Iza-Bren Plus Serplulimab Shows High Efficacy in First-Line ES-SCLC

A combination of the first-in-class bispecific antibody-drug conjugate (ADC) izalontamab brengitecan (iza-bren; BL-B01D1) and the PD-1 inhibitor serplulimab has demonstrated significant antitumor activity in patients with treatment-naive extensive-stage small cell lung cancer (ES-SCLC). According to data from a phase 2 clinical trial (NCT06437509) presented at the 2026 European Lung Cancer Congress, the regimen yielded an overall response rate (ORR) of 88.3%, with 100% of evaluable patients experiencing tumor shrinkage.¹

The findings, reported from a study involving 82 patients, suggest a potential shift in the first-line therapeutic landscape for ES-SCLC, a disease characterized by rapid progression and historically poor outcomes. The investigators identified 2.5 mg/kg of iza-bren as the recommended phase 2 dose (RP2D) for future combination studies, balancing high efficacy with a manageable safety profile.

Efficacy and Survival Outcomes

In the total efficacy analysis set (n = 77), the combination therapy achieved a confirmed ORR (cORR) of 77.9% and a disease control rate (DCR) of 94.8%. Response rates were consistent across dose levels, with the 2.75 mg/kg cohort reaching an ORR of 91.9% compared with 85.0% in the 2.5 mg/kg cohort.

Survival metrics were equally robust for this patient population. The median progression-free survival (mPFS) was 8.2 months (95% CI, 6.7-9.6). The median duration of response (mDOR) was 7.3 months, and the 12-month overall survival (OS) rate was 80.8%. These results compare favorably with current standard-of-care chemo-immunotherapy regimens, which typically yield an mPFS of approximately 5 months.

Mechanism of Action

Iza-bren distinguishes itself as a bispecific ADC targeting both EGFR and HER3, 2 receptors frequently overexpressed in SCLC. The construct utilizes a novel topoisomerase I inhibitor payload (Ed-04) linked via a stable, cathepsin B-cleavable tetrapeptide-based linker. This design allows for targeted delivery of the cytotoxic agent directly to malignant cells, potentially minimizing systemic exposure.

The rationale for combining iza-bren with serplulimab, an anti–PD-1 antibody already approved in China for ES-SCLC, is rooted in the synergistic potential of ADC-induced immunogenic cell death and checkpoint inhibition. Previous phase 1b data for iza-bren monotherapy in advanced SCLC showed a cORR of 44.8%, a figure nearly doubled by the addition of serplulimab in this phase 2 setting.²

Safety and Tolerability

The safety profile of the combination was characterized by frequent but manageable hematologic toxicities. The most common treatment-related adverse events (TRAEs) with an incidence ≥30% included anemia, thrombocytopenia, leukopenia, and neutropenia.¹

While grade ≥3 events occurred, the median resolution time for severe neutropenia was 3 days, and 7 days for severe anemia. Supportive measures, including growth factor support and dose reductions, were effective in managing these toxicities. Notably, the treatment-related discontinuation rate for iza-bren remained low at 7.3% overall. However, a dose-dependent safety trend was observed: the discontinuation rate was significantly lower in the 2.5 mg/kg cohort (2.4%) than in the 2.75 mg/kg cohort (12.2%).

Specific complications of interest included interstitial lung disease, reported in 2.4% of patients (1 grade 2 and 1 grade 3 event), and a 2.4% rate of neutropenic fever. There were 2 treatment-related deaths recorded: 1 due to multiple organ dysfunction syndrome and 1 due to pneumonia/respiratory failure.

Study Design and Future Directions

The trial enrolled 82 patients with a median age of 61.5 years; approximately 70% had an ECOG performance status of 1. At baseline, nearly 40% of the population presented with liver metastases. Stage II of the study randomized treatment-naive patients into 2 cohorts receiving either 2.5 mg/kg or 2.75 mg/kg of iza-bren on days 1 and 8 of a 3-week cycle, combined with 4.5 mg/kg of serplulimab.

Based on the favorable therapeutic index of the 2.5 mg/kg dose, researchers have selected this concentration for upcoming trials. Preparations for a phase 3 confirmatory study in China are currently underway to further validate the efficacy of this ADC-immunotherapy combination in the first-line setting for ES-SCLC.

REFERENCES

1. Zhou F. Phase II study of iza-bren (BL-D01D1) in combination with serplulimab in patients with small cell lung cancer (SCLC). Presented at: 20256 ELCC; March 25–28, 2026; Copenhagen, Denmark. Abstract 3O.

2. Hong SD, Wang YS, Zhao HY, et al.Izalontamab brengitecan (Iza-bren; BL-B01D1), a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, for patients with EGFR-mutated NSCLC: pooled analysis of phase I and phase II trials. Ann Oncol. 2026 Jan 27:S0923-7534(26)00018-9. doi: 10.1016/j.annonc.2026.01.009. Epub ahead of print. PMID: 41611210.