Ongoing studies exploring the role of DLL3 as an emerging diagnostic marker are reviewed. Promising therapeutic options, such as antibody-conjugated drugs, CAR-T cells and radioimmunoconjugates, are also discussed.

P1, N=112, Recruiting, Zai Lab (Shanghai) Co., Ltd. | N=85 --> 112

These results suggest that DB-1314 may be a candidate ADC targeting DLL3 for the treatment of DLL3-positive SCLC, supporting further evaluation in the clinical setting.

Although toxicities exceeding expectations have been observed with Rova-T, drugs targeting TROP-2 (Sacituzumab Govitecan), B7-H3 (DS-7300), and SEZ6 (ABBV-011) have shown exciting clinical benefits. In this review, we collect the latest clinical evidence to describe the therapeutic efficacy and safety of ADCs in SCLC and discuss prospects and challenges.

P1, N=162, Recruiting, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting

DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies.

Rovalpituzumab tesirine (Rova-T) was the first DLL3-targeted antibody-drug conjugate (ADC) to enter clinical studies. The safety profile of FZ-AD005 was favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys. In conclusion, FZ-AD005 has the potential to be a superior DLL3-targeted ADC with a wide therapeutic window and is expected to provide clinical benefits for the treatment of SCLC patients.

P1, N=162, Not yet recruiting, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd.

P1, N=85, Recruiting, Zai Lab (Shanghai) Co., Ltd. | N=140 --> 85

Overall, 73.1% (49/67) of cervical cancer samples are CD138-positive with 38.8% (26/67) of cervical cancer samples showing at least moderate or high expression. (4) TROP2, CEACAM5 or CD138 do seem suitable for further clinical research and the data presented here might be used to guide further clinical trials with ADCs in advanced and recurrent cervical cancer patients.

Although rovalpituzumab tesirine (Rova-T) showed promise in a phase II study, it failed to produce favorable results in subsequent phase III trials, leading to the cessation of its development...Tarlatamab, for instance, demonstrated enhanced response rates and progression-free survival compared to the standard of care in a phase II trial; its biologics license application (BLA) is currently under US Food and Drug Administration (FDA) review...DLL3-targeted therapies hold substantial potential for SCLC management. Future clinical trials will be crucial for comparing treatment outcomes among various approaches and exploring combination therapies to improve patient survival outcomes.

P1, N=140, Recruiting, Zai Lab (Shanghai) Co., Ltd. | Not yet recruiting --> Recruiting

P1, N=140, Not yet recruiting, Zai Lab (Shanghai) Co., Ltd.

Despite the negative results of rovalpituzumab tesirine (Rova-T), other ADCs targeting different antigens, such as B7-H3, seizure-related homolog 6 (SEZ6), and CEACAM5, have also been investigated in clinical trials, including for SCLC, and their results suggest preliminary activity, either alone or in combination with other therapies. More recently, sacituzumab govitecan, an anti-TROP2 ADC, demonstrated promising activity in lung cancer, including SCLC. Furthermore, an anti-B7-H3 (CD276), ifinatamab deruxtecan (DS7300A), showed a high response rate and durable responses in heavily pretreated SCLC...Further studies are needed to determine their efficacy and safety and the best location in the treatment algorithm for SCLC. In this review, we aim to collect and describe the results regarding the past, the present, and the future of ADCs in SCLC.

The Phase III clinical trials of Rova-T, a drug targeting DLL3, have not yielded the expected results. However, other drugs that target DLL3, such as AMG119, AMG757 and DLL3-targeted NIR-PIT, bring new ideas for SCLC treatment. Overall, DLL3 remains a valuable target for SCLC.

A comprehensive genomic characterization of MERU cohort advances understanding of SCLC's tumor heterogeneity though tumor-intrinsic molecular and genetic drivers; An extensive immunogenomic analysis reveals a distinctive tumor-immune interaction subtype of SCLC; Therapeutic vulnerabilities associated with SCLC intrinsic subtypes are uncovered through a computational framework for synthetic drug screening

Delta-like ligand 3 (DLL3)-targeted drug Rova-T was terminated due to insufficient efficacy, considering other factors that may affect efficacy...In addition, patients were divided into low-risk and high-risk for survival analysis based on the best cut-off value of 49.11 for nomogram, indicating that the model had great discrimination ability (mOS 13.33 vs. 7.80m, p<0.001). Table: 2018P Conclusions The OS prediction model for SCLC patients in this study has excellent predictive performance in predicting the 12-m survival probability and may assist clinicians in making more accurate judgments and guiding therapy of SCLC patients.

