Dr Tolaney on the FDA Approval of Frontline T-DXd Plus Pertuzumab For Metastatic HER2+ Breast Cancer

“At the time of the interim analysis, the combination of T-DXd plus pertuzumab [performed] significantly better than THP, taking the [median] PFS from 26.9 months in the THP arm to 40.7 months in the T-DXd/pertuzumab arm. The HR was 0.56, [showing that the T-DXd–based regimen] almost doubled PFS in that upfront setting.”

Sara M. Tolaney, MD, MPH, chief of the Division of Breast Oncology and associate director of the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute, discussed the clinical significance of the FDA approval of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in combination with pertuzumab (Perjeta) as frontline therapy for patients with unresectable or metastatic HER2-positive breast cancer.

The regulatory decision was supported by findings from the phase 3 DESTINY-Breast09 trial (NCT04784715), a randomized study enrolling patients with either de novo metastatic disease or recurrent HER2-positive breast cancer. Patients were randomly assigned to receive T-DXd plus pertuzumab, T-DXd plus placebo, or standard-of-care chemotherapy with trastuzumab (Herceptin), pertuzumab, and a taxane (THP). The primary end point was progression-free survival (PFS) as assessed by blinded independent central review, with overall survival (OS) and objective response rate (ORR) included as key secondary end points. Patients with hormone receptor–positive disease were permitted to initiate endocrine therapy after completion of initial therapy, reflecting real-world treatment considerations.

At the prespecified interim analysis, T-DXd plus pertuzumab demonstrated a substantial improvement in PFS compared with THP. The median PFS was 40.7 months (95% CI, 36.5-not estimable [NE]) with the T-DXd–based combination vs 26.9 months (95% CI, 21.8-NE) with THP (HR, 0.56; 95% CI, 0.44-0.71; P < .0001). This finding translates to a 13.8-month absolute gain in disease control and reflects a near doubling of PFS relative to the longstanding standard CLEOPATRA trial regimen of pertuzumab, trastuzumab, and docetaxel, Tolaney said. The confirmed ORR was also numerically higher with T-DXd plus pertuzumab, at 87% (95% CI, 83%-90%) compared with 81% (95% CI, 77%-85%) in the THP arm, indicating robust antitumor activity across both regimens.

OS data were immature at the time of analysis, with 16% of patients having died across treatment arms, precluding definitive conclusions regarding survival benefit. However, the magnitude and durability of the PFS improvement strongly support the clinical relevance of the regimen in the frontline metastatic setting, Tolaney concluded.