ZL-1310 (Zocilurtatug Pelitecan): A Novel DLL3-Targeted Antibody-Drug Conjugate Leveraging the TMALIN® Platform for the Treatment of Small Cell Lung Cancer and Other Solid Tumors – A Comprehensive Clinical and Regulatory Review

1. Executive Summary

ZL-1310, also known by its proposed non-proprietary name zocilurtatug pelitecan, is an investigational first-in-class antibody-drug conjugate (ADC) targeting Delta-like ligand 3 (DLL3).[1] This therapeutic agent utilizes the proprietary TMALIN® (Tumor Microenvironment Activable LINker-payload) platform technology developed by MediLink Therapeutics and is currently under global development by Zai Lab.[3] ZL-1310 is being evaluated for its potential to address the significant unmet medical need in extensive-stage small cell lung cancer (ES-SCLC), an aggressive malignancy with a historically poor prognosis, and it holds promise for other DLL3-expressing neuroendocrine tumors.[1]

The ongoing global Phase 1a/1b clinical trial (NCT06179069) has yielded encouraging results, particularly highlighted at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. In heavily pretreated ES-SCLC patients, ZL-1310 demonstrated clinically meaningful anti-tumor activity. Specifically, in the second-line (2L) SCLC setting, an objective response rate (ORR) of 67% was observed across all dose levels (n=33), which increased to an impressive 79% at the 1.6 mg/kg dose level (n=14). Notably, clinical activity was also observed in patients with brain metastases and across various levels of DLL3 expression. The safety profile of ZL-1310, especially at doses below 2.0 mg/kg (where Grade ≥3 treatment-related adverse events, or TRAEs, occurred in 6% of patients), appears manageable. Key adverse events requiring careful monitoring include hematological toxicities and interstitial lung disease (ILD).[1]

The therapeutic potential of ZL-1310 has been recognized by regulatory authorities. The U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation (ODD) for SCLC in January 2025 and Fast Track Designation for ES-SCLC in May 2025.[3] These designations are anticipated to expedite its development and review. Zai Lab is planning to initiate a pivotal trial in 2L SCLC later in 2025, with ambitions for a potential accelerated approval as early as 2027 and an initial regulatory submission targeted for 2026.[1]

The rapid progression of ZL-1310 from preclinical validation to promising Phase 1b data, combined with substantive FDA regulatory support, signals a strong validation of both DLL3 as a therapeutic target in SCLC and the TMALIN® ADC platform's capability to deliver a differentiated therapeutic agent. SCLC has seen limited therapeutic advancements for decades. The ability of ZL-1310 to achieve high response rates in a difficult-to-treat, heavily pretreated patient population, including those with brain metastases—a common and challenging complication of SCLC—and those who have progressed on prior immunotherapies, suggests a potentially practice-altering agent. The FDA's ODD and Fast Track designations further underscore the perceived clinical value and the urgency of addressing this unmet need. This suggests ZL-1310 is not merely an incremental improvement but a candidate with the potential for significant clinical impact, likely stemming from the strategic combination of a validated target (DLL3) and an advanced, stable, and efficient payload delivery system (TMALIN®).

Furthermore, the success of ZL-1310 could invigorate broader exploration of DLL3 as a target across a wider range of neuroendocrine tumors and may stimulate the development of additional ADCs utilizing the TMALIN® platform for other challenging targets. DLL3 is expressed in various neuroendocrine tumors beyond SCLC.[3] Positive data in SCLC provide a compelling rationale for broader investigation. If the TMALIN® platform consistently demonstrates a superior therapeutic window for ZL-1310, MediLink Therapeutics will likely see increased interest in licensing this platform for other antibody-payload combinations, potentially unlocking new therapeutic avenues for targets previously considered difficult for ADC development due to toxicity or instability issues.

2. Introduction to ZL-1310 (Zocilurtatug Pelitecan)

ZL-1310, identified by the proposed international non-proprietary name (pINN) zocilurtatug pelitecan, is a novel antibody-drug conjugate currently under clinical investigation.[1] It represents a targeted therapeutic approach for cancers expressing Delta-like ligand 3 (DLL3).

2.1. Target: Delta-like ligand 3 (DLL3)

DLL3 is an atypical member of the Notch ligand family. In normal physiological conditions, DLL3 is primarily an intracellular protein residing in the Golgi apparatus. However, in the context of several malignancies, particularly neuroendocrine tumors such as SCLC, DLL3 undergoes aberrant cell surface expression.[3] This surface expression is a key characteristic exploited by ZL-1310.

The clinical relevance of DLL3 in oncology is significant. Its overexpression is frequently observed in SCLC and other high-grade neuroendocrine tumors, and this expression is often correlated with aggressive disease biology and unfavorable clinical outcomes. A crucial aspect for its selection as an ADC target is its limited expression in normal adult tissues. This differential expression profile suggests a potentially wide therapeutic window, aiming to maximize anti-tumor activity while minimizing on-target, off-tumor toxicities.[3] Consequently, DLL3 is considered a validated therapeutic target for SCLC.[3]

2.2. Drug Class: Antibody-Drug Conjugate (ADC)

ZL-1310 belongs to the class of antibody-drug conjugates. ADCs are complex biopharmaceutical drugs designed to selectively deliver a potent cytotoxic agent (payload) to cancer cells by targeting a specific antigen expressed on the tumor cell surface. This targeted delivery mechanism aims to enhance the therapeutic index of the cytotoxic payload by increasing its concentration at the tumor site while reducing systemic exposure and associated side effects.[3]

2.3. Developers and Collaboration

The development of ZL-1310 is a collaborative effort:

• Primary Clinical Developer: Zai Lab Limited, a global biopharmaceutical company, is responsible for the worldwide clinical development and eventual commercialization of ZL-1310.[3]
• Technology Originator: The ADC was engineered using the proprietary TMALIN® (Tumor Microenvironment Activable LINker-payload) platform technology, which was developed by MediLink Therapeutics (Suzhou) Co., Ltd..[12]
• Partnership Details: Zai Lab and MediLink Therapeutics entered into a strategic collaboration and exclusive worldwide license agreement for ZL-1310 in April 2023.[10] This partnership combines MediLink's innovative ADC platform with Zai Lab's extensive experience in global clinical development. The collaboration has subsequently been expanded, with Zai Lab licensing the TMALIN® platform for an additional ADC candidate, ZL-6201 (targeting LRRC15), underscoring a continued strong belief in the platform's potential.[12]

The strategic choice of DLL3 as a target, characterized by its high tumor-associated expression and minimal presence in normal tissues, provides a strong foundation for the therapeutic rationale of ZL-1310. The partnership structure, wherein Zai Lab leverages MediLink's cutting-edge ADC platform, exemplifies an efficient model in the biotechnology industry to accelerate drug development. This allows Zai Lab to rapidly advance a promising ADC candidate without the extensive timeline and investment required for de novo platform creation, while MediLink gains a robust partner to bring its technology through clinical validation and towards potential market entry.

