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Obrixtamig Leverages DLL3 Targeting to Offer a Potential Treatment Option in Extrapulmonary Neuroendocrine Carcinoma

Supplements and Featured Publications, Broadening Awareness Around DLL3-Directed Therapies in Small Cell Lung Cancer and Neuroendocrine Carcinomas, Volume 1, Issue 1

Balazs Halmos, MD, discusses the DLL3-targeted BiTE obrixtamig for the treatment of patients with extrapulmonary neuroendocrine carcinoma.

Balazs Halmos, MD

Balazs Halmos, MD

After demonstrating response rates well above those of chemotherapy and a manageable safety profile in patients with extrapulmonary neuroendocrine carcinoma (epNEC) in a phase 1 study (NCT04429087), obrixtamig (BI 764532) is being further evaluated in the phase 2 DAREON-5 trial (NCT05882058) and could soon offer a much-needed effective treatment option for these patients, according to Balazs Halmos, MD.1

During the 2025 ASCO Annual Meeting, updated data from the phase 1 trial showed that patients who received the DLL3-targeted bispecific T-cell engager (BiTE; n = 60) achieved a confirmed overall response rate (ORR) of 22% (95% CI, 13%-34%) and a disease control rate (DCR) of 47% (95% CI, 35%-59%). Notably, those with DLL3-high disease (n = 30) achieved a confirmed ORR of 40% (95% CI, 25%-58%) and a DCR of 67% (95% CI, 49%-81%).

“[Data from] this phase 1 study identified activity, identified the biomarker enriching for that activity, and showed a reasonable tolerance of this drug,” Halmos, said in an interview with OncLive®.

Halmos is the associate director of clinical science and a professor in the Departments of Oncology and Medicine at Montefiore Einstein Comprehensive Cancer Center in the Bronx, New York. In the interview, he discussed targeting DLL3 in patients with epNEC, prior data with obrixtamig, and the design of DAREON-5.

OncLive: Why is it important to differentiate neuroendocrine tumors from neuroendocrine carcinomas?

Halmos: This distinction is critical as neuroendocrine tumors [such as] lung carcinoid [tumors], low-grade gastrointestinal [tumors], or neuroendocrine neoplasms, tend to be indolent, and we have an expanding range of new treatments that we can offer to such patients. Patients with neuroendocrine carcinomas are at the aggressive end of the differentiation spectrum. Pathologically, these are cases similar to small cell lung cancer [SCLC] or large cell neuroendocrine carcinoma with very poor differentiation, a high mitotic rate, and a high percentage of Ki67-positive cells.

[Neuroendocrine carcinomas] are not a common entity, [and] treatment is poorly defined. We tend to follow treatment patterns similar to SCLC, [including] chemotherapy and immunotherapy for patients with metastatic disease. But there are poor outcomes and a limited number of choices. Recognizing this and building upon new treatment options for these patients is important.

What evidence supports DLL3 as an actionable target in epNEC?

DLL3 is frequently expressed in [patients with] SCLC and neuroendocrine carcinoma in general. This protein is intricately involved in modulating Notch signaling, and this is key for the development of neuroendocrine differentiation and the behavior of small cell type carcinomas. The frequency of expression is as high as 95% in [patients with] SCLC. As a result, many trials are not necessarily looking at expression specifically, as almost all patients will have it. The expression is more variable but still commonly high in [patients with] neuroendocrine carcinoma, [ranging from approximately] 70% to 90% depending on what subsite you’re talking about. The expression is much lower for neuroendocrine tumors [as these are] more well differentiated tumor types.

What is the mechanism of action of obrixtamig?

[Obrixtamig] is a normalized IgG-like CD3/DLL3 BiTE. It binds to DLL3-positive cancer cells and cytotoxic T cells with its two arms, thereby creating what we call the cytolytic synapse. The cytolytic synapse can then lead to tumor killing but also to adverse effects [AEs] similar to CAR T-cell [agents], including cytokine release syndrome [CRS] and immune effector cell–associated neurotoxicity syndrome [ICANS].

What prior research set the stage for DAREON-5?

A decade of fantastic research from many groups and excellent sponsors [has led to this moment where we] understand small cell neuroendocrine carcinoma and DLL3 biology. There was also prior work on different ways to target DLL3, ultimately yielding a number of exciting biomolecules. Some of these have been more developed and one of them is available for the treatment of patients with SCLC.

Identifying that the same molecules can have treatment relevance for patients with epNEC [was also important]. Prior clinical data with obrixtamig in this rare subset of patients have shown activity and reasonable tolerance, setting the stage for focused studies exploring this agent [in patients with] epNEC.

