Targeting DLL3 in Rare Neuroendocrine Carcinoma: Early Results and Future Direction

Introduction

EpNECs are considered rare and are often associated with a poor prognosis, with up to 85% of patients presenting with advanced, unresectable disease.¹ First-line platinum-based chemotherapy is the only standard-of-care treatment. Disease progression typically occurs within months of receiving first-line chemotherapy, with a median progression-free survival of around 4−9 months, and a median overall survival of around 5−16 months.^2-6 Currently, there is no standard second-line chemotherapy, with limited trials of various regimens showing ORRs of ≤25%.⁷

Around 80% of epNECs express DLL3, a Notch signaling pathway inhibitor involved principally in embryonic development, but also in tumorigenesis.⁸ Because DLL3 is minimally expressed in normal tissue, it is a target for investigational treatment strategies in epNEC.⁹

Obrixtamig, an IgG-like bispecific (DLL3/CD3) T cell engager, redirects a patient’s T cells to destroy DLL3 positive cancer cells. It acts by binding both DLL3 and CD3, bringing T cells into close proximity with DLL3-positive cancer cells to form a major histocompatibility complex-independent immune synapse, leading to T cell-induced lysis of the DLL3 positive cancer cells.^10,11 Obrixtamig, which is an investigational agent not approved outside of clinical trial use, gained U.S. FDA orphan drug¹² and fast track¹³ designations for epNEC in 2023, with orphan drug designation by the EMA in 2024.¹⁴

Efficacy and Safety of Obrixtamig in a Phase I Trial

At ASCO 2025, Capdevila presented an ongoing, Phase I dose-escalation trial of obrixtamig.¹⁵ The study includes patients with DLL3-positive epNEC who failed, or were ineligible for, standard treatment, and have adequate liver, bone marrow, and renal function. Intravenous obrixtamig (active dose range 90−1,080 µg/kg) is administered weekly or every 3 weeks after the first three weekly injections until disease progression or unacceptable toxicity. It is administered in a step-up dosing strategy to mitigate immune-mediated toxicities. Primary endpoints are maximum tolerated dose, and dose-limiting toxicities. Secondary endpoints include ORR, and pharmacokinetic parameters.^15,16

Of the 60 patients with epNEC presented here, 30 were ‘DLL3^high‘ (≥50% tumor cells staining at moderate and/or strong intensity) and 30 were ‘DLL3^low‘ (<50% tumor cells staining at moderate and/or strong intensity). Median age was similar between the subgroups (DLL3^high: 69 [range 36−81] years; DLL3^low: 61 [range 33−77] years); 57% in the DLL3^high subgroup and 87% in the DLL3^low subgroup were male. Primary origin classification was gastrointestinal (47% DLL3^high; 60% DLL3^low), genitourinary (40% DLL3^high; 27% DLL3^low), and cancer of unknown primary site (13% DLL3^high; 10% DLL3^low). Eastern Cooperative Oncology Group performance status was balanced between the DLL3 subgroups. Approximately 67% of patients in the DLL3^high subgroup and 77% in the DLL3^low subgroup had received ≥2 prior lines of therapy,¹⁶ underscoring the poor prognosis of this population.

Safety

Overall, 95% of patients experienced a treatment-related AE, with 22% experiencing Grade ≥3 AEs. While 65% experienced cytokine release syndrome of any Grade, this was Grade ≥3 in only 3%. Other reported AEs included pyrexia (32%), dysgeusia (25%), fatigue (18%), and decreased appetite (17%), none of which were Grade ≥3. Asthenia (23%) and decreased lymphocyte count (15%) were Grade ≥3 in 2% and 12% of patients, respectively. Potential neurological AEs, including immune effector cell-associated neurotoxicity syndrome, occurred in 13% overall, with 5% being Grade ≥3.¹⁶

Efficacy

At data cutoff (June 21^st 2024), in the DLL3^high subgroup, ORR was 40% (95% CI: 25−58%), and DCR was 67% (95% CI: 49−81%), with stable disease in 27%. In the DLL3^low subgroup, ORR was 3% (95% CI: 1−17%), and DCR was 27% (95% CI: 14−44%), with stable disease in 23%. Progressive disease occurred in 27% of evaluable patients in the DLL3^high subgroup (7% not-evaluable [NE]) and in 50% of the evaluable patients in the DLL3^low subgroup (23% NE). Similar efficacy was observed regardless of tumor origin.¹⁶

As illustrated in Figures 1 and 2, a higher proportion of patients in the DLL3^high subgroup achieved partial responses (PR), or tumor shrinkage, compared with those in the DLL3^low subgroup.¹⁶

At a median follow-up of 9.7 months (95% CI: 6.5−13.9), while mDoR in the DLL3^high subgroup was 7.9 months (95% CI: 6.2−NE), with seven patients remaining on treatment at data cutoff, in the DLL3^low subgroup (95% CI: NE−NE), mDoR was 2.8 months. PR was observed within the first 1–3 months in approximately half of the DLL3^highsubgroup (Figure 2).¹⁶

Case Study

Figure 3 illustrates the case of a 79-year-old female diagnosed in September 2021 with multiple liver epNEC lesions. Obrixtamig was initiated following the discontinuation of first-line chemotherapy. The patient achieved a PR after 6 weeks of obrixtamig, and has continued obrixtamig treatment, maintaining good tolerability 2.5 years later.¹⁶

Conclusion

To date, this is the largest prospective dataset for a T cell engager in patients with epNEC. Obrixtamig demonstrated a manageable safety profile, with an ORR of 40% and durable responses observed in the DLL3^high subgroup.¹⁶ An ongoing Phase II trial (DAREON®-5) is investigating obrixtamig in patients with relapsed or refractory DLL3^high epNEC.¹⁷ DAREON®-7 is an ongoing Phase I trial of obrixtamig in combination with platinum and etoposide in patients with DLL3-positive tumors.¹⁸