Frontline Iza-Bren Plus Osimertinib Elicits 100% ORR in EGFR-Mutant NSCLC

Frontline treatment with iza-bren (izalontamab brengitecan; BL-B01D1) plus osimertinib (Tagrisso) was tolerable and induced responses in patients with EGFR-mutated, locally advanced or metastatic non–small cell lung cancer (NSCLC), according to data from a phase 2 study (NCT05880706) presented during the first press briefing of the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer.¹

Notably, when iza-bren was given at a dose of 2.5 mg/kg on days 1 and 8 of an every-3-weeks cycle (D1D8 Q3W) and combined with osimertinib (n = 40), it led to an objective response rate (ORR) of 100% (95% CI, 91.2%-100.0%) and a confirmed ORR of 95.0% (95% CI, 83.1%-99.4%). At a median follow-up of 12.5 months (95% CI, 12.4-12.5), the 12-month progression-free survival (PFS) rate was 92.1% (95% CI, 77.5%-97.4%). At a median follow-up of 12.8 months (95% CI, 12.5-13.1), the 12-month overall survival (OS) rate was 94.8% (95% CI, 80.7%-98.7%). The median duration of response (DOR) and median PFS had not yet been reached at the time of analysis, which had a data cutoff date of June 30, 2025.²

When the first-in-class bispecific antibody-drug conjugate (ADC) was given at doses ranging from 2.2 to 2.75 mg/kg D1D8 Q3W combined with osimertinib, the first-line regimen was found to be tolerable with a manageable toxicity profile. The most common treatment-related adverse effects (TRAEs) were hematologic, and a low incidence of TRAEs led to treatment discontinuation.

“These results are remarkable and suggest that this combination could offer a potentially transformative first-line treatment option for EGFR-mutant NSCLC,” Fei Zhou, MD, presenting author from Shanghai East Hospital, stated in a news release spotlighting the data. “Importantly, the regimen was also manageable from a safety perspective.”

What Is the Design of the Phase 2 Study Examining Iza-Bren Plus Osimertinib in NSCLC?

The phase 2 trial enrolled treatment-naive patients with locally advanced or metastatic NSCLC harboring EGFR-sensitizing mutations. Patients had an ECOG performance status of 0 or 1 and measurable disease by RECIST v1.1 criteria.

Patients received iza-bren at doses of 2.2 mg/kg (n = 41), 2.5 mg/kg (n = 40), and 2.75 mg/kg (n = 42) D1D8 Q3W and 4.0 mg/kg (n = 18) and 4.5 mg/kg (n = 13) on day 1 of an every-3-week cycle (D1 Q3W) in combination with 80 mg of osimertinib given once daily. The primary end points were ORR and to identify the recommended phase 2 dose of iza-bren. Secondary end points include PFS, disease control rate, DOR, and safety. Exploratory end points comprise pharmacokinetics, neutralizing antibody, drug-drug interactions, OS, and biomarker analysis.

A total of 154 patients received the regimen spanning doses. At the time of data cutoff, 111 patients were still receiving treatment, and 43 had discontinued. The most common reasons for discontinuation were progressive disease (n = 14), followed by adverse effects (AEs; n = 7), and death (n = 2). All patients were included in the safety and efficacy analysis sets. The median patient age was 60.0 years (range, 33.0-76.0), and just under half were male (43.5%). More than half were never smokers (60.4%), and most had an ECOG performance status of 1 (80.5%). The median number of metastatic organs was 3 (range, 0-7,) and 27.3% of patients had baseline brain metastases. Moreover, 57.8% and 42.2% of patients had EGFR exon 19 deletion mutations or EGFR L858R mutations, respectively.

What Was the Preliminary Efficacy of Iza-Bren Plus Osimertinib?

In the total population, the regimen induced an ORR of 84.4% (95% CI, 77.7%-89.8%); the confirmed ORR was 80.5% (95% CI, 73.4%-86.5%). At a median follow-up of 12.7 months (95% CI, 12.5-15.0) and 15.0 months (95% CI, 14.2-15.5) for PFS and OS, respectively, the 12-month rates were 86.5% (95% CI, 79.7%-91.2%) and 95.9% (95% CI, 91.2%-98.2%).

In those who received iza-bren at a dose of 2.2 mg/kg D1D8 Q3W, the ORR was 78.0% (95% CI, 62.4%-89.4%), and the confirmed ORR was 73.2% (95% CI, 57.1%-85.8%). In those who received the ADC at a dose of 2.75 mg/kg D1D8 Q3W, the ORR was 78.6% (95% CI, 63.2%-89.7%), and the confirmed ORR was 76.2% (95% CI, 60.5%-87.9%). In those given iza-bren at 4.0 mg/kg on D1 Q3W, the ORR and confirmed ORR were both 77.8% (95% CI, 52.4%-93.6%). In the group of patients who received iza-bren at a dose of 4.5 mg/kg on D1 Q3W, the ORR was 84.6% (95% CI, 54.6%-98.1%) and the confirmed ORR was 76.9% (95% CI, 46.2%-95.0%).

Of the patients who received iza-bren at doses given on the D1D8 Q3W schedule (n = 123), 95.9% experienced tumor shrinkage; the median shrinkage percentage was –53.8%. All patients who received iza-bren at a dose of 2.5 mg/kg D1D8 Q3W experienced tumor shrinkage; the median shrinkage percentage was –56.7%.

What Was the Safety Profile of Iza-bren Plus Osimertinib?

The majority of TRAEs were hematologic, with high incidences of anemia (91.9%), neutropenia (91.1%), leukopenia (91.1%), and thrombocytopenia (75.6%).² Non-hematologic TRAEs comprised nausea, stomatitis, decreased appetite, vomiting, diarrhea, asthenia, elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, hypokalemia, hypoalbuminemia, weight loss, rash, and alopecia.

Grade 3 or higher adverse effects were manageable with supportive measures, including dose reductions and growth factor support.¹ The discontinuation rate of iza-bren due to TRAEs was 13.0%, and no new safety signals were identified. Zhou noted that there were 2 cases of interstitial lung disease reported; one case was grade 2 and the other was grade 3.

What Are the Next Steps for Iza-Bren?

A phase 3 clinical trial (NCT06838273) is further evaluating iza-bren at 2.5 mg/kg D1D8 Q3W in combination with osimertinib as a first-line treatment for patients with EGFR-mutated NSCLC. This trial is currently being conducted in China and is designed to confirm the efficacy and safety of the combination in a larger, randomized population.

References

1. Zhou F, Wang Q, Wang H, et al. Phase II study of iza-bren (BL-B01D1) in combination with osimertinib in patients with EGFR-mutated locally advanced or metastatic non–small cell lung cancer. Presented at: IASLC 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Press Briefing. Abstract 2114.
2. Iza-bren in combination with osimertinib shows 100% response rate in EGFR-mutated NSCLC, phase II study finds. News Release. WCLC. September 6, 2025. Accessed September 6, 2025. https://wclc.iaslc.org/