IDEAYA and Hengrui’s DLL3 ADC IDE849 Shows Promising Phase 1 Results at WCLC 2025
IDEAYA and Hengrui’s IDE849 (SHR-4849) showed strong Phase 1 efficacy and manageable safety in relapsed/refractory SCLC at WCLC 2025. This report covers trial outcomes, CNS activity, dosing, licensing, regulatory status, and the DLL3 competitive landscape.
IDEAYA Biosciences (IDYA) and Hengrui Pharma presented updated Phase 1 results for DLL3-targeting ADC IDE849 (SHR-4849) at the 2025 World Conference on Lung Cancer (WCLC, Barcelona). The investigational TOP1 ADC demonstrated high response rates, durable signals, and a manageable safety profile in relapsed/refractory small cell lung cancer (SCLC).
Phase 1 Data Overview
The study enrolled 100 patients (87 SCLC, 13 neuroendocrine carcinomas) across doses from 0.8–4.2 mg/kg Q3W. Efficacy analysis focused on 71 SCLC patients treated at ≥2.4 mg/kg (data cutoff: June 20, 2025).
Table 1. IDE849 Phase 1 Efficacy in SCLC (≥2.4 mg/kg)
| Setting | ORR % (n) | Confirmed ORR % (n) | Pending % (n) | DCR % (n) |
|---|---|---|---|---|
| 2L (n=10) | 80.0% (8/10) | 70.0% (7/10) | – | 100% (10/10) |
| All-lines (n=19) | 73.7% (14/19) | 57.9% (11/19) | 5.3% (1/19) | 94.7% (18/19) |
| 2L pooled (n=35) | 77.1% (27/35) | 60.0% (21/35) | 11.4% (4/35) | 97.1% (34/35) |
| All-lines (n=71) | 73.2% (52/71) | 47.9% (34/71) | 14.1% (10/71) | 93.0% (66/71) |
Additional efficacy notes:
- Median PFS: 6.7 months (all-lines); not reached in 2L (n=42, 3.5-month median follow-up).
- Brain metastases: Confirmed ORR 66.7% (12/18) at ≥2.4 mg/kg; 83.3% (5/6) at 2.4 mg/kg.
Safety Profile
- Grade ≥3 TRAEs: 48%
- Neutropenia: 33%
- WBC reduction: 27%
- Anemia: 6%
- Serious TRAEs: 16%
- Dose reductions: 15%
- Treatment discontinuations: 2%
- No treatment-related deaths observed
IDE849 demonstrated a manageable hematologic safety profile and notably low discontinuation rates compared with other DLL3-targeted modalities, supporting a wider therapeutic window than earlier programs such as Rova-T.
Origins, Licensing, and Regulatory Status
- Origin: Developed by Hengrui Pharma as SHR-4849
- Licensing: IDEAYA licensed worldwide rights (ex-Greater China) in December 2024
- $75M upfront, up to ~$1.045B milestones, plus tiered royalties
- Regulatory: U.S. IND cleared in May 2025
- Next steps: Global Phase 1/2 expansion planned, including combinations with IDEAYA’s PARG inhibitor IDE161
Competitive Landscape — Who Else Is in the DLL3 Race?
IDE849 is emerging in a crowded DLL3 therapeutic space spanning ADCs, bispecifics, T-cell engagers, CAR-Ts, and radioligands.
- ZL-1310 (Zai Lab): TOP1 ADC, ~74% ORR (unconfirmed) in early Phase 1; Fast Track + Orphan Drug (2025); CNS activity reported
- Peluntamig (PT217, Phanes Therapeutics): DLL3 × CD47 bispecific antibody; Phase I/II SKYBRIDGE trial; Fast Track + Orphan Drug
- MK-6070 / DS-3280 (Merck/Daiichi Sankyo): DLL3 tri-specific T-cell engager; Phase I/II, including combo with atezolizumab; Orphan Drug designation
- Other emerging modalities:
- CAR-T (e.g., LB2102, Legend/Novartis)
- Radioligands (e.g., 225Ac-ABD147)
- Bispecific ADCs (e.g., BI 764532)
- Novel ADC platforms (e.g., ALPS12/RG6524)
- Historical setback: Rova-T (AbbVie) — DLL3-ADC with PBD payload; failed Phase 3 (ORR 12%, PFS ~3 months, 63% Gr3–5 AEs) due to toxicity
Comparative Snapshot
| Candidate | Modality | Stage | ORR (%) | PFS Trend | Notes |
|---|---|---|---|---|---|
| IDE849 (IDEAYA/Hengrui) | ADC (TOP1) | Ph 1/2 planned | 73% (all-lines) | 6.7 mo (not reached 2L) | Low discontinuation, CNS activity |
| ZL-1310 (Zai Lab) | ADC (TOP1) | Ph 1/2 | ~74 (early) | >6 mo est. | Fast Track; strong CNS data |
| Tarlatamab (Amgen) | BiTE (DLL3 × CD3) | Approved (2024) | ~40 | 4–5 mo | CRS risk; 1L/2L label |
| Peluntamig (PT217) | BsAb (DLL3 × CD47) | Ph 1/2 | N/A | TBD | Immune checkpoint angle |
What’s Next for IDE849
- Phase 1/2 expansion (2025): Dose optimization at 2.4–3.5 mg/kg
- Combination development: IDE849 + IDE161 (PARG inhibitor)
- Potential regulatory milestones: Breakthrough or Fast Track designation in SCLC
- Key watchpoints:
- Confirmation of high ORR rates with longer follow-up
- Durability of PFS/OS in 2L setting
- Validation of CNS activity
- Potential registrational pathway in 2L+ SCLC monotherapy
Outlook
IDE849 is a leading candidate in the DLL3 ADC class. While ZL-1310 sets a high efficacy bar, IDE849’s broader dose range, strong CNS activity, and favorable discontinuation profile may support best-in-class positioning as data mature.
Sources
- IDEAYA Biosciences. IDEAYA Biosciences and Hengrui Pharma Present Positive Phase 1 Data for IDE849 (SHR-4849), a Potential First-in-Class DLL3 TOP1 ADC, in Small Cell Lung Cancer at the IASLC 2025 World Conference on Lung Cancer.
- IDEAYA Biosciences. IDEAYA Biosciences Enters Exclusive License with Hengrui Pharma for SHR-4849, a Novel Phase-1 DLL3-Topo-I-Payload ADC Targeting SCLC and NET Solid Tumors.
- IDEAYA Biosciences and Hengrui Pharma. Phase 1 data for IDE849 (SHR-4849) in SCLC. WCLC 2025.
- Zai Lab. Zai Lab Presents Positive Phase 1 Data for ZL-1310, a DLL3-Targeted ADC, in Extensive-Stage Small Cell Lung Cancer at ASCO 2025.
- Yu, J.; et al. ZL-1310, a DLL3 ADC, in Patients with Extensive Stage Small Cell Lung Cancer: A Phase 1 Study. J. Clin. Oncol. 2025, 43 (16_suppl), 3041.
- Zai Lab. ZL-1310 Receives FDA Fast Track Designation for Extensive-Stage Small Cell Lung Cancer.
- Phanes Therapeutics. Peluntamig (PT217) development updates, 2025.
- Merck & Daiichi Sankyo. MK-6070/DS-3280 clinical trial disclosures, 2025.
- Legend Biotech/Novartis. DLL3 CAR-T (LB2102) pipeline update, 2025.
Disclaimer: This article is for informational purposes only and does not constitute medical or investment advice. Readers should consult primary literature and official regulatory sources for verification.