Trastuzumab Deruxtecan in Patients with HER2+ Metastatic Breast Cancer

Extension of PFS and OS in pre-treated HER2⁺ mBC

The phase III DESTINY-Breast03 study compared the efficacy and safety of trastuzumab deruxtecan to trastuzumab emtansine in pre-treated patients with HER2⁺ mBC. The first interim analysis already demonstrated a significant improvement in progression-free survival (PFS). Results of the second interim analysis published at the beginning of 2023 showed significant extension of overall survival (OS) and provided additional safety data on the evaluated treatment.

This open-label multicenter study enrolled 524 adults with unresectable/metastatic HER2⁺ breast cancer previously treated with trastuzumab and a taxane, with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1 and at least one measurable lesion. Patients were randomized 1:1 to receive trastuzumab deruxtecan (5.4 mg/kg) or trastuzumab emtansine (3.6 mg/kg) intravenously every 3 weeks. Stratification was based on hormone receptor expression, prior pertuzumab use, and presence of visceral metastases. The primary endpoint was PFS evaluated by a blinded central review committee.

The median follow-up duration at the second interim OS analysis was 28.4 months for trastuzumab deruxtecan and 26.5 months for trastuzumab emtansine. The median PFS was 28.8 months in the trastuzumab deruxtecan arm compared to 6.8 months in the trastuzumab emtansine arm (hazard ratio [HR] 0.33; 95% confidence interval [CI] 0.26–0.43; p < 0.0001). The median OS was not reached, with 28% of patients randomized to trastuzumab deruxtecan and 37% to trastuzumab emtansine dying by the analysis date. However, the second interim analysis demonstrated a statistically and clinically significant 36% reduction in the risk of death for patients treated with trastuzumab deruxtecan compared to trastuzumab emtansine (HR 0.64; 95% CI 0.47–0.87; p = 0.0037). The incidence of ≥ grade 3 adverse events was comparable in both treatment arms (56% vs. 52%). Treatment-related interstitial lung disease (ILD) or pneumonitis occurred in 15% of cases with trastuzumab deruxtecan and 3% with trastuzumab emtansine; no grade 4 or 5 ILD/pneumonitis was observed in either treatment arm.

Extension of PFS after prior therapy failure

In the earlier phase II single-arm DESTINY-Breast01 study, trastuzumab deruxtecan demonstrated significant efficacy in patients with HER2⁺ mBC following progression on trastuzumab emtansine, a population with very limited therapeutic options. In 2023, results from the DESTINY-Breast02 study were published, comparing the efficacy and safety of trastuzumab deruxtecan to treatment of the physician's choice in patients with unresectable HER2⁺ mBC after previous trastuzumab emtansine therapy. This was an open-label randomized multicenter phase III study for patients over 18 years old, with ECOG PS 0/1 and adequate liver and kidney function. Randomization was 2:1 to receive trastuzumab deruxtecan (5.4 mg/kg IV every 3 weeks) or physician's choice of therapy (either capecitabine + trastuzumab or capecitabine + lapatinib). The primary endpoint was PFS evaluated by a blinded central review committee.

A total of 608 patients (including 5 men) were enrolled. The median follow-up duration was 21.5 months in the trastuzumab deruxtecan group and 18.6 months in the physician's choice group. The median PFS was 17.8 months in the trastuzumab deruxtecan arm compared to 6.9 months in the control group (HR 0.36; 95% CI 0.28–0.45; p < 0.0001). Trastuzumab deruxtecan also demonstrated significant efficacy in overall survival extension – mOS was 39.2 months in the trastuzumab deruxtecan arm and 26.5 months in the control arm (HR 0.66; 95% CI 0.50–0.86; p = 0.0021). The most common adverse events were nausea (73% with trastuzumab deruxtecan vs. 37% with physician's choice treatment), vomiting (38% vs. 13%), alopecia (37% vs. 4%), fatigue (36% vs. 27%), diarrhea (27% vs. 54%), and palmoplantar erythrodysesthesia (2% vs. 51%). Grade ≥ 3 adverse events occurred in 53% of patients in the trastuzumab deruxtecan arm and in 44% in the control group, with treatment-related ILD occurring in 10% of patients in the trastuzumab deruxtecan arm (including 2 fatal events) and <1% in the control arm.

Conclusion

Recently published clinical trial results have confirmed the significant benefits of trastuzumab deruxtecan in the treatment of patients with HER2⁺ mBC – not only in terms of extending progression-free survival but also overall survival compared to existing standard therapies. The DESTINY-Breast03 study demonstrated the longest median PFS published for this population to date. The safety profile of trastuzumab deruxtecan is manageable even with prolonged therapy duration.

The above results confirm the position of trastuzumab deruxtecan in the 2nd line treatment of HER2⁺ mBC, where it is the clearly preferred choice according to international guidelines, both in patients without brain metastases and those with stable brain metastases.

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Sources:
1. Hurvitz S. A., Hegg R., Chung W. P. et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet 2023 Jan 14; 401 (10371): 105−117, doi: 10.1016/S0140-6736(22)02420-5.
2. André F., Hee Park Y., Kim S. B. et al. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet 2023 May 27; 401 (10390): 1773−1785, doi: 10.1016/S0140-6736(23)00725-0.