The European Commission has approved ado-trastuzumab emtansine for the adjuvant treatment of adult patients with HER2-positive early breast cancer who have residual invasive disease (breast and/or lymph nodes) following neoadjuvant taxane-based chemotherapy and HER2-targeted therapy.
Levi Garraway, MD, PhD
The European Commission has approved ado-trastuzumab emtansine (T-DM1; Kadcyla) for the adjuvant treatment of adult patients with HER2-positive early breast cancer who have residual invasive disease (breast and/or lymph nodes) following neoadjuvant taxane-based chemotherapy and HER2-targeted therapy.1
The approval is based on findings from the phase III KATHERINE study, in which T-DM1 reduced the risk of invasive disease recurrence or death by 50% compared with trastuzumab (Herceptin) in this setting (HR, 0.50; 95% CI, 0.39-0.64; P <.0001). The 3-year invasive disease-free survival (iDFS) rate was 88.3% with T-DM1 versus 77.0% with trastuzumab, leading to an absolute improvement of 11.3%.
“Optimal treatment is vital for every patient with early-stage breast cancer, a setting where cures are possible,” Levi Garraway, MD, PhD, chief medical officer, head of global product development of Genentech (Roche), the developer of T-DM1, stated in a press release. “This approval of Kadcyla will allow many more women with HER2-positive early breast cancer to be given a transformative treatment that may cut the risk of their disease returning or progressing."
The iDFS benefit with T-DM1 was upheld across key patient subgroups, according to results presented at the 2018 San Antonio Breast Cancer Symposium and simultaneously published in the New England Journal of Medicine.2,3
The open-label KATHERINE trial included 1486 patients with centrally confirmed HER2-positive, nonmetastatic, invasive primary breast cancer who were found to have residual invasive tumor in the breast or axillary nodes at surgery after completing neoadjuvant chemotherapy. Neoadjuvant chemotherapy had to consist of ≥6 cycles of chemotherapy containing a taxane (with or without anthracycline) and ≥9 weeks of trastuzumab.
Patient characteristics were well balanced between the 2 study arms. Across the study population, the median age was 49, three-fourths of patients were white, and 75% of patients had operable breast cancer at presentation. Three-fourths of patients in both arms were ER-positive, PR-positive, or both.
Over seventy-six percent of patients had prior anthracycline use. Across both arms, neoadjuvant HER2-targeted therapy consisted of trastuzumab alone for approximately 80% of patients, trastuzumab plus pertuzumab (Perjeta) for 19%, and trastuzumab plus other HER2-targeted therapy (neratinib, dacomitinib, afatinib, and lapatinib) for 1%.
Patients were randomized within 12 weeks of surgery to either T-DM1 at 3.6 mg/kg IV (n = 743) or trastuzumab at 6 mg/kg IV (n = 743). Both agents were administered every 3 weeks for 14 cycles.
The consistent iDFS benefit with T-DM1 was shown across several key subgroups: operable disease at presentation (HR, 0.47), inoperable disease at presentation (HR, 0.54), negative hormone receptor status (HR, 0.50), positive hormone receptor status (HR, 0.48), trastuzumab as only anti-HER2 agent in neoadjuvant setting (HR, 0.49), trastuzumab plus ≥1 anti-HER2 agent in neoadjuvant setting (HR, 0.54), node-positive disease after neoadjuvant treatment (HR, 0.52), and node-negative disease after neoadjuvant treatment (HR, 0.44).
The safety analysis included 740 patients in the T-DM1 arm and 720 patients in the trastuzumab arm.
The rate of grade ≥3 adverse events (AEs) was 25.7% versus 15.4%, and the rate of serious AEs was 12.7% versus 8.1%, respectively. AE-related discontinuations occurred in 18% of the T-DM1 arm versus 2.1% in the trastuzumab arm.
The most common grade ≥3 AEs across the overall population included thrombocytopenia (5.7%) with T-DM1 vs 0.3% with trastuzumab) and hypertension (2.0% vs 1.2%, respectively).
The FDA reviewed and approved T-DM1 for this indication in April 2019 under the agency's Real-Time Oncology Review and Assessment Aid pilot programs; the approval occurred 12 weeks following completion of the submission of the application. It is was previously approved by the FDA for the treatment of patients with metastatic HER2-positive breast cancer who previously received trastuzumab and a taxane, either alone or in combination.