Adjuvant T-DM1 Approved by FDA for HER2+ Early Breast Cancer

Ado-trastuzumab emtansine has been approved by the FDA for use as an adjuvant treatment option for patients with HER2-positive early breast cancer who have residual invasive disease following neoadjuvant treatment with trastuzumab and chemotherapy.

Ado-trastuzumab emtansine (T-DM1; Kadcyla) has been approved by the FDA for use as an adjuvant treatment option for patients with HER2-positive early breast cancer who have residual invasive disease following neoadjuvant treatment with trastuzumab (Herceptin) and chemotherapy.1

According to findings from the phase III KATHERINE study, which the approval was based on, risk of invasive disease recurrence or death was reduced by 50% with T-DM1 compared to trastuzumab in this setting (HR, 0.50; 95% CI, 0.39-0.64;P<.0001). In addition, the 3-year invasive disease-free survival (iDFS) rate was 88.3% versus 77.0% with T-DM1 versus trastuzumab, respectively. This led to an absolute improvement in iDFS of 11.3%.

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 FDA reviewed and approved the application 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.

"This approval is a significant treatment advance for HER2-positive early breast cancer. By working closely with the FDA and participating in the Real-Time Oncology Review pilot program, we are able to make Kadcyla available for people with residual invasive disease after neoadjuvant therapy much sooner than anticipated," said Sandra Horning, MD, chief medical officer and head of Global Product Development, Genentech (Roche), the developer of T-DM1. "With every step forward in reducing the risk of disease recurrence, we come closer to the goal of helping each person with early breast cancer have the greatest opportunity for cure."

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 majority of adverse events were grad 1/2—milder symptoms,” said Geyer.

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%).

In a discussion session following his data presentation, Geyer addressed a question on whether trastuzumab alone is the current standard for this high-risk patient population, or whether it is trastuzumab plus pertuzumab.

“That would be variable globally. Pertuzumab is becoming used more frequently. If you’ve used the 2 antibodies preoperatively, they tend to be carried postoperatively. But [given] the fact that [T-DM1] has a 50% reduction in hazard versus trastuzumab, [it] is just very unlikely that pertuzumab could have that much benefit in this patient population,” explained Geyer.

T-DM1 is currently 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.


  1. FDA Approves Genentech's Kadcyla for Adjuvant Treatment of People With HER2-Positive Early Breast Cancer With Residual Invasive Disease After Neoadjuvant Treatment. Genentech. