Dr Waks on Ongoing Research in Residual HER2+ Breast Cancer

Adrienne G. Waks, MD, associate director, Breast Oncology Clinical Research, Dana-Farber Cancer Institute; associate professor, medicine, Harvard Medical School, discusses the adjuvant standard of care (SOC) used to lower the risk of disease recurrence in patients with HER2-positive breast cancer who have residual disease, as well as ongoing research investigating ways to improve standard treatment outcomes in this population.

The current SOC for reducing recurrence risk in this population is ado-trastuzumab emtansine (T-DM1; Kadcyla), which elicited an overall survival (OS) advantage compared with trastuzumab (Herceptin) in the phase 3 KATHERINE trial (NCT01772472), Waks begins. In KATHERINE, T-DM1 was associated with OS benefits in patients with minimal residual disease or those whose residual disease had converted to HER2-negative disease at the time of surgery.

Two ongoing clinical trials are exploring potential enhancements to the efficacy of T-DM1, Waks says. The phase 3 CompassHER2 RD trial (NCT04457596) is evaluating the addition of tucatinib, a HER2-directed TKI, to T-DM1 in patients with residual HER2-positive invasive breast cancer after neoadjuvant therapy. If this trial is successful, this regimen could become a new SOC for certain patients, particularly because dual HER2 blockade has proven more effective than single-agent HER2 blockade in select populations, Waks notes. Furthermore, tucatinib’s activity in the central nervous system (CNS) is particularly promising, she says. This could address a limitation observed in the KATHERINE trial, where T-DM1 did not significantly reduce CNS recurrences despite reducing overall recurrences, Waks explains.

The second trial is the phase 3 DESTINY-Breast05 trial (NCT04622319), which is comparing T-DM1 with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in patients with high-risk, HER2-positive residual invasive breast cancer following neoadjuvant therapy. T-DXd’s performance is superior to that of T-DM1 in the metastatic setting, raising the possibility that it could also outperform T-DM1 in the residual disease setting, Waks emphasizes. Although the results from DESTINY-Breast05 are not yet available, its outcomes may alter the SOC for patients with HER2-positive breast cancer.