Dr. Dhakal on the Implementation of Trastuzumab Deruxtecan Across the HER2+ Breast Cancer Landscape

Ajay Dhakal, MBBS, assistant professor, Department of Medicine, Hematology/Oncology, the University of Rochester Medical Center, discusses the evolution and implementation of the antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu) across the landscape of HER2-positive breast cancer landscape.

The recent success of trastuzumab deruxtecan in clinical trials, plus its FDA approvals in breast, lung, and gastric cancers, have made it the most notable ADC currently in the cancer treatment landscape, Dhakal notes. Within the breast cancer space, another indication was added with theFDA approval of the ADC for the treatment of patients with unresectable or metastatic HER2-low breast cancer in August 2022.

The design of trastuzumab deruxtecan has led the way in the development of next-generation ADCs due to trastuzumab deruxtecan’s fundamental differences when compared with ado-trastuzumab emtansine (T-DM1; Kadcyla). Trastuzumab deruxtecan has a higher drug-to-antibody ratio compared with T-DM1, and trastuzumab deruxtecan has a unique cleavable linker. Once the ADC enters the cell, the cleavable linker does not have to wait for the cells to come in and dissolve the linker; instead, the linker easily detaches from the ADC, creating a bystander effect, Dhakal adds.

Trastuzumab deruxtecan’s superiority over T-DM1 in the second-line setting of HER2-positive metastatic breast cancer was demonstrated in the phase 3 DESTINY-Breast03 trial (NCT03529110). The multicenter, randomized, open-label study compared the antitumor activity, safety, and efficacy of trastuzumab deruxtecan vs T-DM1 in unresectable, metastatic HER2-positive breast cancers.

Trastuzumab deruxtecan significantly improved progression-free survival (PFS) vs T-DM1, with patients in the experimental arm experiencing a median PFS that was not yet reached, compared with 6.8 months in the control arm. These data led to the regular FDA approval of trastuzumab deruxtecan for adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received an anti–HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting, Dhakal concludes.