As reported in The Lancet by Sara A. Hurvitz, MD, of the David Geffen School of Medicine, University of California, Los Angeles, Jonsson Comprehensive Cancer Center, and colleagues, updated results of the phase III DESTINY-Breast03 trial showed significantly improved overall survival with fam-trastuzumab deruxtecan-nxki (T-DXd) vs ado-trastuzumab emtansine (T-DM1) in patients with HER2-positive unresectable or metastatic breast cancer who had received a prior anti-HER2–based regimen.1
An interim analysis of the trial2 showing superior progression-free survival supported the May 2022 regular approval of the agent for patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2–based regimen in the metastatic setting or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy.
Sara A. Hurvitz, MD
In the open-label trial, 524 patients previously treated with trastuzumab and a taxane from sites in North America, Asia, Europe, Australia, and South America were randomly assigned between July 2018 and June 2020 to receive T-DXd at 5.4 mg/kg (n = 261) or T-DM1 at 3.6 mg/kg (n = 263) every 3 weeks until disease progression or unacceptable toxicity. Randomization was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease. The primary endpoint was progression-free survival on blinded independent central review.
For the T-DXd group vs the T-DM1 group, median age was 54.3 years (interquartile range [IQR] = 47.0–62.8 years) vs 54.2 years (IQR = 45.3–63.1 years), 58% vs 62% were Asian, 27% vs 27% were White, 4% vs 3% were Black/African American, and 11% vs 8% were other. Overall, 50% vs 51% had hormone receptor–positive status, 62% vs 60% had received prior pertuzumab, 70% vs 70% had a history of visceral disease, 28% vs 27% had received at least three prior lines of systemic therapy, and 16% vs 15% had baseline brain metastases.
In the interim analysis of progression-free survival, median progression-free survival was not reached (95% confidence interval [CI] = 18.5 months to not evaluable) in the T-DXd group vs 6.8 months (95% CI = 5.6–8.2 months) in the T-DM1 group (hazard ratio [HR] = 0.28, 95% CI = 0.22–0.37, P < .001).2 The hazard ratio for overall survival at the time of that analysis was 0.55 (95% CI = 0.36–0.86, P = .007), although the P value did not cross the prespecified threshold of statistical significance.
The median follow-up for the updated analysis was 28.4 months (IQR = 22.1–32.9 months) in the T-DXd group and 26.5 months (IQR = 14.5–31.3 months) in the T-DM1 group. The median study treatment duration was 18.2 months vs 6.9 months.
At the second prespecified interim analysis of overall survival, overall survival events had occurred in 28% of patients in the T-DXd group vs 37% of the T-DM1 group (HR = 0.64, 95% CI = 0.47–0.87, P = .0037). The median overall survival was not reached (95% CI = 40.5 months to not estimable) vs not reached (95% CI = 34.0 months to not estimable). Rates at 12 and 24 months were 94.1% (95% CI = 90.4%–96.4%) vs 86.0% (95% CI = 81.1%–89.8%) and 77.4% (95% CI = 71.7%–82.1%) vs 69.9% (95% CI = 63.7%–75.2%), respectively.
In subgroup analyses, hazard ratios for overall survival were 0.76 (95% CI = 0.50–1.14) for hormone receptor–positive and 0.55 (95% CI = 0.35–0.87) for hormone receptor–negative status, 0.70 (95% CI = 0.46–1.06) for prior pertuzumab and 0.59 (95% CI = 0.38–0.93) for no prior pertuzumab, 0.68 (95% CI = 0.49–0.95) for baseline visceral disease and 0.44 (95% CI = 0.19–1.02) for no baseline visceral disease, 0.70 (95% CI = 0.47–1.04) for fewer than three and 0.55 (95% CI = 0.34–0.89) for three or more lines of previous systemic therapy, and 0.54 (95% CI = 0.29–1.03) for baseline brain metastases and 0.66 (95% CI = 0.47–0.94) for no baseline brain metastases.
In the updated analysis, the median progression-free survival was 28.8 months (95% CI = 22.4–37.9 months) in the T-DXd group vs 6.8 months (95% CI = 5.6–8.2 months) in the T-DM1 group (HR = 0.33, 95% CI = 0.26–0.43, nominal P < .0001). Rates at 12 and 24 months were 75.2% vs 33.9% and 53.7% vs 26.4%, respectively.
Among patients who discontinued study treatment, subsequent systemic anticancer therapies were received by 130 of 182 patients (71%) in the T-DXd group vs 191 of 243 patients (79%) in the T-DM1 group. Among these patients, subsequent therapies included trastuzumab (24% vs 37%), T-DXd (2% vs 17%), T-DM1 (35% vs 10%), other anti-HER2 therapies (21% vs 36%), and other systemic therapies (41% vs 60%).
With longer follow-up, the safety profile of T-DXd was consistent with that in the previously reported analysis of progression-free survival. Grade ≥ 3 adverse events occurred in 56% of the T-DXd group (most commonly decreased neutrophils, anemia, and decreased platelets) vs 52% of the T-DM1 group (most commonly decreased platelets, anemia, and increased transaminases); the study treatment exposure–adjusted incidence rate was 0.36 vs 0.65. Treatment-related adverse events led to discontinuation of treatment in 20% vs 7% of patients. Treatment-related interstitial lung disease or pneumonitis occurred in 15% vs 3% of patients, with no grade ≥ 4 events being reported.
The investigators concluded: “[T-DXd] showed a significant improvement in overall survival versus [T-DM1] in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming [T-DXd] as the standard of care in the second-line setting. A manageable safety profile of [T-DXd] was confirmed with longer treatment duration.”
DISCLOSURE: The study was funded by Daiichi Sankyo and AstraZeneca. Dr. Hurvitz has received support for The Lancet article from Daiichi Sankyo and AstraZeneca; has received grants or contracts from Ambrx, Amgen, Arvinas, Bayer, CytomX, Dantari, Dignitana, Genentech/Roche, G1 Therapeutics, Gilead Sciences, GSK, Immunomedics, Eli Lilly, MacroGenics, Novartis, OBI, Pharma, Orinove, Pfizer, Phoenix Molecular Designs, Pieris, Puma Biotechnology, Radius, Samumed, Sanofi, Seattle Genetics/Seagen, and Zymeworks; has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Daiichi Sankyo and continuing medical education (CME) companies (PER, Clinical Care Options, Research to Practice, etc); has received support for attending meetings or travel from the San Antonio Breast Cancer Symposium, ASCO, National Comprehensive Cancer Network, and CME companies (PER, Clinical Care Options, and Research to Practice); has participated as a data safety monitoring board member for the I-SPY trial (unpaid); and has served a leadership or fiduciary role in another board for TRIO-US (unpaid chief medical officer of site management organization).
1. Hurvitz SA, Hegg R, Chung WP, et al: Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: Updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet 401:105-117, 2023.
2. Cortés J, Kim SB, Chung WP, et al: Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med 386:1143-1154, 2022.