What was your interpretation of the data from the phase 1 trial of obrixtamig and how do they support DAREON-5?

This study was a hidden gem at ASCO and was a nice presentation on the dose-finding [portion of the] study with obrixtamig. Looking at the activity of obrixtamig, the ORR was 22%, which is somewhat on the modest side. But when the investigators looked at patients with DLL3-high vs -low expression, defined at least 50% of the cells positive for DLL3 by immunohistochemistry vs less than 50%, [respectively], the ORR [in the DLL3-high group] was 40% and the median duration of response [DOR] was 7.9 months [95% CI, 6.2-not estimable (NE)]. This compared favorably with the DLL3-low cohort [n = 30], which had an ORR of 3% [95% CI, 1%-17%] and a median DOR of 2.8 months [95% CI, NE-NE].

Are there any safety concerns with obrixtamig?

This class of agents, including CAR T cells and BiTEs, have similar AE profiles. They yield a high frequency of CRS and neurological events such as ICANS. These tend to [occur] mostly in the first couple of weeks of treatment. Fortunately, in this trial, it did seem that although the frequency of any-grade CRS was high at 65%, very few of these were high-grade events that called for interventions. The same goes for ICANS, which occurred in 13% of patients but was mostly grade 1 or 2.

We’ve learned as a community how to identify patients with these AEs. We have grading and treatment guidelines, as well as algorithms for the management of these AEs. At this point, I do not believe that they are of particular concern. They are expected and manageable AEs associated with these molecules. The continued development of obrixtamig seems to be reasonable and hopefully it will ultimately be used for the treatment of our patients in clinic.

What questions are DAREON-5 designed to answer?

DAREON-5 is being reshaped based on the current understanding of which patients obrixtamig could be the most effective in. In its present form, the study will be enrolling patients with DLL3-high epNEC. It is identifying a patient pool where there might be a clinical niche for a drug that’s needed and one with a higher level of activity that’s been noticed in prior trials.

The primary end point is ORR. Secondary end points include progression-free survival, overall survival, and safety.

There are a lot of questions related to AEs that we need to answer. Are inpatient management [and] monitoring critical for the first couple of doses? Can patients be managed in the outpatient setting? [In terms of] the biomarker [of DLL3], I’m certain that the study team will continue to invest [in learning more from] this high-risk cohort of patients. Can we learn even more about the right patient profiles who could benefit the most from this exciting new drug?

How do you see obrixtamig positioning itself in the treatment landscape and are there other investigational agents in development that could fill the same role?

Our hope is that we’ll have more [treatments] for our patients with epNEC who presently have limited options and poor outcomes. It will be welcome news to have a new agent with significant activity. Having seen how other DLL3-targeted agents are transforming the SCLC treatment landscape, I’m hopeful that we’ll see exciting data with obrixtamig as well. If that is the case and there’s sufficient activity for its approval, then this platform can be expanded to combination and maintenance studies to find even more of a role for patients with epNEC and maybe some other cohorts as well.

[In terms of other agents], whenever we see one successful drug, many times we see a lot of other successful drugs follow in its footsteps. There are a wide range of DLL3-targeted drugs, not just BiTEs but antibody-drug conjugates and other molecules in development. The next couple of years will be exciting to understand how this biology and this class of agents will shape the treatment landscape in oncology.

What is important to know to not miss the window for enrollment for DAREON-5?

Patients [will need] to be identified correctly and new grading classification systems are important to be aware of. We need to recognize that despite [this being] a rare disease, there are efforts ongoing to make a difference, such as DAREON-5. I presume it will be available at a [small] number of sites around the US, so it might be one of those trials that patients might need to travel for. But many of these new studies have resources built in that make it feasible for a patient who is farther away from the site to still participate.

It’s also important to be aware that the trial will be selective. [Investigators] will not be enrolling every patient with SCLC or epNEC, because [the patient must have a] specific pathology. I’m sure there will be some patients who would love to qualify but who ultimately might not be able to. Hopefully in the future, the horizon will be expanding for them with other clinical trials.

Reference

Capdevila J, Gambardella V, Kuboki Y, et al. Efficacy and safety of the DLL3/CD3 T-cell engager obrixtamig in patients with extrapulmonary neuroendocrine carcinomas with high or low DLL3 expression: results from an ongoing phase I trial. J Clin Oncol. 2025;43(suppl 16):3004. doi:10.1200/JCO.2025.43.16_suppl.3004


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