The first patient (FIP) has been dosed in a Phase 1 clinical trial combining IDE849 (also known as SHR-4849), a potential first-in-class delta-like ligand 3 (DLL3)-targeting Topoisomerase I (Topo-I-) payload antibody drug conjugate (ADC), with IDE161, a potential first-in-class poly(ADP-ribose) glycohydrolase (PARG) inhibitor. Both drugs are being developed by IDEAYA Biosciences. The Phase 1 combination study will be evaluated in DLL3 upregulated solid tumor indications, including small cell lung cancer (SCLC), neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs), and melanoma.
According to the International Agency for Research on Cancer, there were 2.48 million people diagnosed with lung cancer in 2022. Of those, small-cell lung cancer was diagnosed in 11.5% of men and 9.7% of women. Small-cell lung cancer has limited treatment options and a poor prognosis.
Delta-like ligand-3 (DLL3)
Delta-like ligand-3 (DLL3) is a single-pass, type I transmembrane protein that inhibits Notch signaling. The Notch signaling pathway is a highly conserved intercellular signaling pathway that regulates embryonic development. The Notch signaling pathway is driven through the DSL family of Notch ligands. However, because DLL3 is a divergent, or mutated member of the DSL family expressed due to a mutation in the Notch gene. This mutation drives the overexpression of DLL3, which, in turn, inhibits Notch signaling in the DLL3-expressing cell and does not initiate Notch signaling in adjacent cells.
Clinically, DLL3 is a clear biomarker for SCLC, with its overexpression observed in 75% to 80% of SCLC clinical trial populations and unlikely to be found in normal or healthy cells. Notch mutations that drive DLL3 expression are exclusive to the lung, further emphasizing DLL3’s role as a biomarker for SCLC. However, DLL3 expression in SCLC and other neuroendocrine neoplasms (NEN) is heterogeneous and not well characterized.[1] And while highly expressed in SCLC, DLL3 expression in early clinical trials with other DLL3-targeting ADCs did not correlate with clinical benefit.
IDE849 is a humanized anti-DLL3 IgG1 monoclonal antibody conjugated to a DNA topoisomerase I inhibitor via a cleavable linker. Given the high expression of DLL3 in SCLC, the drug is being explored as a targeted treatment option for patients with limited therapeutic alternatives.
“We are excited about the progress in our Phase 1 IDE849 monotherapy study to determine the RP2D and to initiate a registrational study by year-end, and the advancement of our wholly owned first-in-class clinical combination of IDE849 and IDE161 in DLL3 upregulated solid tumor indications,” noted Yujiro S. Hata, President and Chief Executive Officer, IDEAYA Biosciences.
“We are leveraging our deep scientific expertise in DNA damage repair to enable this rational combination with IDE161, with the goal of inducing accumulation of TOP1 lesions to enhance the clinical efficacy and durability of our proprietary TOP1-payload ADCs, including IDE849 and IDE034, a Phase 1 B7H3/PTK7 bispecific TOP1 ADC,” added Michael White, Ph.D., Chief Scientific Officer, IDEAYA Biosciences.
Clinical studies
IDEAYA is advancing a multi-site global Phase 1 clinical trial for IDE849 in DLL3 upregulated solid tumor indications, including SCLC, NETs, and NECs, and melanoma (NCT07174583). The study will be enrolling patients globally, including in North America, Europe, Australia, South America, and Asia. In this ongoing Phase 1 dose-escalation study, IDE849 is evaluating a 3.5 mg/kg IV dose every 3 weeks (Q3W).
Next, to determine the recommended Phase 2 dose (RP2D), IDEAYA is also enrolling patients in an IDE849 expansion cohort at the 2.4 mg/kg IV dose Q3W, where multiple partial responses (PRs) have been observed by RECIST 1.1, including 3 PRs out of 4 SCLC patients pre-treated with tarlatamab (Imdelltra®; Amgen).[3] The preliminary safety and efficacy profile observed to date in the IDEAYA-sponsored study is consistent with the clinical data presented by the company’s China-region partner, Jiangsu Hengrui Pharmaceuticals Co., Ltd., at the IASLC World Conference on Lung Cancer 2025, held September 6 – 9, 2025, in the Fira de Barcelona Gran Via, in Barcelona, Spain.
In addition, IDE849 is being evaluated in a clinical combination with IDEAYA’s potential first-in-class Phase 1 PARG inhibitor, IDE161. IDEAYA has presented preclinical combination mechanism-of-action and synergy efficacy data for IDE161/PARG with TOP1-payload-based ADCs at WCLC 2025. IDE161 prevents the removal of poly(ADP-ribose) chains generated by PARP during the DNA damage response, leading to persistent PARylation and impaired resolution of DNA repair complexes. Together with TOP1-payload ADCs, this unique mechanism of action (MOA) results in sustained TOP1 cleavage complexes and the accumulation of DNA damage, thereby delivering enhanced anti-tumor activity. We believe this potential first-in-class combination could enhance the durability of IDEAYA’s TOP1-payload-based ADC pipeline, including IDE849 and IDE034 (Phase 1 B7H3/PTK7 Bispecific TOP1 ADC).
DLL3 has been reported to be upregulated in multiple solid tumor types, including SCLC, NETs, NSCLC, and melanoma, among others. DLL3 has limited extracellular expression in normal tissues, making it a promising potential therapeutic target in these solid tumors, for which there remains a significant unmet medical need.
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Clinical trials
A Study of IDE849 in Patients With DLL3 Expressing Tumors Including Small Cell Lung Cancer – ClinicalTrials.gov ID NCT07174583
A Study of PARG Inhibitor IDE161 in Participants With Advanced Solid Tumors – ClinicalTrials.gov ID NCT05787587
Prescribing Information
Tarlatamab (Imdelltra®; Amgen)[Prescribing Information]
Reference
[1] Serrano AG, Rocha P, Freitas Lima C, Stewart A, Zhang B, Diao L, Fujimoto J, Cardnell RJ, Lu W, Khan K, Sable B, Ellison AR, Wistuba II, Concannon KF, Halperin DM, Bogdan C, Sircar K, Zhang M, Cargill K, Wang Q, Aparicio A, Lazar A, Hernandez S, Estrella J, Ramalingam P, El-Naggar A, Kalhor N, Gay CM, Byers LA, Solis Soto LM. Delta-like ligand 3 (DLL3) landscape in pulmonary and extra-pulmonary neuroendocrine neoplasms. NPJ Precis Oncol. 2024 Nov 19;8(1):268. doi: 10.1038/s41698-024-00739-y. PMID: 39558076; PMCID: PMC11574146.
[2] Meng Y, Wang X, Yang J, Zhu M, Yu M, Li L, Liang Y, Kong F. Antibody-drug conjugates treatment of small cell lung cancer: advances in clinical research. Discov Oncol. 2024 Aug 1;15(1):327. doi: 10.1007/s12672-024-01171-1. PMID: 39090431; PMCID: PMC11294301.
[3] Dhillon S. Tarlatamab: First Approval. Drugs. 2024 Aug;84(8):995-1003. doi: 10.1007/s40265-024-02070-z. Epub 2024 Jul 18. PMID: 39023700.
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