The EMA review of trastuzumab emtansine (T-DM1) for the adjuvant treatment of adult patients with HER2-positive early breast cancer

J Delgado,C Vleminckx,S Sarac,A Sosa,J Bergh,R Giuliani,H Enzmann,F Pignatti

doi:10.1016/j.esmoop.2021.100074

Abstract

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate of trastuzumab [a monoclonal antibody against human epidermal growth factor receptor 2 (HER2)] and DM1 (an inhibitor of tubulin polymerisation). It was initially approved in the European Union for the treatment of adult patients with HER2-positive unresectable locally advanced or metastatic breast cancer (BC) who had previously received trastuzumab and taxanes. On 18 December 2019, a variation of the marketing authorisation was approved extending this use to the adjuvant therapy of adult patients with HER2-positive early BC who have residual invasive disease in the breast and/or lymph nodes after neoadjuvant taxane-based and HER2-targeted therapy. A phase III randomised, multicentre, open-label trial compared T-DM1 with trastuzumab as adjuvant therapy in patients with HER2-positive early BC who had received preoperative chemotherapy and HER2-targeted therapy followed by surgery, with a finding of invasive residual disease in the breast and/or axillary lymph nodes. The study met its primary endpoint by showing an increased 3-year invasive disease-free survival rate in the T-DM1 arm (88.3%) compared with the trastuzumab arm (77.0%), with an unstratified hazard ratio of 0.50 (95% confidence interval: 0.39-0.64). There was a higher incidence of hepatotoxicity (37.3% versus 10.6%), thrombocytopenia (28.5% versus 2.4%), peripheral neuropathy (32.3% versus 16.9%), haemorrhage (29.2% versus 9.6%) and pulmonary toxicity (2.8% versus 0.8%) in the T-DM1 arm compared with the control arm. The aim of this manuscript was to summarise the scientific review of the application leading to regulatory approval of this additional indication in the European Union.

Highlights

Patients with human epidermal growth factor receptor 2 (HER2)-positive tumours >2 cm are recommended to receive neoadjuvant therapy with chemotherapy and trastuzumab, the first-in-class anti-HER2 monoclonal antibody.[3,9]
Pertuzumab, another anti-HER2 monoclonal antibody (mAb), has been approved in combination with trastuzumab and chemotherapy for neoadjuvant (NeoSphere and TRYPHAENA trials) and adjuvant (APHINITY trial) therapy in patients with high-risk HER2-positive EBC10; and neratinib was approved for extended adjuvant therapy in patients with HER2-positive early BC (EBC) in patients who are
No difference in serum trastuzumab or plasma DM1 Cmax or Cmin was observed between the KATHERINE and EMILIA studies. This application was based on the primary analysis of the KATHERINE study, a phase III randomised, multicentre, open-label trial comparing T-DM1 versus trastuzumab as adjuvant therapy in patients with HER2-positive EBC who had received preoperative taxane-based chemotherapy and HER2-targeted therapy followed by surgery, with a finding of invasive residual disease in the breast and/or lymph nodes.[19]

Summary

Introduction

Breast cancer (BC) is the second most common cancer in the world and the most common female cancer, with 2.09 million new cases and approximately 627 000 deaths in 2018 (522 513 new cases and 137 707 deaths in Europe).[1,2] Important prognostic and predictive factors in patients with early BC (EBC) are: expression of estrogen/progesterone receptors, human epidermal growth factor receptor 2 (HER2) and proliferation markers (e.g. Ki67); number of involved regional lymph nodes; tumour histology, size and grade; and the presence of peritumoral vascular invasion.[3]Volume 6 - Issue 2 - 2021Approximately 10%-20% of tumours overexpress HER2, which is associated with poor clinical outcome, including a 15%-25% risk of recurrence.[4,5,6,7,8] Locoregional surgery, radiotherapy and systemic therapy (neoadjuvant chemotherapy, HER2-targeted therapy or endocrine therapy) are part of the treatment algorithm for HER2-positive EBC. This application was based on the primary analysis of the KATHERINE study, a phase III randomised, multicentre, open-label trial comparing T-DM1 versus trastuzumab as adjuvant therapy in patients with HER2-positive EBC who had received preoperative taxane-based chemotherapy and HER2-targeted therapy followed by surgery, with a finding of invasive residual disease in the breast and/or lymph nodes.[19] Supportive safety data from the phase II study BO22857 were provided.[21]

Results

Conclusion