Ado-trastuzumab emtansine has been approved by the European Commission for the treatment of adult patients with HER2-positive early breast cancer, in the adjuvant setting who have residual invasive disease after taxane-based chemotherapy and HER2-targeted therapy, in the neoadjuvant setting.<sup>1</sup>
Levi Garraway, MD, PhD
Levi Garraway, MD, PhD
Ado-trastuzumab emtansine (T-DM1; Kadcyla) has been approved by the European Commission for the treatment of adult patients with HER2-positive early breast cancer, in the adjuvant setting who have residual invasive disease after taxane-based chemotherapy and HER2-targeted therapy, in the neoadjuvant setting.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 theNew 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.