Izalontamab Brengitecan Shows Promising Clinical Activity in Previously Treated Extensive-Stage Small Cell Lung Cancer

Clinical Summary:

• Design/Population: This multicenter, open-label, phase 1b dose-expansion study evaluated the EGFR/HER3-targeting bispecific antibody-drug conjugate izalontamab brengitecan in patients with relapsed extensive-stage small cell lung cancer. 
• Key Outcomes: Izalontamab brengitecan achieved an objective response rate of 48.1%, with a median progression-free survival of 4.1 months and median overall survival of 12.2 months. Activity was particularly notable in the second-line setting, where the objective response rate reached 72.7%. The safety profile was characterized primarily by hematologic toxicities.
• Clinical Relevance: These findings support continued clinical evaluation of izalontamab brengitecan as a potential treatment option for relapsed extensive-stage small cell lung cancer, with a randomized phase 3 trial currently underway.

Results from a phase 1b dose-expansion study demonstrated that izalontamab brengitecan, a bispecific antibody-drug conjugate targeting EGFR and HER3, produced encouraging antitumor activity in patients with relapsed extensive-stage small cell lung cancer (ES-SCLC), particularly when administered as second-line therapy.

“SCLC remains one of the most aggressive and lethal malignancies, with limited treatment options beyond frontline chemo-immunotherapy,” stated Yuanyuan Zhao, MD, Sun Yat-sen University Cancer Center, Guangzhou, China, and coauthors. “In the previous phase 1 [portion of this] study, [izalontamab brengitecan] demonstrated encouraging preliminary antitumor activity in patients with advanced solid tumors.” 

In this multicenter, open-label trial, investigators enrolled 52 patients with ES-SCLC whose disease had progressed following at least 1 prior platinum-based chemotherapy regimen and PD-(L)1 inhibitor therapy. Patients received 2.5 mg/kg of intravenous izalontamab brengitecan on days 1 and 8 of each 21-day cycle. Coprimary end points were objective response rate (ORR) and safety. Secondary end points included disease control rate, duration of response,  progression-free survival (PFS), and overall survival (OS).

At the data cutoff point, the confirmed ORR was 48.1%, including 25 partial responses, while the disease control rate was 80.8%. Median duration of response was 4.9 months, median PFS was 4.1 months, and median OS was 12.2 months.

Clinical activity was greatest among the 22 patients treated in the second-line setting. In this subgroup, ORR reached 72.7% and the disease control rate was 90.9%. Median PFS was 6.2 months, and median OS was 15 months.  Among patients previously treated with irinotecan, ORR was 31.6%.

Treatment-related adverse events were reported in all patients. The most common toxicities were hematologic, including neutropenia, thrombocytopenia, anemia, and leukopenia. Grade ≥3 treatment-related adverse events occurred in 75% of patients, resulting in dose reductions in 46% of patients, treatment discontinuation in 13.5% of patients, and 2 treatment-related deaths. No treatment-related interstitial lung disease was observed.

Exploratory biomarker analyses suggested that HER3 expression may be associated with improved treatment response. Among patients evaluable for biomarker analyses, ORR was 68.8% in HER3-positive tumors compared with 14.3% in HER3-negative tumors, whereas EGFR expression was not associated with response. Investigators emphasized that these findings were exploratory and require prospective validation.

“[Izalontamab brengitecan] demonstrated encouraging antitumor activity and a manageable safety profile in relapsed ES-SCLC,” concluded Dr Zhao et al. “The ongoing phase 3 trial will provide more definitive evidence.”

“Additional trials of izalontamab brengitecan in SCLC are warranted based on the preliminary efficacy and safety data,” added Journal of Clinical Oncology associate editor Thomas Stinchcombe, MD, Duke Cancer Institute, Durham, North Carolina.  

Source: 

Zhao Y, Zhao H, Wang Q, et al. Izalontamab brengitecan (Iza-Bren), a first-in-class EGFR-HER3 bispecific antibody-drug conjugate in extensive-stage small cell lung cancer: Results from a phase Ib study. J Clin Oncol. Published online: July 24, 2026. doi: 10.1200/JCO-26-00243