First, we discuss the clinical experience with rovalpituzumab tesirine (Rova-T), a DLL3-targeting ADC, the development of which was halted due to a lack of efficacy in phase 3 studies, with a view to understanding the lessons that can be garnered for the rapidly evolving therapeutic landscape in SCLC. We then review preclinical and clinical data for several DLL3-targeting agents that are currently in development, including the TCE molecules-tarlatamab (formerly known as AMG 757), BI 764532, and HPN328-and the CAR T-cell therapy AMG 119. We conclude with a discussion of the future challenges and opportunities for DLL3-targeting therapies, including the utility of DLL3 as a biomarker for patient selection and disease progression, and the potential of rational combinatorial approaches that can enhance efficacy.

ADCs seem to provide efficacy benefits, even with potential toxicity. The results of most prospective ongoing studies are still awaited, and a longer follow-up time is warranted to evaluate the real impact of ADCs in PCa.

Delta-like canonical Notch ligand 3 is a protein frequently overexpressed in SCLC and is therefore being explored as a potentially promising therapeutic target in high-grade neuroendocrine lung cancer. In this article, we critically review the activity and efficacy of old DLL3 inhibitors antibody-drug conjugate (ADC) and their failures through new compounds and their possible applications in clinical practice, with a focus on new molecular classification of SCLC.

SSP/SG compare themselves favorably to those of other options available in relapse. A phase II test is being recruited in the CBPC 3L+ (NCT05060016).

Strong membranous staining was necessary, but not sufficient, for anti-tumor activity. Rova-T has activity in a subset of neuroblastoma preclinical models, but heterogeneous expression in these models and the near absence of expression seen in human tumors suggests that any DLL3-targeting clinical trial should be only performed with a robust companion diagnostic to evaluate DLL3 expression for patient selection.

Currently, early-phase trials of ADCs in non-small cell lung cancer are rapidly gaining ground, with promising results targeting HER2 (human epidermal growth factor 2), HER3, TROP2 (trophoblast cell surface antigen 2), MET, CEACAM5 (carcinoembryonic antigen-related cell adhesion molecule 5), and PTK7 (tyrosine protein kinase-like 7). Unfortunately, in small cell lung cancer, trials targeting the ubiquitous DLL3 (delta-like ligand 3) protein have failed to show clinically relevant results, despite significant toxicity.

Current treatment options for NEN do not provide sustained responses. DLL3 is expressed on the cell surface of many NEN types and is associated with poor clinical outcomes. Initial clinical studies targeting DLL3 therapeutically in SCLC have been promising, and additional studies are expanding this approach to the broader group of NEN.

One BiTE® molecule in development, AMG 757, is directed against delta-like ligand 3 (DLL3), which is expressed in small cell lung cancer tumor cells...During the course of development of this bioassay, characterization of the SHP-77-Luc line showed an increase in the luminescence assay signal and Maximum-to-Minimum (Max-to-Min) ratio of the dose response curve as the passage number of the cells increased. Our research revealed an increase in not only luciferase expression but also an increase in the cell surface and intracellular expression levels of DLL3 over time in culture, which ultimately resulted in the increased assay signal window.

The immunotoxins had the right structure and can be produced in a prokaryotic host. The recombinant immunotoxins against DLL3 can be promising therapeutic agents for SCLC cancer.

ADC agents including trastuzumab emtansine, trastuzumab deruxtecan, sacituzumab govitecan, enfortumab vedotin, and rovalpituzumab tesirine were highly studied. Further clinical trials of ADCs and designs of the next generation of ADCs are the current focuses of the field. Acquired resistance of ADCs and biomarkers for ADC therapy efficacy monitoring are future concerns.

P1, N=182, Completed, AbbVie | Active, not recruiting --> Completed

Understanding the evolution of CAR structure and the generalizable requirements for manufacturing CAR T cells as well as the interplay between lung tumor immunology and CAR T cells will improve clinical translation of this therapeutic modality in lung cancer. In this review, we systematically summarize the latest advances in CAR T-cell therapy in lung cancer, focusing on the CAR structure, target antigens, challenges, and corresponding new strategies.

"Third-line therapies included rovalpituzumab tesirine (n=1), checkpoint kinase 1 inhibitor (n=1), irinotecan (n=1), or paclitaxel (n=4). In patients with relapsed SCLC, early clearance of ctDNA predicts an improvement in PFS and OS, and an early increase in peak VAF suggests chemoresistance. Larger cohorts are needed to validate this finding, and we are currently compiling additional patients and samples for a larger analysis."

