In an interim analysis from the DESTINY-Breast09 study, the combination of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) plus pertuzumab, nearly doubled progression-free survival compared to the currently accepted standard treatment with taxane chemotherapy plus trastuzumab and pertuzumab (THP) for first-line therapy of metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer.
The study results will be submitted to regulators and will likely change clinical practice for first-line treatment of metastatic HER2-positive breast cancer. This is the first study showing a statistically significant and clinically meaningful improvement in progression free survival in this patient group since the CLEOPATRA trial established the current standard of care over a decade ago.
T-DXd plus pertuzumab nearly doubled progression free survival for patients and met the high level of statistical significance required to show superiority in an interim analysis.
"While this is data from an interim analysis, the combination of T-DXd and pertuzumab is so dramatically better than THP that it is reasonable to consider changing practice based on the data," says Dr. Sara Tolaney, chief of the Division of Breast Oncology at Dana-Farber Cancer Institute, who presented the findings at today's American Society for Clinical Oncology (ASCO) annual meeting.
HER2-positive breast cancer accounts for approximately 15 to 20 percent of metastatic breast cancers. HER2-targeted therapies have improved outcomes dramatically for patients with metastatic HER2-positive breast cancer, with a median survival of more than five years. However, most patients experience progression of their disease within two years of treatment with the current first-line standard of care and approximately 30 percent of patients are unable to receive a second line of therapy.
"We are fortunate that we have so many good HER2-directed therapies that have helped improve survival, but there is clearly room for improvement," says Tolaney. "We want to improve outcomes from the get-go by offering treatment that has the highest chance of delaying disease progression so that patients can live longer and better lives."
The global, open-label study randomized 383 patients to receive T-DXd plus pertuzumab and 387 to receive the standard of care THP. Median progression free survival with T-DXd plus pertuzumab was 40.7 months, compared to 26.9 months for patients who received the current standard of treatment. Fifteen percent of patients on the T-DXd combination experienced complete responses, in which their cancer disappeared. Progression free survival improvements were observed regardless of whether the patient had been newly diagnosed with metastatic disease or had a metastatic recurrence, and regardless of hormone receptor or PIK3CA mutation status.
Side-effects that were seen with T-DXd plus pertuzumab were consistent with the known profiles of the individual treatments with no new safety signals identified. Overall survival results are immature but show a trend favoring the T-DXd plus pertuzumab arm. A third arm of the study randomized patients to receive T-DXd monotherapy; the efficacy in this arm did not meet the threshold set for the interim analysis, and patients will continued to be followed on this arm, with data to be reported at the time of the final PFS analysis.
T-DXd is an antibody-drug conjugate designed to direct a potent chemotherapy drug into cancer cells that express the HER2 protein. Pertuzumab is a monoclonal antibody that also blocks HER2, though differently than trastuzumab. Data from preclinical research suggested that T-DXd and pertuzumab might work synergistically. These studies supported the design of DESTINY-Breast09 to evaluate the efficacy of T-DXd as a first-line treatment alone or with pertuzumab compared to standard of care.
Dana-Farber investigators were involved in the first studies of T-DXd in humans and were subsequently involved in several trials evaluating the efficacy of T-DXd in HER2-positive breast cancer. In 2019, T-DXd showed striking improvements in progression free survival among patients with metastatic HER2-positive breast cancer who had already received up to six lines of treatment. It is currently approved worldwide as second-line or later therapy for patients with metastatic HER2-positive breast cancer.
The Destiny-Breast09 study was funded by AstraZeneca Pharmaceuticals LP.
