Human epidermal growth factor receptor 2 (HER2)-positive breast cancer, affecting approximately 20% of breast cancer cases, is characterized by HER2 gene amplification and/or HER2 protein overexpression. This leads to aggressive tumor growth and faster metastasis. The discovery of HER2 alterations prompted the development of targeted therapies, improving patient prognosis. Trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1) are antibody-drug conjugates targeting HER2, linked to cytotoxic payloads. T-DM1 uses a microtubule-disrupting agent, while T-DXd employs a topoisomerase I inhibitor, offering potentially greater specificity and reduced toxicity. T-DXd has a higher drug-to-antibody ratio than T-DM1. The DESTINY-Breast03 trial, a phase 3 study, compared T-DXd and T-DM1 in patients with HER2-positive metastatic breast cancer previously treated with taxanes and trastuzumab. Prior analyses demonstrated superior progression-free survival (PFS) with T-DXd. This study presents updated efficacy and safety data with longer follow-up, focusing on overall survival (OS).

The literature extensively covers HER2-positive breast cancer, its aggressive nature, and the development of targeted therapies. Studies have demonstrated the correlation between HER2 overexpression and poor prognosis. Trastuzumab, a HER2-targeting antibody, revolutionized treatment. However, resistance often develops, leading to the search for more effective agents. Antibody-drug conjugates (ADCs) emerged as promising alternatives, combining the targeted delivery of antibodies with the cytotoxic effects of chemotherapy. Trastuzumab emtansine (T-DM1) has shown clinical benefits in the treatment of HER2-positive metastatic breast cancer. However, further improvements were sought, leading to the development of trastuzumab deruxtecan (T-DXd) with its unique mechanism of action and higher drug-to-antibody ratio. Several clinical trials have evaluated T-DXd demonstrating significant improvement in PFS compared to T-DM1. This necessitates a detailed analysis of long-term survival data, to understand its efficacy and establish its role in treatment guidelines.

The DESTINY-Breast03 trial (NCT03529110) was an open-label, multicenter, phase 3, randomized (1:1) study. Patients with HER2-positive, unresectable or metastatic breast cancer, previously treated with trastuzumab and taxane, were eligible. Patients were stratified based on hormone receptor status, prior pertuzumab treatment, and history of visceral disease. They received either T-DXd (5.4 mg/kg) or T-DM1 (3.6 mg/kg) intravenously every 3 weeks. The primary endpoint was PFS by blinded independent central review (BICR). The key secondary endpoint was OS. Other secondary and exploratory endpoints included objective response rate (ORR), duration of response (DoR), PFS, PFS2 (PFS from randomization to progression on next therapy or death) by investigator assessment, and safety. Adverse events were graded using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Suspected ILD/pneumonitis was adjudicated by an external committee. Statistical analyses included stratified log-rank tests for PFS and OS, Cox proportional hazards models for HRs, and Cochran-Mantel-Haenszel tests for ORR. A sensitivity analysis using a median rank-preserving structural failure time model (RPSFTM) was performed.

As of November 20, 2023, the median follow-up was 43.0 months for T-DXd and 35.4 months for T-DM1. The confirmed ORR by investigator assessment was 78.9% for T-DXd and 36.9% for T-DM1. Median DoR was 30.5 months for T-DXd and 17.0 months for T-DM1. Median PFS by investigator assessment was 29.0 months for T-DXd and 7.2 months for T-DM1 (HR 0.30; 95% CI 0.24-0.38). The 36-month PFS rate was 45.7% for T-DXd and 12.4% for T-DM1. Median PFS2 was 45.2 months for T-DXd and 23.1 months for T-DM1 (HR 0.53; 95% CI 0.41-0.68). Median OS was 52.6 months for T-DXd and 42.7 months for T-DM1 (HR 0.73; 95% CI 0.56-0.94), representing a 27% reduction in the risk of death. The 36-month OS rate was 67.6% for T-DXd and 55.7% for T-DM1. Treatment-emergent adverse events (TEAEs) were consistent with previous analyses. Adjudicated drug-related ILD/pneumonitis occurred in 16.7% of T-DXd patients and 3.4% of T-DM1 patients. Since the previous data cutoff, four new grade 2 ILD events were reported in the T-DXd group.

This updated analysis of DESTINY-Breast03 confirms the superior efficacy of T-DXd over T-DM1 in previously treated HER2-positive metastatic breast cancer. The prolonged median PFS and OS with T-DXd, along with a manageable safety profile, highlight its clinical benefit. The significantly improved OS observed with T-DXd is notable, exceeding the improvement previously seen with other therapies in this setting. The longer duration of response observed with T-DXd suggests a more durable clinical benefit compared to T-DM1. Although the safety profile of T-DXd reveals a higher incidence of TEAEs, particularly ILD/pneumonitis, these events are manageable with appropriate monitoring and intervention. The study's results support the use of T-DXd as a preferred treatment option in this patient population, emphasizing the importance of careful patient selection and monitoring for potential toxicities.

This long-term analysis reinforces the superiority of T-DXd over T-DM1 in previously treated HER2-positive metastatic breast cancer, showing the longest reported median OS (52.6 months) in this setting. The consistent efficacy improvement and manageable safety profile support T-DXd's clinical benefit. Ongoing studies are exploring the impact of T-DXd on long-term responders and its efficacy in earlier-line metastatic settings.

The study was open-label, precluding blinding. PFS, ORR, and DoR in this updated analysis were assessed by investigators, not BICR, limiting direct statistical comparison. The OS analysis was exploratory as the prespecified statistical significance threshold was met earlier. The number of censored patients in the T-DXd group affects the precision of median OS estimates. Longer follow-up is necessary for a more definitive conclusion.