Table 1: ZL-1310 (Zocilurtatug Pelitecan) Key Characteristics

Characteristic	Detail	Reference(s)
Target	Delta-like ligand 3 (DLL3)	3
Antibody Type	Humanized anti-DLL3 monoclonal antibody	1
Payload	Novel camptothecin derivative (Topoisomerase 1 inhibitor, C24)	3
Linker Type	Cleavable tripeptide-based linker	4
Drug-to-Antibody Ratio (DAR)	8	9
ADC Platform	TMALIN® (Tumor Microenvironment Activable LINker-payload)	12
Developer (Clinical & Commercial)	Zai Lab Limited	3
Technology Originator	MediLink Therapeutics (Suzhou) Co., Ltd.	12

This table provides a concise summary of ZL-1310's fundamental components and attributes, crucial for understanding its design and therapeutic rationale.

3. Mechanism of Action and TMALIN® Platform Technology

The therapeutic activity of ZL-1310 is derived from the specific targeting of DLL3-expressing cells by its antibody component and the subsequent delivery of a potent cytotoxic payload, facilitated by the innovative TMALIN® ADC platform.

3.1. ZL-1310 Mechanism of Action

The mechanism of ZL-1310 involves several sequential steps:

1. Target Binding: The humanized anti-DLL3 monoclonal antibody component of ZL-1310 is engineered for high-affinity binding (picomolar range) to DLL3 expressed on the surface of tumor cells.[9]
2. Internalization: Upon binding to DLL3, the ADC-antigen complex is internalized by the tumor cell, a necessary step for many ADCs to deliver their payload to intracellular compartments.[10]
3. Payload Release: The cytotoxic agent, a novel and potent camptothecin derivative (a topoisomerase 1 inhibitor designated C24), is conjugated to the antibody with a drug-to-antibody ratio (DAR) of 8.[9] This payload is released from the antibody through the cleavage of the TMALIN® linker. A key feature of this platform is its dual-cleavage mechanism, allowing payload release both intracellularly (e.g., within lysosomes) and extracellularly within the tumor microenvironment (TME).[12]
4. Cytotoxicity: The released topoisomerase 1 inhibitor payload exerts its anti-cancer effect by disrupting DNA replication and repair. Topoisomerase I is an essential enzyme that relieves torsional stress in DNA during replication and transcription. Its inhibition by the camptothecin derivative leads to the accumulation of DNA single-strand breaks, which, if unrepaired, convert to double-strand breaks during DNA replication, ultimately triggering cell cycle arrest and apoptosis (programmed cell death) in the DLL3-expressing tumor cells.[1]
5. Bystander Antitumor Effect: The TMALIN® platform is specifically designed to enable a "strong bystander effect".[9] This phenomenon occurs when the payload, once released (particularly via extracellular cleavage in the TME), can diffuse across cell membranes and kill nearby tumor cells. This is advantageous as it can eliminate neighboring tumor cells that may have low or no DLL3 expression, or those that have not efficiently internalized the ADC, thereby broadening the therapeutic impact beyond directly targeted cells.

3.2. TMALIN® ADC Technology Platform

The TMALIN® platform, developed by MediLink Therapeutics, represents a next-generation ADC technology engineered to overcome many of the limitations associated with earlier ADC designs.

• Design Philosophy: The platform aims to improve the therapeutic index of ADCs by enhancing their stability in systemic circulation while ensuring efficient and tumor-specific payload release. It achieves this by incorporating linkers that are activatable within the unique conditions of the tumor microenvironment, thereby minimizing off-target toxicity and expanding applicability to tumors with heterogeneous or low antigen expression.[12]
• Key Technical Components [13]:
• Irreversible Pyrimidine Coupling Anchor: TMALIN® utilizes a proprietary pyrimidine-based coupling chemistry. This technology facilitates site-specific and homogeneous conjugation of the linker-payload to the antibody. Site-specific conjugation is critical for producing ADCs with a well-defined and consistent DAR (ZL-1310 has a DAR of 8 [9]). This homogeneity contributes to more predictable pharmacokinetic behavior, potentially improved manufacturing consistency, and a better overall therapeutic index compared to randomly conjugated ADCs. The irreversible nature of the coupling enhances the stability of the ADC.
• Cleavable Linker Sequence: The platform employs a specifically designed cleavable sequence: valyl dipropyl-lysyl glycinamide-methylene (-VK*G-NHCH2-O-). This peptide-based linker is engineered to be susceptible to enzymatic cleavage by proteases that are abundant or uniquely active both extracellularly within the TME and intracellularly within lysosomes.
• Dual Cleavage Mechanism [12]: This is a distinctive and innovative feature of the TMALIN® platform.
• Extracellular Cleavage in the TME: The linker is designed to be cleaved by enzymes (e.g., proteases like cathepsins, matrix metalloproteinases) that are often dysregulated and overexpressed in the tumor microenvironment. This allows for the release of the payload in the interstitial space of the tumor, facilitating the bystander effect on adjacent tumor cells, including those that may not have internalized the ADC.
• Intracellular Cleavage within Lysosomes: Following receptor-mediated endocytosis of the ADC into the target tumor cell, the ADC is trafficked to lysosomes. The acidic environment and high concentration of proteolytic enzymes within lysosomes efficiently cleave the linker, releasing the payload directly into the cytoplasm of the cancer cell.
• Advantages and Differentiating Features of TMALIN® [12]:
• High Hydrophilicity: The linker-payload construct exhibits high hydrophilicity. This property can improve the ADC's solubility, reduce aggregation tendencies, and lead to more favorable pharmacokinetic profiles, potentially minimizing non-specific uptake by healthy tissues.
• Homogeneous High DAR: As mentioned, the platform enables the production of ADCs with a high and uniform DAR (e.g., DAR=8 for ZL-1310). This ensures a potent cytotoxic payload is delivered by each antibody molecule, maximizing the potential for tumor cell kill.
• Exceptional Plasma Stability: A critical attribute for ADCs is stability in systemic circulation to prevent premature payload release, which can cause systemic toxicity. The TMALIN® platform demonstrates remarkable stability. In vitro studies have shown less than 2% payload deconjugation after 21 days of incubation in plasma under physiological conditions. This stability is further corroborated by in vivo pharmacokinetic studies in non-human primates (NHPs) and early clinical trial data, where the pharmacokinetic profiles of the intact ADC and the total antibody (TAb) closely overlap. This overlap signifies that the payload remains securely attached to the antibody during its transit through the bloodstream.
• Specific Tumor Accumulation and Efficient Payload Release: The design promotes preferential accumulation of the ADC in tumor tissues, likely due to the enhanced permeability and retention (EPR) effect and specific antigen binding, followed by efficient payload release via the dual-cleavage mechanisms within the tumor context.
• Improved Therapeutic Window: Preclinical studies utilizing TMALIN®-based ADCs have shown significant tumor regressions, even in challenging models with low antigen expression. This efficacy is coupled with good tolerability. Pivotal NHP toxicology studies have indicated favorable safety profiles, with no significant drug-related adverse effects observed in major organs such as the lungs, liver, or kidneys for ADCs developed using this platform. This combination of enhanced efficacy and improved safety points to an expanded therapeutic window.

