Dr Huppert on Evolving First-Line Treatment Standards for HER2+ Metastatic Breast Cancer

“The question remains: Does everyone need T-DXd first?”

Laura Huppert, MD, an assistant professor of medicine in the Department of Medicine at the University of California, San Francisco School of Medicine, discussed ways that the use of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in the first-line HER2-positive metastatic breast cancer setting may displace the current standard of care and affect later-line treatment decisions.

Currently, there is limited clinical evidence regarding the efficacy of taxane-based chemotherapy combined with trastuzumab (Herceptin) and pertuzumab (Perjeta; THP) following prior treatment with T-DXd, Huppert began. As a result, although the THP regimen is likely to remain a therapeutic option, its optimal placement in the treatment sequence—shifted from the first-line standard to the second- or third-line setting—remains an open question, particularly for patients who have received T-DXd in the first-line setting, she explained.

Another area of uncertainty following the readout of the phase 3 DESTINY-Breast09 trial (NCT04784715) of frontline T-DXd plus pertuzumab in patients with HER2-positive metastatic breast cancer involves the feasibility and clinical benefit of rechallenging patients with T-DXd following initial treatment and subsequent progression after a maintenance strategy, Huppert said. These scenarios underscore the need for additional clinical experience and prospective trials to better define treatment sequencing and re-treatment strategies, she emphasized.

Additionally, the role of taxanes in the evolving treatment paradigm for HER2-positive metastatic breast cancer continues to be debated, according to Huppert. Questions remain regarding the most appropriate sequencing of regimens, such as the phase 2 HER2CLIMB trial (NCT02614794) regimen of tucatinib (Tukysa) plus capecitabine and trastuzumab vs taxane-based therapies, she noted. For example, should the HER2CLIMB regimen precede taxane administration, or vice versa? Furthermore, there may be clinical scenarios in which initiating treatment with the THP regimen remains appropriate, particularly in patients with indolent disease biology or pre-existing pulmonary comorbidities, given the known risk of interstitial lung disease associated with T-DXd, she reported.

Finally, there is an ongoing discussion regarding whether T-DXd should be universally employed as first-line therapy, Huppert summarized. In certain populations, such as older adults or those with significant comorbidities, first-line THP may be more appropriate, deferring T-DXd to later lines of therapy, she stated. These nuanced decisions will require further clarification through future studies and real-world data following the release of the DESTINY-Breast09 trial results, Huppert concluded.