Assessing ADC Combinations for Treatment in Breast Cancer

Results from the phase 3 DESTINY-Breast09 (NCT04784715) and ASCENT-04 (NCT05382286) trials show promising activity when combining antibody-drug conjugates (ADCs), according to Paolo Tarantino, MD, PhD.^1,2 However, assessing the toxicity risks of the combinations will be important to consider as well.

In the DESTINY-Breast09 trial, the median progression-free survival (PFS) by blinded independent central review was 40.7 months in the fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and pertuzumab (Perjeta) arm vs 26.9 months in the chemotherapy arm.

The ASCENT-04 trial showed a median PFS of 11.2 months in the sacituzumab govitecan-hziy (Trodelvy) plus pembrolizumab (Keytruda) arm vs 7.8 months in the chemotherapy plus pembrolizumab arm.

During the conversation at the 2025 International Congress on the Future of Breast Cancer® East hosted by Physicians' Education Resource®, LLC, Tarantino, a clinical research fellow at the Dana-Farber Cancer Institute, noted that there is a “brave new world” ahead for these combinations.

Transcript:

We are realizing that ADCs are, of course, extremely active, but combinations with the right drugs can make them even more active and effective. The first 2 phase 3 trials with ADC combinations that show the major benefit are the DESTINY-Breast09 trial, which looked at first-line T-DXd and pertuzumab, with an extremely long PFS of 40 months, which is practice changing, [and] the ASCENT-04 trial, with first-line sacituzumab govitecan and pembrolizumab for the first-line treatment of metastatic triple-negative breast cancer with PD-L1 positivity, [which] also reached a very long PFS of 11 months plus for the type of disease.

In truth, we’re realizing that adding another agent with a different toxicity profile can be beneficial. Still, combinations always can increase toxicity. It’s important to be mindful, to be rational, and to find the right combinations. In the future, we’re going to start to try combining ADCs. They already did it for urothelial cancer, combining enfortumab vedotin-ejfv [Padcev] and sacituzumab govitecan with very high efficacy but also with toxicity. We’ll need to modulate the dose of ADCs to maximize their benefit and, in the future, probably combine them just like we combine anthracyclines with cyclophosphamide, carboplatin with paclitaxel, etc. It’s a brave new world ahead, and we’re just at the beginning of it.

Reference

1. Tolaney S, Jiang Z, Zhang Q, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): interim results from DESTINY-Breast09. J Clin Oncol. 2025;43(suppl 17):LBA1008. doi:10.1200/JCO.2025.43.17_suppl.LBA1008
2. Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in previously untreated PD-L1–positive advanced triple-negative breast cancer (TNBC): primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study. J Clin Oncol. 2025;43(suppl 17):LBA109. doi:10.1200/JCO.2025.43.17_suppl.LBA109