Zocilurtatug Pelitecan Shows Potential in Small Cell Lung Cancer

Updated data from a phase 1 clinical trial (NCT06179069) show that zocilurtatug pelitecan (formerly ZL-1310) has potential as a first-in-class/best-in-class DLL3-targeted antibody-drug conjugate (ADC) for patients with small cell lung cancer (SCLC).¹

Zocilurtatug pelitecan demonstrated a high overall response rate (ORR) across all dose levels in patients who progressed on or after platinum-based chemotherapy. In a subset of 53 patients who received zocilurtatug pelitecan as a second-line therapy, the best ORR was 68%, specifically in the 1.6-mg cohort (n = 19). Out of 7 patients who progressed after prior tarlatamab (Imdelltra), 3 responded. The median progression-free survival (PFS) was 5.4 months across all dose levels and lines of therapy. Additionally, enrollment continues for the 1.2-mg and 1.6-mg cohorts and is expected to complete before the end of the year.

There was a total of 115 patients across 6 cohorts in the monotherapy dose-escalation and dose-expansion portions of the study (0.8 mg, 1.2 mg, 1.6 mg, 2 mg, 2.4 mg, and 2.8 mg) as of the data cutoff on September 15, 2025.

There was compelling activity in patients with baseline brain metastases (n = 32), and an 80% ORR was observed in patients without prior brain radiotherapy.

The duration of response (DOR) was 6.1 months across all doses and all lines of therapy. Enrollment continued for 1.2 mg and 1.6 mg, with nearly half of the total patients ongoing at the data cutoff.

All patients had progressed following platinum-based chemotherapy, and 90% of patients had progressed after immune checkpoint inhibitors. Of the patients, 44% had failed 2 prior lines of therapy.

Safety Results

In the 1.6-mg arm, treatment-related adverse events (AEs) of grade 3 or greater occurred in 13% of patients, and serious AEs occurred in 9% of patients. No patients discontinued treatment due to toxicity. Of the 72 patients in the 1.2-mg and 1.6-mg arms, there were 2 cases of grade 1 pneumonitis and interstitial lung disease. Across all dose levels, treatment-related AEs of grade 3 or greater occurred in 20% of patients, and serious treatment-related AEs occurred in 8%. The most reported AEs were anemia (10%) and neutropenia (11%). Five patients discontinued treatment due to AEs, all in the higher dose levels.

“DLL3 represents a validated target in extensive-stage [SCLC], where there is high need for new therapies given the disease’s aggressive nature and limited treatment options,” Grace Dy, MD, Roswell Park Comprehensive Cancer Center and study investigator, said in a press release.¹ “These new phase 1 results for zoci[lurtatug pelitecan], including data that show rapid and sustained responses among the patient population, especially those with poor prognostic factors, are the latest clinical evidence that further demonstrate zoci[lurtatug pelitecan]’s potential as a differentiated, DLL3-targeted ADC.”

Patient Eligibility Criteria

Patient inclusion criteria included, but were not limited to, having an ECOG performance score of 0 or 1, having at least 1 measurable target lesion as defined by RECIST v1.1, being willing to undergo a tumor biopsy or provide an archived tumor tissue sample, and having a life expectancy of 3 months or more.²

Patient exclusion criteria included, but were not limited to, having another known malignancy that is progressing or requires active treatment within the last 2 years, having symptomatic or untreated brain metastases requiring concurrent treatment, having leptomeningeal disease, and receiving nonpalliative radiotherapy within 2 weeks before the first dose of study treatment or having a history of radiation pneumonitis.²

Next Steps in Research

The global phase 3 trial (NCT07218146) will enroll approximately 665 patients throughout North America, Asia, and Europe. The randomized, open-label study will further evaluate the safety and efficacy of zocilurtatug pelitecan in patients with relapsed SCLC who have progressed on or after platinum-based first-line therapy as second-line therapy or 1 line of chemotherapy followed by tarlatamab. The primary end points of the trial are ORR and overall survival (OS), and the secondary end points include DOR, PFS, and safety. First-line SCLC and neuroendocrine carcinoma programs are advancing toward the registrational phase in 2026.¹ 

REFERENCES:

1. Zai Lab announces updated phase 1 data for zocilurtatug pelitecan (formerly ZL-1310), demonstrating potential as a first-in-class/best-in-class DLL3-targeted ADC for small cell lung cancer, and initiation of global phase 3 registrational study. Press release. Zai Laboratory. October 24, 2025. Accessed October 30, 2025. https://tinyurl.com/bd8pvz2r2. A study of ZL-1310 in subjects with small cell lung cancer. ClinicalTrials.gov. Updated August 15, 2025. Accessed October 30, 2025. https://clinicaltrials.gov/study/NCT06179069