Izalontamab brengitecan (iza-bren; formerly BL-B01D1) significantly improved progression-free survival (PFS) and overall survival (OS) compared with physician’s choice of chemotherapy in patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC), meeting the co-primary end points of the phase 3 PANKU-Breast02 trial (NCT06382142).1
The results, which were presented during the 2026 ASCO Annual Meeting, showed that the median PFS was 8.5 months (95% CI, 6.9-9.8) by blinded independent review (BICR) with iza-bren (n = 207) vs 3.1 months (95% CI, 2.7-4.1) with chemotherapy (n = 205), translating to a 71% reduction in the risk of disease progression or death (HR, 0.29; 95% CI, 0.22-0.38; P < .0001). The estimated 6-month PFS rates in the respective arms were 62.0% (95% CI, 54.3%-68.8%) and 17.6% (95% CI, 12.0%-24.0%); the 9-month PFS rates were 47.7% (95% CI, 39.4%-55.6%) and 7.7% (95% CI, 3.8%-13.4%), respectively.
The median OS with iza-bren was 15.9 months (95% CI, 13.3-not reached [NR]) vs 12.5 months (95% CI, 11.4-NR) with chemotherapy, translating to a 40% reduction in the risk of death (HR, 0.60; 95% CI, 0.42-0.85; P = .0019). In the iza-bren arm, the 9- and 12-month OS rates were 79.9% (95% CI, 73.1%-85.2%) and 67.5% (95% CI, 58.7%-74.8%), respectively; these rates were 68.7% (95% CI, 61.0%-75.2%) and 53.5% (95% CI, 44.4%-61.7%), respectively, in the chemotherapy arm.
“Results from this phase 3 study support iza-bren as a new standard of care for patients with pretreated metastatic TNBC,” Jiong Wu, MD, PhD, of Fudan University Shanghai Cancer Center, in Shanghai, China, said in a presentation of the data.
What was the rationale for examining iza-bren in PANKU-Breast02?
It is known that patients who receive taxane-based regimens and have subsequent disease progression experience poor outcomes, thus underscoring an unmet need for effective therapeutic options.
The first-in-class bispecific antibody-drug conjugate (ADC) iza-bren targets EGFR and HER3 and has a topoisomerase I inhibitor payload; it has previously elicited responses with acceptable safety in heavily pretreated patients with advanced or metastatic HER2-negative or HER2-low breast cancer.2 Data from a phase 1 study (NCT05470348) showed that at a median follow-up of 11.7 months, iza-bren elicited an overall response rate (ORR) of 42.1% and a confirmed ORR of 36.4%. The disease control rate (DCR) was 80.2%, the median duration of response (DOR) was 9.7 months (95% CI, 5.8-11.7), and the median PFS was 6.9 months (95% CI, 5.5-8.4).
What was the design of the PANKU-Breast02 study of iza-bren?
The multicenter, open-label, randomized, phase 3 study enrolled patients with unresectable locally advanced or metastatic TNBC who had progressed following 1 to 2 lines of systemic therapy, including taxanes, for advanced disease.1 Patients were required to have a measurable lesion by RECIST 1.1 criteria and an ECOG performance no higher than 1.
Patients (n = 406) were randomly assigned 1:1 to receive iza-bren at 2.5 mg/kg on days 1 and 8 every 3 weeks or physician’s choice of chemotherapy every 3 weeks in the form of eribulin on days 1 and 8, capecitabine twice daily, gemcitabine on days 1 and 8, and vinorelbine on days 1 and 8. Patients were stratified based on prior lines of chemotherapy (1 vs 2), previous anti–PD(L)1 therapy (yes vs no), and HER2 expression (immunohistochemistry [IHC] 0 vs IHC 1+/2+ in situ hybridization [ISH] negative).
In addition to the dual primary end points of PFS by BICR and OS, secondary end points included ORR by BICR, investigator-assessed PFS, DCR, DOR, safety, pharmacokinetics, and immunogenicity.
