As reported in The Lancet by Sara A. Hurvitz, MD, 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.
An interim analysis of the trial showing superior progression-free survival supported the May 2022 full approval of the agent.
In the international open-label trial, 524 patients previously treated with trastuzumab and a taxane 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. The primary endpoint was progression-free survival on blinded independent central review.
[T-DXd] showed a significant improvement in overall survival vs [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.— Sara A. Hurvitz, MD, and colleagues
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Median follow-up for the updated analysis was 28.4 months (interquartile range [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. Median treatment duration was 18.2 months vs 6.9 months.
Median progression-free survival was 28.8 months (95% confidence interval [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 (hazard ratio [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.
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). 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% vs 86.0% and 77.4% vs 69.9%, respectively.
Among patients who discontinued study treatment, subsequent systemic anticancer therapies were received by 130 (71%) of 182 patients in the T-DXd group and 191 (79%) of 243 patients in the T-DM1 group.
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 patients in 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 rates were 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/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 vs [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.”
Dr. Hurvitz, of David Geffen School of Medicine, UCLA, Jonsson Comprehensive Cancer Center, is the corresponding author for The Lancet article.
Disclosure: The study was funded by Daiichi Sankyo and AstraZeneca. For full disclosures of the study authors, visit thelancet.com.
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