Fam-trastuzumab deruxtecan-nxki significantly improved progression-free survival over ado-trastuzumab emtansine in patients with HER2-positive, unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane, meeting the primary end point of the phase 3 DESTINY-Breast03 trial.
Fam-trastuzumab deruxtecan-nxki (Enhertu) significantly improved progression-free survival (PFS) over ado-trastuzumab emtansine (Kadcyla; T-DM1) in patients with HER2-positive, unresectable and/or metastatic breast cancer previously treated with trastuzumab (Herceptin) and a taxane, meeting the primary end point of the phase 3 DESTINY-Breast03 trial (NCT03529110).1
Moreover, at the time of the planned interim analysis, the antibody-drug conjugate (ADC) was also found to showcase a strong trend toward improved overall survival (OS) vs T-DM1, which is a key secondary end point of the trial. However, the OS data are still immature.
The toxicity profile of trastuzumab deruxtecan proved to be consistent with what has been reported in prior trials. No new safety signals were observed, and no patients experienced grade 4 or 5 treatment-associated interstitial lung disease (ILD).
The findings from the trial will be shared at an upcoming medical conference, as well as with health authorities.
“There is a continued need for new options and better outcomes for patients with HER2-positive metastatic breast cancer who often experience disease progression after initial treatment with available standards of care,” Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, stated in a press release. “These transformative PFS results demonstrate the superiority of [trastuzumab deruxtecan] compared with T-DM1, and the encouraging safety data may open future opportunities to bring this benefit to patients in earlier treatment settings.”
To be eligible for participation on the global, head-to-head, open-label, registrational phase 3 trial, patients needed to be of the age of the majority in their country, have documented radiologic progression during or after their most recent treatment or within 6 months following neoadjuvant or adjuvant treatment involving a regimen that included trastuzumab and a taxane, and acceptable renal and hepatic function.2
If patients previously received a HER2-targeted ADC in the metastatic setting; had uncontrolled or significant cardiovascular disease; a history of, current, or suspected ILD or pneumonitis that needed steroids; or spinal cord compression or clinically active central nervous system metastases, they were excluded.
The trial launched in July 2018 and recruited patients from approximately 160 clinical sites throughout North America, South America, Europe, and Asia.3 About 500 participants were randomized 1:1 to receive either intravenous trastuzumab deruxtecan at a dose of 5.4 mg/kg or intravenous T-DM1 at a dose of 3.6 mg/kg once every 3 weeks. Those who were assigned to the control arm received treatment in accordance with the approved label of the agent.
Patients were stratified based on hormone receptor status, previous treatment with pertuzumab (Perjeta), and history of visceral disease.
The primary end point of the trial was PFS based on blinded, independent central review utilizing RECIST v1.1 criteria, and key secondary end points included OS, overall response rate, duration of response (DOR), clinical benefit rate, and investigator-assessed PFS.
Regarding safety, investigators examined serious and treatment-emergent toxicities, physical examinations, vital signs, and clinical laboratory parameters. They are also evaluating health-related quality of life in study participants.
Previously, in December 2019, the FDA approved trastuzumab deruxtecan for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who previously received at least 2 anti–HER2-based regimens in the metastatic setting based on findings from the phase 2 DESTINY-Breast01 trial (NCT03248492).4
At a median follow-up of 11.1 months (range, 0.7-19.9), 60.9% of patients in the intent-to-treat population (n = 112/184) responded to treatment (95% CI, 53.4%-68.0%). The median DOR was 14.8 months (95% CI, 13.8-16.9) and the median PFS was 14.8 months (95% CI, 12.7–not reached).5
“DESTINY-Breast03 is the first global Phase III head-to-head trial of [trastuzumab deruxtecan] against an active control and supports the potential of this medicine to become the new standard of care for patients with HER2-positive metastatic breast cancer following initial treatment with trastuzumab and a taxane," Ken Takeshita, global head of Research and Development at Daiichi Sankyo, stated in a press release. "We believe this highly sophisticated and specifically engineered ADC is fulfilling its promise to reshape the treatment of HER2-positive metastatic breast cancer, with the goal to move into earlier lines of treatment for HER2-positive breast cancer and many other HER2-expressing tumour types across our broad clinical trial programme.”