What should be known about the patients enrolled to PANKU-Breast02?
A total of 584 patients were screened, and 418 underwent random assignment. Of the 207 patients who were treated with iza-bren and the 205 patients given chemotherapy, 64 and 15 patients, respectively, were still receiving treatment at the time of the data cutoff date of January 13, 2026.
The baseline characteristics were balanced between the arms, according to Wu. The median patient age was 53.0 years (range, 28.0-73.0) with iza-bren vs 54.0 years (range, 27.0-71.0) with chemotherapy. Most patients in the iza-bren and chemotherapy arms, respectively, were under 65 years of age (88.9%; 91.2%), had an ECOG performance status of 1 (72.9%; 69.3%), had received 1 prior line of chemotherapy (70.5%; 69.8%), and had received no prior anti–PD-(L)1 therapy (76.3%; 75.1%). Approximately half of patients in both arms had received prior radiotherapy (51.7%; 55.1%).
Moreover, the majority of patients had stage IV disease (98.6%; 99.0%), had received prior (neo)adjuvant chemotherapy (79.2%; 78.5%), and had metastatic disease in the lymph node (70.0%; 65.4%). In the iza-bren arm, 53.1% of patients had HER2 expression of IHC 0, and 46.9% of patients had HER2 expression of IHC1+ or IHC2+/ISH negative; in the chemotherapy arms, these respective rates were 54.1% and 45.9%.
What were the additional efficacy data reported with iza-bren in PANKU-Breast02?
“Consistent PFS benefit was seen across the various subgroups,” Wu said.
Iza-Bren Shows Promise in the TNBC Paradigm
- Izalontamab brengitecan significantly improved progression-free and overall survival vs physician’s choice chemotherapy in previously treated metastatic TNBC, meeting both co-primary end points of the PANKU-Breast02 trial.
- The EGFR/HER3-targeting bispecific ADC reduced the risk of disease progression or death by 71% and the risk of death by 40%. It also more than doubled the ORR compared with chemotherapy.
- Responses were observed regardless of HER2 expression status, and the agent demonstrated a manageable safety profile with no new safety signals identified.
In the HER2 IHC 0 population, the median PFS with iza-bren (n = 111) was 8.3 months (95% CI, 6.2-9.8) vs 2.6 months (95% CI, 1.6-3.7) with chemotherapy (n = 110), translating to a 72% reduction in the risk of disease progression or death (HR, 0.28; 95% CI, 0.20-0.41; P < .0001). The 6-month PFS rates in the respective arms were 61.2% (95% CI, 50.6%-70.3%) and 16.3% (95% CI, 9.2%-25.1%); the 9-month rates in the respective arms were 44.1% (95% CI, 32.9%-54.6%) and 8.3% (95% CI, 3.2%-16.4%).
In the HER2-low population, the median PFS was 9.7 months (95% CI, 6.1-11.3) with iza-bren (n = 96) vs 4.1 months (95% CI, 2.9-4.2) with chemotherapy (n = 95), translating to a 68% reduction in the risk of disease progression or death (HR, 0.32; 95% CI, 0.22-0.46; P < .0001). The 6- and 9-month PFS rates in the iza-bren arm were 62.8% (95% CI, 51.1%-72.4%) and 52.7% (95% CI, 40.4%-63.5%), respectively; in the chemotherapy arm, these rates were 19.0% (95% CI, 11.0%-28.6%) and 8.6% (95% CI, 3.4%-17.1%).
In the overall population, Iza-bren elicited a confirmed ORR of 51.7% (95% CI, 44.7%-58.7%) by BICR vs 20.5% (95% CI, 15.2%-26.7%) with chemotherapy (odds ratio, 4.3; 95% CI, 2.8-6.7). In the iza-bren arm, 3.9% of patients had a complete response (CR) as a best overall response, and 47.8% had a best overall response of a partial response (PR). In this arm, the DCR was 83.1%, the clinical benefit rate (CBR) was 64.3%, and the median DOR was 8.3 months (95% CI, 8.1-11.0). In the chemotherapy arm, 0.5% and 20.0% of patients, respectively, had a CR or a PR as a best overall response. In this group, the DCR was 59.0%, the CBR was 31.2%, and the median DOR was 4.0 months (95% CI, 2.9-5.2).