The dual-cleavage mechanism of the TMALIN® platform is a significant innovation in ADC technology. Traditional ADCs often rely solely on internalization and lysosomal degradation for payload release. This can be a limiting factor if target antigen expression is heterogeneous, internalization is inefficient, or if tumor cells develop resistance mechanisms involving lysosomal pathways. By enabling extracellular payload release within the TME, TMALIN® ADCs can exert a potent bystander effect, killing nearby tumor cells that might otherwise escape direct targeting. This is particularly relevant for solid tumors, which often exhibit considerable heterogeneity. The observed efficacy of ZL-1310 across a range of DLL3 expression levels [5] supports the potential benefits of this dual-release strategy and bystander effect.

The successful engineering of an ADC with a high, homogeneous DAR of 8, while maintaining excellent plasma stability and a dual-release capability, signifies a sophisticated balance of payload potency, linker chemistry, and conjugation strategy. Achieving a high DAR is often associated with increased hydrophobicity, aggregation, faster clearance, and greater systemic toxicity with older ADC technologies. The TMALIN® platform appears to have overcome these hurdles, suggesting it can effectively deliver a substantial cytotoxic load specifically to the tumor. This robust platform technology could, therefore, be applicable to a wider array of antibody-target combinations and payload types, potentially enabling the development of ADCs against targets previously considered "undruggable" due to challenges in achieving an adequate therapeutic index with less advanced delivery systems. The strong bystander effect further enhances its utility for tackling the complexities of solid tumor microenvironments.[9]

4. Preclinical Development

The progression of ZL-1310 into clinical trials was underpinned by a comprehensive preclinical evaluation program. Key findings from these IND (Investigational New Drug)-enabling studies were presented at the European Lung Cancer Congress (ELCC) in March 2024, providing the foundational evidence for its therapeutic potential.[10]

• Target Binding and Specificity: Preclinical assessments confirmed that ZL-1310 exhibits strong and specific binding to the DLL3 antigen expressed on the cell surface. High-affinity binding is a prerequisite for effective ADC targeting and subsequent payload delivery to tumor cells.[10]
• Internalization and Cellular Effects: Following binding to DLL3, ZL-1310 was shown to be efficiently internalized by DLL3-expressing tumor cells. Once inside the cell, the ADC induced cell cycle arrest and apoptosis. These cellular effects are consistent with the known mechanism of action of its camptothecin-derived topoisomerase I inhibitor payload, which causes DNA damage leading to programmed cell death.[10]
• In Vivo Antitumor Efficacy: The anti-tumor activity of ZL-1310 was evaluated in various in vivo models:
• ZL-1310 demonstrated dose-dependent suppression of tumor growth in established human tumor xenografts.
• Crucially, this efficacy was observed not only in cancer cell-derived xenograft (CDX) models but also in SCLC patient-derived xenograft (PDX) models.[10] PDX models, which involve implanting tumor tissue from patients directly into immunodeficient mice, are generally considered to better recapitulate the heterogeneity, microenvironment, and drug response characteristics of human cancers compared to CDX models.

The consistent, dose-dependent anti-tumor activity demonstrated by ZL-1310 in these preclinical models, particularly in the more clinically relevant PDX models, provided a strong scientific rationale for advancing the compound into human clinical trials. The ability to show efficacy in PDX models is often viewed as a more reliable indicator of potential clinical activity. This robust preclinical data package likely contributed to the swift transition of ZL-1310 into Phase 1 clinical studies, which were initiated by Zai Lab in January 2024, shortly after the licensing agreement with MediLink Therapeutics in April 2023.[10] While the available summaries confirm effective tumor growth suppression, more granular details from the full ELCC 2024 presentation, such as the magnitude of tumor regression (e.g., achievement of complete responses in PDX models), the durability of these preclinical responses, and any comparative efficacy data against other DLL3-targeted agents in these specific models, would offer even deeper insights into its preclinical differentiation and therapeutic potential.

5. Clinical Development Program: Phase 1a/1b Trial (NCT06179069)

The clinical development of ZL-1310 is centered around an ongoing global Phase 1a/1b trial (NCT06179069), designed to assess its safety, tolerability, pharmacokinetics, and preliminary efficacy in patients with SCLC and other solid tumors.

