The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended approval of 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 Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of 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 CHMP based its recommendation 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 <.001).2,3 The 3-year invasive disease-free survival (iDFS) rate was 88.3% with T-DM1 versus 77.0% with trastuzumab, translating to an absolute improvement of 11.3%.
The European Commission will now make a final approval decision.
“In the early breast cancer setting where cure is achievable, it is important to do everything possible to prevent progression to an advanced, incurable stage.” Levi Garraway, MD, PhD, chief medical officer and head of global product development at Roche, the developer of T-DM1, said in a press release. “This recommendation therefore marks a significant step forward in bringing a potentially transformative treatment option to patients in Europe with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant therapy.”
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).
Safety data were consistent with the known toxicities of T-DM1, with expected increases in manageable adverse events associated with T-DM1 compared to trastuzumab.
The safety analysis included 740 patients in the T-DM1 arm and 720 patients in the trastuzumab arm. The majority of adverse events were grad 1/2—milder symptoms.
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 decreased platelet count (5.7% with T-DM1 vs 0.3% with trastuzumab), hypertension (2.0% vs 1.2%, respectively), peripheral sensory neuropathy (1.4% vs 0), decreased neutrophil count (1.2% vs 0.7%), hypokalemia (1.2% vs 0.1%), fatigue (1.1% vs 0.1%), and anemia (1.1% vs 0.1%).
T-DM1 is approved in the United States and European Union for the treatment of patients with HER2-positive metastatic breast cancer who have previously received trastuzumab and taxane-based chemotherapy, separately or in combination.
In the United States, T-DM1 is also approved for the adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease following neoadjuvant trastuzumab and chemotherapy.