Fam-trastuzumab deruxtecan-nxki is under investigation with or without pertuzumab vs a standard-of-care regimen comprised of a taxane, trastuzumab, and pertuzumab in the frontline treatment of patients with HER2-positive metastatic breast cancer as part of the phase 3 DESTINY-Breast09 trial.
Fam-trastuzumab deruxtecan-nxki (Enhertu; DS-8201) is under investigation with or without pertuzumab (Perjeta) vs a standard-of-care regimen comprised of a taxane, trastuzumab (Herceptin), and pertuzumab (THP) in the frontline treatment of patients with HER2-positive metastatic breast cancer as part of the phase 3 DESTINY-Breast09 trial (NCT04784715).1
Previously, in December 2019, the antibody-drug conjugate (ADC) was approved by the FDA for use in adult patients with unresectable or metastatic HER2-positive breast cancer who had previously received an anti–HER2-based regimen in the metastatic setting.2 The decision was supported by data from the pivotal phase 2 DESTINY-Breast01 trial (NCT03248492), in which the agent was found to induce a confirmed objective response rate (ORR) of 60.9% per independent central review (ICR) assessment (95% CI, 53.4%-68.0%), at a median follow-up of 11.1 months (range, 0.7-19.9).3
Updated findings showed that with an additional 9.4 months of follow-up, the confirmed ORR was 61.4% (95% CI, 54.0%-68.5%) among the 184 participants.4 The median duration of response (DOR) was 20.8 months. Moreover, the estimated 12-month overall survival (OS) rate was 85% (95% CI, 79%-90%) with the agent; at 18 months, this rate was estimated to be 74% (95% CI, 67%-80%). The median progression-free survival (PFS) was 19.4 months (95% CI, 14.1–not estimable [NE]), and the preliminary median OS was 24.6 months (95% CI, 23.1–NE).
“Based on the encouraging results we are seeing in patients who have received prior treatment for HER2-positive metastatic breast cancer, we have initiated DESTINY-Breast09 to evaluate whether earlier use of [trastuzumab deruxtecan] alone or as part of a novel combination regimen may help improve outcomes for patients in the first-line metastatic setting as compared to the current standard of care,” Gilles Gallant, BPharm, PhD, FOPQ, senior vice president and global head of Oncology Development, Oncology R&D, at Daiichi Sankyo, stated in a press release.
In the global head-to-head phase 3 trial, investigators have set out to examine the safety and efficacy of trastuzumab deruxtecan, at a dose of 5.4 mg/kg, with or without pertuzumab vs standard-of-care THP in the frontline treatment of patients with HER2-positive metastatic breast cancer.
To be eligible for enrollment, patients had to be at least 18 years of age; have pathologically documented disease that was advanced or metastatic, locally assessed and prospectively centrally confirmed to have HER2 positivity; have disease that was documented by local testing as either hormone receptor positive or negative in the metastatic setting.5
Patients could not have previously received chemotherapy or HER2-targeted treatment for advanced or metastatic disease, but they were able to have received 1 prior line of endocrine therapy in the metastatic setting.
Study participants are to be randomized 1:1:1 to receive single-agent trastuzumab deruxtecan, the ADC with pertuzumab, or THP. Patients will be stratified by previous treatment (de novo vs recurrent with de novo capped at 50%), hormone receptor status, and PIK3CA mutational status.
The primary end point of the trial is PFS per blinded independent central review assessment, while secondary end points included investigator-assessed PFS, OS, ORR, DOR, time to second progression or death, health-related quality of life (QoL), time to deterioration of physical and role function, as well as global health status/QoL and pain scores. Investigators will also examine the generation of antibodies against trastuzumab deruxtecan or pertuzumab, immunogenicity, pharmacokinetics, and safety.
In June 2021, Daiichi Sankyo Company, Limited, announced that the first patient on the trial had been dosed with trastuzumab deruxtecan. The trial is expected to enroll about 1,134 patients at several clinical sites throughout Africa, Asia, Europe, North America, Oceania, and South America.
Previously, in January 2021, the FDA approved trastuzumab deruxtecan for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who had received a prior trastuzumab-based regimen based on data from the phase 2 DESTINY-Gastric01 trial (NCT04014075).6 In this population, the ADC resulted in improved OS over irinotecan or paclitaxel, at 12.5 months (95% CI, 9.6-14.3) and 8.4 months (95% CI, 6.9-10.7), respectively.7 The median DOR was 11.3 months (95% CI, 5.6–not reached) vs 3.9 months (95% CI, 3.0-4.9) with chemotherapy.
The agent has also been shown to have activity in patients with HER2-overexpressing metastatic colorectal cancer. Data from a cohort of 53 patients with HER2-positive disease showed that the ADC elicited a confirmed ORR of 45.3% (95% CI, 31.6%-59.6%), with all responders achieving a partial response.8 The median DOR was 7.0 months (95% CI, 5.8-9.5). Moreover, 37.7% of patients achieved disease stability. The disease control rate in this population was 83.0% (95% CI, 70.2%-91.9%) with the agent.