Iza-Bren Elicits 33% ORR, 6.9-Month PFS in Post-Osimertinib EGFR-Mutated NSCLC

The EGFR x HER3 bispecific antibody-drug conjugate (ADC) izalontamab brengitecan (iza-bren; BL-B01D1) was associated with an objective response rate (ORR) of 33.3% (95% CI, 16.5 - 54.0), a confirmed ORR of 29.6% (95% CI, 13.8 - 50.2), and a median progression-free survival (PFS) of 6.9 months (95% CI, 4.0 - not reached [NR]) at the 2.5 mg/kg dose level in patients with EGFR-mutated non–small cell lung cancer (NSCLC) that progressed on a third-generation EGFR TKI.¹

According to the findings from the randomized dose-expansion cohort of a global phase 1 study (NCT05983432) presented in a late-breaking oral session at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC), the median duration of response (DOR) at 2.5 mg/kg was 9.7 months (95% CI, 4.1 - NR), and 74.1% of patients at that dose level (n= 20) experienced tumor shrinkage.

Across all 81 patients randomly assigned 1:1:1 to iza-bren at 1.5 mg/kg, 2.0 mg/kg, or 2.5 mg/kg on days 1 and 8 of every 3-week cycle, the ORR was 30.9% (95% CI, 21.1 - 42.1), the confirmed ORR was 27.2% (95% CI, 17.9 - 38.2), the disease control rate (DCR) was 72.8% (95% CI, 61.8 - 82.1), and the median PFS was 5.5 months (95% CI, 4.0 - 6.9) at a median follow-up of 8.5 months.

Investigators concluded that the totality of safety, efficacy, and pharmacokinetic data supports 2.5 mg/kg on days 1 and 8 every 3 weeks as the recommended phase 3 dose for the ongoing global registrational IZABRIGHT-Lung01 trial in this population.

"These findings support continued development of iza-bren and provide the rationale for advancing the 2.5 mg/kg regimen into the global phase 3 IZABRIGHT-Lung01 trial for patients with previously treated EGFR-mutated NSCLC," presenting author Alexander I. Spira, MD, PhD, of the Virginia Cancer Specialists and NEXT Oncology Virginia, said in a news release issued by the IASLC.²

What Is Iza-Bren and Why Was It Evaluated in This Setting?

Iza-bren comprises a bispecific antibody with high affinity for EGFR and low affinity for HER3, a wild-type IgG1 Fc, and a topoisomerase I inhibitor payload (Ed-04) attached via a cathepsin B–cleavable tetrapeptide linker at a drug-to-antibody ratio of 8. The US Food and Drug Administration (FDA) granted the agent breakthrough therapy designation for EGFR-mutated NSCLC in August 2025, and it has been approved in China for previously treated nasopharyngeal carcinoma and esophageal squamous cell carcinoma, which investigators noted was the first approval of a bispecific ADC.

In the dose-escalation phase of the global phase 1 study, reported at the 2025 European Society for Medical Oncology (ESMO) Congress, the confirmed ORR at 2.5 mg/kg was 30% in heavily pretreated patients with EGFR-mutated NSCLC.¹

The post-osimertinib setting is increasingly contested. Topline data from the phase 3 SAFFRON trial (NCT05261399) showed that osimertinib (Tagrisso) plus savolitinib improved PFS and overall survival (OS) vs chemotherapy in patients with MET-driven, osimertinib-resistant EGFR-mutated NSCLC,³ and faculty at a recent OncLive Scientific Interchange and Workshop highlighted TP53 status and cumulative toxicity burden as considerations in second-line sequencing.⁴

How Was the Randomized Dose-Expansion Cohort Designed?

Eligible patients had locally advanced or metastatic NSCLC with an EGFR sensitizing mutation, disease progression on a prior third-generation EGFR TKI, ≤2 prior lines of systemic chemotherapy in the metastatic setting, and an ECOG performance status of 0 or 1. The primary end point was safety; secondary end points included pharmacokinetics, ORR, DCR, DOR, time to response, PFS, and OS.¹

Baseline characteristics were generally balanced across the 3 dose arms (n = 27 each). In the overall population, median patient age was 61 years, 25.9% of patients were male, 60.5% had an ECOG performance status of 1, and 32.1% had central nervous system metastases at baseline.

