The updated results from the DESTINY-Breast03 phase 3 trial showed that trastuzumab deruxtecan significantly prolonged progression-free survival (PFS) and overall survival (OS) among patients with human epidermal growth factor receptor 2-positive (HER2-positive) unresectable and/or metastatic breast cancer (mBC).¹ Together with the manageable safety profile, the role of trastuzumab deruxtecan as a standard of care (SoC) in the second-line setting of HER2-positive unresectable and/or mBC was reaffirmed.¹

The over-expression of HER2, a tyrosine kinase receptor, occurs in 15%-20% of BCs.² Despite the first-line treatment with pertuzumab or trastuzumab and a taxane, patients with HER2-positive mBC often require second-line treatment options for prolonging their survival, with trastuzumab deruxtecan being the preferred option and trastuzumab emtansine as an alternative.³ These drugs are antibody-drug conjugates (ADCs) that contain a humanized anti-HER2 monoclonal antibody linked to a cytotoxic payload, with deruxtecan inhibiting topoisomerase I and emtansine inhibiting microtubules.⁴ The rational design of trastuzumab deruxtecan's peptide linker ensures efficient delivery and enzymatic cleavage to HER2-expressing cancer cells, reducing off-target toxic effects.⁴ Notably, trastuzumab deruxtecan has a higher drug-to-antibody ratio (DAR) of around 8, compared with 3.5 for trastuzumab emtansine, and is deemed to have comparable safety and a higher clinical efficacy among patients.⁴

DESTINY-Breast03 (NCT03529110) was a global, open-label, randomized, multicenter, phase 3 trial designed to compare the safety and efficacy of trastuzumab deruxtecan with trastuzumab emtansine among patients with HER2-positive unresectable and/or mBC who have previously been treated with trastuzumab and a taxane.¹ From July 20, 2018 to June 23, 2020, a total of 524 eligible patients were enrolled and randomly assigned to receive either trastuzumab deruxtecan 5.4mg/kg (n=261) or trastuzumab emtansine 3.6mg/kg (n=263) by every 3 weeks.¹ In the interim analysis (data cut-off date: May 21, 2021), trastuzumab deruxtecan showed a significant risk reduction in PFS vs. trastuzumab emtansine (HR=0.28; 95% CI: 0.22-0.37; p<0.001).¹ Based on the promising data, trastuzumab deruxtecan was subsequently approved for the treatment of patients with unresectable or metastatic HER2-positive BC who had previously received an anti-HER2-based regimen.¹

The extended follow-up of DESTINY-Breast03 confirmed the efficacy of trastuzumab deruxtecan in the second-line setting of HER2-positive unresectable and/or mBC.¹ With a median follow-up of 28.4 months (data cut-off date: July 25, 2022), trastuzumab deruxtecan demonstrated a significantly longer median PFS of 28.8 months vs. 6.8 months with trastuzumab emtansine (HR=0.33; 95% CI: 0.26-0.43; nominal p<0.0001).¹ In addition, trastuzumab deruxtecan was shown to reduce the risk of death by 36% when compared with trastuzumab emtansine (HR=0.64; 95% CI: 0.47-0.87; p=0.0037), with 2-year OS rates of 77.4% and 69.9%, respectively.¹ The observed survival advantage was consistent across all subgroups studied.¹ Furthermore, trastuzumab deruxtecan also achieved a higher confirmed objective response rate (ORR: 79% vs. 35%) and complete response rate (CRR: 21% vs. 10%) when compared with trastuzumab emtansine, together with a longer median duration of response (DoR: 36.6 months vs. 23.8 months).¹

According to the safety dataset of DESTINY-Breast03 (n=518), trastuzumab deruxtecan (median treatment duration: 18.2 months) showed a consistent and similar safety profile with trastuzumab emtansine (median treatment duration: 6.9 months), with no new safety signals identified, implying a manageable safety profile with longer treatment duration.¹ The most common treatment-emergent adverse events (TEAEs) of any grade were nausea, vomiting, alopecia, constipation, and anemia.¹

In summary, the clinically meaningful and statistically significant improvement in PFS and OS observed in DESTINY-Breast03 consolidates the role of trastuzumab deruxtecan as the SoC for second-line treatment in HER2-positive mBC.¹ In light of its demonstrated safety and efficacy, additional studies are underway to establish the role of trastuzumab deruxtecan in the first-line setting as well as in patients with early-stage BC.¹