ANTICANCER RESEARCH 35: 5085-5090 (2015) T-DM1 as a New Treatment Option for Patients with Metastatic HER2-positive Breast Cancer in Clinical Practice LAURA L. MICHEL1,2, JUSTO LORENZO BERMEJO3, ADAM GONDOS4, FREDERIK MARMÉ1,2 and ANDREAS SCHNEEWEISS1,2 1National Center for Tumor Diseases and 2Department of Obstetrics and Gynecology, University Hospital, Heidelberg, Germany; 3Institute of Medical Biometry and Informatics, University of Heidelberg, Germany; 4Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany Abstract. Aim: To compare results of trastuzumab- targeted approach (1, 2). Within the last few years, additional emtansine (T-DM1) treatment in our clinical practice with HER2-directed agents such as the monoclonal antibody data from phase III clinical trials. Patients and Methods: A pertuzumab and the dual epidermal growth factor receptor retrospective chart review of all 23 patients with metastatic (EGFR)/HER2 tyrosine kinase inhibitor, lapatinib, were human epidermal growth factor receptor 2 (HER2)-positive developed to overcome resistance to trastuzumab and provide breast cancer who were started on T-DM1 until April 2014 additional treatment options for these patients (3, 4). was performed. Results: Four patients (17.4%) received The newest agent, which was approved by the Food and T-DM1 as first-line, three (13.0%) as second-line, six Drug Administration (FDA) in February 2013 for HER2- (26.0%) as third-line, and 10 (43.5%) as fifth- or further-line positive metastatic breast cancer is trastuzumab-emtansine therapy. Overall, the response rate (ORR) was 26.0%, (T-DM1, Roche, Basel). T-DM1 represents a new generation disease control rate 78.3% and median progression-free of cytotoxic drugs. It is an antibody–drug conjugate survival (PFS) 8.4 months. The only toxicities of grade 3 or consisting of the monoclonal antibody trastuzumab linked to more were fatigue (21.7%), thrombocytopenia (4.3%) and the cytotoxic agent emtansine (DM1), a microtubule elevation of liver enzymes (8.7%). ORR and PFS were polymerization inhibitor (5-7). T-DM1, therefore, combines similar to the TH3RESA and EMILIA trials. Compared to the the tumor selectivity of antibodies with the cytotoxic EMILIA study, we recorded higher rates of newly-diagnosed potential of chemotherapeutics. cerebral metastasis and cerebral progression in patients with T-DM1 binds to the HER2 receptor, is internalized and stable peripheral metastases. Conclusion: T-DM1 is effective undergoes lysosomal degradation. The active cytotoxic DM1 and well-tolerated even in intensively pre-treated patients. moiety is released inside HER2-expressing cells. This reduces systemic exposure. Additionally to inhibiting tubulin Over the past decade, the management of human epidermal polymerization similarly to the vinca alkaloids, T-DM1 also growth factor receptor 2 (HER2)-positive breast cancer has acts by trastuzumab-mediated HER2-targeting antitumor improved dramatically. The monoclonal antibody trastuzumab properties: it inhibits HER2 extracellular domain shedding, as was the first HER2-directed agent for the treatment of HER2- well as the phosphatidylinositol-3-kinase signaling pathway positive breast cancer. It was approved in 2000 in the EU. Its and induces antibody-dependent cellular cytotoxicity (7). introduction into clinical therapy represented a paradigm shift Results from multiple phase III studies have confirmed the in oncology from non-specific chemotherapy to a molecularly- efficacy and safety of T-DM1 in patients with metastatic breast cancer. The EMILIA (TDM4370) study is an international, randomized phase III study that compares the efficacy and safety of T-DM1 to capecitabine plus lapatinib. A total of 991 Correspondence to: Laura L. Michel, MD, National Center for Tumor women with metastatic HER2-positive breast cancer whose Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, disease progressed on or within 6 months after receiving D-69120 Heidelberg, Germany. Tel: +49 62215638795, e-mail: trastuzumab and who had received taxane chemotherapy were [email protected] included (8). Patients received T-DM1 at a dose of 3.6 mg/kg Key Words: HER2-positive metastatic breast cancer, T-DM1, once every 21 days or oral lapatinib plus capecitabine. The chemotherapy. primary end-points were progression-free survival (PFS) and 0250-7005/2015 $2.00+.40 5085 ANTICANCER RESEARCH 35: 5085-5090 (2015) overall survival (OS). Patients had previously received a mg/kg. In cases of toxicities of grade 3 or more, the dose was reduced median of three systemic agents for metastatic disease. 