ADC Iza-Bren Generates Responses and Improves PFS vs Chemo in Metastatic NPC

Izalontamab brengitecan (iza-bren; BL-B01D1) produced a statistically significant and clinically meaningful improvement in overall response rate (ORR) and more durable responses compared with chemotherapy in heavily pretreated patients with recurrent or metastatic nasopharyngeal carcinoma (NPC), according to data from the phase 3 BL-B01D1-301 study (NCT06118333) presented at the 2025 ESMO Congress and simultaneously published in The Lancet.1,2

The ORR by blinded independent central review was 54.6% (95% CI, 45.2%-63.8%) with iza-bren vs 27.0% (95% CI, 19.1%-36.0%) with chemotherapy, with an odds ratio of 3.3 (95% CI, 1.9-5.8; P < .0001).1

“This was the first randomized phase 3 study evaluating iza-bren in recurrent or metastatic NPC. Our study has met its primary end point for ORR, we can see a clinically meaningful improvement in progression-free survival [PFS], and it has a management safety profile,” said Huaqiang Zhou, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China, in his presentation.1

Approximately 20% to 30% of patients with NPC have recurrent or distant metastases, and current treatment options have low response rates. Iza-bren is a potentially first-in-class topoisomerase 1 inhibitor-based EGFR- and HER3-directed bispecific antibody-drug conjugate (ADC).

The multicenter, randomized, open-label BL-B01D1-301 trial was designed to investigate this ADC in patients who had previously received at least 2 lines of systemic chemotherapy, including at least 1 platinum-containing regimen and a PD-1 or PD-L1 inhibitor. The primary end points were ORR and overall survival (OS), with secondary end points including PFS, duration of response (DOR), and safety.

Patients were enrolled in 55 hospitals in China. They were stratified by number of prior lines of platinum-based treatment, ECOG performance status of 0 vs 1, and presence/absence of liver metastases.

Of 522 patients who were screened, 386 were randomly assigned on a 1:1 basis, with 191 receiving 2.5 mg/kg of iza-bren on days 1 and 8 of a 3-week cycle, and 195 receiving physician’s choice of chemotherapy.1

The median age of patients was 50.0 years in the treatment arm and 49.0 years in the chemotherapy arm, with the majority of patients being male in each arm (85.3% and 81.0%, respectively). Most patients had an ECOG performance status of 1 (75.9% in both arms). Over half of patients in both arms had received 2 prior lines of therapy, with the rest of patients having received at least 3 lines. The majority of patients had received 2 prior lines of chemotherapy, with 48.2% of those in each arm having received 2 prior lines of platinum-based chemotherapy. Prior radiotherapy had been used in 89.5% of patients in the experimental arm and 88.2% of those in the control arm.

Metastases were present at baseline in the liver, bones, and lungs in 47.6%, 49.2%, and 46.6% of patients in the experimental arm and 48.7%, 46.7%, and 37.4% of those in the control arm, respectively.

Results were reported at a median follow-up of 7.66 months for the iza-bren arm and 7.10 months for the chemotherapy arm. There was 1 complete response in the iza-bren arm and none in the control arm. The disease control rate was 82.4% with iza-bren vs 69.6% with chemotherapy. Outcomes favored iza-bren across all subgroups in this analysis.

The median DOR was 8.5 months for iza-bren vs 4.8 months for physician's choice of chemotherapy (HR, 0.43; 95% CI, 0.22-0.83). The median PFS was 8.38 months with iza-bren vs 4.34 months for chemotherapy (HR, 0.44; 95% CI, 0.32-0.62), and this trend was consistent across subgroups. At this time, OS was not mature.

Treatment-related adverse events (TRAEs) of grade 3 or higher were reported in 79.9% of patients receiving iza-bren vs 61.6% of those receiving chemotherapy. Serious TRAEs occurred in 43.4% of patients in the iza-bren arm vs 27.0% of those in the chemotherapy arm, and 4 (2%) treatment-related deaths occurred in the iza-bren group. Dose reductions due to TRAEs were needed in 41.8% of patients who received iza-bren vs 24.3% of those who received chemotherapy, and TRAEs leading to dose interruption occurred in 61.4% vs 18.4% of patients, respectively. TRAEs led to treatment discontinuation in 2.6% vs 3.2% of patients, respectively.

Hematological AEs were reported more frequently with iza-bren vs chemotherapy, including anemia in 50% vs 10% of respective patients and decreased platelet count in 43% vs 7% of patients, respectively. Decreased white blood cell counts occurred in 43% vs 44% of respective patients, and decreased neutrophil counts occurred in 38% vs 41% of patients, respectively. According to Zhou, these were well managed by standard supportive care. The majority of nonhematologic TRAEs were grade 1 or 2, and no new safety signals were identified.

Two cases of grade 2 interstitial lung disease (ILD) occurred in the experimental arm, and 2 cases of grade 3 ILD occurred in the chemotherapy arm.

“Based on this trial, iza-bren represents a potential new standard of care for heavily pretreated patients with recurrent or metastatic NPC,” concluded Zhou.

References

1. Yang Y, Zhou H, Tang L, et al. Iza-bren (BL-B01D1), an EGFR×HER3 bispecific antibody-drug conjugate, versus physician's choice of chemotherapy in heavily pretreated recurrent/metastatic nasopharyngeal carcinoma: a randomized, open-label, multicenter, phase III, pivotal study (BL-B01D1-303). Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA35.
2. Yang Y, Zhou H, Tang L, et al. Izalontamab brengitecan, an EGFR and HER3 bispecific antibody–drug conjugate, versus chemotherapy in heavily pretreated recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 study in China. Lancet. Published online October 19, 2025. doi:10.1016/S0140-6736(25)01954-3