Dr Tarantino on the Expanding Role of T-DXd in HER2+ Breast Cancer

"We're going to use [T-DXd] more and more. It's an extremely active drug, but it does come with this challenging [adverse] effect [profile]; therefore, we want patients to be able to benefit from this drug in the safest [way] possible."

Paolo Tarantino, MD, a breast medical oncologist at Dana-Farber Cancer Institute and researcher at the University of Milan, discussed the expanding role of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in the treatment of HER2-positive breast cancer and emphasized the importance of early recognition and management of interstitial lung disease (ILD), a known adverse effect (AE) associated with the agent.

Tarantino noted that T-DXd, an antibody-drug conjugate composed of a humanized anti-HER2 antibody linked to a topoisomerase I inhibitor payload, has significantly reshaped treatment paradigms for patients with HER2-positive disease. The agent demonstrated superior efficacy in the phase 3 DESTINY-Breast03 trial (NCT03529110), where it became the new standard of care in the second-line metastatic setting. T-DXd significantly improved progression-free survival compared with ado-trastuzumab emtansine (T-DM1; Kadcyla) during the study, establishing its role as the preferred therapy following first-line trastuzumab (Herceptin) plus pertuzumab (Perjeta) and a taxane (THP).

Looking ahead, Tarantino highlighted the potential of T-DXd to move earlier in the treatment continuum. The phase 3 DESTINY-Breast09 trial (NCT04784715) evaluated T-DXd in the first-line metastatic setting; full data from an interim analysis of DESTINY-Breast09 will be presented at the 2025 ASCO Annual Meeting; it was previously announced that the study generated a significant PFS improvement with T-DXd compared with THP, potentially challenging the current standard of care in the frontline setting.

\Additionally, the phase 3 DESTINY-Breast05 (NCT04622319) and DESTINY-Breast11 (NCT05113251) trials are assessing the role of T-DXd in the early-stage, neoadjuvant and adjuvant settings.

Despite the agent’s high level of clinical activity, Tarantino cautioned that ILD remains a significant toxicity to monitor. He noted that ILD has been observed in approximately 10% to 15% of patients treated with T-DXd. Although most cases are low grade, early detection and intervention are critical to prevent progression to severe or fatal instances. Tarantino emphasized the importance of routine surveillance and prompt initiation of corticosteroids at the first sign of pulmonary symptoms.

He advocated for increased awareness among providers, given the growing use of T-DXd across multiple lines of therapy, different stages of treatment, and into different tumor types. With appropriate monitoring and management strategies, the risk of ILD can be mitigated, allowing patients to benefit from the therapeutic efficacy of T-DXd.