5.1. Study Design and Objectives

• Trial Identifier and Design: NCT06179069 is a global, open-label, multicenter study. It includes sites in the United States, Europe, and China, reflecting a broad development strategy.[1]
• Phased Approach:
• Part 1a (Monotherapy Dose Escalation): This initial phase aimed to evaluate the safety and tolerability of ZL-1310 monotherapy across escalating dose levels to determine the maximum tolerated dose (MTD) and identify the recommended Phase 2 dose (RP2D). Six dose cohorts were investigated: 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, administered intravenously every 3 weeks (IV Q3W).[1]
• Part 1b/Part 2 (Randomized Dose Optimization/Expansion): This subsequent phase is designed to further assess the safety and preliminary efficacy of ZL-1310 at selected dose levels. It includes both monotherapy expansion cohorts and combination therapy arms.[5] The combination arms are evaluating ZL-1310 with the immune checkpoint inhibitor atezolizumab, and ZL-1310 with atezolizumab plus carboplatin (as induction therapy), followed by ZL-1310 and atezolizumab as maintenance treatment.[6]
• Endpoints:
• Primary Endpoints: Incidence of Dose-Limiting Toxicities (DLTs) during the dose escalation phase, overall incidence and severity of adverse events (AEs), determination of MTD, and selection of RP2D(s).[5]
• Secondary and Exploratory Endpoints: Objective Response Rate (ORR) assessed by RECIST v1.1 criteria, Duration of Response (DOR), Disease Control Rate (DCR), pharmacokinetic (PK) parameters of ZL-1310 and its payload, and investigation of exploratory tumor biomarkers, including DLL3 expression levels (typically reported as H-score).[5]

5.2. Patient Population (Monotherapy Cohorts)

Data presented at ASCO 2025 (cut-off April 1, 2025) included 89 patients evaluable for safety and 74 for efficacy from the monotherapy dose escalation and expansion cohorts.[1]

• Diagnosis: Patients had histologically or cytologically confirmed metastatic or extensive-stage SCLC (ES-SCLC) with documented disease progression during or after at least one prior platinum-based chemotherapy regimen. For some cohorts, a maximum of three prior regimens in the metastatic/extensive stage setting was permitted.[5]
• Performance Status: Patients generally had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.[5]
• Prior Treatment History: The enrolled population was heavily pretreated. Approximately 90% of patients had progressed after prior anti-PD-(L)1 immunotherapy. About 47% had received one prior line of therapy, while 53% had received two or more prior lines (with 33% having failed two or more, and 20% having failed three or more lines). Notably, 10 patients (11% of the ASCO 2025 cohort) had received a prior DLL3-targeted bispecific antibody, such as tarlatamab.[1]
• Brain Metastases: A significant proportion of patients (30%, or 27 out of 89 in the ASCO 2025 cohort) presented with brain metastases at baseline; 8 of these cases had untreated brain lesions.[1]
• DLL3 Expression: Tumor tissue (either archived samples or fresh biopsies) was collected for the assessment of DLL3 expression levels (H-score). Clinical responses were observed across the full spectrum of DLL3 expression evaluated (H-score range: 0-260).[5]

5.3. Pharmacokinetics (PK)

Pharmacokinetic data from 25 patients in the dose escalation phase indicated [5]:

• ZL-1310 exhibited dose-proportional increases in systemic exposure for both the intact ADC and its cytotoxic payload.
• The systemic exposure to the free (unconjugated) payload was relatively low, suggesting good stability of the TMALIN® linker in circulation.
• No significant accumulation of either the ADC or the payload was observed with the Q3W dosing schedule.

5.4. Efficacy Results (Monotherapy)

The efficacy data, primarily from the ASCO 2025 presentation (data cut-off April 1, 2025; n=74 efficacy-evaluable patients from monotherapy cohorts unless otherwise specified), demonstrated promising anti-tumor activity.[1] Earlier data from the EORTC-NCI-AACR (ENA) Symposium 2024 (n=19 evaluable) provide additional context.[6]

• Overall Antitumor Activity (all doses, all lines of therapy, n=74):
• An objective response (confirmed or unconfirmed) was observed in 38 patients.
• Of these 38 responders, 29 (76%) remained on study treatment at the time of data cut-off.
• The longest duration of response was ongoing at over 9 months.
• A reduction in tumor burden was experienced by 89% of patients.
• Second-Line (2L) ES-SCLC (n=33, across all tested dose levels):
• Unconfirmed ORR (uORR): 67%
• DCR: 97%
• Second-Line (2L) ES-SCLC (1.6 mg/kg dose, n=14):
• uORR: 79%
• DCR: 100%
• This dose level was highlighted as demonstrating the most promising balance of efficacy and tolerability.[1]
• Activity in Patients with Brain Metastases (n=22 response-evaluable with baseline brain metastases, ASCO 2025):
• ORR: 68%
• Notably, in patients who had not received prior cranial irradiation (potentially indicating more active or untreated brain lesions), the ORR was 86%.
• The ENA 2024 presentation reported that all 6 evaluable patients with baseline brain metastases achieved a Partial Response (PR).[6]
• Impact of DLL3 Expression Levels: Clinical responses were observed across the entire spectrum of DLL3 expression levels evaluated (H-score range: 0-260), suggesting that high DLL3 expression may not be an absolute prerequisite for activity.[5] The ENA 2024 data also noted responses in tumors with H-scores as low as 5, although one patient with a DLL3-negative tumor did not respond.[6]
• Activity Post-Prior DLL3 Bispecific Therapy: Encouragingly, responses were also seen in patients who had previously been treated with a DLL3-targeted bispecific antibody (e.g., tarlatamab), indicating potential non-cross-resistance.[1]
• Response Trends: As might be expected, response rates appeared to decline with an increasing number of prior treatment lines and at the higher dose levels (above 2.0 mg/kg). This could reflect the more advanced and refractory nature of the disease in heavily pretreated patients, as well as potential tolerability limitations at the uppermost doses.[1]
• Duration of Response (DOR): The median DOR was not yet reached at the ASCO 2025 data cut-off, with a median follow-up of 3.4 months for the overall population. Many responses were ongoing.[1]
• Early ENA 2024 Data (n=19 evaluable, October 2024 cut-off [6]):
• ORR: 74% (14 PRs) (95% CI, 48.8%-90.9%).
• Median Time to Response (TTR): 1.38 months (range, 1.2-2.8 months).

