T-DXD real world

Dr Paolo Tarantino and Dr Elisa Agostinetto discuss the results of a real-world study of trastuzumab deruxtecan in metastatic breast cancer.

Trastuzumab deruxtecan is significantly changing breast cancer treatment, especially for HER2+ and HER2-low subtypes. To understand its real-world performance, a study analysed a large database of 1,500 patients who received the drug. Most patients had HER2+ metastatic breast cancer, while others had HER2-low or HER2-zero disease.

The study found that trastuzumab deruxtecan has prolonged activity, particularly in HER2+ breast cancer, with somewhat less activity in HER2-low and HER2-zero patients. However, real-world PFS in HER2+ metastatic breast cancer is significantly shorter than in clinical trials. While clinical trials report PFS of 24 months or more, real-world data show about 11 to 12 months. This discrepancy may be due to patient selection criteria, the definition of HER2+ status, and how PFS is calculated. Patient selection in clinical trials tends to be more stringent, excluding those with comorbidities or prior interstitial lung disease. In contrast, real-world patients present a broader and often more complex health profile. Additionally, the real-world study defined HER2+ status based on any time point before receiving trastuzumab deruxtecan, which might include patients whose current status is different. Clinical trials usually require a more recent confirmation of HER2+ status.

In terms of safety, it is challenging to capture real-world toxicities as precisely as in clinical trials. A separate study of 200 patients found similar side effect profiles to clinical trials, with about 13% experiencing interstitial lung disease (ILD). Dose reductions were common, mainly due to fatigue. Understanding ILD and other toxicities in real-world settings remains crucial to ensure patient safety and optimal treatment management.

A recent trial showed that trastuzumab deruxtecan is effective in HER2-ultra-low breast cancer. It demonstrated significant activity with a PFS of more than one year and a response rate of 50-60%. This suggests that even minimal HER2 expression can lead to the drug’s efficacy, likely due to mechanisms like the bystander effect or the drug’s activity in the bloodstream.

The trial also explored whether trastuzumab deruxtecan could replace first-line cytotoxic treatments. While it showed prolonged PFS compared to chemotherapy (capecitabine or taxanes), overall survival was not statistically significant. The trial’s population was specific, with most patients having measurable disease and very few with bone-only disease. This highlights the need to tailor treatment based on individual patient profiles and preferences. Some patients may prefer oral treatments like capecitabine, which do not cause hair loss, while others may prioritise the longest possible PFS.

In conclusion, trastuzumab deruxtecan shows promising real-world efficacy across different HER2 statuses, though its PFS is shorter than in clinical trials due to various factors. Safety remains a key consideration, especially regarding ILD. The drug’s role in treating HER2-ultra-low breast cancer and its potential as a first-line treatment option continues to evolve, emphasising the importance of personalised treatment approaches.