SHR-4849 Shows Preliminary Activity With Manageable Safety in Relapsed Small Cell Lung Cancer

The DLL3-directed antibody-drug conjugate (ADC) SHR-4849 (IDE849) showed a tolerable safety profile and induced responses in patients with relapsed small cell lung cancer (SCLC), according to preliminary findings from a first-in-human phase 1 study (NCT06443489).1

The data shared during the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer showed that any treatment-related adverse effects (TRAEs) occurred in 92.0% of patients, with 48.0% at grade 3 or higher; only 2.0% of patients experienced TRAEs that led to treatment discontinuation, and none were fatal. Moreover, the most common grade 3 or 4 TRAEs were hematological toxicities.

When the agent was administered at a dose of 2.4 mg/kg or higher, it elicited an objective response rate (ORR) of 73.2% (95% CI, 61.4%-83.1%) in all patients (n = 71); the confirmed ORR was 47.9% (95% CI, 35.9%-60.1%), and 14.1% of patients had responses pending confirmation. The disease control rate (DCR) was 93.0% (95% CI, 84.3%-97.7%). When SHR-4849 was given at a dose of at least 2.4 mg/kg in the second-line setting (n = 35), it led to an ORR of 77.1% (95% CI, 59.9%-89.6%); the confirmed ORR was 60.0% (95% CI, 42.1%-76.1%), and 11.4% of patients had responses pending confirmation. In this group, the DCR was 97.1% (95% CI, 85.1%-99.9%).

“SHR-4849 demonstrated a tolerable and manageable safety profile in patients with relapsed SCLC,” Linlin Wang, MD, PhD, of Affiliated Cancer Hospital of Shandong First Medical University, in Jinan, China, said in a presentation of the data. “SHR-4849 [given] at [a dose of] 2.4 mg/kg or higher exhibited promising antitumor activity, especially in the second-line setting. Follow-up is ongoing to assess the long-term outcomes.”

What Was the Design of the Phase 1 Study Examining SHR-4849?

The open-label, multicenter, phase 1 study enrolled patients with histologically or cytologically confirmed relapsed or metastatic SCLC and other neuroendocrine carcinomas expressing DLL3. These patients had progressive or recurrent disease following standard therapy and an ECOG performance status no higher than 1.

The ADC was given intravenously every 3 weeks (Q3W) at a starting dose of 0.8 mg/kg using an accelerated titration dose-escalation followed by Bayesian design. Other doses evaluated included 2.4 mg/kg, 3.5 mg/kg, 4.2 mg/kg, and 5.0 mg/kg. The primary end points of the study were safety, identification of the maximum tolerated dose and maximum administered dose, and the recommended phase 2 dose (RP2D). The secondary end points comprised efficacy, pharmacokinetics, and immunogenicity.

At a data cutoff date of June 20, 2025, 100 patients had received treatment: 1 patient at the 0.8-mg/kg dose, 25 at the 2.4-mg/kg dose, 29 at the 3.0-mg/kg dose, 42 at the 3.5-mg/kg dose, and 3 at the 4.2-mg/kg dose. One dose-limiting toxicity was reported at the 4.2-mg/kg dose in the form of grade 4 decreased platelet count. The following doses were selected for further expansion: 2.4 mg/kg, 3.0 mg/kg, and 3.5 mg/kg. The median duration of follow-up was 3.5 months (interquartile range, 1.4-5.8).

What Was the Safety Profile of SHR-4849?

Any treatment-emergent adverse effects (TEAEs) occurred in 92.0% of patients, and 52.0% of them were grade 3 or higher. In terms of TRAEs, 16.0% were serious and 15.0% led to dose reduction. The most common TRAEs included decreased white blood cell count (grade 1 or 2, 46.0%; grade ≥3, 27.0%), decreased neutrophil count (36.0%; 33.0%), anemia (60.0%; 6.0%), and nausea (47.0%; 0%).

What Additional Efficacy Data Were Reported With SHR-4849?

In those with brain metastases who received the agent at 2.4 mg/kg or higher (n = 18), the ORR was 83.3% (95% CI, 58.6%-96.4%), the confirmed ORR was 66.7% (95% CI, 41.0%-86.7%), and DCR was 100.0% (95% CI, 81.5%-100.0%).

When SHR-4849 was given at a dose of 2.4 mg/kg or higher (n = 86), the median progression-free survival (PFS) was 6.7 months (95% CI, 4.4-not reached [NR]); the 3- and 6-month PFS rates were 83.3% (95% CI, 71.0%-90.7%) and 55.3% (95% CI, 37.8%-69.7%), respectively. When the ADC was given at a dose of 2.4 mg/kg or higher in the second-line setting (n = 42), the median PFS was NR (95% CI, 4.4-NR); the PFS rate at 3 months was 93.3% (95% CI, 75.2%-98.3%) and the rate at 6 months was 59.0% (95% CI, 31.2%-78.8%).

What Are the Next Steps for SHR-4849?

Dose expansion is ongoing to identify the RP2D.2 “These encouraging early data support further investigation of SHR-4849 as a potential treatment for patients with DLL3-positive relapsed SCLC,” Wang noted in a news release issued by IASLC. Follow-up is also going to evaluate long-term outcomes with the agent.1

References

1. Wang L, Cheng Y, Wu C, et al. A first-in-human phase 1 study of SHR-4849 (IDE849), a DLL3-directed antibody-drug conjugate, in relapsed SCLC. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract OA06.01.
2. First-in-human trial shows promising results for DLL3-targeted antibody-drug conjugate SHR-4849 in relapsed small cell lung cancer. News release. International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer. September 7, 2025. Accessed September 17, 2025. https://www.iaslc.org/iaslc-news/press-release/first-human-trial-shows-promising-results-dll3-targeted-antibody-drug