DLL3 expression

P1, N=20, Recruiting, Boehringer Ingelheim | N=35 --> 20 | Trial completion date: Aug 2026 --> Sep 2025 | Trial primary completion date: Aug 2026 --> Sep 2025

Her tumor strongly expressed DLL3 protein and had clinical response to tarlatamab therapy. This case indicates that this novel therapy may be an efficacious option in other pulmonary neuroendocrine cancers.

P1/2, N=203, Recruiting, Phanes Therapeutics | N=61 --> 203 | Trial completion date: Jun 2025 --> Aug 2028 | Trial primary completion date: Jan 2025 --> Dec 2027

We describe heterogenous DLL3 expression not only in SCLC but also in different NEN types. This comprehensive characterization of DLL3 can help guide future clinical trial design targeting DLL3 in NEN including LCNEC and EP-NEN that are lacking standard of care treatment options.

Our results suggest that ICI+chemo and DLL3-targeting agents are worth further exploration in EGFR+ NSCLC undergoing SCT.

The use of digital pathology software QuPath enhanced the accuracy and depth of analysis, allowing for detailed morphometric analysis and potentially informing more personalized treatment approaches. The findings emphasize the need for further research into the role of these markers in the management and treatment of SCLC, considering the poor prognosis and high mortality rate observed in the cohort.

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=282, Recruiting, Boehringer Ingelheim | Trial primary completion date: Sep 2024 --> Sep 2025

Both IHC and mRNA ISH showed significant correlation in tumors and lymph node metastasis. An observed trend suggested improved survival in patients with no DLL3 expression.

High-grade and low-grade MTC have different expression profiles. DLL3 should be explored as a predictor of aggressive disease and poor outcome in MTC.

Preclinical and nonclinical characterization suggests that HPN328 is a highly efficacious, safe, and novel therapeutic candidate. A phase 1/2 clinical trial is currently underway testing safety and efficacy in patients with DLL3 expressing malignancies.

Furthermore, we observed elevated memory phenotypes, induced durable responses, and activation under antigen-presenting cells in DLL3-DT CAR-T cells. Collectively, these findings suggest that DLL3-DT CAR-T cells may offer a novel and potentially effective therapeutic strategy for treating DLL3-expressing SCLC and other solid tumours.

Thus, our findings provide novel insights into the simultaneous evaluation of PDL1 and DLL3 biomarkers in SCLC patients. These insights have significant clinical implications for therapeutic strategies, survival prediction, and development of combination immunotherapies.

Integrating CellSearch, DEPArray, and low-pass sequencing provides a minimally-invasive approach to compare genomic characteristics in DLL3-positive and negative CTCs from SCLC patients. Extension of this approach to a larger patient cohort and employing machine learning algorithms will facilitate identification of patterns within diverse CNA profiles, improving patient stratification and predicting treatment responses for personalized therapeutic strategies in SCLC.

This study highlights the discordance of subtype-specific proteins and therapeutic markers between SCLC primary tumors and LN metastases. Additionally, our findings have therapeutic and prognostic implications and warrant further clinical investigation.

P1/2, N=30, Recruiting, Boehringer Ingelheim | Trial completion date: Oct 2024 --> Feb 2025 | Trial primary completion date: Oct 2024 --> Feb 2025

In patients diagnosed at an early stage who did not have metastasis and who underwent chemotherapy, DLL3high and ASCL1high SCLCs and type I LCNECs were associated with a better prognosis and a lower risk of death. The present findings suggested that DLL3/ASCL1 are potential therapeutic targets and prognostic indicators in patients with SCLCs or LCNECs.

P1, N=35, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

HPN328 is well tolerated and clinically active. MTD determination, dose escalation, and dose optimization are ongoing. Updated safety and efficacy results including recently enrolled NEPC and SCBC pts will be presented.

P1, N=250, Recruiting, Boehringer Ingelheim | Trial completion date: Sep 2024 --> Jul 2025

P1, N=35, Not yet recruiting, Boehringer Ingelheim | Trial completion date: Nov 2025 --> Aug 2026 | Trial primary completion date: Oct 2025 --> Aug 2026

No abstract available

There is a high prevalence of DLL3 expression in SCLC. Further research and analytical methods may help to characterize different populations of patients with SCLC based on DLL3 expression. While no significant prognostic factor in the included studies was identified, additional cohort studies using standardized methodology, with longer follow-up, are needed to better characterize any potential differences in patient survival or response by DLL3 expression level in SCLC.

P=N/A, N=41, Recruiting, Memorial Sloan Kettering Cancer Center | N=31 --> 41

Therefore, DLL3 could be considered a biomarker for better prognosis in resectable PDAC patients as well as a therapeutic biomarker for immunotherapy response. These facts set a rationale for testing anti-DLL3-based treatments either alone or combined with immunotherapy or other NOTCH1 inhibitors.

Our results provide clinical insights into the diagnostic, prognostic and predictive significance of SCLC molecular subtype classifications.

While treatment with platinum and etoposide chemotherapy and a programmed death-ligand 1 (PD-L1) inhibitor has modest benefit for a subset of patients, most patients develop resistance and relapse. The increased cytotoxic activity observed with the combination of tarlatamab and chemotherapy and/or anti-PD-L1 treatment suggests that tarlatamab may be used together with standard of care therapy to increase response rate or durability. These data support the continued clinical evaluation of tarlatamab in patients with SCLC, including in combination with chemo-immune therapy in the first-line setting.

Furthermore, the tumor lysing capacity of CD70 armored CAR-T cells was not compromised to TGF-β (transforming growth factor β) inhibition compared to the conventional CAR-T cells. Conclusions Collectively, our study indicates a combine of a proximal targeting CAR and an armored CD70 construct improve CAR-T persistence and antitumor activity in vitro and in vivo, and result in a potential DLL3 CAR candidate for further preclinical and clinical studies.

Although SCLC with DLL3 had a higher neoantigen load, these tumors were resistant to immunochemotherapy due to suppressed tumor immunity by inhibiting antigen-presenting functions.

In the dose escalation part, the primary endpoint is dose-limiting toxicity (DLT) occurrence in the MTD evaluation period; secondary endpoints include DLT occurrence in the on-treatment period, objective response and pharmacokinetics. Enrolment is ongoing.

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.

Conclusions High DLL3 expression is associated with poor overall survival, advanced pathologic grade, and distinct immune landscape. Further development of DLL3-targeted therapies for high-grade NENs is warranted.

Future planned cohorts include every other week dosing and HPN328 + atezolizumab. Updated safety and efficacy results including pts recently enrolled in backfill cohorts will be presented.

Gastric NET G3 is a distinct entity with unique genetic characteristics, which are different from those of gNEC than gNET G2. Our results provide insight into some molecular alterations that may contribute to the development and progression of gNET G3 and serve as potential therapeutic targets.

P1, N=193, Recruiting, Boehringer Ingelheim | Trial completion date: Apr 2024 --> Sep 2024 | Trial primary completion date: Apr 2024 --> Sep 2024

P1, N=35, Not yet recruiting, Boehringer Ingelheim

P=N/A, N=31, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jun 2023 --> Jun 2026 | Trial primary completion date: Jun 2023 --> Jun 2026

P1, N=58, Recruiting, Phanes Therapeutics | Not yet recruiting --> Recruiting | Initiation date: Jan 2023 --> Jun 2023

P1/2, N=30, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

DLL3 expression was associated with stage and high DLL3 expression was observed to predict poorer overall survival (p = 0.004). It suggested that DLL3 may offer prognostic value and therapeutic potential for individualized treatment of COAD, and that it may has a diagnostic role in COAD.