Antibody-drug conjugates (ADCs) are rapidly establishing their place and have shown promising preliminary data in lung cancer with impressive response rates and survival outcomes in previously treated patients.There are several ADCs currently in clinical trials for NSCLC and small cell lung cancer (SCLC). These ADCs often have different targets which include HER2, HER3, TROP2, CEACAM5, and MET in NSCLC and DLL3 in SCLC.Here we review the safety, and efficacy of newer ADCs in lung cancer including ado-trastuzumab emtansine, trastuzumab deruxetecan, patritomab deruxetecan, datopotamab deruxetecan, sacituzumab govitecan, SAR408701, Telisotuzumab vedotin, rovalpituzumab tesirine, lorvotuzumab mertansine, and sacituzumab govitecan.  Several novel methods are underway to improve the safety and efficacy of ADCs which include increasing the drug to antibody ratio (DAR), the potency of the payload, using more innovative payloads and replacing the antibody.

Small cell lung cancer (SCLC) is frequently found disseminated at first presentation and holds a poor prognosis due to emerging resistance to first-line platinum-based and second-line topotecan chemotherapy. Chemosensitivity of the cell lines is not correlated with DLL3 protein expression possibly due to toxicity of the free payload in tissue culture. The clinical trials and experimental results demonstrate that refractoriness to ROVA-T is linked to a low initial tumor expression of DLL3, loss of DLL3 expression, higher chemoresistance to ROVA-T and the putative formation of resistant spheroids by the SCLC cells.

Rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate directed against Delta-like protein 3 (DLL3), is under development for patients with small cell lung cancer (SCLC). Unlike in chemonaive samples, a high DLL3 expression in chemorelapsed samples indicated a trend for a more favorable prognosis. Our results highlight the importance to investigate DLL3 in latest chemorelapsed SCLC tumor tissue.

Lower Rova-T doses may be associated with lower incidence of some Rova-T-related AESI. Rova-T 0.2 mg/kg + CE (Cohort 3) was tolerable; however, there was no clear efficacy benefit of adding Rova-T to CE.

However, the development of ROVA-T was suspended because of shorter overall survival compared to topotecan, the second-line standard treatment. Thus, several studies on the mechanism and function of DLL3 in several malignancies are underway to find a new strategy for targeting DLL3. In this review, we discuss the roles of DLL3 in various malignancies and the future perspectives of DLL3-related research, especially as a therapeutic target.

A DLL3-targeted antibody-drug conjugate, rovalpituzumab tesirine (Rova-T) has recently been developed for treatment of SCLC...The patients with ASCL1 and DLL3 high expression may represent a distinct subgroup of SCLC benefit from targeted therapy. Therefore, ASCL1 and DLL3 could be potential biomarkers served for selection of related patients.

Responses were confirmed in 15/145 patients (10%) treated at 0.3 mg/kg, including 9/69 patients (13%) with NEC/NET. Rova-T at 0.3 mg/kg q6w had manageable toxicity, with antitumor activity observed in patients with NEC/NET, melanoma, MTC, and glioblastoma.

Combination therapy with budigalimab and Rova-T had promising efficacy and appeared to be tolerated in patients with SCLC. Although Rova-T development has been discontinued, development of budigalimab combined with other anticancer agents is ongoing.

P1, N=182, Active, not recruiting, AbbVie | Trial completion date: Mar 2021 --> May 2022 | Trial primary completion date: Mar 2021 --> May 2022

Due to the lack of survival benefit in the Rova-T arm, the study did not meet its primary endpoint and was terminated early. As a result, CRAC assessment of PFS was not performed. The frequency of Grade ≥3 and drug-related toxicities were higher with Rova-T vs placebo. Rova-T was associated with unique toxicities such as pleural and pericardial effusions, photosensitivity reaction, and peripheral edema, which should be carefully considered in the ES SCLC population.

Kaplan-Meier analyses of statin use and HER2+gastric cancer disease outcome in patients treated with trastuzumab suggested that patients without statin treatment have worse survival than patients treated with a statin. Additionally, statins synergize with therapeutic antibodies to decrease oncogenic signaling pathways.Our data suggest that acute statin treatment with appropriate pharmacokinetics/pharmacodynamics are potential adjuvants for specific antibody-targeted therapies.

Despite encouraging antitumor activity in previously treated ES SCLC, combination therapy with Rova-T and nivolumab ± ipilimumab was not well tolerated at the dose levels and administration schedules evaluated.