Shots:
- Recently, Zai Lab presented data from a Phase Ia/Ib study evaluating ZL‑1310, a DLL3 ADC, in patients with extensive‑stage small cell lung cancer, both as a monotherapy and in combination with atezolizumab
- ZL‑1310 leverages TMALIN technology, enabling clinicians to deliver more targeted doses of chemotherapy to cancer cells, distinguishing the compound from current standard‑of‑care treatments
- Rafael G. Amado, President and Head of Global Research and Development at Zai Lab, highlighted the findings from the Phase Ia/Ib study, the drug’s mechanism of action, its benefits, and the innovative ways in which ZL‑1310 addresses current limitations in standard‑of‑care treatments.
Saurabh: What is the MOA (Mechanism of Action) of the Investigational New Drug?
Rafael: Zocilurtatug pelitecan, or ZL-1310, was designed to minimize the limitations of previous generations of antibody-drug conjugates (ADCs). As a potential first-in-class, Delta-like ligand (DLL3) ADC for patients with extensive-stage small cell lung cancer (ES-SCLC), ZL-1310 comprises a humanized anti-DLL3 monoclonal antibody connected via a cleavable linker to a novel camptothecin derivative (a topoisomerase 1 inhibitor) as its payload. ZL-1310 was designed with a novel ADC technology platform called TMALIN®, which leverages the tumor microenvironment to overcome challenges associated with first-generation ADC therapies. The TMALIN® technology binds the linker to three amino acids in the antibody; and relies on both internalization into the cancer cell and on the extracellular cleavage via enzymes in the tumor microenvironment, allowing it to kill nearby cells that may not be DLL3 positive, a so-called “bystander” effect. As a next-generation ADC, ZL-1310 is able to enrich ADCs in the tumor microenvironment enabling us to apply more targeted doses of chemotherapy to fight the tumor with a broader therapeutic window than that of first-generation ADCs.
Saurabh: How does the TMALIN® technology in ZL-1310 address payload release limitations of first-generation ADCs like rovalpituzumab tesirine? What specific linker-payload attributes reduce off-target toxicity while maintaining potency in DLL3-expressing tumors?
Rafael: ADCs are undergoing a bit of a renaissance. Previous generations of ADCs were limited by a very narrow therapeutic window – meaning the dose that was effective was very close to the dose that was toxic. This is mostly due to an unstable linker that allowed for high systemic exposure of “free toxic payload” leading to significant toxicity, and imprecise payload number and release triggers. As the years have progressed, we have continued to see how the ADC class is an incredibly valuable therapeutic class. Additionally, with our novel ADC technology platform, TMALIN®, we’ve been able to make advancements in our ability to modify linker design and payload properties to deliver higher concentrations of cytotoxic agents, reduce off-target side effects and decrease the amount of systemic exposure of the payload with our more stable linker. ADCs continue to possess the potential to provide a more impactful benefit to patients than chemotherapy alone, with a more limited toxicity profile. In situations where the target is a signaling growth factor, ADCs may also work as blocking antibodies thereby potentiating its therapeutic effect.
Given the prevalence of DLL3 overexpression across a variety of neuroendocrine tumors, at Zai we are continuing to advance a clear strategy to expand the reach of ZL-1310 across multiple high-need DLL3-expressing solid tumor types, with our first regulatory submission targeted in 2027.
Saurabh: Could you describe the study design of the Phase 1a/1b trial?
Rafael: The global Phase 1a/1b clinical trial is evaluating ZL-1310 as a monotherapy and in combination with atezolizumab, an immune checkpoint inhibitor, for the treatment of ES-SCLC, in patients with previously treated ES-SCLC after at least one prior platinum-based chemotherapy regimen or in combination with atezolizumab and carboplatin in previously untreated ES-SCLC patients in the United States, Europe and China. Our global study comprises a patient population of 40% from Europe, 30% from the U.S. and 30% from China.
We recently presented data at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, that highlighted updated results from our ongoing Phase 1 monotherapy dose escalation and dose expansion portion of the study. As of the data cut-off date, we shared results from 89 patients across six dose cohorts (0.8 mg/kg, 1.2 mg/kg, 1.6 mg/kg, 2.0 mg/kg, 2.4 mg/kg and 2.8 mg/kg), where 74 patients had at least one post-baseline tumor assessment per RECIST v1.1.
All patients in the study had progressed following platinum-based chemotherapy, and 90% of patients had progressed after immune checkpoint inhibitors. Of all patients, 33% had failed two prior lines of therapy, and 20% had failed three or more prior lines of therapy, making this a highly pretreated population with limited therapeutic options. 10 patients received a prior DLL3 bi-specific antibody. A total of 30% of patients had brain metastases at baseline, a common and ominous complication of this disease. This study included patients in the United States, Europe and China.
Saurabh: What current limitations is ZL-1310 able to address compared to the present standard of care treatments?
Rafael: ZL-1310’s unique design, which utilizes the novel ADC technology platform called TMALIN® to leverage the tumor microenvironment to allow clinicians to potentially deliver more targeted doses of chemotherapy to cancer cells, sets the compound apart from current standard of care treatments.
