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.

Study Details

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.

Progression-Free Survival

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%.

Adverse Events

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.