Dr Lloyd on the Potential Role for T-DXd in Early-Stage HER2+ Breast Cancer

"Selecting the right patient with early-stage HER2-positive breast cancer in whom we should utilize neoadjuvant or adjuvant T-DXd remains of utmost importance to maximize benefit and minimize unnecessary toxicities."

Maxwell Lloyd, MD, a hematology/oncology fellow in the Department of Medicine at Beth Israel Deaconess Medical Center discussed the shifting treatment paradigm for early-stage HER2-positive breast cancer, and the potential role for fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in this setting.

Although the efficacy of T-DXd has been well established in later-line metastatic settings, its recent first-line approval in combination with pertuzumab (Perjeta) for metastatic disease signals that the agent may be moving into earlier stages, as well as the curative-intent setting, Lloyd began. Additional positive data with the agent in neoadjuvant and adjuvant spaces, as seen in the phase 3 DESTINY-Breast11 (NCT04455841) and DESTINY-Breast05 (NCT04154956) trials, further suggest that incorporating T-DXd into neoadjuvant and adjuvant regimens may improve pathologic complete response (pCR) rates and invasive disease–free survival (iDFS) in high-risk populations, he added.

In the neoadjuvant setting, investigators must balance the high activity of T-DXd against emerging de-escalation strategies, such as comparing THP (a taxane, trastuzumab [Herceptin], and pertuzumab) with TCHP (taxane, carboplatin, trastuzumab, and pertuzumab). Lloyd noted that identifying the specific high-risk patients who truly benefit from an antibody-drug conjugate (ADC) over standard or de-escalated chemotherapy remains a critical clinical challenge.

In the adjuvant space, the iDFS benefit observed with T-DXd compared with standard ado-trastuzumab emtansine (T-DM1; Kadcyla) in DESTINY-Breast05 appears convincing, Lloyd stated. This benefit was particularly evident in patients with high-risk residual disease burden in the lymph nodes who failed to achieve an adequate response to neoadjuvant therapy, he noted. However, the adoption of T-DXd in this setting must be weighed against potential toxicities associated with 14 cycles of treatment. Specifically, approximately 10% of patients developed interstitial lung disease, including 2 deaths.

Overall, validating biomarkers and clinical characteristics will be essential for personalizing therapy in early-stage breast cancer, Lloyd emphasized. This approach will help ensure investigators select the right patients for de-escalated therapy and identify those who require the addition of an ADC to their regimen, he concluded.