Trastuzumab deruxtecan heralds new era in the treatment of metastatic breast cancer

Abstract

Trastuzumab deruxtecan is a new generation Her2-directed antibody-cytostatic conjugate. The unique structure of the molecule, innovative pharmacokinetic and pharmacodynamic properties of the drug allows its effect to be extended not only to the target cells, but also to nearby tumour cells, causing their death. This phenomenon has become known as the abscopal effect, due to which the drug demonstrates effectiveness regardless of the degree of Her2 expression. In clinical trials, trastuzumab deruxtecan therapy significantly outperformed the standard treatment options in patients with Her2-positive breast cancer. Thus, the median time to progression was 17.8 months in patients who were exposed to multiple lines of therapy, including trastuzumab-emtansine, vs 6.9 months in the control group treated with the combination of capecitabine and anti-Her2 agents (RR 0.36, 95% CI 0.28–0.45), which has resulted in a significant prolongation of patients’ lives. The median overall survival reached 39.2 months, while it remained at the level of 26.5 months in the control group (RR 0.6575; 95% CI 0.5023–0.8605; p = 0.0021). In a direct comparison of treatment, trastuzumab deruxtecan was superior to trastuzumab emtansine, significantly increasing the median progression-free survival by 4 times: 28.8 vs. 6.8 months (RR 0.33, 95% CI 0.26–0.43). It also had advantages in terms of objective response rates, quality of life measures, and overall survival. Trastuzumab deruxtecan demonstrated high efficacy in the treatment of HER2-low tumours (Her2-low mBC), surpassing the standard chemotherapy options in all evaluated parameters in pre-treated patients. This article presents the results ofthe main clinical trials of trastuzumab derukstecan, additionally discusses its efficacy in CNS metastatic lesions, highlights the safety issues of the drug.