A first-in-class bispecific antibody-drug conjugate (ADC) nearly doubled progression-free survival (PFS) compared with chemotherapy in patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) who progressed on third-generation EGFR tyrosine kinase inhibitors (TKIs), a phase III trial from China showed.
Median PFS was 11.1 months with izalontamab brengitecan (iza-bren) compared with 5.7 months with pemetrexed plus carboplatin or cisplatin (HR 0.40, 95% CI 0.31-0.51, one-sided P<0.0001), reported Li Zhang, MD, of Sun Yat-sen University Cancer Center in Guangzhou, at the European Society for Medical Oncology (ESMO) annual congress in Madrid.
The benefit extended to all prespecified subgroups in the PANKU-Lung01 trial, which was also published in The Lancet.
Confirmed objective responses occurred in 60.2% of patients receiving iza-bren versus 34.5% of those receiving chemotherapy (OR 2.83, 95% CI 1.91-4.20). Disease control rates were 88.9% and 85%, respectively, with a median duration of response of 10.5 months versus 5.7 months (HR 0.41, 95% CI 0.29-0.60).
While overall survival data were immature, the interim estimate favored iza-bren (not reached vs 19.4 months with chemotherapy; stratified HR 0.66, 95% CI 0.47-0.91).
“These results support iza-bren as a promising new treatment option for EGFR-mutant NSCLC patients with EGFR TKI resistance,” Zhang said.
He pointed out that while EGFR TKIs are the standard therapy for advanced EGFR-mutant NSCLC, most patients will eventually develop resistance.
“Following disease progression on third-generation TKIs, platinum-based chemotherapy remains a common treatment option,” he said. “So, therapeutic options with improved efficacy are still needed.”
Iza-bren, which targets EGFR and HER3, was granted a breakthrough therapy designation from the FDA for previously treated advanced EGFR-mutated NSCLC, based on results from phase I and II studies. Iza-bren was also shown to double PFS in patients with heavily pretreated hormone receptor-positive breast cancer in a randomized trial that was also presented at the ESMO meeting.
Invited discussant Simon Ekman, MD, PhD, of the Karolinska University Hospital in Stockholm, pointed out that other studies are underway, including global registration studies in EGFR-mutated NSCLC patients after progression on a third-generation EGFR TKI (IZABRIGHT-Lung01), as well as in the first-line setting (IZABRIGHT-Lung02).
“HER3 is an attractive target because it may address different resistance mechanisms,” Ekman said. “But, to realize the full potential of [HER3 ADCs], we need to do more biomarker research to have more precise patient selection, we need to study CNS [central nervous system] metastases more, understand resistance, and define the treatment sequences and combinations that are optimal.”
PANKU-Lung01 was conducted at 73 sites in China. Eligible participants had EGFR-mutated locally advanced or metastatic non-squamous NSCLC, disease progression after third-generation EGFR TKIs, and had received no previous chemotherapy for advanced disease.
The researchers randomized 432 patients to iza-bren monotherapy or pemetrexed plus carboplatin or cisplatin, with pemetrexed maintenance permitted in participants without progression, from May 2024 to September 2025. The primary endpoint was PFS assessed by blinded independent central review.
Median age was 59.5 years in the iza-bren group and 61 years in the chemotherapy group, and the majority of patients were women. Almost every patient (98%) had stage IV disease, while a history of CNS metastases at study entry was recorded in 10%. All patients had received a third-generation EGFR TKI, and most (72-73%) had received one previous line of systemic therapy.
Grade ≥3 treatment-related adverse events (TRAEs) occurred in 79% of patients in the iza-bren group and 62% in the chemotherapy group, and serious TRAEs occurred in 43% and 19%, respectively.
The most common grade ≥3 TRAEs were hematologic — neutrophil count decreases (46% in the iza-bren group vs 37% in the chemotherapy group), white blood cell count decreases (42% vs 20%), platelet count decreases (38% vs 21%), and anemia (33% vs 18%).
Febrile neutropenia occurred in 6% of patients receiving iza-bren and none receiving chemotherapy.
“The safety profile of iza-bren was manageable through standard supportive care, including dose delays and dose reductions,” Zhang said, and treatment discontinuation rates due to TRAEs were low in both groups (2%).
