As reported in The New England Journal of Medicine by Javier Cortés, MD, PhD, of the International Breast Cancer Center, Barcelona, and colleagues, the phase III DESTINY-Breast03 trial has shown significantly prolonged progression-free survival with fam-trastuzumab deruxtecan-nxki (T-DXd) vs ado-trastuzumab emtansine (T-DM1) in patients with metastatic HER2-positive breast cancer previously treated with trastuzumab and a taxane.¹

Javier Cortés, MD, PhD

Study Details

In the open-label trial, 524 patients from sites in 15 countries were randomly assigned between July 2018 and June 2020 to receive T-DXd at 5.4 mg/kg every 3 weeks (n = 261) or T-DM1 at 3.6 mg/kg every 3 weeks (n = 263). Randomization was stratified according to hormone receptor status, prior treatment with pertuzumab for metastatic disease, and history of visceral disease. Patients with clinically stable previously treated brain metastases were eligible for the trial. Patients were excluded if they had received a HER2 antibody-drug conjugate for metastatic disease and if they had a history of noninfectious interstitial lung disease treated with glucocorticoids or suspected interstitial lung disease that could not be ruled out by screening imaging. The primary endpoint was progression-free survival on blinded independent central review.

For the T-DXd group vs the T-DM1 group, the median patient age was 54 years in both, 58.2% vs 61.6% were Asian and 27.2% vs 27.4% were White, 50.2% vs 51.0% had hormone receptor–positive disease, and 70.5% vs 70.3% had a history of visceral disease. The median number of lines of therapy for metastatic disease was one vs two (one prior line in 49.8% vs 46.8%, two prior lines in 21.5% vs 24.7%), and 62.1% vs 60.1% had received pertuzumab.

Progression-Free Survival

At a prespecified interim analysis, median follow-up was 16.2 months (range = 0–32.7 months) in the T-DXd group and 15.3 months (range = 0–31.3 months) in the T-DM1 group. Median progression-free survival was not reached (95% confidence interval [CI] = 18.5 months to not estimable) with T-DXd vs 6.8 months (95% CI = 5.6–8.2 months) with T-DM1; the rates at 1 year were 75.8% (95% CI = 69.8%–80.7%) with T-DXd and 34.1% (95% CI = 27.7%–40.5%) with T-DM1 (hazard ratio [HR] = 0.28, 95% CI = 0.22–0.37, P < .001). The independent data and safety monitoring committee recommended that the trial be unblinded in July 2021, since the prespecified efficacy boundary of superiority had been crossed.

In stratification subgroups, hazard ratios were 0.32 (95% CI = 0.22–0.46) for hormone receptor–positive disease and 0.30 (95% CI = 0.20–0.44) for hormone receptor–negative disease, 0.30 (95% CI = 0.22–0.43) for prior pertuzumab treatment and 0.30 (95% CI = 0.19–0.47) for no prior pertuzumab, and 0.28 (95% CI = 0.21–0.38) for visceral disease and 0.32 (95% CI = 0.17–0.58) for no visceral disease. In additional subgroups, hazard ratios were 0.33 (95% CI = 0.23–0.48) among 132 vs 126 patients with zero to one prior line of therapy and 0.28 (95% CI = 0.19–0.41) among 129 vs 137 with at least two prior lines, and 0.38 (95% CI = 0.23–0.64) among 62 vs 52 patients with stable brain metastases and 0.27 (95% CI = 0.19–0.37) among 199 vs 211 without brain metastases.

An objective response was observed in 79.7% (95% CI = 74.3%–84.4%) vs 34.2% (95% CI = 28.5%–40.3%) of patients (P < .0001), with a complete response in 16.1% vs 8.7%. Disease control rate was 96.6% vs 76.8%. Progressive disease was the best overall response in 1.1% vs 17.5% of patients.

Poststudy systemic therapy was received by 29.9% of the T-DXd group vs 62.4% of the T-DM1 group. Subsequent therapies in the T-DXd group included T-DM1 (16.5%) and trastuzumab (8.8%); subsequent therapies in the T-DM1 group included trastuzumab (25.1%), trastuzumab deruxtecan (11.4%), and other HER2-targeted therapies (27.8%).

At data cutoff (May 2021), death had occurred in 12.6% of the T-DXd group and 20.2% of the T-DM1 group. Overall survival at 1 year was 94.1% (95% CI = 90.3%–96.4%) with T-DXd and 85.9% (95% CI = 80.9%–89.7%) with T-DM1 (HR = 0.55, 95% CI = 0.36–0.86, P = .007), with the prespecified significance boundary of P < .000265 not being reached.

Adverse Events

Treatment-related grade 3 or 4 adverse events occurred in 45.1% of the T-DXd group vs 39.8% of the T-DM1 group. The most common adverse events were neutropenia (19.1%) and thrombocytopenia (7.0%) in the T-DXd group and thrombocytopenia (24.9%) and increased aspartate aminotransferase (5.0%) in the T-DM1 group. Irrespective of causality attribution, serious adverse events occurred in 19.1% vs 18.0% of patients, and adverse events led to discontinuation of treatment in 13.6% vs 7.3%.

Adjudicated drug-related interstitial lung disease or pneumonitis of any grade occurred in 10.5% of the T-DXd group (grade 3 in two patients, none grade ≥ 4) and in 1.9% of the T-DM1 group (none grade ≥ 3). Interstitial lung disease or pneumonitis led to treatment discontinuation in 8.2% vs 1.1% of patients.

The investigators concluded: “Among patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, the risk of disease progression or death was lower among those who received trastuzumab deruxtecan than among those who received trastuzumab emtansine. Treatment with trastuzumab deruxtecan was associated with interstitial lung disease and pneumonitis.” 

DISCLOSURE: The study was funded by Daiichi Sankyo and AstraZeneca. Dr. Cortés has served as a consultant or advisor for Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, and Reveal Genomics; has received honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, and Daiichi Sankyo; has received research funding to his institution from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma C, and Queen Mary University of London; owns stock in MedSIR and Nektar Pharmaceuticals and has a relative with stock in Leuko; has been reimbursed for travel, accommodations, or other expenses from Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, AstraZeneca, and Gilead; and holds patents related to a PI3K inhibitor and microtubule-destabilizing agent as well as a predictor of response to dual HER2 blockade.  For full disclosures of the study authors, visit www.nejm.org.

REFERENCE

1. Cortes J, Kim SB, Chung WP, et al: Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med 386:1143-1154, 2022.