BioNTech’s HER2 ADC Hits Phase 3 Goal, but Companies See Limited Benefit

BioNTech and DualityBio’s HER2-directed antibody-drug conjugate (ADC) trastuzumab pamirtecan (BNT323/DB-1303) met its primary endpoint in the global Phase 3 DYNASTY-Breast02 trial, but the companies said the potential benefit to patients would likely be limited.¹ The ADC produced a statistically significant but modest improvement in progression-free survival (PFS) compared with investigator’s choice of chemotherapy in chemotherapy-naïve patients with hormone receptor-positive (HR+), HER2-low metastatic breast cancer that had progressed on endocrine therapy.¹

The trial also showed a higher rate of interstitial lung disease (ILD) than earlier studies of the drug.¹ “The available efficacy and safety data, as of this data cut-off date, suggest that the potential benefit to patients would be limited in the context of the HR+/HER2-low metastatic breast cancer treatment landscape,” the companies said, adding that they will discuss the data and determine next steps.¹

How does trastuzumab pamirtecan work?

Trastuzumab pamirtecan is a third-generation ADC that pairs a HER2-targeting antibody with a topoisomerase-1 inhibitor payload.¹ It was built on DualityBio’s Duality Immune Toxin Antibody Conjugates platform.¹ HER2 is a protein expressed on the surface of solid tumors and has been linked to aggressive cancer growth and spread.¹

HER2-low tumors express the protein at levels below the threshold traditionally used to define HER2-positive disease, at immunohistochemistry (IHC) scores of 1+ or 2+ with a negative in situ hybridization (ISH) test.^1,2

What did DYNASTY-Breast02 show?

The randomized, open-label, multicenter trial (NCT06018337) enrolled 541 patients with HER2-low (IHC 1+ or IHC 2+/ISH-) metastatic breast cancer whose disease progressed on at least two lines of hormone therapy or within six months of first-line hormone therapy plus a CDK4/6 inhibitor.^1,3 Patients were randomized 1:1 to trastuzumab pamirtecan or single-agent chemotherapy with capecitabine, paclitaxel, or nab-paclitaxel.¹

Overall survival, the key secondary endpoint, was not mature at this interim analysis.¹ The companies did not disclose median PFS or hazard ratio figures.¹

Most ILD cases were Grade 1 or 2, though severe and fatal events (Grades 3 to 5) were reported in a small proportion of patients.¹ The companies did not report ILD rates. Otherwise, the safety profile was consistent with prior trials, and no new safety signals were identified.¹

Why is the benefit limited?

Trastuzumab pamirtecan would enter a setting where another topoisomerase-1 inhibitor ADC is already approved. FDA approved AstraZeneca and Daiichi Sankyo’s trastuzumab deruxtecan (Enhertu) in January 2025 for adults with HR+, HER2-low or HER2-ultralow metastatic breast cancer that progressed on one or more endocrine therapies, as BioPharm International® reported.² In the chemotherapy-naïve population of the Phase 3 DESTINY-Breast06 trial, trastuzumab deruxtecan improved median PFS to 13.2 months, compared with 8.1 months for chemotherapy (hazard ratio, 0.64).²

As ADCs move into earlier treatment lines, safety is increasingly shaping how they compete. In a BioPharm International interview at BIO 2026, Sabeen Mekan, MD, senior vice president and chief medical officer of Zymeworks, said, “We are getting to a point where safety is becoming much, much more important than it used to be.” She added, “Patients want that, they deserve that. Clinicians are choosing those ADCs as well.”

What happens next?

Trastuzumab pamirtecan remains in two other ongoing trials.¹ The global Phase 3 Fern-EC-01 trial (NCT06340568) is comparing it with investigator’s choice of chemotherapy in previously treated patients with HER2-expressing advanced recurrent endometrial cancer, and a phase 1/2 trial (NCT05150691) is evaluating it in advanced or metastatic solid tumors.¹

In April, BioPharm International reported that the ADC showed an objective response rate of approximately 50% in HER2-expressing endometrial cancer in the phase 1/2 study, an indication for which it holds FDA Breakthrough Therapy designation.

References

1. BioNTech and DualityBio announce topline results of the DYNASTY-Breast02 global Phase 3 clinical trial evaluating trastuzumab pamirtecan in HR+/HER2-low metastatic breast cancer. News release. BioNTech SE. October 26, 2026. Accessed October 26, 2026.
2. Enhertu approved in US as first HER2-directed therapy for patients with HER2-low or HER2-ultralow metastatic breast cancer following disease progression after one or more endocrine therapies. News release. AstraZeneca. January 27, 2025. Accessed October 26, 2026.
3. A study of DB-1303/​BNT323 vs investigator’s choice chemotherapy in HER2-low, hormone receptor positive breast cancer (DYNASTY-Breast02). ClinicalTrials.gov. Updated 2026. Accessed October 26, 2026.