Loading ...

Izalontamab brengitecan (iza-bren), an investigational bispecific antibody-drug conjugate (ADC), improved progression-free and overall survival among patients with previously treated metastatic or unresectable locally advanced triple-negative breast cancer (TNBC), according to interim results from a phase 3 trial.

Compared with standard chemotherapy, iza-bren extended median progression-free survival by 5.4 months and median overall survival by 3.4 months.

The results suggest that iza-bren could become a new standard of care, lead researcher Jiong Wu, MD, of Fudan University Shanghai Cancer Center in Shanghai, China, said during a presentation at the American Society of Clinical Oncology (ASCO) 2026 in Chicago.

Kathy Miller, MD, a breast cancer medical oncologist at Indiana University in Indianapolis, offered a measured take. She told Medscape Medical News that iza-bren, which is designed to target both epidermal growth factor receptor (EGFR) and HER3, is “clearly an active ADC with a different targeting mechanism.”

But while it’s “always exciting” to see overall survival gains, Miller said, the trial did not permit patients in the control group to crossover to iza-bren after progression.

“It’s tough to know if the [overall survival] advantage would hold up if crossover had been allowed,” said Miller, who is also a Medscape contributor.

In addition, questions were raised about how well these findings would translate to contemporary care, where many patients are now receiving other ADCs earlier in the course of the disease.

A Novel Targeting Strategy

Despite recent treatment advances, TNBC remains a therapeutic challenge, and survival improvements in metastatic disease have historically been limited compared with other breast cancer subtypes.

Iza-bren is an investigational, potentially first-in-class bispecific ADC that targets EGFR and HER3 with a potent topoisomerase I inhibitor payload. It’s currently under study for several cancer types, including advanced esophageal squamous cell carcinoma.

To investigate iza-bren in TNBC, the PANKU-Breast02 trial enrolled 418 patients whose disease had progressed after one or two prior lines of systemic therapy for advanced disease, including prior taxane treatment.

Patients were randomly assigned 1:1 to receive iza-bren (2.5 mg/kg on days 1 and 8 of a 21-day cycle) or physician’s choice of chemotherapy, which included eribulin, capecitabine, gemcitabine, or vinorelbine.

Baseline characteristics were generally balanced between the treatment groups. Patients were stratified by prior lines of chemotherapy, prior anti-PD(L)-1 treatment, and HER2 expression levels.

The confirmed objective response rate was significantly higher with iza-bren (51.7%) than chemotherapy (20.5%).

With a median follow-up of 11 months, median progression-free survival was 8.5 months with iza-bren compared with 3.1 months with chemotherapy — representing a 71% reduction in the risk for progression or death, Wu said.

That benefit was observed across all key predefined subgroups and appeared consistent regardless of HER2 expression status.

Median overall survival was 15.9 months with iza-bren vs 12.5 months with chemotherapy, representing a 40% reduction in the risk for death. Overall survival with longer follow-up will be reported in the future.

Iza-bren, Wu said, now stands as the first bispecific ADC to show improved progression-free and overall survival in a phase 3 study in this patient population.

Notably, she added, the survival advantage was seen despite greater use of subsequent therapies in the chemotherapy group (63.4% vs 38.6%), including ADCs (42%).

The benefit did come with increased toxicity: Grade 3 or higher treatment-emergent adverse events occurred in 89% of patients receiving iza-bren and 63% of those receiving chemotherapy. The most common with iza-bren were anemia and decreased blood counts.

Those events were effectively managed with dose reductions and standard supportive care, Wu reported. About 63% of the patients on iza-bren needed dosing interruption or reduction, but few (1.9%) discontinued treatment due to adverse events. There was one adjudicated case of grade 2 interstitial lung disease.

Remaining Questions

ASCO discussant Valentina Guarneri, MD, of the University of Padova in Padua, Italy, framed the findings in their larger context.

Although PARP inhibitors, immune checkpoint inhibitors, and other ADCs have improved outcomes in select patients with TNBC, she said, there is a clear need for new approaches, including next-generation ADCs and bispecific platforms.

Guarneri noted there’s a strong biologic basis for a bispecific like iza-bren, given that both EGFR and HER3 have been linked to tumor aggressiveness, treatment resistance, and poor prognosis in patients with TNBC.

She did question the trial’s use of chemotherapy as the control, in an era when multiple ADCs have demonstrated superiority over standard chemotherapy. The magnitude of the iza-bren benefit, Guarneri said, “may not be entirely replicated in contemporary patients” because many now receive ADCs earlier, including in the first-line setting.

At the same time, she acknowledged that this is a common challenge across oncology trials as treatment landscapes rapidly evolve. And because treatment availability varies considerably across healthcare systems and geographic regions, Guarneri said, the iza-bren findings are still clinically important.

She stressed that validation across a broader and more ethnically diverse global cohort is needed.

According to Miller, the key question for clinicians in the US and parts of Europe will be how iza-bren compares with available ADCs.

She also pointed out that because iza-bren uses a topoisomerase I-based payload, that creates uncertainty about its efficacy for patients who’ve been exposed to existing ADCs carrying similar payloads.

“If resistance is to the payload, that will be a problem,” Miller said. “If resistance is due to targeting, that’s less of a problem. This is an issue globally with sequencing ADC after ADC.”

The study was sponsored by Baili-Bio (Chengdu) Pharmaceutical, the developer of iza-bren. Wu reported serving as a consultant for Lilly. Guarneri disclosed having relationships with AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, and other pharmaceutical companies.