12.0% by ~20%, corresponding to 3.0 mg/kg (level −1) and 2.4 mg/kg (level of the patients received T-DM1 as a first -line treatment. The −2). T-DM1 was given every three weeks. Echocardiography was performed every 12 weeks to rule out cardiotoxicity. median PFS was 9.6 months in the T-DM1 group vs. 6.4 For follow-up, patients were seen on a regular basis at least months in the lapatinib-plus-capecitabine group. The hazard quarterly at our Outpatient Clinic. According to our center's ratio (HR) for PFS was 0.65 with T-DM1 vs. capecitabine- guidelines, response was evaluated every third cycle by magnetic plus-lapatinib. The median survival was 30.9 months in the T- resonance imaging or computed tomographic scans and evaluation DM1-treated group vs. 25.1 months in the group treated with of tumor markers. lapatinib plus capecitabine (8). The TH3RESA study investigated the use of T-DM1 in Statistical analysis. Descriptive statistics were used to summarize patient and tumor characteristics. The overall response rate (ORR) comparison to the treatment of the physician's choice in was defined as complete and partial response (CR+PR) according to patients with HER2-positive breast cancer who had received the Response Evaluation Criteria in Solid Tumors (RECIST) version at least two prior regimens of HER2-directed therapy. The 1.1 (11). Disease control rate (DCR) was defined as CR plus PR plus primary end-points were PFS and OS. The median PFS was stable disease (SD) according to RECIST criteria. PFS was defined 6.2 months in the T-DM1-treated group vs. 3.3 months in the as the interval between the first dose of T-DM1 and the time of physician's choice group. Interim OS analysis showed a trend disease progression or death. OS was defined as the time interval favoring T-DM1 (stratified HR=0.552; 95% confidence between the first dose of T-DM1 and death. OS and PFS were examined using the Kaplan–Meier method. The follow-up of patients interval (CI)=0.369-0.826; p=0.0034) without crossing the without documented events at the last follow-up was censored. stopping boundary (9). Analysis of adverse events (AEs), combining available data Results from all single-agent T-DM1 studies to date including 884 T- DM1-exposed patients, revealed that the most commonly Patients' characteristics. Patient and tumor characteristics are reported all-grade AEs were fatigue (46.4%), nausea (43.0%), summarized in Table I and reflected the typical population thrombocytopenia (32.2%), headache (29.4%), and of patients with MBC seen in our clinical practice. Overall, constipation (26.5%). The most common grade 3 to 4 AEs 23 patients with MBC were treated with T-DM1 between observed were thrombocytopenia (11.9%) and increased serum November 2010 to April 2014. The median follow-up was aspertate transaminase (AST) concentration (4.3%). There 285 (range=21-1016) days. At the cut-off date (October, 8th, were 12 AE-related deaths. AEs resulted in dose reductions in 2014), nine patients were still under therapy with T-DM1. 17.2% of patients and drug discontinuations in 7.0% (10). The median age was 54 (range=32-79) years. Overall 91.3% It is common belief that controlled clinical trials provide the of patients had visceral metastases. A total of 73.9% patients highest level of evidence. Yet it is also undisputed that clinical had received prior (neo-) adjuvant cytotoxic therapy; 91.3% trials are prone to selection bias and do not always reflect received prior anti-HER2 treatment either in the (neo-) clinical reality. After the introduction of T-DM1 in the EU at adjuvant (47.8%) or palliative (82.6%) setting, or both. Most the beginning of 2014, use of T-DM1 is still not common in patients (91.3%) had received prior antibody therapy with German clinical practice. At our Institution, T-DM1 has been trastuzumab for a median of 32 (range=5-120) months. integrated into routine treatment of HER2-positive metastatic Fourteen patients (60.9%) had been treated with lapatinib breast cancer (MBC). In this retrospective study, we report our and eight (34.8%) had received pertuzumab before. first experiences with T-DM1 in routine clinical practice and aim to determine how our treatment results compare to the Treatment. Details of T-DM1 treatment are outlined in Table data generated in controlled clinical trials. II. Four patients (17.4%) received T-DM1 as first-line treatment, 10 patients (43.5%) had received more than four Patients and Methods prior lines of systemic treatment for metastatic disease. All patients started with T-DM1 at 3.6 mg/kg. The median Patients. We performed a retrospective chart review of all 29 number of cycles administered was 10 (range=1-42). Dose patients who started treatment with T-DM1 at our Department from delay was required for 10 patients (43.5%) and dose November 2010 to April 2014. Six patients were excluded from our reduction was necessary for three patients (13.0%). patient cohort: two of them received T-DM1 in a post-neoadjuvant setting; in four other patients, therapy with T-DM1 was initiated at Efficacy. Efficacy data are summarized in Table III. No CR our Clinic and was continued after the first two cycles at other was observed.