DLL3 Therapeutics Surge: Bispecific Antibodies and ADCs Show Breakthrough Efficacy in Small Cell Lung Cancer and Neuroendocrine Carcinomas

Last year5Month,AmgenAnnounce,FDAAccelerated approval of its targetedDLL3/CD3Bispecific AntibodytarlatamabLaunched for the treatment ofExtensive-Stage Small Cell Lung Cancer（ES-SCLC) Adult patients.This is the first targeted therapy for solid tumors in the true sense.TCE, and successfully brokeTCEThe curse of the difficulty in developing entity drugs has also brought new hope to patients with extensive-stage small cell lung cancer. And at the upcoming event this year.ASCOAt the meeting, targetedDLL3Bispecific antibody targeting,ADCAll disclosed astonishing efficacy data,IncludingBI(Boehringer Ingelheim) ofTCEBispecific Antibodyobrixtamig, Zai Lab'sADC ZL-1310And Zelgen'sZG006。

First is Zai Lab'sADC ZL-1310, Currently, the drug has already been2025Year5Month19Day, received the U.S. Food and Drug Administration (FDA) Granted Fast Track Designation for the Treatment of Extensive-Stage Small Cell Lung Cancer (ES-SCLC). In the upcomingASCOAt the meeting, Zai Lab will update the Phase I clinical data of this therapy.

This clinical study is mainly divided into two parts for research.ZL-1310Treatment after progression on at least one platinum-containing chemotherapy regimenr/r SCLCPatient,Part 1AFor single-agent dose escalation,Part 2It is random dose optimization./Expansion.

As of2025Year1Month28Day, dose escalation phase (Part 1A) Total28Example: Patient Enrollment and AcceptanceZL-1310Treatment (Dose Range)0.8-2.8 mg/kg). The median study follow-up time was5.1Months (Range2.4-10.1+Month). Median age of patients66Years (Range36-79）；43%For women;75% ECOGPerformance status score is1Points;93%Previously received anti-PD-L1Progression after treatment;39%History of lung radiation therapy;36%Baseline brain metastases exist.

In28Observed in the example patients19Example of Objective Response (ORR 68%, including1Example pending confirmation), Disease Control Rate (DCR) Reach93%. Relief was observed in all dose groups and differentDLL3Expression Level (H-scoreScope0-260）, including1Example Previously ReceivedtarlatamabPatients treated.The response rate of patients with baseline brain metastases was80%，DCRAchieve100%。19Example of remitters14Example (74%) is still undergoing treatment.

In terms of safety：89%Patients experienced treatment-related adverse events of any grade (TRAEs）（≥3LevelTRAEsOccupying39%）。1Example patient (2.4 mg/kgGroup) experienced dose-limiting toxicity (neutropenia and thrombocytopenia);5Example: Patient due toTRAEsReduce the dose,5ExampleTRAEsDiscontinuation of the drug. The incidence rate exceeds1Example of≥3LevelTRAEsIncluding: Anemia (6Example), Neutropenia (5Example), Thrombocytopenia (3Example), Leukopenia (2Example) and interstitial lung disease (2Example)

BITheobrixtamig（BI 764532) is targetedDLL3TheTCEDual Antibody, which is1+1Asymmetry isIgG-likeThe bispecific antibody, andAmgen, Zelgen, Zai Lab are different, they are not focused onSCLC, but to develop treatments for neuroendocrine cancer in clinical practice.

NCT04429087 Is an ongoing IDose-escalation trial, evaluationobrixtamigInFailure of Standard TreatmentOf DLL3+Pulmonary and Extra-pulmonary Neuroendocrine Carcinoma (epNEC) PatientEfficacy and safety in China. This analysis compared DLL3High Expression vs. Low Expression epNECPatientDifference in efficacy. The clinical trial design is as follows:4Dose escalation regimen (R）Intravenous Administration:RA(Fixed dose, per3Once a week);RB1(Fixed dose, once a week);RB2(After stepwise dose escalation, once a week);RB3(After the stepwise dose escalation, the previous3Once a week, followed by every3Once a week);

The baseline of clinical patients disclosed this time is:60ExampleepNECPatients Included in the Analysis (Gastrointestinal and Pancreatic Origins)[GEP] 45.0%, Genitourinary System Origin[GU] 30.0%, Other/Unknown Primary 25.0%), among which DLL3High/Low expression each30ExampleAll patients had received systemic treatment,DLL3High-expression Group30.0%, Low-expression Group50.0% Have received＞2Line therapy.