5.5. Safety and Tolerability (Monotherapy)

The safety profile of ZL-1310, particularly at doses below 2.0 mg/kg, was reported as generally well-tolerated. Data are primarily from the ASCO 2025 presentation (n=89 safety-evaluable patients from monotherapy cohorts) [1], with earlier data from ENA 2024 (n=25) for context.[6]

• Dose-Limiting Toxicities (DLTs) in Part 1a: A single DLT, consisting of Grade 4 transient neutropenia and thrombocytopenia, was reported in one patient at the 2.4 mg/kg dose level.[5]
• Safety in Dose Cohorts <2.0 mg/kg (ASCO 2025 Data):
• Grade ≥3 TRAEs: 6%
• Serious TRAEs: 4%
• Most Common Grade ≥3 TRAEs: Anemia (2%), Neutropenia (4%).
• Treatment Discontinuations due to TRAEs: 0%
• Grade ≥3 Interstitial Lung Disease (ILD): 0%
• Safety Across All Dose Cohorts (ASCO 2025 Data, n=89):
• Any-grade TRAEs: 73%.[9] (The JCO abstract [5] reported 89% for "any-grade treatment-related adverse events (TRAEs)" in 28 patients; this discrepancy may be due to different patient numbers, data cut-off dates, or reporting conventions for all TEAEs versus specifically TRAEs).
• Grade ≥3 TRAEs: 23%.[1] (The JCO abstract [5] reported 39% in its cohort of 28 patients).
• Serious TRAEs: 21%.
• Most Common Grade ≥3 TRAEs: Anemia (11%), Neutropenia (14%). (The JCO abstract [5] also listed thrombocytopenia (3 patients) and decreased white blood cell count (2 patients) in its smaller cohort).
• Treatment Discontinuations due to TRAEs: 5 patients (6%), all of whom were in the higher dose cohorts (≥2.0 mg/kg).
• Grade ≥3 Treatment-Related ILD: 2 cases (2.2%) were reported; one occurred at the 2.0 mg/kg dose and one at the 2.4 mg/kg dose.[1]
• Earlier ENA 2024 Safety Data (n=25 safety-evaluable [6]):
• Any-grade TEAEs: 96.0%; ZL-1310 related TEAEs: 84.0%.
• Grade ≥3 TEAEs: 40%; ZL-1310 related Grade ≥3 TEAEs: 20%.
• Serious TEAEs: 24.0%; ZL-1310 related Serious TEAEs: 8.0%.
• No patients had discontinued therapy due to TEAEs at that earlier data cut-off.

The Phase 1a/1b trial data, particularly from the ASCO 2025 update, strongly suggest that ZL-1310, especially at doses around 1.6 mg/kg, offers a highly encouraging efficacy-safety profile for patients with 2L ES-SCLC. The ORR of 79% in this specific cohort is noteworthy, especially when coupled with a relatively low rate of Grade ≥3 TRAEs (6% for doses <2.0 mg/kg) and no treatment discontinuations due to TRAEs at these lower doses. The observed clinical activity in patients with brain metastases, a frequent and particularly challenging manifestation of SCLC, further underscores its potential clinical value. SCLC is characterized by its aggressive nature and initial sensitivity to chemotherapy, often followed by rapid relapse and the development of treatment resistance. Consequently, effective second-line options are scarce. An ORR of 79% in this challenging setting is exceptionally high. The ability to identify an optimal dose range (specifically <2.0 mg/kg, with 1.6 mg/kg demonstrating excellent responses) where ZL-1310 can be administered effectively with manageable toxicity is crucial for any ADC. Intracranial activity is a significant differentiating factor for SCLC therapeutics, as brain metastases are prevalent and often poorly responsive to systemic treatments.

The observation of clinical efficacy across the full spectrum of DLL3 expression levels (H-score 0-260) and, notably, in a patient previously treated with a DLL3-targeted bispecific antibody (tarlatamab) [5], implies that ZL-1310's mechanism of action—potentially amplified by the TMALIN® platform's bystander effect and the potency of its payload—may circumvent some limitations associated with target density-dependent therapies or certain acquired resistance mechanisms. This finding significantly broadens its potential applicability within the SCLC patient population and possibly to other DLL3-expressing tumors. If ZL-1310's efficacy were strictly confined to tumors with very high DLL3 expression, a substantial fraction of SCLC patients might not derive benefit. Activity in tumors with low H-scores suggests that either very few ADC molecules are required for cell kill (owing to high payload potency or efficient delivery and release) or that the bystander effect is sufficiently robust to eradicate nearby low-expressing cells. Furthermore, achieving a response after prior DLL3-targeted therapy is a critical observation. It suggests a lack of complete cross-resistance, which could be attributed to several factors: ZL-1310 might bind to a different epitope on DLL3, its ADC mechanism of action is distinct from that of a BiTE, or it may overcome specific resistance mechanisms that developed against the prior BiTE therapy. While requiring further investigation, this is a very positive signal for its potential role in the SCLC treatment armamentarium.

Table 2: Overview of Phase 1a/1b Clinical Trial Design (NCT06179069)

Parameter	Detail	Reference(s)
Phase	1a (Monotherapy Dose Escalation) / 1b (Dose Optimization/Expansion)	5
Study Type	Open-label, multicenter, global (USA, Europe, China)	1
Key Primary Endpoints	Safety, Tolerability, Dose-Limiting Toxicities (DLTs), Maximum Tolerated Dose (MTD), Recommended Phase 2 Dose (RP2D)	5
Key Secondary Endpoints	Objective Response Rate (ORR per RECIST v1.1), Duration of Response (DOR), Disease Control Rate (DCR), Pharmacokinetics (PK)	5
Key Eligibility Criteria	Extensive-Stage Small Cell Lung Cancer (ES-SCLC), progression after ≥1 prior platinum-based chemotherapy, ECOG performance status 0-1	5
Dose Cohorts (Monotherapy)	0.8, 1.2, 1.6, 2.0, 2.4, 2.8 mg/kg Intravenously (IV) every 3 weeks (Q3W)	1
Combination Arms Planned	ZL-1310 + Atezolizumab; ZL-1310 + Atezolizumab + Carboplatin	6

Table 3: Summary of Efficacy Results for ZL-1310 Monotherapy in ES-SCLC (ASCO 2025 Data)

Patient Subgroup	N (Evaluable)	ORR (uORR)	DCR	Median DOR (months)	Notes	Reference(s)
Overall (All Doses, All Lines)	74	38/74 (Includes confirmed & unconfirmed)	N/A	NE (29/38 responders ongoing)	89% experienced tumor burden reduction; longest response >9 months.	1
2L SCLC (All Doses)	33	67%	97%	NE		1
2L SCLC (1.6 mg/kg)	14	79%	100%	NE	Most promising efficacy/tolerability.	1
Patients with Baseline Brain Metastases	22	68%	N/A	NE	ORR 86% in those without prior cranial irradiation.	1
Activity by DLL3 H-score	N/A	-	-	-	Responses observed across all DLL3 expression levels (H-score 0-260); including after prior DLL3 BiTE.	5

NE: Not Estimable; uORR: unconfirmed Objective Response Rate; DCR: Disease Control Rate; 2L: Second-Line.

