The first-in-class EGFR × HER3 bispecific antibody-drug conjugate izalontamab brengitecan (also referred to as iza-bren; BL-B01D1) demonstrated promising efficacy results plus a manageable safety profile in the treatment of patients with previously treated EGFR-mutated non–small cell lung cancer (NSCLC) in two phase I/II studies of patients with solid tumors. Results from the two studies with this agent were presented at the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer (WCLC; Abstract OA10.03).
“[These] early data suggest iza-bren may offer a promising treatment option for patients with EGFR-mutated NSCLC,” said lead study investigator Wenfeng Fang, MD, PhD, Associate Professor, Sun Yat-sen University Cancer Center, Guangzhou, China. “Phase III registrational study of iza-bren as monotherapy in EGFR-mutated NSCLC after progression on a third-generation TKI is ongoing in China.”
Rationale and Study Methods
Even with third-generation EGFR tyrosine kinase inhibitors, patients with EGFR-mutated NSCLC eventually develop drug resistance.
Izalontamab brengitecan is a first-in-class antibody-drug conjugate comprises an EGFR × HER3 bispecific antibody that is conjugated to a topo-I inhibitor payload through a stable tetrapeptide-based cleavable linker. The antibody-drug conjugate showed activity in a prior phase I study of patients with solid tumors.
The two phase I/II studies of izalontamab brengitecan monotherapy included 746 patients with solid tumors; 171of these patients had EGFR-mutant NSCLC. In the two studies, patients received varying doses of the antibody-drug conjugate across two treatment schedules. The majority of patients were treated on a schedule of day 1 and day 8 doses every 3 weeks, with doses from 2.0 mg/kg to 3.5 mg/kg (n = 150); a second dosing schedule gave izalontamab brengitecan only on day 1 of the every-3-week schedule, at doses from 4.5 mg/kg to 6.0 mg/kg (n = 21).
At the time of the presentation, 26 patients were continuing on study treatment.
Key Study Findings
Responses were highest among a subgroup of patients treated with the day 1 and day 8 dosing schedule (at a dose of 2.5 mg/kg) who were naive to chemotherapy but had already received treatment with an EGFR tyrosine kinase inhibitor (n = 50). In this subgroup, the objective response rate was 66% (95% confidence interval [CI] = 51.2%–78.8%), and the disease control rate was 90% (95% CI = 78.2%–96.7%). The median duration of response was 13.7 months (95% CI = 5.5–19.5 months).
At a median follow-up of 20.5 months, the median progression-free survival was 12.5 months (95% CI = 6.9–18.0 months). The median overall survival was not reached, but at 12 months, the overall survival rate was 80.3% and at 18 months, 69.2%.
Response rates were similar in patients who had exposure to a prior third-generation EGFR tyrosine kinase inhibitor but no prior chemotherapy. Comparable efficacy was seen across EGFR mutation subtypes.
Few grade 3 or higher treatment-related adverse events were observed in the study and were mostly hematologic. All grade 3 or higher events were reported to be effectively managed with standard supportive measures. A total of 1.2% of patients discontinued treatment because of a treatment-related adverse event, and no treatment-related deaths were observed.
Overall, the most frequent hematologic treatment-related toxicities were anemia (90.6%), leukopenia (80.7%), and neutropenia (78.4%). Common nonhematologic events included nausea, alopecia, and asthenia. One case of grade 1 interstitial lung disease was reported.
Going forward, izalontamab brengitecan is being evaluated further in an ongoing phase III study for the treatment of patients with EGFR-mutated advanced NSCLC after failure to respond to a third-generation EGFR tyrosine kinase inhibitor.
Disclosure: For full disclosures of the study authors, visit abstractsonline.com.
