New TROP2-Targeted ADC Shows Promise in TNBC: Erika Hamilton, MD

A recent clinical trial found that a new TROP2-targeted antibody-drug conjugate (ADC) showed encouraging efficacy in treating a majority Asian population with triple-negative breast cancer (TNBC). The abstract findings were presented at the European Society for Medical Oncology earlier this year.1

DB-1305/​BNT325 is an investigational ADC with a humanized TROP2 IgG1 monoclonal antibody linked to a DNA topoisomerase I inhibitor via a cleavable linker. Prior research has consistently supported TROP2-targeted ADCs’ efficacy and safety profile in treating various types of breast cancer.1 Adding prospective ADCs to this landscape serves to benefit patients with breast cancer, said Erika Hamilton, MD, the abstract presenter at ESMO and breast cancer researcher and oncologist at the Sarah Cannon Research Institute, in an interview with The American Journal of Managed Care®.

“We're hoping that this is a broader target where we can really boost response rates and move this drug into the earlier-line setting for triple-negative, where we know immunotherapies are most efficacious,” she said.

There were 26 patients with TNBC in the phase 1/2 clinical trial (NCT05438329), all of whom received 1 or more doses of DB-1305/​BNT325. The median age was 49 years, and 92.3% of patients were Asian. The objective response rate was 34.6% (95% CI, 17.21-55.67), and the disease control rate was 80.8% (95% CI, 60.65-93.45).

Treatment-related adverse events occurred in all 26 patients. A severity grade of 3 or higher occurred in 9 patients (34.6%), with only one patient discontinuing treatment. Adverse events included stomatitis, anemia, nausea, and a decrease in neutrophils and white blood cells.

DB-1305/BNT325 is still being evaluated in combination with BNT327, an investigational anti-PD-L1/VEGF-A bispecific antibody, in patients with TNBC.

This transcript was lightly edited. Captions were auto-generated.

Transcript

What makes DB-1305/BNT325 unique among TROP2-targeted ADCs, especially with its DNA topoisomerase-1 payload and cleavable linker?

I think you allude to a good point. We do have multiple TROP2-targeting antibody-drug conjugates. We have sacituzumab govitecan as well as datopotamab deruxtecan. We actually just saw data from both of those in the 1st-line triple-negative breast setting at ESMO this year in Berlin. This is a similar drug, and it's also targeting TROP2. It also has a topo-1 payload, and it has a drug-to-antibody ratio of 4. Another option in this space.

Are there plans to study DB-1305/BNT325 in a more diverse patient population beyond the mostly Asian, ECOG 1 group?

This trial was open in the United States. It was open here in Nashville, Tennessee. But as you point out, it was also open in China. And the majority of patients were enrolled in China. They opened the trial first, so, yes, the majority of patients were of Asian descent.

I think in terms of their performance status, that's very real-world. That's what we would expect for patients who had at least 3rd-line metastatic triple-negative breast cancer. It’s probably rarer to have a performance status of 0 in that population. I think that was very reasonable, and yes, this trial is ongoing. We're actually looking at combinations with a PD-L/VEGF bispecific antibody called pumidimig, and that continues to roll out in the United States as well.

All patients had treatment-related adverse events—what stood out about the safety profile, and how was tolerability maintained?

The side effect profile from ADC to ADC is quite different, and it's tempting to group all these drugs into one class, right? With tyrosine kinase inhibitors, we can assume patients are going to have rash and diarrhea. For antibody drug conjugates, we can't assume that. Even within our 2 TROP2-targeting antibody-drug conjugates that we're very familiar with, sacituzumab govitecan predominantly causes neutropenia and diarrhea. Whereas datopotamab deruxtecan has eye effects as well as mucositis.

And if we had to kind of classify this into one of those buckets, it's more similar to datopotamab deruxtecan, meaning one of the prominent side effects we saw was stomatitis, or mucosal inflammation in the mouth. And we know that one of the ways we can prevent this is with a prophylactic steroid mouth rinse that really helps prevent inflammation in the mouth.

This was recommended as part of the protocol, but it was not mandated. And in fact, there are multiple areas in the world that have trouble accessing this steroid mouthwash, and China is one of them. I think that's a great point. Moving forward, we should be able to quantify how frequent that stomatitis is if patients receive that steroid mouthwash in a prophylactic fashion.

What's the rationale for combining DB-1305/BNT325 with BNT327, and what do you hope to learn from that combination arm?

We’ve seen a lot of data emerging around antibody-drug conjugates combining with immunotherapy-type molecules, particularly in triple-negative breast cancer. We don't have as much data that immunotherapy is efficacious in triple-negative or HER2, but certainly from KEYNOTE trials, as well as other trials, we have a good body of evidence that adding immunotherapy to these antibody-drug conjugates can be efficacious.

This particular molecule is a PD-L1/VEGF bispecific, so it not only hits that immunotherapy but also hits VEGF, which, for drugs like bevacizumab, etc, is their target. We're hoping that this is a broader target where we can really boost response rates and move this drug into the earlier-line setting for triple-negative, where we know immunotherapies are most efficacious.

References

1. Hamilton E, Yang H, Shi J, et al. 557P First clinical data of DB-1305/BNT325 (TROP2 antibody-drug conjugate [ADC]) in patients (pts) with pretreated triple-negative breast cancer (TNBC): Efficacy and safety data from a phase 1/2 trial. Ann Oncol. 2025; 36:(439). doi:10.1016/j.annonc.2025.08.980