Patients had received a median of 2 prior lines of therapy (range, 1 - 7); 28.4% had received 1 prior line, 35.8% had received 2, and 35.8% had received ≥3. All patients had received a prior third-generation EGFR TKI, 64.2% had received platinum-based chemotherapy, and 17.3% had received amivantamab-vmjw (Rybrevant). EGFR exon 19 deletions were present in 60.5% of patients, L858R mutations in 25.9%, and other EGFR driver mutations in 23.5%. The data cutoff was June 5, 2026.

How Did Efficacy Compare Across Dose Levels and Subgroups?

At 1.5 mg/kg and 2.0 mg/kg, respectively, the ORR was 29.6% (95% CI, 13.8 - 50.2) in each arm, the confirmed ORR was 29.6% (95% CI, 13.8 - 50.2) and 22.2% (95% CI, 8.6 - 42.3), and the DCR was 74.1% (95% CI, 53.7 - 88.9) and 66.7% (95% CI, 46.0 - 83.5). Median DOR was 5.6 months (95% CI, 2.8 - NR) at 1.5 mg/kg and NR (95% CI, 2.8 - NR) at 2.0 mg/kg, and median PFS was 5.5 months (95% CI, 2.0 - 9.5) and 2.9 months (95% CI, 1.4 - 5.6), respectively.

The DCR at 2.5 mg/kg was 77.8% (95% CI, 57.7 - 91.4). Median OS was NR in all 3 arms, and best overall response at 2.5 mg/kg comprised partial responses in 33.3% of patients, stable disease in 44.4%, and progressive disease in 18.5%.

Among the 14 patients who had previously received amivantamab, who had a median of 3 prior lines of therapy (range, 2 - 7), the ORR was 35.7% (95% CI, 12.8 - 64.9), the confirmed ORR was 28.6% (95% CI, 8.4 - 58.1), and the median PFS was 5.4 months (95% CI, 1.2 - NR). In the 67 patients without prior amivantamab, the ORR was 29.9% (95% CI, 19.3 - 42.3), the confirmed ORR was 26.9% (95% CI, 16.8 - 39.1), and the median PFS was 5.5 months (95% CI, 2.9 - 7.3). Investigators noted that efficacy in this global population was consistent with previously reported results in Chinese patients.

What Was the Safety Profile With Mandatory G-CSF Prophylaxis?

All patients received mandatory primary G-CSF prophylaxis, which investigators reported reduced hematologic toxicity and the dose-reduction rate relative to historical experience; the practice has been implemented across the agent's registrational studies. The most common grade ≥3 treatment-related adverse events (TRAEs) across dose levels were hematologic and manageable with standard measures.

Grade ≥3 neutropenia was described as largely transient, reversible, and non-recurrent, and grade ≥3 nonhematologic TRAEs occurred in no more than 2.5% of patients for any event.

TRAEs led to dose reduction in 19.8% of patients and to discontinuation in 3.7%. Investigator-assessed interstitial lung disease (ILD)/pneumonitis occurred in 3 patients (3.7%). Neutropenic fever occurred in 1 patient (1.2%). No treatment-related deaths and no new safety signals were reported.

At the 2.5 mg/kg dose level, grade ≥3 anemia and neutropenia each occurred in 33.3% of patients and grade ≥3 thrombocytopenia in 7.4%; the single case of neutropenic fever occurred in this arm, and no ILD/pneumonitis was observed.

References

1. Spira A, Chae Y, Gregorc V, et al. Phase 1 global study of iza-bren in patients with metastatic EGFR-mutated NSCLC: results of the randomized dose expansion cohort. Presented at: International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract OA10.01.
2. Phase 1 study supports recommended phase 3 dose for investigational EGFR x HER3 antibody-drug conjugate in EGFR-mutated lung cancer. News release. International Association for the Study of Lung Cancer. September 12, 2026. Accessed September 13, 2026.
3. Osimertinib Plus Savolitinib Improves PFS and OS in Pretreated, MET+, EGFR+ NSCLC. OncLive. Published August 17, 2026. Accessed September 13, 2026. https://www.onclive.com/view/osimertinib-plus-savolitinib-improves-pfs-and-os-in-pretreated-met-egfr-nsclc
4. TP53 Status and Treatment Toxicity Burden Guide Sequencing in EGFR-Mutated NSCLC. OncLive. Published September 1, 2026. Accessed September 13, 2026. https://www.onclive.com/view/tp53-status-treatment-toxicity-burden-guide-sequencing-egfr-mutated-nsclc