Trastuzumab deruxtecan as potential novel standard of care for second-line HER2-positive metastatic breast cancer

Trastuzumab deruxtecan (T-DXd) is a HER2-targeting antibody–drug conjugate approved for patients with advanced HER2-positive metastatic breast cancer (HER2+ mBC). The first results from the randomised, phase III DESTINY-Breast03 study now demonstrate that treatment with T-DXd results in a highly statistically significant and clinically meaningful improvement in progression-free survival vs. trastuzumab emtansine (T-DM1) in HER2+ mBC patients previously treated with trastuzumab and taxane.

Although impressive progress has been made in HER2-positive (HER2+) metastatic breast cancer (mBC), unmet need still persists. Thus far, trastuzumab deruxtecan (T-DXd) was investigated in the third-line or beyond setting in the single-arm phase II DESTINY-Breast01 study. Robust activity was observed and has led to regulatory approvals globally. Given these data, T-DXd was evaluated head-to-head versus trastuzumab emtansine (T-DM1) in previously treated HER2+ mBC patients in the phase III DESTINY-Breast03 study.

DESTINY-Breast03 study design

DESTINY-Breast03 enrolled patients with unresectable or metastatic HER2+ breast cancer who were previously treated with trastuzumab and a taxane in the advanced/metastatic setting or who progressed during or less than six months after completing adjuvant therapy involving trastuzumab and taxane. Patients were allowed to have clinically stable, treated brain metastases. Patients were randomly assigned (1:1) to T-DXd 5.4 mg/kg once every three weeks (N= 261) or T-DM1 3.6 mg/kg once every three weeks (N= 263). Primary endpoint of the study was progression-free survival (PFS) as assessed by blinded independent central review (BICR).

Study results

Baseline characteristics were well balanced between the two treatment groups. Median age was approximately 54 years and over 20% had brain metastases. Approximately 10% of patients in each arm did not receive prior treatment for mBC. Roughly 60% of patients had received previous pertuzumab treatment. After a median follow-up of 16.2 months for T-DXd and 15.3 months for T-DM1, the PFS by BICR was significantly in favour of the T-DXd arm (HR[95%CI]: 0.28[0.22-0.37], p= 7.8 x 10^-22). The median PFS was not reached in the T-DXd arm and was reported at 6.8 months for patients treated with T-DM1. The 12-month PFS rates were 75.8% and 34.1%, respectively. Furthermore, a consistent benefit was seen across key subgroups, including hormone receptor status, prior treatment with pertuzumab, visceral disease, number of prior lines of therapy and the presence or absence of brain metastases. The estimated overall survival (OS) rate at 12 months was 94.1% in the T-DXd arm and 85.9% with T-DM1. The hazard ratio for OS was 0.56 (95%CI: 0.36-0.86) with a p-value of 0.007172. However, this did not cross the pre-specified boundary for statistical significance of p< 0.000265. The majority of patients in the T-DXd arm experienced a reduction in tumour size, with a confirmed objective response rate (ORR) for T-DXd of 79.7% as compared to 34.2% for T-DM1 (including 16.1% and 8.7% of complete responses, respectively).

At the time of the data cut-off, the median treatment duration was 14.3 months in the T-DXd arm and 6.9 months for T-DM1. The most common treatment-emergent adverse event (TEAE) associated with treatment discontinuation was interstitial lung disease (ILD)/pneumonitis (8.2%) for T-DXd and was thrombocytopenia (2.7%) for T-DM1. The most common TEAEs associated with dose reduction for T-DXd were nausea (6.2%) and neutropenia (3.5%). For T-DM1 this was thrombocytopenia (4.2%), increased alanine aminotransferase (ALT, 2.7%) and increased aspartate aminotransferase (AST, 2.7%). Similar rates of all grade and grade ≥3 drug-related TEAEs were observed between arms. Most drug-related TEAEs were gastrointestinal or haematological in nature. Importantly, there were no grade 4-5 adjudicated drug-related ILD/pneumonitis events observed with T-DXd. Furthermore, in the T-DXd arm, all reported adverse events of left ventricular ejection fraction decrease were asymptomatic and no cases of cardiac failure occurred.

Conclusion

In the randomised, phase III DESTINY-Breast03 study, T-DXd demonstrated a highly clinically meaningful and statistically significant improvement in PFS compared with T-DM1 in patients with HER2-positive mBC. In addition, at the time of first interim analysis, T-DXd demonstrated an encouraging OS trend and a safety profile that is comparable between both study arms. Therefore, these data support T-DXd becoming the standard of care for second-line HER2-positive mBC.

Reference

Cortés J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): results of the randomized rhase 3 DESTINY-Breast03 study. Presented at ESMO 2021; Abstract LBA1.