Development and responses of brain metastases during treatment with trastuzumab emtansine (T-DM1) for HER2 positive advanced breast cancer: A single institution experience

Abstract

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that does not cross an intact blood-brain barrier. In the EMILIA trial of T-DM1 vs capecitabine/lapatinib for HER2 positive advanced breast cancer, all patients had baseline brain imaging, and 9/450 (2%) of patients with negative baseline imaging developed new brain disease during T-DM1. We assessed the frequency of brain progression in clinical practice, without routine baseline imaging. We undertook a retrospective study of all patients treated with T-DM1 at the Royal Marsden Hospital from 2011 to 2016. Data collected included baseline characteristics, previous treatment for advanced breast cancer, sites of metastatic disease, duration of T-DM1, sites of progression, and treatment of CNS progression. Fifty-five patients were identified who had received a median of two prior lines of treatment (range 0-5). All were HER2 positive; 45 patients had IHC 3+ tumors and 10 were ISH positive. Patients received a median of 12 cycles of T-DM1 (range 1-34), and six remain on treatment at the time of analysis. Before commencing T-DM1, 16/55 (29%) had known brain metastases (treated with whole brain [9] stereotactic radiotherapy [6] or both [1]). Brain was the first site of progression in 56% (9/16) patients, with a median time to brain progression of 9.9 months (95% CI 3.9-12.2). In patients without known baseline brain metastases, 17.9% (7/39) developed new symptomatic brain disease during T-DM1, after a median of 7.5 months (95%CI 3.8-9.6). Brain progression was isolated, with control of extra-cranial disease in 4/7 patients. Only one patient was suitable for stereotactic radiotherapy. Median time to extra-cranial progression in all patients was 11.5 months (95% CI 9.1-17.7), and median OS in all patients was 17.8 months (95% CI 14.2-22). In patients not screened for brain metastases at baseline, the brain was the first site of progression in a significant proportion. Baseline brain imaging may have a role in standard practice for patients commencing T-DM1 therapy.

Targeted therapeutic options and future perspectives for HER2-positive breast cancer

“…In previous retrospective studies, T-DM1 seemed to be an effective and well-tolerated treatment for brain metastasis in HER2-positive breast cancer patients. 325,326 These findings require a prospective validation. Thus, clinical trials of new drugs related to the CNS remains a high priority.…”

Systemic therapy for brain metastases

“…However, enthusiasm for this agent has resurfaced due to the development of trastuzumab-emtansine (T-DM1), which is trastuzumab linked to the cytotoxic tubule inhibitor emtansine (Escrivá-de-Romaní et al, 2018). A growing body of case series and small cohort studies have shown a reduction in brain metastases and prolonged progression-free survival (Ricciardi et al, 2018; Keith et al, 2016; Okines et al, 2017; Bartsch et al, 2015). Most intriguing is the work by Krop et al who performed a retrospective analysis of the phase 3 EMILIA trial and found significant survival benefit for T-DM1 when compared to capecitabine-lapatinib (HR = 0.38; P = 0.008; median, 26.8 versus 12.9 months).…”

Ado-trastuzumab Emtansine-Associated Spider Naevi in Metastatic HER2-positive Breast Cancer

“…For example, in this trial, one patient who received T-DM1 experienced a grade 4 gastrointestinal bleeding event despite having a normal platelet count. Furthermore, cases of intra-cranial hemorrhage [5,6] and expansion of radiation necrosis due to telangiectasia and hemorrhage [7] have been reported. Based on these findings, the FDA revised the label for T-DM1 in July 2014 to highlight this increased risk of bleeding with recommendations for careful follow-up for patients during treatment with T-DM1 [8].…”