Iza-Bren Improves PFS vs Platinum Chemo in EGFR-Mutated NSCLC After Third-Generation TKI

Izalontamab brengitecan (iza-bren) significantly improved progression-free survival (PFS) vs platinum-based chemotherapy in patients with EGFR-mutated nonsquamous non–small cell lung cancer (NSCLC) whose disease progressed on a third-generation EGFR TKI, according to interim findings from the phase 3 PANKU-Lung01 trial (NCT06382116) presented at the 2026 ESMO Congress.¹ The findings were published simultaneously in The Lancet.²

At a median follow-up of 14.6 months, the median PFS by blinded independent central review (BICR) was 11.1 months (95% CI, 9.2-12.7) with iza-bren (n = 216) vs 5.7 months (95% CI, 5.5-5.9) with chemotherapy (n = 206; HR, 0.40; 95% CI, 0.31-0.51; 1-sided P < .0001).¹ The 6-month PFS rates were 75.1% and 42.9%, respectively, and the 12-month rates were 46.5% and 14.4%.

Overall survival (OS) data were immature at the interim analysis. The median OS was not reached (95% CI, 19.3-not reached) with iza-bren vs 19.4 months (95% CI, 16.4-22.5) with chemotherapy, and the 12-month OS rates were 83.0% (95% CI, 77.3%-87.5%) and 72.9% (95% CI, 66.1%-78.5%), respectively. Moreover, the confirmed objective response rate (ORR) by BICR was 60.2% (95% CI, 53.3%-66.8%) with iza-bren vs 34.5% (95% CI, 28.0%-41.4%) with chemotherapy, a difference of 25.6% (95% CI, 16.2%-34.6%; odds ratio, 2.9; 95% CI, 1.9-4.3).

Presenting author Li Zhang, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China, said that “these results support iza-bren as a promising new treatment option for [patients with] EGFR-mutant NSCLC with EGFR TKI resistance.”

How was the phase 3 PANKU-Lung01 trial evaluating iza-bren in EGFR-mutated NSCLC designed?

Iza-bren is a bispecific antibody-drug conjugate (ADC) that targets EGFR and HER3 and carries a topoisomerase I inhibitor payload via a cleavable linker. In a global phase 1 dose-expansion study (NCT05983432), the agent produced responses in patients with EGFR-mutated NSCLC after osimertinib, and those data established the recommended phase 3 dose for the global IZABRIGHT-Lung01 trial (NCT07100080).³

The open-label, multicenter PANKU-Lung01 trial enrolled patients with locally advanced or metastatic nonsquamous NSCLC harboring an EGFR exon 19 deletion or L858R mutation whose disease progressed on a third-generation EGFR TKI, after up to 2 prior lines of EGFR TKI therapy.¹ Patients had measurable disease, and an ECOG performance status of 0 or 1. Those with treated or stable central nervous system (CNS) metastases were permitted.

Patients were randomly assigned 1:1 to iza-bren at 2.5 mg/kg on days 1 and 8 every 3 weeks or to pemetrexed at 500 mg/m² plus cisplatin at 75 mg/m² or carboplatin at an area under the curve of 5 every 3 weeks. Randomization was stratified by ECOG performance status (0 vs 1), CNS metastases (yes vs no), and prior antiangiogenic therapy (yes vs no). Treatment continued until progressive disease by RECIST 1.1 or unacceptable toxicity.

The primary end point was PFS by BICR, and OS was the key secondary end point, tested hierarchically. Other secondary end points included investigator-assessed PFS, ORR, disease control rate (DCR), duration of response (DOR), and safety.

Of 432 patients randomly assigned, 216 in the iza-bren arm and 206 in the chemotherapy arm received treatment. The median age was 59.5 years (range, 37.0-78.0) in the iza-bren arm and 61.0 years (range, 31.0-79.0) in the chemotherapy arm. Across the arms, most patients were younger than 65 years (71.8%; 67.5%), had an ECOG performance status of 1 (76.4%; 77.2%), were never smokers (70.8%; 71.4%), and did not have CNS metastases (90.3%; 89.8%). Moreover, 58.3% and 56.8% of patients, respectively, had metastases in 3 or more organs, and 77.8% and 74.3% had received only a third-generation EGFR TKI.

What secondary efficacy outcomes did iza-bren produce in PANKU-Lung01?

The DCR with iza-

b

ren was 88.9% (95% CI, 83.9%-92.8%) vs 85.0% (95% CI, 79.3%-89.5%) with chemotherapy, and the median DOR was 10.4 months (95% CI, 9.2-12.7) vs 5.7 months (95% CI, 4.4-7.1; HR, 0.41; 95% CI, 0.29-0.60).

The PFS benefit was consistent across prespecified subgroups. The HRs were 0.31 (95% CI, 0.22-0.43) in patients with exon 19 deletions and 0.59 (95% CI, 0.41-0.83) in those with L858R mutations, and 0.75 (95% CI, 0.37-1.50) in the 41 patients with CNS metastases.

What was the safety profile of iza-bren in EGFR-mutated NSCLC after a third-generation TKI?

The median treatment duration was 10.3 months with iza-bren and 5.7 months with pemetrexed. Grade 3 or higher treatment-related adverse effects (TRAEs) occurred in 78.7% of patients in the iza-bren arm vs 62.1% in the chemotherapy arm, and serious TRAEs occurred in 42.6% vs 19.4%. TRAEs led to dose reductions in 60.2% vs 23.3% of patients and to discontinuation in 1.9% of patients in each arm. One TRAE leading to death occurred in each arm.

The most common grade 3 or higher TRAEs with iza-bren vs chemotherapy were neutropenia (46.3% vs 37.4%), leukopenia (42.1% vs 19.9%), thrombocytopenia (38.4% vs 20.9%), and anemia (33.3% vs 18.0%). Grade 3 or higher anemia resolved in a median of 8.0 days. Grade 3 or higher neutropenia and thrombocytopenia resolved within 2 to 3 days; febrile neutropenia occurred in 6.0% of patients receiving iza-bren. Alopecia occurred in 77.3% of patients in the iza-bren arm. Treatment-related interstitial lung disease occurred in 2 patients (0.9%) receiving iza-bren; 1 event was grade 1 and the other event was grade 3.

Global registrational trials of iza-bren are ongoing in EGFR-mutated NSCLC after progression on a third-generation EGFR TKI (IZABRIGHT-Lung01) and in the first-line setting (IZABRIGHT-Lung02; NCT07680790).

References

1. Zhang L, Yang Y, Meng X, et al. PANKU-Lung01: randomized phase III study of izalontamab brengitecan (iza-bren) vs platinum-based chemotherapy (PBC) in patients with EGFR-mutant non-squamous non-small cell lung cancer (NSCLC) after progression on a third-generation EGFR tyrosine kinase inhibitor (TKI). Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA71.
2. Hong S, Zhou T, Hou X, et al. Izalontamab brengitecan versus platinum-based chemotherapy in EGFR-mutated advanced non-squamous non-small-cell lung cancer after progression on third-generation EGFR tyrosine kinase inhibitors (PANKU-Lung01): a multicentre, randomised, open-label, phase 3 trial in China. Lancet. Published online October 26, 2026. doi:10.1016/S0140-6736(26)02026-X
3. Iza-bren elicits 33% ORR, 6.9-month PFS in post-osimertinib EGFR-mutated NSCLC. OncLive. Published September 12, 2026. Accessed October 26, 2026. https://www.onclive.com/view/iza-bren-orr-pfs-post-osimertinib-egfr-mutated-nsclc