What is the Breast Destiny 03 trial for breast cancer?

DESTINY-Breast03 Trial Overview

DESTINY-Breast03 was a pivotal phase 3 randomized trial that established trastuzumab deruxtecan (T-DXd) as superior to trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. 1, 2

Trial Design and Patient Population

• This open-label, multicenter, phase 3 trial enrolled 524 patients across 169 study centers in North America, Asia, Europe, Australia, and South America between July 2018 and June 2020 2
• Eligible patients were aged 18 or older with HER2-positive unresectable or metastatic breast cancer, ECOG performance status 0-1, and at least one measurable lesion 2
• All patients had received previous treatment with trastuzumab and a taxane 2
• Patients were randomized 1:1 to receive either T-DXd 5.4 mg/kg (n=261) or T-DM1 3.6 mg/kg (n=263), both administered intravenously every 3 weeks 2
• Randomization was stratified by hormone receptor status, previous pertuzumab treatment, and history of visceral disease 2

Primary Efficacy Results

The trial demonstrated dramatic superiority of T-DXd over T-DM1 in progression-free survival, with a 67% reduction in risk of disease progression or death. 2

• Median progression-free survival by blinded independent central review was 28.8 months (95% CI 22.4-37.9) with T-DXd versus 6.8 months (95% CI 5.6-8.2) with T-DM1 2
• Hazard ratio for progression-free survival was 0.33 (95% CI 0.26-0.43; p<0.0001), representing the longest reported median progression-free survival in this setting 1, 2
• This represents a clinically meaningful improvement of over 22 months in median progression-free survival 2

Overall Survival Results

At the second interim analysis with median follow-up of 28.4 months, T-DXd demonstrated a significant 36% reduction in risk of death compared to T-DM1. 2

• Median overall survival was not reached in either arm at this analysis 2
• The T-DXd group had 72 (28%) overall survival events versus 97 (37%) events in the T-DM1 group 2
• Hazard ratio for overall survival was 0.64 (95% CI 0.47-0.87; p=0.0037), meeting the prespecified significance threshold 2
• These results established T-DXd as the new standard of care in the second-line setting for HER2-positive metastatic breast cancer 2

Safety Profile

Grade 3 or higher treatment-emergent adverse events occurred at similar rates between arms (56% with T-DXd versus 52% with T-DM1), but interstitial lung disease was more common with T-DXd. 2

• Drug-related treatment-emergent adverse events were higher with T-DXd (relative risk 1.38,95% CI 1.14-1.66) 1
• Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 39 (15%) patients treated with T-DXd versus 8 (3%) patients treated with T-DM1 2
• Critically, no grade 4 or 5 interstitial lung disease events occurred in either arm, representing improved safety compared to earlier trials 1, 2
• The lower rate of severe interstitial lung disease compared to the more heavily pretreated DESTINY-Breast01 population suggests earlier use may be safer 1

Patient-Reported Outcomes

Quality of life was maintained throughout treatment with T-DXd despite longer treatment duration, and time to deterioration numerically favored T-DXd over T-DM1. 3

• Baseline EORTC QLQ-C30 global health status scores were similar between arms, with no clinically meaningful change (<10-point change) while on either treatment 3
• Median treatment duration was 14.3 months with T-DXd versus 6.9 months with T-DM1 3
• Time to definitive deterioration hazard ratios numerically favored T-DXd over T-DM1 for all prespecified patient-reported outcome variables, including pain 3
• Quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis showed T-DXd produced a substantial improvement of 3.80 months (95% CI 1.91-5.62; p<0.001) compared to T-DM1, representing an 11.64% relative gain 4

Hospitalization Data

• Only 6.9% of patients receiving T-DXd versus 7.2% receiving T-DM1 were hospitalized during the study 3
• Median time to first hospitalization was 219.5 days with T-DXd versus 60.0 days with T-DM1—three times longer with T-DXd 3

Clinical Practice Implications

Based on DESTINY-Breast03 results, ASCO guidelines now recommend T-DXd as the preferred second-line therapy for HER2-positive metastatic breast cancer after progression on trastuzumab and a taxane. 1

• T-DXd has replaced T-DM1 as the standard second-line treatment in this setting 1, 2
• The trial results led to regulatory approval and guideline updates establishing T-DXd as the preferred option 1
• Clinicians must maintain active surveillance for interstitial lung disease, which requires specific management protocols, though severe cases (grade 3-5) remain uncommon at 15% overall incidence with no grade 4-5 events 1, 2
• The optimal sequencing after T-DXd progression remains an area of ongoing investigation, as patients in DESTINY-Breast03 had not received prior T-DXd 1