An additional point of differentiation is how ZL-1310 is administered. T-cell engagers must be administered in a hospital setting because of immunological toxicities that are mostly due to interferon release upon T-cell activation. With this, the utilization of standard of care treatments to date has been low given it can be difficult to give to patients. The unique design of ZL-1310 utilizes a novel antibody of high affinity and relatively long half-life, selected with the goal of allowing more flexible administration and high payload discharge in the tumor deposits, with a more targeted delivery of the cytotoxic treatment.
Saurabh: What are your findings from the Phase 1a/1b clinical study of ZL-1310?
Rafael: In our recent data presentation highlighting updated results at ASCO, ZL-1310 demonstrated clinically meaningful anti-tumor activity in the heavily pretreated population of patients with small cell lung cancer (SCLC) across dose escalation and expansion cohorts. In the second-line setting (2L) SCLC, our objective response rate (ORR) was 67% across all dose levels (n=33) and 79% at 1.6 mg/kg dose (n=14). Additionally, the median duration of response has not yet been reached, with 29 of 38 responders remaining on study; 27 of 31 patients with stable disease remaining on study, the majority of whom had tumor regressions. ZL-1310 demonstrated a well-tolerated safety profile across all doses up to 2.0 mg/kg, with the 1.6 mg/kg dose as our potentially most effective dose, demonstrating very strong efficacy and a fast antitumor effect to date. Furthermore, in seven evaluable patients with brain metastases who did not receive prior brain irradiation, we observed an 87% overall response rate indicating that ZL-1310 may have significant clinical activity in the central nervous system (CNS), an observation with high relevance to the SCLC population who often needs to postpone systemic chemotherapy for the local treatment of brain metastasis.
The safety and efficacy profile of ZL-1310 continues to highlight a compelling opportunity to significantly improve the outcomes for patients with extensive-stage small cell lung cancer and underscores its potential to become the first-in-class, DLL3-targeted ADC in this setting. Based on our recent results, Zai plans to initiate a randomized registrational study in 2L ES-SCLC later this year, evaluating the selected dose of ZL-1310 versus standard of care. Zai is also actively enrolling patients in front-line SCLC and in other neuroendocrine carcinomas, with data updates anticipated later this year.
Saurabh: How does the safety profile of ZL-1310 compare to existing therapies for small cell lung cancer?
Rafael: In our recent data presentation at ASCO, updated results for ZL-1310 demonstrated a well-tolerated safety profile at target doses of less than 2.0 mg/kg, with Grade ≥3 treatment-related adverse events (TRAEs) of 6%, and no drug discontinuations. Of the 89 patients we reported results for, ZL-1310 continues to demonstrate a well-tolerated safety profile, particularly in doses less than 2.0 mg/kg. In the dose cohort <2.0 mg/kg, Grade 3 or higher TRAEs occurred in 6% of patients and serious TRAEs in 4%. The most common TRAEs were anemia (Gr≥3 2%) and neutropenia (Gr≥3 4%). There were no treatment discontinuations and no Gr≥3 interstitial lung diseases (ILDs). Across all dose cohorts, Grade 3 or higher TRAEs occurred in 23% of patients and serious TRAEs in 21%. The most common TRAEs were anemia (Gr≥3 11%) and neutropenia (Gr≥3 14%). There were five discontinuations due to TRAEs, all in the higher dose cohort. There were two cases of Gr≥3 treatment-related ILD, one at the 2.0 g/kg dose and one at the 2.4 mg/kg dose. Interestingly, in addition to better safety and tolerability profiles, response rates were higher in the cohorts below 2 mg/kg.
Saurabh: How does ZL-1310 compare to other compounds that are in the pipeline or in development? Could you reflect on it?
Rafael: Small cell lung cancer is an aggressive disease, with rapid disease progression and brain metastases developing in up to 70% of patients. We know there remains a significant unmet need for effective and well-tolerated therapies in the relapsed setting. We are encouraged by what the data has shown within our Phase 1 study to date, demonstrating strong anti-tumor activity, including intracranial responses with a manageable safety profile, which reinforces the potential of ZL-1310 as a meaningful treatment option for patients with previously treated extensive-stage small cell lung cancer. We look forward to continuing our efforts to generate more data for ZL-1310, as what we have seen so far continues to demonstrate a compelling opportunity for ZL-1310 to become the first-in-class, DLL3-targeted ADC in this setting which could offer a novel therapeutic option alone and in combination with chemotherapy and other emerging agents acting through alternative mechanisms of action such as targeted immunotherapy. We are making rapid progress in the development of ZL-1310 and look forward to continuing its development in registrational trials starting in the second half of 2025.
About the Author:
Rafael G. Amado, MD
Prior to joining Zai Lab, Dr. Amado was the Executive Vice President, Head of Research and Development and Chief Medical Officer for Allogene Therapeutics, Inc. Before joining Allogene, Dr. Amado served as President of Research and Development and Chief Medical Officer of Adaptimmune, LLC from August 2018 to July 2019 and as Chief Medical Officer from March 2015 to July 2018.
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