As reported in The Lancet by André et al, the phase III DESTINY-Breast02 trial has shown improved progression-free survival with fam-trastuzumab deruxtecan-nxki vs physician’s choice of treatment in patients with HER2-positive metastatic breast cancer who had received prior ado-trastuzumab emtansine.
In the open-label trial, 608 patients from sites in North America, Europe, Asia, Australia, Brazil, Israel, and Turkey were randomly assigned 2:1 between September 2018 and December 2020 to receive trastuzumab deruxtecan at 5.4 mg/kg once every 3 weeks (n = 406) or physician’s choice of treatment (n = 202). Physician’s options were either capecitabine at 1,250 mg/m² twice per day on days 1 to 14 plus trastuzumab at 8 mg/kg on day 1 then 6 mg/kg every 3 weeks in 21-day cycles; or capecitabine at 1,000 mg/m² twice daily plus lapatinib at 1,250 mg once daily on days 1 to 21 in 21-day cycles.
Trastuzumab and trastuzumab emtansine had been received by more than 99% of patients, and 77% to 78% had received pertuzumab. The primary endpoint was progression-free survival based on blinded independent central review.
Median follow-up was 21.5 months (interquartile range [IQR] = 15.2–28.4 months) in the trastuzumab deruxtecan group and 18.6 months (IQR = 8.8–26.0 months) in the physician’s choice group. Median progression-free survival was 17.8 months (95% confidence interval [CI] = 14.3–20.8 months) in the trastuzumab deruxtecan group vs 6.9 months (95% CI = 5.5–8.4 months) in the physician’s choice group (hazard ratio [HR] = 0.36, 95% CI = 0.28–0.45, P <.0001). Rates at 12 and 24 months were 62.3% vs 27.2% and 42.2% vs 13.9%. Prespecified subgroup analyses showed a consistent benefit of trastuzumab deruxtecan according to hormone receptor status, previous treatment with pertuzumab, history of visceral disease, and brain metastases at baseline.
Median overall survival was 39.2 months (95% CI = 32.7 months to not estimable) in the trastuzumab deruxtecan group vs 26.5 months (95% CI = 21.0 months to not estimable) in the physician’s choice group (HR = 0.66, 95% CI = 0.50–0.86, P = .0021, crossing the significance boundary of P = .0040 for this analysis. Rates at 12 and 24 months were 89.4% vs 74.7% and 65.9% vs 54.3%.
Grade ≥ 3 adverse events occurred in 53% of the trastuzumab deruxtecan group vs 44% of the physician’s choice group. The most common events in the trastuzumab deruxtecan group were decreased neutrophils (11% vs 2% in the physician’s choice group), anemia (8% vs 3%), neutropenia (8% vs 2%), nausea (7% vs 3%), diarrhea (3% vs 7%), and palmar-plantar erythrodysesthesia (< 1% vs 10%).
Drug-related interstitial lung disease (ILD) occurred in 42 patients (10%, grade 5 in 2 patients) vs 1 patient (< 1%). Drug-related adverse events led to death in four patients (< 1%) in the trastuzumab deruxtecan group (from ILD in two, acute myeloid leukemia in one, and pneumonia in one) and in no patients in the physician’s choice group.
The investigators concluded: “DESTINY-Breast02 shows the favorable benefit–risk profile of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer, as previously reported in [the phase II] DESTINY-Breast01, and is the first randomized study to show that one antibody-drug conjugate can overcome resistance to a previous one.”
Ian Krop, MD, of Yale Cancer Center, is the corresponding author of The Lancet article.
Disclosure: The study was funded by Daiichi Sankyo and AstraZeneca. For full disclosures of the study authors, visit thelancet.com.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.