Combining Smart Strategies in 1 Molecule

In recent years, we have seen many examples of novel therapies—based on smart, innovative designs and better understanding of the biology driving cancers—favorably impact outcomes for patients with cancer. Examples of such therapies include targeted drugs, antibody-drug conjugates (ADCs), bispecific antibodies, chimeric antigen receptor (CAR) T-cell therapies, and more recently proteolysis targeting chimeras (PROTACs) and trispecific antibodies. Recently, I learned of a molecule that combines 2 of these mechanisms: the first-in-class izalontamab brengitecan (iza-bren), which is not only a bispecific antibody but also an ADC.

Iza-bren is unique in that, as a bispecific antibody, it has 2 different targets—epidermal growth factor receptor (EGFR) and HER3—both of which are often overexpressed in epithelial cancers including lung cancer and are associated with cancer cell proliferation and survival. But it doesn’t stop there; iza-bren carries a topoisomerase I inhibitor chemotherapy payload, which is released upon internalization into the cancer cells. In August 2025, iza-bren was granted breakthrough therapy designation by the FDA for patients with previously treated, advanced EGFR-mutated non-small cell lung cancer.

At the 2026 European Lung Cancer Congress, the results of a phase 2 trial of iza-bren in combination with the anti–PD-1 checkpoint inhibitor serplulimab in patients with extensive stage small cell lung cancer (SCLC) were presented.¹ The trial was conducted largely in China. Of the 77 evaluable patients, efficacy measures included an objective response rate of 88%, median progression-free survival of 8.2 months, and 12-month overall survival of 80.8%. Adverse events included cytopenias, interstitial lung disease in 2.4%, and 2 treatment-related deaths—one from multi-organ failure and the other from pneumonia. Two different doses of iza-bren were used; the rate of treatment discontinuation was lower in the 2.5 mg/kg group (2.4%) as compared with the 2.75 mg/kg group (12.2%). Because of the superior therapeutic index, the 2.5 mg/kg dose has been selected for a phase 3 study. These efficacy measures compare favorably with standard-of-care chemoimmunotherapy, where objective response rates are on the order of 60% to 70%, median progression-free survival about 5 months, and rate of overall survival at 1 year about 50%.

The results add to evidence that targeting multiple different antigens simultaneously with immunotherapy drugs may be more effective than targeting just 1 antigen at a time. In multiple myeloma, we have seen that the combination of the BCMA-targeting teclistamab (Tecvayli) and the GPRC5D-targeting talquetamab (Talvey) provides substantial benefit in patients with extramedullary disease. We have also seen in multiple myeloma that a trispecific antibody targeting BCMA and GPRC5D with 1 molecule has exceptional activity in early studies. Thus, targeting multiple antigens simultaneously may turn out to provide even more value than targeting just 1. The early experience with iza-bren raises the possibility that having a bispecific antibody deliver a chemotherapy drug may add even more value.

References

1. Zhou F, Gao Y, Zhou J, et al. Phase II study of iza-bren (BL-B01D1) in combination with serplulimab in patients with small cell lung cancer (SCLC). Presented at: European Lung Cancer Congress 2026; abstract 408O, Accessed April 12, 2026. https://tinyurl.com/v56ktwpe