Approximately half of patients with human epidermal growth factor receptor 2positive (HER2+) metastatic breast cancer (MBC) develop brain metastases (BM) during the course of their disease, and these patients are difficult to treat. Evidence indicates that this population of patients may benefit from treatment with EGFR/HER2 targeted tyrosine kinase inhibitors (TKIs) such as lapatinib and neratinib, alone or in combination with capecitabine, or treatment with the HER2 specific TKI tucatinib in combination with trastuzumab and capecitabine. In contrast, it has been considered that monoclonal antibodies, including antibody drug conjugates (ADCs), are not effective in patients with brain metastases due to their large size and inability to cross the blood brain barrier. Consequently, these patients have been commonly excluded from clinical trials with ADCs. However, increasing preclinical and clinical evidence suggests that ADCs such as trastuzumab-emtansine (T-DM1) are also active in patients with brain metastases. This is supported by a recently reported exploratory analysis from the KAMILLA trial.

KAMILLA is an ongoing, international, single-arm, open-label phase IIIb study evaluating the safety and efficacy of T-DM1 in patients with previously treated, HER2+ MBC. The primary data analysis after a median follow-up of 20.6 months demonstrated that T-DM1 was safe and well tolerated with efficacy consistent with that reported from previous randomized studies. A post hoc, exploratory analysis further assessed the efficacy and safety of T-DM1 in 398 patients with baseline BM. Among these patients, 126 had measurable baseline BM and, on treatment with T-DM1, 3 patients achieved a complete response and 24 patients achieved a partial response, corresponding to a best overall response of 21.4%. Furthermore, an additional 27 patients experienced stable disease lasting ≥ 6 months, translating to a clinical benefit rate of 42.9%. Additionally, a reduction of ≥ 30% in the sum of the largest diameters of BM was observed in 42.9% of patients (irrespective of prior radiotherapy). Overall, in 398 patients with baseline BM, median progression free survival and overall survival were 5.5 and 18.9 months, respectively. While the safety profile of T-DM1 was similar in patients with or without baseline BM, nervous system adverse events (confusional state, seizure and brain edema) were more common in patients with baseline BM (52.3% versus 43.7%, respectively). Based on these results, the investigators concluded that T-DM1 is active and well tolerated in patients withHER2+ MBC with BM and should be investigated further.

In an accompanying editorial, Dr. Lin (Dana-Farber Cancer Institute, Boston, Massachusets, USA) highlights that the study ’’solidifies the clinical evidence supporting central nervous system activity of T-DM1 in patients with HER2+ breast cancer brain metastases’’ and states that T-DM1, and other ADCs, should be explored as treatments for patients with BM in breast and other cancers.

References

F. Montemurro et al. Annals of Oncology 2020;

Lin, N.U. Annals of Oncology 2020;