Table 4: Summary of Treatment-Related Adverse Events (TRAEs) for ZL-1310 Monotherapy (ASCO 2025 Data, n=89 Safety Evaluable)

Adverse Event Category	Incidence in <2.0 mg/kg Cohorts (%)	Incidence Across All Dose Cohorts (%)	Key Specific TRAEs (All Cohorts, Grade ≥3, %)	Reference(s)
Any TRAE	N/A (reported as 73% overall)	73%	-	9
Grade ≥3 TRAE	6%	23%	Anemia (11%), Neutropenia (14%)	1
Serious TRAE	4%	21%	-	1
Discontinuation due to TRAE	0%	6% (5 patients, all in ≥2.0 mg/kg)	-	1
Grade ≥3 Treatment-Related ILD	0%	2.2% (2 cases: one at 2.0, one at 2.4 mg/kg)	Interstitial Lung Disease (2.2%)	1

N/A: Not explicitly provided for this subgroup in summarized sources but implied by "well-tolerated safety profile".

6. Therapeutic Indications and Potential

ZL-1310 is being developed primarily for ES-SCLC, with potential applications in other DLL3-expressing malignancies.

6.1. Primary Indication: Extensive-Stage Small Cell Lung Cancer (ES-SCLC)

The main focus of ZL-1310's clinical development is for patients with ES-SCLC, particularly in the relapsed/refractory setting after progression on at least one prior platinum-based chemotherapy regimen.[1] SCLC is an aggressive neuroendocrine carcinoma characterized by rapid growth, early metastasis, and poor prognosis, with limited effective treatment options after first-line therapy.[9]

6.2. Potential for Other DLL3-Expressing Tumors

DLL3 is known to be overexpressed in a variety of neuroendocrine tumors beyond SCLC, and its expression is generally associated with poor clinical outcomes.[3] Zai Lab has indicated a strategy to expand the clinical investigation of ZL-1310 across multiple high-need DLL3-expressing solid tumor types.[1] While the primary ongoing trial (NCT06179069) is focused on SCLC, another NCI-supported trial is listed as "A Study of ZL-1310 in Participants With Selected Solid Tumors," which may encompass a broader range of malignancies.[20]

6.3. Positioning in SCLC Treatment Landscape

ZL-1310 aims to be a potential first-in-class DLL3-targeted ADC for SCLC.[1] It addresses a significant unmet medical need in recurrent SCLC, where current therapeutic options are limited and often provide only modest and transient benefits.[3]

The "first-in-class" designation for a DLL3 ADC in SCLC is particularly relevant. While other therapeutic modalities targeting DLL3, such as Bi-specific T-cell Engagers (BiTEs) like tarlatamab, are also in development or approved, an ADC offers a distinct mechanism of cytotoxic payload delivery. This could provide a different efficacy and safety profile, potentially benefiting patients who are not candidates for, or who progress on, other DLL3-targeted agents. The observation of responses to ZL-1310 in a patient previously treated with tarlatamab supports this potential for non-cross-resistance and sequential use.[5]

If ZL-1310 demonstrates significant and durable efficacy in other DLL3-expressing neuroendocrine tumors, it could evolve into a "pipeline-in-a-product" for Zai Lab. This would substantially expand its market potential beyond SCLC. Given that many neuroendocrine tumors share molecular characteristics, including DLL3 expression, a successful outcome in SCLC—often considered one of the most aggressive and challenging neuroendocrine cancers—would provide a strong biological and clinical rationale for its evaluation in other DLL3-positive tumors, such as neuroendocrine prostate cancer or large cell neuroendocrine carcinoma of the lung.

7. Regulatory Status and Milestones

ZL-1310 has received significant regulatory support from the U.S. FDA, acknowledging its potential to address a serious unmet medical need in SCLC.

• FDA Orphan Drug Designation (ODD):
• ZL-1310 was granted ODD by the FDA in January 2025 for the treatment of Small Cell Lung Cancer (SCLC).[1]
• Significance: ODD is granted to drugs intended for rare diseases or conditions (affecting fewer than 200,000 people in the U.S.) or for drugs that may not be profitable to develop without incentives. This designation provides Zai Lab with several benefits, including potential market exclusivity for seven years upon approval, tax credits for qualified clinical trials, and waiver of the FDA Prescription Drug User Fee Act (PDUFA) filing fee.[3] It recognizes the potential of ZL-1310 to treat a patient population with high unmet needs.
• FDA Fast Track Designation:
• In May 2025, the FDA granted Fast Track Designation to ZL-1310 for the treatment of patients with extensive-stage SCLC.[6]
• Significance: Fast Track Designation is intended to facilitate the development and expedite the review of drugs that treat serious conditions and fill an unmet medical need. This designation allows for more frequent interactions with the FDA throughout the drug development process, eligibility for Accelerated Approval and Priority Review if relevant criteria are met, and Rolling Review, where a company can submit completed sections of its New Drug Application (NDA) for review by FDA, rather than waiting until every section of the NDA is completed.
• Future Plans and Timelines:
• Zai Lab plans to initiate a pivotal clinical trial for ZL-1310 in the second-line SCLC setting later in 2025, based on the encouraging Phase 1 data and an optimized dose selection.[1]
• The company is positioning ZL-1310 for a potential accelerated approval pathway, with a target approval date as early as 2027.[6]
• The first regulatory submission for ZL-1310 is anticipated as early as 2026.[1]

The rapid succession of ODD and Fast Track designations from the FDA is a strong positive signal. These designations are not granted routinely and reflect the FDA's assessment that ZL-1310 has shown promising early clinical data for a serious condition where current therapeutic options are insufficient. This can significantly de-risk the regulatory pathway, potentially shorten the time to market, attract further investment, and facilitate patient recruitment for pivotal trials by highlighting the drug's potential importance.

