Zocilurtatug Pelitecan Shows Activity in epNEC Across DLL3 Expression Levels

Zocilurtatug pelitecan (zoci), an antibody-drug conjugate (ADC) that targets delta-like ligand 3 (DLL3), produced clinically meaningful responses with a manageable safety profile in patients with previously treated extrapulmonary neuroendocrine carcinoma (epNEC), and responses occurred even in tumors with little or no DLL3 expression, according to phase 1b/2 data presented by Amr Mohamed, MD, associate professor and director of the Neuroendocrine Tumor Program at University Hospitals Seidman Cancer Center and Case Western Reserve University, at the 2026 North American Neuroendocrine Tumor Society (NANETS) Symposium.¹

Zoci Responses Across epNEC Subtypes

The efficacy analysis included the first 60 patients with epNEC enrolled in the study who had at least 5 months of follow-up. In this group, the confirmed objective response rate (ORR) was 40.0% (95% CI, 27.6%-53.5%), including 2 complete responses, and the disease control rate was 55.0%. The confirmed ORR was 41.9% in the phase 1b portion of the study and 35.3% in the phase 2 portion.

Activity was seen across tumor origins. Among patients with gastroenteropancreatic NEC (GEP-NEC), the confirmed ORR was 35.9%, all partial responses. Among patients with other, non-GEP epNECs, the ORR was 47.6%, and both complete responses occurred in this group.

Spider plots showed tumor shrinkage over time, and some patients with initial stable disease went on to achieve partial responses with continued treatment. Mohamed highlighted a patient with a complete response who was approaching 1 year in response at the time of the presentation.

Zoci Durability and Survival Outcomes

With a median follow-up of 7.7 months, the median duration of response was 5.6 months and the median progression-free survival was 4.1 months. Among 18 responders who had at least 6 months of follow-up from initial response or who had an event before the data cutoff, one-third maintained their response for 6 months or longer, and several patients with GEP-NEC and other epNECs remained on treatment.

“Some of them definitely are getting a durable response,” Mohamed said.

The investigators noted that this antitumor activity compares favorably with historical outcomes for chemotherapy in similar treatment settings.

Zoci Shows Manageable Safety Profile

Safety was evaluated in all 133 patients who received at least 1 dose of zoci at 1.6 mg/kg every 3 weeks. Treatment-related adverse events (TRAEs) were common, but most were low grade. Grade 3 or higher TRAEs occurred in 12.8% of patients, and treatment-related serious AEs occurred in 4.5%.

Among selected treatment-emergent AEs reported, the most common were nausea, anemia, vomiting, neutropenia, and fatigue. “Most of this side effect was either grade 1 or grade 2,” Mohamed said.

Few patients needed changes to treatment because of toxicity. Treatment-related dose interruptions occurred in 9.0% of patients, dose reductions in 3.0%, and discontinuations in 0.8%. There were no treatment-related deaths; 1 fatal AE, cardiac arrest and respiratory failure, was judged by the investigator to be unrelated to the study drug.

Interstitial lung disease (ILD) or pneumonitis, a known concern with some ADCs, occurred in 2 patients (1.5%), and both cases were grade 2. One patient permanently discontinued treatment, and the event resolved; the other was managed with a dose interruption and was ongoing at the data cutoff.

DLL3 Expression Did Not Clearly Predict Response to Zoci

A key question was whether DLL3 expression level would identify the patients most likely to benefit. DLL3 positivity was not required for patients with NEC to enroll, and DLL3 was assessed retrospectively using an H-score that combines the percentage of stained cells and staining intensity.

Of 56 patients with evaluable DLL3 H-scores, 87.5% were DLL3 positive. Responses occurred across the full range of expression, including 2 partial responses among 7 patients whose tumors had no detectable DLL3. Some patients with progressive disease had high H-scores.

Response rates were numerically higher in tumors with higher DLL3 expression, but differences were not statistically significant at any of the 3 cutoffs tested (H-score of 1, 50, or 100), with P values ranging from .092 to .688 in these exploratory comparisons.

“So we are not sure if DLL3 is a good predictor for this specific antibody,” Mohamed said.

Mohamed added that there is no consensus on how DLL3 should be scored, noting that the H-score depends on both intensity and percentage of positive cells and can vary between pathologists. The investigators hope to explore simpler measures, such as the percentage of DLL3-positive cells, as well as artificial intelligence-based image analysis and other potential biomarkers.

Study Design and Patient Population

The open-label phase 1b/2 study (NCT06885281) enrolled patients with advanced or metastatic NEC that had progressed on or after platinum-based chemotherapy.⁴ In phase 1b, cohort 1 enrolled patients with GEP-NEC, and cohort 2 enrolled patients with other NECs and DLL3-expressing solid tumors. Phase 2 was a single-arm extension in patients with epNEC receiving second-line or later therapy, and a separate cohort is evaluating patients with previously untreated advanced or metastatic NEC. Tumor response was assessed by investigators per RECIST v1.1.

Of the 133 patients in the safety population, 116 had epNEC. Most had GEP-NEC, and genitourinary NECs were the next most common. Nearly all patients had received prior platinum-based chemotherapy, about one-fifth had received 2 or more prior lines, and the median Ki-67 index was 80%, reflecting the highly proliferative nature of these tumors. Data from the remaining 56 epNEC patients were not yet mature, and follow-up is ongoing.

Phase 3 Trial of Zoci Planned

The investigators concluded that zoci demonstrated clinically meaningful responses across multiple epNEC primary sites with a manageable safety profile, and a phase 3 trial is planned to further evaluate the agent in this population. Work to identify a reliable predictive biomarker continues.

“So I think still we are learning what is a good predictive biomarker for this antibody specifically,” Mohamed said.

References

1. Mohamed A. Phase 1b/2 study of zocilurtatug pelitecan in patients with advanced extrapulmonary neuroendocrine carcinomas (epNEC). Presented at: 2026 North American Neuroendocrine Tumor Society (NANETS) Symposium; November 5-7, 2026; Las Vegas, NV.

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. Saunders LR, Bankovich AJ, Anderson WC, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7(302):302ra136. doi:10.1126/scitranslmed.aac9459

4. A study of ZL-1310 in participants with selected solid tumors. ClinicalTrials.gov identifier: NCT06885281. Accessed November 6, 2026. https://clinicaltrials.gov/study/NCT06885281