Dr Kalinsky on Evolving Roles for the CLEOPATRA and DESTINY-Breast09 Regimens in HER2+ Breast Cancer

“For patients, the main question now is: ‘What do we do about [the] CLEOPATRA [regimen]?’ The way I am contextualizing these data right now, there are some patients who [would benefit most from receiving] T-DXd and pertuzumab, [such as those with] visceral metastases who need a response or [those with] CNS disease.”

Kevin Kalinsky, MD, MS, FASCO, a professor and director in the Division of Medical Oncology of the Department of Hematology and Medical Oncology at Emory University School of Medicine, as well as director of the Glenn Family Breast Center at Winship Cancer Institute, discussed the shifting role of pertuzumab (Perjeta), trastuzumab (Herceptin), and docetaxel (THP) from the phase 3 CLEOPATRA study (NCT00567190) in light of positive results from the phase 3 DESTINY-Breast09 trial (NCT04784715) of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) plus pertuzumab in HER2-positive breast cancer.

Interim data from DESTINY-Breast09, which were presented at the 2025 ASCO Annual Meeting, demonstrated a significant progression-free survival (PFS) improvement with T-DXd plus pertuzumab over THP. However, the superior benefit observed with the T-DXd combination indicates that the CLEOPATRA regimen may no longer serve as a standard of care in the first-line, HER2-positive breast cancer treatment paradigm, Kalinsky began.

Among patients who received T-DXd plus pertuzumab (n = 383), the median PFS was 40.7 months (95% CI, 36.5-not calculable [NC]) vs 26.9 months (95% CI, 21.8-NC) in patients treated with THP (n = 387; HR, 0.56; 95% CI, 0.44-0.71; P < .00001).

Kalinsky noted that some patients may benefit more from receiving T-DXd plus pertuzumab over THP, including patients with central nervous system disease or visceral metastases. For patients with estrogen receptor (ER)–positive disease who demonstrate an improvement on scans following approximately 6 months of treatment, endocrine therapy, palbociclib (Ibrance), and HER2-targeted therapy consisting of either pertuzumab or trastuzumab is a viable option, as demonstrated in the phase 3 PATINA trial (NCT02947685), he said. In this scenario, T-DXd may be best utilized as needed, Kalinsky explained.

Ultimately, there are nuances to every disease, and the treatment paradigm in HER2-positive breast cancer is moving further away from a one-size-fits-all approach, Kalinsky asserted. Accordingly, it’s important to have a variety of effective treatment options available for patients, he emphasized. Although the data from DESTINY-Breast09 demonstrated improvements with T-DXd plus pertuzumab, not every patient will need to stay on this exact regimen throughout their entire treatment journey, Kalinsky concluded.