In terms of efficacy:DLL3High-expression groupORR、DCRAnd the duration of relief (DoR）All were superior to the low-expression group.GEP（50.0%) andGU（60.0%) Source:DLL3Patients with high expression had the highest remission rate.7ExampleDLL3High-expression patients are still receiving treatment.IThe preliminary analysis of the phase study indicates,obrixtamigInDLL3Highly ExpressedepNECPatients showed better efficacy, especially with significant relief observed in tumors of gastrointestinal, pancreatic, and genitourinary origin.. The detailed clinical efficacy is shown in the table below, and will not be repeated here.

Let's take another look at the Phase II dose expansion clinical trial，60Patient with1：1Randomly assigned in10mgAnd30mgTwo Dose Groups（Q2W), as of2024Year12Month31Day,40Patients who have received at least oneZG006Treatment (10mg:19；30mg:21). All patients receivedZG006Before TreatmentHave all received2Line and above treatment, among which45%The patient has received3Line and above treatment，72.5%The patient previously receivedSubjected to immune checkpointTreatment.52.5%Hepatic metastasis occurred,20%Brain metastasis occurred.

In terms of efficacy,27Patients were evaluated (10mg:13；30mg:14），Its overallORRFor66.7%，DCRFor92.6%. Among them, in10mgDose Group,ORRFor53.8%，DCRFor84.6%；30mgDose Group,ORRUp to78.6%，DCRFor100%. Among themDoRAndPFSNot arrived yet. Besides, forDLL3Expression Analysis,21st
DLL3Low or medium expression overallORRFor71.4%。

In terms of safety: treatment-related adverse events (TRAEs) Occurs in35Example patients (87.5%); the most common (≥20%) including: fever (57.5%), Cytokine Release Syndrome (CRS，47.5%), vomiting (27.5%), Rash (25.0%), decreased appetite (25.0%), Elevated aspartate aminotransferase (22.5%), leukocyte count reduction (22.5%) and decreased platelet count (22.5%). Only5Example patient (12.5%) Appear3/4LevelTRAEs，Including1Example3LevelCRS`, without leading to treatment discontinuation or death`TRAEsCase

For comparison, let's take a look atAmgen tarlatamabClinical data,tarlatamabThe approval was based on a global2Phase Clinical TrialDeLLphi-301The result.From the perspective of admitted patients, whether it is the average number of treatment lines received by patients, the proportion of patients with metastasis, or whether they have previously received...PD-(L)1Treatment, which is equivalent to ZG006.

tarlatamabIn terms of efficacyAmong the patients who received treatment and were evaluated,10 mgThe median follow-up time for the group was10.6Months,100 mgGroup as10.3Months.10 mgGroup and100 mgGroups were divided into40%（97.5%  [CI]，29~52) and32%（97.5% CI，21~44) of patients achieved objective remission. Among these patients who achieved objective remission,59%（68Example patients40Example) The duration of relief is at least6months. As of the data cutoff,10 mgGroup40Among the patients22Example (55%) and100 mgGroup28Example patients16Example (57%) still maintains objective remission。10 mgGroupTheMedian progression-free survival was4.9Months（95% CI，2.9~6.7），100 mgGroupFor3.9Months（95% CI，2.6~4.4）。9The estimated overall survival rates at months were respectively68%And66%

Summary

tarlatamabThe approval and market launch means targeted activationTCell (TCE) Bispecific antibodies have achieved breakthroughs in solid tumors. AndZG006As the second generationDLL3 TCE, from the current clinical perspective, its efficacy is still very impressive, which also paves the way for subsequent other second-generationDLL3 TCEBrings hope. Given the current relatively small number of clinical patients, we look forward to subsequent clinical performance. Additionally, Zai Lab's ADC has also shown good efficacy in clinical settings. Although it has relatively high toxicity, it has broken our previous belief that low-expression targets are unsuitable for ADCs.

Scan the WeChat QR code, add the editor of the Antibody Circle, and those who meet the requirements can join the Antibody Circle WeChat group!

Please indicate: Name + Research Direction!

All reproduced articles in this official account are intended to convey more information, with clear attribution of sources and authors. Media or individuals who do not wish to be reproduced can contact us (cbplib@163.com), and we will immediately proceed with deletion. All articles represent the views of the authors and do not represent the position of this website.