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Erika P. Hamilton, MD, discusses initial efficacy and safety data with the TROP2-targeted ADC DB-1305/BNT325 in pretreated metastatic TNBC.
Early antitumor activity and tolerability seen with the TROP-2–directed antibody-drug conjugate (ADC) DB-1305/BNT325 in select patients with heavily pretreated metastatic triple-negative breast cancer (TNBC) from a phase 1/2 study (NCT05438329) support the continued evaluation of this agent alone and in other combination strategies, according to Erika P. Hamilton, MD.1
Initial data from response-evaluable patients with TNBC from dose-expansion cohort 7 (n = 26) were shared in a poster presentation at the 2025 ESMO Congress.1,2 Regarding safety, treatment-related adverse effects (TRAEs) occurred in all patients, with grade 3 or higher TRAEs reported in 34.6% of patients.1 Dose discontinuation or reduction due to TRAEs occurred in 3.8% and 19.2% of patients, respectively. No treatment-related deaths were reported.
In the interview, Hamilton discussed the mechanistic rationale for developing DB-1305 for the treatment of patients with advanced/metastatic solid tumors, including TNBC; expanded on key efficacy and safety data with DB-1305 from this first-in-human trial; and noted the potential use of this agent in combination with novel immunotherapies in breast cancer.
Hamilton is the director of Breast Cancer Research at Sarah Cannon Research Institute in Nashville, Tennessee.
Hamilton: DB-1305 is a TROP-2–targeting ADC. It has a topoisomerase-1 inhibitor payload, which is what we are kind of familiar with, and a drug-to-antibody ratio of 4.
We currently have 2 FDA-approved TROP2-targeting ADCs: sacituzumab govitecan-hziy [Trodelvy] and datopotamab deruxtecan [Dato-DXd; Datroway]. They both have a topoisomerase payload, but they are different in terms of schedule and [adverse] effect [profiles]. We did see data looking at moving these drugs up into the earlier setting for first-line TNBC. This really is a proven target with a proven payload, but again, it is a novel drug looking to provide benefit for these patients.
The data that we shared at ESMO focused on patients enrolled [onto our study] who had TNBC. They were treated at the recommended phase 2 dose [RP2D] of 3.5 mg/kg, and they had not previously seen sacituzumab govitecan.1,2 There were many other tumor types [included on this trial], including post–sacituzumab govitecan TNBC, as well as other histologies.2 Over 400 patients have been treated [on our study], but we specifically shared the information about these 26 patients with TNBC who were treated at the RP2D and were naive to sacituzumab govitecan.
These patients were heavily pretreated. It was a phase 1, so [they had] a median of 2 prior lines for TNBC.1 Some patients were more heavily pretreated than that.
We did see good [early] activity. We saw a disease control rate of 80.8% [95% CI, 60.65%-93.45%] and a confirmed overall response rate of 34.6% [95% CI, 17.21%-55.67%]. A third of our patients [experienced] substantial tumor shrinkage in response to this drug, and [the median] progression-free survival was 5.55 months [95% CI, 2.76-9.13] for these patients. We also showed that some of these responses were quite durable over a longer period of time. All [of these] data indicate that [DB-1305] is an active drug in this setting.
Just like we are learning with other TROP-2 targeting ADCs, the adverse effects [AEs] can be different from compound to compound. We know that with sacituzumab govitecan, [neutropenia] and diarrhea are the most prevalent [AEs]. With Dato-DXd, we think about stomatitis as well as dry eye. For DB-1305, the most frequent AE was stomatitis, making it similar to Dato-DXd in that regard. Only 2 patients had grade 3 stomatitis, so this was [primarily] a mild, grade 1/2 AE in most patients. Other common AEs were anemia and neutropenia. Only 1 patient discontinued treatment due to an AE. Although we did see AEs [with DB-1305], these were generally manageable [enough] for the patients to remain on study.
Development of this compound is ongoing. Specific to breast cancer, this TROP-2 ADC is now being combined with pumitamig [BNT327/BMS986545], which is a VEGF and PD-L1 bispecific drug. This follows the common strategy of taking an ADC and combining it with immunotherapy. We look forward to seeing data [with this regimen] in the future.
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