SHR-4849 ADC Shows Promising SCLC Response & Tolerable Safety

The DLL3-directed antibody-drug conjugate (ADC) SHR-4849 (IDE849) yielded responses with a tolerable toxicity profile in patients with relapsed small cell lung cancer (SCLC), according to early data from a first-in-human phase 1 study (NCT06443489).¹

The findings, which were presented during the IASLC 2025 World Conference on Lung Cancer, indicated that any treatment-related adverse effects (TRAEs) occurred in 92.0% of patients, with 48.0% grade 3 or higher; only 2.0% of patients experienced TRAEs that led to treatment discontinuation, and none proved fatal. Moreover, the most common grade 3 or 4 TRAEs were hematological toxicities.

When the agent was given at a dose of 2.4 mg/kg or higher, it led to 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 administered at a dose of at least 2.4 mg/kg in the second-line setting (n = 35), it induced 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 Is SHR-4849?

A significant unmet need exists in SCLC, which was estimated to account for approximately 15% of all lung cancers in 2025 and about 350K global annual incidence.² In December 2024, IDEAYA Biosciences estimated 33K patients with SCLC in the United States, 89K patients with SCLC in Europe, and 17K patients with SCLC in Japan. Moreover, 6% of patients have localized disease at diagnosis, 22% had regional disease, and 71% had distant disease; this is unknown for 1% of patients. Five-year survival rates for those with localized, regional, or distant disease were 33%, 19%, and 4%, respectively.

The ADC is comprised of a humanized anti-DLL3 IgG1 monoclonal antibody that is linked to a DNA topoisomerase I inhibitor payload via a cleavable linker.¹ Preclinical data have demonstrated that the ADC strongly hindered the proliferation of human lung cancer cell lines with varying DLL3 expression levels, showed a robust bystander killing effect, and led to sustained inhibition of tumor growth in xenograft models expressing DLL3.

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 (IQR, 1.4–5.8).

In the 100 patients who received treatment, the median age was 60 years (range, 33-75). The majority of patients were male (71.0%), had an ECOG performance status of 1 (95.0%), had SCLC (87.0%), and stage IV disease (86.0%). Moreover, 24.0% of patients had brain metastases and 30.0% had liver metastases. Regarding prior treatment, 51.0% of patients had 1 prior line of therapy, 33.0% had 2 prior lines, and 15.0% had 3 or more prior lines. Most patients had previously received immunotherapy (72.4%).

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 experienced by at least 10% of patients who received the ADC 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%), nausea (47.0%; 0%), decreased platelet count (36.0%; 7.0%), decreased appetite (31.0%; 0%), increased alanine aminotransferase (21.0%; 0%), asthenia (20.0%; 0%), vomiting (19.0%; 1.0%), decreased lymphocyte count (14.0%; 5.0%), increased blood bilirubin (19.0%; 0%), hyponatremia (18.0%; 0%), increased aspartate aminotransferase (17.0%; 0%), increased gamma-glutamyltransferase (13.0%; 0%), increased blood creatinine (13.0%; 0%), hypercholesterolemia (11.0%; 0%), hyperglycemia (10.0%; 0%), and increased blood lactate dehydrogenase (10.0%; 0%).

What Additional Efficacy Data Were Reported With SHR-4849?

When the ADC was given at a dose of 2.4 mg/kg (n = 19), it led to an ORR of 73.7% (95% CI, 48.8%–90.9%); the DCR was 94.7% (95% CI, 74.0%–99.9%). When given at the same dose in the second-line setting (n = 10), the ORR was 80.0% (95% CI, 44.4%–97.5%) and the DCR was 100.0% (95% CI, 69.2%–100.0%). When SHR-4849 was given at a dose of 3.0 mg/kg (n = 18), it resulted in an ORR of 66.7% (95% CI, 41.0%–86.7%); the DCR was 94.4% (95% CI, 72.7%-99.9%). When administered at the same dose in the second-line setting (n = 8), the ORR was 75.0% (95% CI, 34.9%–96.8%) and the DCR was 100.0% (95% CI, 63.1%–100.0%).

Moreover, when the ADC was given at a dose of 3.5 mg/kg (n = 31), it induced an ORR of 74.2% (95% CI, 55.4%–88.1%); the DCR was 90.3% (95% CI, 74.2%–98.0%). When given at the same dose in the second-line setting (n = 16), the agent elicited an ORR of 75.0% (95% CI, 47.6%–92.7%); the DCR was 93.8% (95% CI, 69.8%–99.8%). When SHR-4849 was given at a dose of 4.2 mg/kg (n = 3), the ORR and DCR were 100.0% (95% CI, 29.2%–100.0%). When administered at the same dose in the second-line setting (n = 1), the ORR and DCR were 100.0% (95% CI, 2.5%–100.0%).

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 broken down by dose, the ORRs in the 2.4-mg/kg (n = 6), 3.0-mg/kg (n = 4), 3.5-mg/kg (n = 7), and 4.2-mg/kg (n = 1) groups were 100.0% (95% CI, 54.1%–100.0%), 75.0% (95% CI, 19.4%–99.4%), 71.4% (95% CI, 29.0%-96.3%), and 100.0% (95% CI, 2.5%–100.0%), respectively; the DCR in all groups was 100%.

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 months–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 Pharmacokinetic Insights Were Revealed About SHR-4849?

After a single dose of the ADC, systemic exposure, total antibody, and payload increased proportionally with doses ranging from 2.4 mg/kg to 4.2 mg/kg. Across this dose range, the mean half-life of the agent ranged from 10.2 days to 11.5 days. Moreover, it was noted that a tumor stasis concentration of 3.0 μg/mL supported the clinically effective dose range. Across these doses, exposure of free plasma payload was low; the mean half-life ranged from 4.4 days to 5.2 days.

What Are the Next Steps for SHR-4849?

Dose expansion is ongoing to identify the RP2D.³ “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. IDEAYA Biosciences Corporate Presentation. December 2024. Accessed September 17, 2025. https://tinyurl.com/mbp8yd3s

3. 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://tinyurl.com/ytebr32n