily available.
• Neurotoxicity monitoring: Regular neurological assessments for signs of ICANS (eg, confusion, seizures) using tools like the Immune effector Cell-associated Encephalopathy (ICE) score.
• General AE management: Monitor for fatigue, gastrointestinal symptoms, and rare severe events like respiratory failure through regular clinical evaluations and imaging (eg, chest X-rays for pneumonitis).
• Laboratory monitoring: Routine bloodwork to assess liver, kidney, and hematologic function, given the potential for systemic AEs.
• Patient education: Inform patients about early signs of CRS (eg, fever, chills) and ICANS (eg, confusion, headache) to ensure prompt reporting.

Pharmacy Times: Are there any ongoing studies evaluating obrixtamig in combination with other agents, such as immunotherapies or chemotherapy in epNECs?

Capdevila: The DAREON-7 trial (NCT06132113) is an ongoing phase 1, open-label, dose-escalation, and dose-expansion study evaluating obrixtamig in combination with first-line platinum-based chemotherapy (carboplatin/etoposide or cisplatin/etoposide) for patients with DLL3-positive epNECs. The trial aims to determine the maximum tolerated dose, recommended dose for expansion/recommended phase 2 dose, and assess the safety and efficacy of this combination therapy. Eligible patients include those with no prior systemic treatment for locally advanced or metastatic DLL3+ epNEC (except possibly 1 cycle of platinum/etoposide) and at least one measurable lesion per Response Evaluation Criteria in Solid Tumors v1.1. The study is actively recruiting.

Pharmacy Times: Do you have any guidance for clinicians on the practical implications of these data on the efficacy of obrixtamig for epNECs with high DLL3 expression in clinical practice for this patient population?

Capdevila: For advanced epNECs, first-line therapy typically involves platinum-based regimens (eg, cisplatin/etoposide), with response rates of 31% to 67% but median OS of 5.8 to 19 months. Second-line options such as FOLFIRI or topotecan have limited efficacy, and checkpoint inhibitors have shown disappointing results. Given its promising ORR and DCR in high DLL3-expressing epNECs, obrixtamig could be positioned as a preferred second-line therapy for patients with confirmed DLL3 high expression (≥50% tumor cells positive for IHC) who progress after platinum-based chemotherapy. The ongoing phase 2 DAREON-5 trial (NCT05882058) will further clarify its role, with ORR as the primary end point.