Enhertu, an antibody drug conjugate, being jointly developed by Daiichi Sankyo and AstraZeneca, has demonstrated a statistically significant and clinically meaningful improvement in overall survival.
Updated results from DESTINY-Breast03 phase 3 trial showed Enhertu (trastuzumab deruxtecan) was performing better than trastuzumab emtansine (T-DM1) in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with with trastuzumab and a taxane.
In the key secondary endpoint analysis of overall survival in DESTINY-Breast03, Enhertu demonstrated a 36% reduction in risk of death versus T-DM1. In both treatment arms, median overall survival was not yet reached after a median duration of follow-up of 28.4 months for Enhertu and 26.5 months for T-DM1.
In the Enhertu arm, an estimated 77.4% of patients were alive at two years compared to 69.9% of patients treated with T-DM1. The observed survival benefit was consistent across all analyzed subgroups. These included patients with or without baseline brain metastases, with or without baseline visceral disease. Additionally, those who were hormone receptor (HR) positive or HR negative and patients regardless of prior pertuzumab or lines of systemic therapy were also included.
Enhertu demonstrates reduction in risk of death
Sara Hurvitz, medical oncologist, said: “The main goals of therapy for advanced breast cancer are to control the disease and improve survival, and it is therefore critical to continue to improve upon existing treatment options, particularly in the metastatic setting.
“For patients with HER2 positive breast cancer who experience disease progression following initial treatment in the metastatic setting, Enhertu has shown significant improvement in survival compared to T-DM1, further confirming this medicine as the new standard of care.”
With the additional follow-up in DESTINY-Breast03, Enhertu also continued to demonstrate a clinically meaningful improvement in progression-free survival (PFS) with a 22-month improvement in median PFS over T-DM1, reaffirming the statistically significant finding at the previous interim analysis.
The updated exploratory analysis was not tested for statistical significance and not powered to show differences between treatment arms. The median PFS for patients in the Enhertu arm was 28.8 months compared to 6.8 months for T-DM1 as assessed by blinded independent central review (BICR).
No new safety concerns
Confirmed objective response rate (ORR) was 78.5% in the Enhertu arm with 21.1% of patients demonstrating a complete response (CR) versus an ORR of 35.0% in the T-DM1 arm where 9.5% of patients achieved a CR. The median duration of response (DoR) was 36.6 months in the Enhertu arm and 23.8 months in the T-DM1 arm.
The safety profile observed with Enhertu in DESTINY-Breast03 was consistent with previous clinical trials with no new safety concerns identified. Grade 3 or higher treatment-related treatment emergent adverse events (TEAEs) occurred in 47.1% of patients receiving Enhertu.
The most common grade 3 or higher treatment-related TEAEs in the Enhertu arm were decreased neutrophil count (16.0%), anemia (9.3%), decreased platelet count (7.8%), nausea (7.0%), decreased white blood cell count (6.2%) and fatigue (5.8%).
In the Enhertu arm, 15.2% of patients experienced interstitial lung disease (ILD) or pneumonitis related to treatment as determined by an independent adjudication committee. The majority of ILD or pneumonitis events were low grade (grade 1 or grade 2) with two grade 3 events and no grade 4 or grade 5 events observed in patients treated with Enhertu.
Further validating the role of Enhertu
Ken Takeshita, global head, research and development, Daiichi Sankyo, said: “The overall survival benefits shown in both the DESTINY-Breast03 and DESTINY-Breast02 trials further validate the role of Enhertu in potentially extending the lives of patients with previously treated HER2 positive breast cancer.
“Additionally, median progression-free survival was four times longer with one in five patients showing no detectable signs of disease when treated with Enhertu compared to T-DM1 in DESTINY-Breast03, which is particularly impressive in the metastatic setting of HER2 positive breast cancer.”
All patients in DESTINY-Breast03 received at least one prior cancer therapy, including trastuzumab or pertuzumab. In the Enhertu arm, 41.4% of patients had received one prior line of therapy in the metastatic setting. At baseline, 16.5% of patients in the Enhertu arm and 14.8% of patients in the T-DM1 arm had a history of brain metastases. As of data cut-off on July 25, 2022, 75 patients remained on treatment with Enhertu and 18 patients on T-DM1.
Patients have more disease-free time
Susan Galbraith, executive vice president, oncology research and development at AstraZeneca, said: “The updated results for DESTINY-Breast03 showing that Enhertu extends patients’ lives and also delays progression by nearly two years reinforces our belief that this medicine has the potential to set a new standard of care for patients with HER2 positive metastatic breast cancer treated in the second-line setting.
“Complemented by DESTINY-Breast02, we now have two phase 3 trials in HER2 positive metastatic breast cancer showing patients in these trials have more disease-free time and live longer when they receive Enhertu versus the previous standard of care.”