The novel antibody-drug conjugate izalontamab brengitecan (also referred to as iza-bren, BL-B01D1) in combination with osimertinib induced a response in all patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) and EGFR-sensitizing mutations treated with the combination in the first-line setting. These findings from a phase II trial were presented at the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer (WCLC; Abstract OA10.04).
“These results are remarkable and suggest that this combination could offer a potentially transformative first-line treatment option for EGFR-mutant NSCLC,” stated presenting author Fei Zhou, MD, PhD, Associate Chief Physician, Shanghai East Hospital, Shanghai, China. “Importantly, the regimen was also manageable from a safety perspective.”
Background and Study Methods
Izalontamab brengitecan is a first-in-class antibody-drug conjugate that comprises an EGFR × HER3 bispecific antibody conjugated to a novel topo-I inhibitor payload through a stable tetrapeptide-based cleavable linker.
The phase II study enrolled 154 patients with locally advanced or metastatic NSCLC with EGFR-sensitizing mutations. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1 and were treatment-naive.
Patients were treated across two separate dosing schedules for izalontamab brengitecan. The majority of patients received izalontamab brengitecan on days 1 and 8 of every 3-week cycle, at doses from 2.2 mg/kg to 2.75 mg/kg, in combination with 80 mg daily of osimertinib. The remaining patients received izalontamab brengitecan on day 1 only of the every-3-week cycle, at either 4.0 mg/kg or 4.5 mg/kg, with the same dose of osimertinib.
At the time of the presentation, 111 patients were continuing on treatment in the study.
Key Study Findings
Across all patients treated with the combination regimen, the objective response rate was 84.4% (95% confidence interval [CI] = 77.7%–89.8%), with confirmed responses in 80.5% (95% CI = 73.4%–86.5%). At 12 months, the progression-free survival rate was 86.5% (95% CI = 79.7%–91.2%), and the overall survival rate was 95.9% (95% CI = 91.2%–98.2%).
Patients treated with izalontamab brengitecan at 2.5 mg/kg on days 1 and 8 of every 3-week cycle had an objective response rate of 100% (95% CI = 91.2%–100.0%); the confirmed objective response rate was 95.0% (95% CI = 83.1%–99.4%). At a median follow-up of 12.5 months for progression-free survival and 12.8 months for overall survival, the 1-year rates for progression-free survival and overall survival were 92.1% (95% CI = 77.5%–97.4%) and 94.8% (95% CI = 80.7%–98.7%), respectively. The median duration of response and median progression-free survival have not yet been reached in this subgroup.
The majority of treatment-related adverse events were hematologic, including anemia (91.9%), neutropenia (91.1%), leukopenia (91.1%), and thrombocytopenia (75.6%). Common nonhematologic treatment-related events included nausea, stomatitis, decreased appetite, vomiting, diarrhea, asthenia, transaminase increases, hypokalemia, hypoalbuminemia, weight loss, rash, and alopecia.
Grade 3 or higher treatment-related toxicities were infrequent and mostly hematologic; these events could be treated with standard supportive measures such as dose reductions and growth factor support. Of note, two cases of interstitial lung disease were observed in the study (one grade 2 and one grade 3). A total of 13% of patients discontinued treatment with izalontamab brengitecan because of treatment-related adverse events.
“Iza-bren in combination with osimertinib has demonstrated promising activity with a manageable safety profile in first-line EGFR-mutated patients [with NSCLC],” Dr. Zhou reported.
A phase III trial is ongoing in China with izalontamab brengitecan at 2.5 mg/kg on days 1 and 8 of an every-3-week cycle in combination with osimertinib as a first-line treatment for patients with EGFR-mutant NSCLC.
Disclosure: For full disclosures of the study authors, visit abstractsonline.com.
