First-Line Serplulimab Plus Iza-Bren Is Deemed Tolerable and Has Antitumor Activity in ES-SCLC

Izalontamab brengitecan (iza-bren; BL-B01D1) in combination with serplulimab was associated with a tolerable and manageable safety profile and elicited responses in the first-line setting in patients with extensive-stage small cell lung cancer (ES-SCLC), according to findings from a phase 2 clinical trial (NCT06437509), which were presented at the 2026 European Lung Cancer Congress.¹

The findings, reported from a study involving 82 patients, indicate a potential shift in the first-line therapeutic paradigm 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 for future combination studies.

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

In the total efficacy analysis set (n = 77), the regimen yielded an overall response rate (ORR) of 88.3%, and 100% of evaluable patients experienced tumor shrinkage. The combination therapy generated a confirmed ORR (cORR) of 77.9% and a disease control rate 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.

What is the mechanism of action of iza-bren?

Iza-bren distinguishes itself as a bispecific antibody-drug conjugate (ADC) targeting both EGFR and HER3, 2 receptors frequently overexpressed in SCLC. The construct uses 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 the treatment of patients with ES-SCLC, is rooted in the synergistic potential of ADC-induced immunogenic cell death and checkpoint inhibition. Previous phase 1b trial data for iza-bren monotherapy in patients with advanced SCLC showed a cORR of 44.8%, a figure nearly doubled by the addition of serplulimab in this phase 2 setting.²

What additional efficacy and safety findings were seen in the phase 2 trial investigating iza-bren plus serplulimab in ES-SCLC?

In the phase 2 trial, although grade 3 or higher AEs occurred, the median resolution time for severe neutropenia was 3 days, and 7 days for severe anemia.¹ 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.

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

What is important to note about the design of the phase 2 trial of serplulimab plus iza-bren in ES-SCLC? What more might be learned here?

The trial enrolled patients with a median age of 61.5 years (range, 56.0-67.0); 70.7% of patients had an ECOG performance status of 1. At baseline, 39.0% of the patient population presented with liver metastases. Stage II of the study randomly assigned treatment-naive patients into 2 cohorts to receive 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 patients with ES-SCLC.

References

1. Zhou F. Gao Y, Zhou J, et al. Phase II study of iza-bren (BL-D01D1) in combination with serplulimab in patients with small cell lung cancer (SCLC). Presented at: 2026 European Lung Cancer Congress; 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. Published online January 27, 2026. doi:10.1016/j.annonc.2026.01.009