Table 5: Regulatory Milestones for ZL-1310

Designation	Regulatory Agency	Indication	Date Granted	Key Implications	Reference(s)
Orphan Drug Designation	FDA	Small Cell Lung Cancer (SCLC)	Jan 2025	Market exclusivity, tax credits, fee waivers, recognition of unmet need.	3
Fast Track Designation	FDA	Extensive-Stage Small Cell Lung Cancer (ES-SCLC)	May 2025	Facilitated development, expedited review, more frequent FDA interactions, potential for Accelerated Approval and Priority Review, Rolling Review.	6

8. Discussion and Future Perspectives

ZL-1310 has emerged as a highly promising ADC candidate, particularly for patients with ES-SCLC, a disease historically characterized by limited treatment advances and poor outcomes.

8.1. Summary of ZL-1310's Clinical Profile

The clinical data from the Phase 1a/1b trial (NCT06179069) reveal a compelling balance of efficacy and safety, especially at optimized dose levels.

• Efficacy: ZL-1310 has demonstrated impressive ORRs, particularly the 79% uORR at the 1.6 mg/kg dose in 2L ES-SCLC patients. Its activity in heavily pre-treated patients, those with challenging brain metastases, and across a range of DLL3 expression levels further underscores its potential breadth of benefit.[1]
• Safety: The safety profile appears manageable, especially at doses below 2.0 mg/kg, where Grade ≥3 TRAEs were reported in only 6% of patients with no treatment discontinuations due to TRAEs.[1] Hematological toxicities (anemia, neutropenia) are the most common significant TRAEs, which is not unexpected for an ADC with a topoisomerase I inhibitor payload. Interstitial Lung Disease (ILD) has been observed in a small number of patients (2.2% Grade ≥3 across all doses, none at <2.0 mg/kg), primarily at higher dose levels, and will require careful monitoring and management strategies in future studies.[1]

8.2. Potential Impact on SCLC Treatment Landscape

If the efficacy and safety profile of ZL-1310 are confirmed in pivotal trials, it could significantly alter the treatment landscape for r/r ES-SCLC. Given the limited options and modest outcomes with current standard-of-care therapies in this setting, a new agent with high response rates and manageable toxicity would be a major advancement. Its potential as a first-in-class DLL3-targeted ADC offers a novel mechanism of action for SCLC patients.

8.3. Future Development Plans

Zai Lab has outlined a clear path forward for ZL-1310:

• Pivotal Trial: Initiation of a registrational study in 2L ES-SCLC is planned for later in 2025, focusing on an optimized dose (likely around 1.6 mg/kg) versus standard of care.[1]
• Combination Therapies: The ongoing Phase 1b expansion cohorts are evaluating ZL-1310 in combination with atezolizumab, with or without carboplatin.[6] These studies are critical for understanding how ZL-1310 might integrate with current first-line chemo-immunotherapy backbones or be used in maintenance settings.
• Expansion to Other Tumors: There is a clear intent to explore ZL-1310 in other DLL3-expressing solid tumors, leveraging the biological rationale for DLL3 as a target in various neuroendocrine malignancies.[1]

8.4. Unmet Needs Addressed

ZL-1310 directly addresses the profound unmet medical need for more effective and better-tolerated therapies for SCLC, especially in the relapsed/refractory setting following progression on platinum-based chemotherapy and immunotherapy, where prognosis is particularly grim.

The decision to advance ZL-1310 into a pivotal trial based on Phase 1b data, with the goal of potential accelerated approval, reflects both the robustness of the current clinical results and the pressing need for new treatments in SCLC. Accelerated approval pathways are typically reserved for drugs that demonstrate a substantial improvement over available therapies for serious or life-threatening conditions. The high ORR observed, particularly the 79% at the 1.6 mg/kg dose in 2L SCLC, likely meets the threshold for such consideration. Concurrently, the exploration of ZL-1310 in combination with atezolizumab is a strategically important step. Since chemo-immunotherapy is the established first-line standard of care for ES-SCLC, understanding ZL-1310's efficacy and safety in combination, or its optimal sequencing with these agents, will be crucial for defining its ultimate role in the SCLC treatment algorithm.

The emergence of ILD as a TRAE, even if infrequent and primarily at higher doses, warrants diligent characterization and proactive mitigation strategies in upcoming pivotal trials. A thorough understanding of potential risk factors for ILD, along with clear guidelines for monitoring and management, will be essential for ensuring patient safety. Similarly, while hematological toxicities are common with topoisomerase I inhibitor-based ADCs and appear manageable with ZL-1310 based on current data [5], establishing well-defined protocols for supportive care (e.g., use of G-CSF) and dose modifications will be critical for maintaining dose intensity and preserving patient quality of life in larger studies.

9. Conclusion

ZL-1310 (zocilurtatug pelitecan) has rapidly emerged as a highly promising, investigational first-in-class Delta-like ligand 3 (DLL3)-targeted antibody-drug conjugate. Its development is significantly enhanced by the innovative TMALIN® platform, which appears to confer a favorable therapeutic window by ensuring payload stability in circulation and enabling efficient, dual-mechanism (extracellular and intracellular) payload release within the tumor microenvironment.

The key strengths of ZL-1310, as evidenced by the latest Phase 1a/1b clinical trial data, include potent anti-tumor activity in heavily pretreated patients with extensive-stage small cell lung cancer (ES-SCLC). This includes remarkable objective response rates, particularly at the 1.6 mg/kg dose level in the second-line setting, and encouraging activity in challenging patient subgroups such as those with brain metastases and across a range of DLL3 expression levels. The safety profile, especially at doses below 2.0 mg/kg, appears manageable, with hematological toxicities being the most common significant treatment-related adverse events, and a low incidence of severe interstitial lung disease observed primarily at higher doses.

With strong regulatory support from the FDA in the form of Orphan Drug and Fast Track Designations, and with pivotal trials planned for initiation in late 2025, ZL-1310 is well-positioned to potentially become a significant new therapeutic option for patients with SCLC. Its future development will focus on confirming its efficacy and safety in larger, randomized studies, further optimizing its use in combination regimens, and exploring its potential in other DLL3-expressing malignancies. If successful, ZL-1310 could offer a much-needed breakthrough for a patient population with historically limited treatment options and poor prognoses.