What should be known about subsequent anticancer therapy received by the patients in PANKU-Breast02 following disease progression with iza-bren?
In the iza-bren arm, 38.6% of patients received at least 1 subsequent anticancer therapy; this rate was 63.4% in the chemotherapy arm. Subsequent anticancer therapies in these respective arms included an ADC (16.4%; 42.0%), chemotherapy (25.1%; 34.6%), antibody therapy (12.6%; 20.5%), and small molecule therapy (9.7%; 7.8%).
“Iza-bren showed a statistically significant and clinically meaningful improvement in OS vs chemotherapy, despite more patients receiving subsequent therapies in the chemotherapy arm, including 42.0% with an ADC,” Wu noted.
What was the safety profile of iza-bren in these patients with TNBC?
“Iza-bren had a manageable safety profile,” Wu said.
Treatment-emergent adverse effects (TEAEs) occurred in all patients in the iza-bren arm vs 98.5% of those treated with chemotherapy; these TEAEs were grade 3 or higher for 88.9% and 62.9% of patients, respectively. Serious toxicities were reported in 44.0% of those given iza-bren vs 19.0% of those who received chemotherapy.
“Most AEs were effectively managed by dose modification and standard supportive care,” Wu said. TEAEs resulted in dose reduction and interruption for 63.3% and 63.3% of patients, respectively, in the iza-bren arm and 11.2% and 35.1% of those, respectively, in the chemotherapy arm; TEAEs resulted in treatment discontinuation for 1.9% and 0.5% of patients in these respective arms. TEAEs led to death for 6 patients in the iza-bren arm and 2 patients in the chemotherapy arm.
The most common TEAEs reported in at least 25% of patients in the iza-bren arm included anemia, decreased white blood cell count, decreased platelet count, decreased neutrophil count, nausea, alopecia, increased alanine aminotransferase level, increased aspartate aminotransferase level, asthenia, decreased appetite, vomiting, hypertriglyceridemia, and hypokalemia.
“The most frequent grade 3 or higher TEAEs in the iza-bren arm were hematologic and were effectively managed by standard supportive care,” Wu said. The median time to resolution of grade 3/4 neutropenia was 4 days. Moreover, 5.3% of patients in the iza-bren arm had febrile neutropenia vs 0.5% of those in the chemotherapy arm. Grade 3 or higher infection rates were reported in 6.8% and 5.4% of patients, respectively.
Additionally, 1.4% of patients who received iza-bren experienced all-grade interstitial lung disease (ILD) per investigator assessment; this included 1 case of grade 1 ILD and 2 cases of grade 2 ILD. Per independent ILD adjudication committee, only 1 case of grade 2 ILD was reported with iza-bren.
“No new safety signals were observed,” Wu concluded.
Disclosures: Wu disclosed serving in a consulting or advisory role for Lilly, and being a recipient of patents or royalties for vascular support dilator of microsurgery.
References
- Wu J, Zhang J, Ouyang Q, et al. A randomized phase III study evaluating izalontamab brengitecan (iza-bren) versus physician’s choice of chemotherapy in patients with locally advanced or metastatic triple-negative breast cancer (TNBC). J Clin Oncol. 2026;44(suppl 17):LBA1003. doi:10.1200/JCO.2026.44.17_suppl.LBA1003
- Zhang J, Wu J, Du Y, et al. Phase I study of iza-bren (BL-B01D1), an EGFR x HER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic breast cancer (BC). Ann Oncol. 2025;10(suppl 4):104874. doi:10.1016/j.esmoop.2025.104874
