T-DXd Plus Pertuzumab and New Data in HER2+ Metastatic Breast Cancer
Key Points
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Trastuzumab deruxtecan (T-DXd) plus pertuzumab was approved for first-line treatment of HER2–positive metastatic breast cancer based on the DESTINY-Breast09 trial.
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More recently, the HER2CLIMB-05 and PATINA trials showed that intensified maintenance regimens after chemotherapy induction improved survival outcomes for HER2–positive breast cancer.
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The future standard-of-care model may involve starting patients on T-DXd, then switching to an intensified maintenance regimen based on hormone receptor (HR) status.
T-DXd and Maintenance Therapy Strategies in HER2+ Breast Cancer
On the Oncology Brothers podcast, cohosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Goasin, MD, of Roswell Park Comprehensive Cancer Center, met with lead author of the DESTINY-Breast09 trial, Sara Tolaney, MD, MPH, of Dana-Farber Cancer Institute, to discuss the FDA approval for T-DXd plus pertuzumab in HER2–positive metastatic breast cancer. In addition, the doctors considered how to incorporate the approval into clinical practice in light of recent positive reports from the HER2CLIMB-05 and PATINA trials.
DESTINY-Breast09 Leads to FDA Approval
In DESTINY-Breast09, patients were randomized to receive T-DXd plus placebo, T-DXd plus pertuzumab, or a taxane plus trastuzumab and pertuzumab (THP) as first-line therapy for HER2–positive advanced or metastatic breast cancer. The median progression-free survival (PFS) was 40.7 months with T-DXd plus pertuzumab versus 26.9 months with THP (hazard ratio [HR], 0.56; 95% CI, 0.44-0.71; P < .00001), according to the interim analysis. Further analyses showed the relative benefit of T-DXd plus pertuzumab was maintained for both recurrent and de novo disease subgroups. Based on these analyses, the FDA approved first-line T-DXd plus pertuzumab for HER2–positive unresectable or metastatic breast cancer in December 2025.
Positive Data From HER2CLIMB-05 and PATINA
The HER2CLIMB-05 trial evaluated the addition of tucatinib to first-line maintenance with trastuzumab plus pertuzumab (HP) after induction with THP. The median PFS was 24.9 months in the tucatinib arm versus 16.3 months in the control (HR, 0.641; 95% CI, 0.514-0.799; P < .0001). Tucatinib provided a PFS benefit regardless of brain metastases or HR status, the study stated. Similar to HER2CLIMB-05, the PATINA trial evaluated intensifying HP maintenance by adding palbociclib and endocrine therapy for patients with HR–positive, HER2–positive metastatic breast cancer. In PATINA, the palbociclib arm had significantly longer PFS at 44.3 months versus the control at 29.1 months (HR, 0.75; 95% CI, 0.59-0.96; P = .02), the authors reported.
Updating the Standard of Care
The DESTINY-Breast09, HER2CLIMB-05, and PATINA trials all improved outcomes versus THP induction into HP maintenance, but it’s unclear how each trial’s findings will be synthesized into a new standard of care. The data for T-DXd are very impressive, but continuing chemotherapy for several years can be challenging. As a result, many breast medical oncologists, including Dr. Tolaney, are considering starting patients on T-DXd plus pertuzumab and then switching to HP maintenance plus palbociclib and endocrine therapy for HR–positive patients or tucatinib for HR–negative patients.
Ongoing trials such as DEMETHER are seeking to refine this approach and determine the optimal duration of T-DXd before transitioning to maintenance regimens. Future trials might also evaluate the potential of circulating tumor DNA to inform treatment decisions, said Dr. Tolaney.
To conclude the discussion, the doctors briefly reviewed the side-effect profile of T-DXd and the necessary management strategies, including antiemetic prophylaxis and monitoring for interstitial lung disease.