Dr Rugo on Ongoing ADC Investigations Set to Shift Practice in HER2+ Breast Cancer

"There are a lot of studies going on that may affect what we do in the future, after we do induction with T-DXd and pertuzumab, [provided that it] ends up being the better arm [vs T-DXd monotherapy]."

Hope S. Rugo, MD, a professor in the Department of Medical Oncology & Therapeutics Research, division chief of Breast Medical Oncology, and director of the Women’s Cancers Program at City of Hope, discussed the ongoing development and evolving role of antibody-drug conjugates (ADCs), particularly fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), in HER2-positive breast cancer. 

Significant shifts in clinical practice are expected over the next year with the forthcoming data from the phase 3 DESTINY-Breast05 trial (NCT04622319), which is evaluating ado-trastuzumab emtansine (T-DM1; Kadcyla) vs T-DXd for patients with residual disease after neoadjuvant therapy, including trastuzumab (Herceptin) and pertuzumab (Perjeta; HP), Rugo explained. Previously reported data have shown that T-DM1 generated improvements in both recurrence risk and survival compared with trastuzumab, although the survival benefit emerged only after extended follow-up, Rugo noted. It is anticipated that T-DXd will demonstrate superior efficacy compared with T-DM1 in this setting, prompting a likely shift to T-DXd as the preferred adjuvant therapy for these patients, Rugo commented.

The implications of the phase 3 DESTINY-Breast09 trial (NCT04784715), which is evaluating T-DXd in combination with pertuzumab (Perjeta) compared with other regimens, remain to be clarified, Rugo reported. T-DM1 will likely be relegated to later-line settings, particularly in patients with recurrent or de novo metastatic disease, Rugo stated. For patients who develop progressive disease after T-DXd, treatment sequencing will likely involve T-DM1 in the third-line setting or beyond, with trastuzumab plus capecitabine and tucatinib (Tukysa) potentially being favored in the second-line setting, especially in patients with brain metastases, Rugo detailed.

Both T-DXd and tucatinib have demonstrated activity in patients with brain metastases, including those who did not require immediate radiation therapy, highlighting the importance of these agents in disease control, Rugo elaborated. Additional HER2-targeted ADCs are under investigation in the later-line setting, including a new ADC for HER2-positive disease: zanidatamab, according to Rugo. This agent has shown activity following progression on T-DXd and is currently being evaluated in the phase 3 EmpowHER 303 trial (NCT06435429), Rugo stated.

Further complexity in treatment sequencing may arise as ongoing studies explore maintenance strategies, including the potential role of HP plus tucatinib in patients with hormone receptor (HR)–negative disease and the addition of PI3K inhibitors, such as alpelisib (Piqray), in HR-positive, HER2-positive disease with PIK3CA mutations, Rugo noted. Awaiting results from these studies is important to inform optimal induction and maintenance strategies, particularly following first-line therapy with T-DXd and pertuzumab, Rugo concluded.

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