Works cited

1. Zai Lab Presents Positive Phase 1 Data for ZL-1310, a DLL3-Targeted ADC, Demonstrating Robust Anti-Tumor Activity and Safety in Patients with Extensive-Stage Small Cell Lung Cancer at 2025 ASCO Annual Meeting - BioSpace, accessed June 11, 2025, https://www.biospace.com/press-releases/zai-lab-presents-positive-phase-1-data-for-zl-1310-a-dll3-targeted-adc-demonstrating-robust-anti-tumor-activity-and-safety-in-patients-with-extensive-stage-small-cell-lung-cancer-at-2025-asco-annual-meeting
2. Zai Lab Presents Positive Phase 1 Data for ZL-1310, a DLL3-Targeted ADC, Demonstrating Robust Anti-Tumor Activity and Safety in Patients with Extensive-Stage Small Cell Lung Cancer at 2025 ASCO Annual Meeting, accessed June 11, 2025, https://ir.zailaboratory.com/news-releases/news-release-details/zai-lab-presents-positive-phase-1-data-zl-1310-dll3-targeted-adc
3. Zai Lab Receives Orphan Drug Designation from the U.S. FDA for ..., accessed June 11, 2025, https://zailab.gcs-web.com/news-releases/news-release-details/zai-lab-receives-orphan-drug-designation-us-fda-zl-1310-dll3-adc/
4. Zai Lab to Present Data from Phase 1 Trial of DLL3-Targeted Antibody-Drug Conjugate (ADC) ZL-1310 at 2025 ASCO Annual Meeting, accessed June 11, 2025, https://zailab.gcs-web.com/zh-hant/node/13696/pdf
5. ZL-1310, a DLL3 ADC, in patients with extensive stage small cell ..., accessed June 11, 2025, https://ascopubs.org/doi/abs/10.1200/JCO.2025.43.16_suppl.3041
6. FDA Grants Fast Track Designation to ZL-1310 in Extensive Stage ..., accessed June 11, 2025, https://www.oncnursingnews.com/view/fda-grants-fast-track-designation-to-zl-1310-in-extensive-stage-sclc
7. ZL-1310 Receives FDA Fast Track Designation for Extensive-Stage SCLC - CancerNetwork, accessed June 11, 2025, https://www.cancernetwork.com/view/zl-1310-receives-fda-fast-track-designation-for-extensive-stage-sclc
8. FDA grants ODD status to Zai Lab's lung cancer treatment - Pharmaceutical Technology, accessed June 11, 2025, https://www.pharmaceutical-technology.com/news/fda-zai-lung-cancer/
9. ZL-1310 ASCO 2025 Highlights - Public now, accessed June 11, 2025, https://docs.publicnow.com/viewDoc.aspx?filename=176963\EXT\51DAE5F37DDBAB9B03C798E0B597347A8F077662_441A6B11C019486015A051981F89D48D05C257AF.PDF
10. Zai Lab to Present Data Highlighting ZL-1310, a Novel Antibody ..., accessed June 11, 2025, https://ir.zailaboratory.com/news-releases/news-release-details/zai-lab-present-data-highlighting-zl-1310-novel-antibody-drug/
11. Zai Lab Announces Strategic Partnership with MediLink Therapeutics to Develop a Novel LRRC15 Antibody-Drug Conjugate, accessed June 11, 2025, https://ir.zailaboratory.com/news-releases/news-release-details/zai-lab-announces-strategic-partnership-medilink-therapeutics/
12. MediLink Therapeutics Announces Strategic Partnership with Zai Lab to Develop a Novel LRRC15 Antibody-Drug Conjugate, accessed June 11, 2025, https://medilinkthera.com/news-details/43
13. Abstract 4702: MediLink's TMALIN ADC linker technology: Tumor ..., accessed June 11, 2025, https://aacrjournals.org/cancerres/article/84/6_Supplement/4702/740109/Abstract-4702-MediLink-s-TMALIN-ADC-linker
14. ZL-1310 ASCO 2025 Highlights - Zai Lab Limited, accessed June 11, 2025, https://ir.zailaboratory.com/static-files/2bdf1162-491d-44f8-9f11-e774f27ecaa4
15. www.cancer.gov, accessed June 11, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/anti-dll3-adc-zl-1310#:~:text=Upon%20administration%2C%20anti%2DDLL3%20ADC,yet%20unknown%20mechanism%20of%20action.
16. Definition of anti-DLL3 ADC ZL-1310 - NCI Drug Dictionary, accessed June 11, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/anti-dll3-adc-zl-1310
17. Zai Lab Presents Positive Phase 1 Data for ZL-1310, a DLL3-Targeted ADC, Demonstrating Robust Anti-Tumor Activity and Safety in Patients with Extensive-Stage Small Cell Lung Cancer at 2025 ASCO Annual Meeting - 1stOncology, accessed June 11, 2025, https://www.1stoncology.com/blog/zai-lab-presents-positive-phase-1-data-for-zl-1310-a-dll3-targeted-adc-demonstrating-robust-anti-tumor-activitysafety-in-patients-with-extensive-stage-small-cell-lung-cancer-at-2025-asco-annual-meeti1/
18. Zai Lab Presents Positive Phase 1 Data for ZL-1310, a DLL3-Targeted ADC, Demonstrating Robust Anti-Tumor Activity and Safety in Patients with Extensive-Stage Small Cell Lung Cancer at 2025 ASCO Annual Meeting, accessed June 11, 2025, https://ir.zailaboratory.com/zh-hant/news-releases/news-release-details/zai-lab-presents-positive-phase-1-data-zl-1310-dll3-targeted-adc/
19. A Study of ZL-1310 in Patients With Small Cell Lung Cancer > Clinical Trials > Yale Medicine, accessed June 11, 2025, https://www.yalemedicine.org/clinical-trials/zl-1310-001-an-open-label-multicenter-study-of-zl-1310-in-subjects-with-small-cell-lung-cancer
20. Clinical Trials Using Anti-DLL3 ADC ZL-1310 - NCI, accessed June 11, 2025, https://www.cancer.gov/research/participate/clinical-trials/intervention/anti-dll3-adc-zl-1310
21. Zai Lab Announces Acceptance of Supplemental New Drug Application for Repotrectinib for Patients with NTRK-Positive Solid Tumors - Stock Titan, accessed June 11, 2025, https://www.stocktitan.net/news/ZLAB/zai-lab-announces-acceptance-of-supplemental-new-drug-application-umog9p4v4qbr.html