Zai Lab and Amgen collaborate on DLL3-targeting dual mechanism strategy for SCLC

Zai Lab (NASDAQ: ZLAB; HKEX: 9688) and Amgen (NASDAQ: AMGN) have entered a global clinical trial collaboration and supply agreement to evaluate whether combining two mechanistically distinct DLL3-targeting agents can improve outcomes in extensive-stage small cell lung cancer (ES-SCLC), one of the most treatment-resistant solid tumor types. The Zai Lab Amgen clinical trial arrangement centers on pairing Zai Lab’s investigational DLL3-targeting antibody drug conjugate (ADC), zocilurtatug pelitecan, with Amgen’s FDA-approved Imdelltra bispecific T-cell engager tarlatamab-dlle in a global Phase Ib study.

Under the terms of the agreement, Amgen will sponsor and lead the Phase Ib study. Zai Lab retains full ownership of zocilurtatug pelitecan and will supply the compound as the investigational drug for the trial. No financial terms, upfront payments, milestone structures, or royalty arrangements were disclosed, consistent with the agreement’s structure as a clinical supply and co-development arrangement rather than a licensing or commercialization transaction.

Scientific rationale: Two mechanisms, one target

The collaboration is built on the premise that simultaneous engagement of DLL3 through distinct biological mechanisms may produce additive or complementary effects against ES-SCLC tumors. DLL3 is a cell-surface antigen overexpressed in small cell lung cancer and other neuroendocrine tumors, and it has emerged as a validated therapeutic target in this indication.

Zocilurtatug pelitecan, formerly designated ZL-1310, is a DLL3-targeting antibody drug conjugate constructed using Zai Lab’s TMALIN platform technology. The ADC comprises a humanized anti-DLL3 monoclonal antibody linked to a camptothecin derivative, a topoisomerase I inhibitor, as its cytotoxic payload. The TMALIN design is intended to leverage the tumor microenvironment to reduce off-target payload toxicity associated with earlier-generation ADC constructs. The compound has received FDA Orphan Drug Designation and FDA Fast Track Designation for SCLC.

Imdelltra, a bispecific T-cell engager therapy, operates through a different mechanism. It simultaneously binds DLL3 on tumor cells and CD3 on T cells, redirecting cytotoxic immune activity toward DLL3-expressing cancer cells. The agent received FDA approval for adult patients with ES-SCLC whose disease has progressed on or after platinum-based chemotherapy and is currently marketed in the United States by Amgen.

The combination strategy positions the ADC as a direct cytotoxic agent delivering payload intracellularly to DLL3-expressing cells, while the BiTE engages the immune system through T-cell redirection against the same antigen.

Disease context

SCLC accounts for approximately 15% of the roughly 2.5 million lung cancer diagnoses worldwide each year. Two-thirds of SCLC patients present at extensive stage, where median overall survival following initial therapy is approximately 12 months and five-year survival rates are estimated at five to ten percent. Treatment options have historically been limited following disease progression on first-line platinum-based chemotherapy combined with immune checkpoint inhibition.

Imdelltra represented the first DLL3-targeting bispecific T-cell engager to demonstrate an overall survival benefit in this patient population, establishing proof-of-concept for DLL3 as a clinically actionable target in ES-SCLC.

Zai Lab has presented clinical data from a Phase I/II trial of zocilurtatug pelitecan at the EORTC-NCI-AACR Symposium 2025 and the American Society of Clinical Oncology 2025 Annual Meeting. The company reported a high response rate in heavily pretreated SCLC patients, including intracranial activity, alongside a tolerable safety profile. The compound is now also being evaluated in the DLLEVATE pivotal trial, a Phase III study comparing zoci against investigator’s choice single-agent therapy in patients with relapsed ES-SCLC. Additional programs include a Phase Ib/II study in extrapulmonary neuroendocrine carcinoma and other selected solid tumors, and a Phase Ia/Ib trial evaluating zoci as monotherapy and in combination with atezolizumab.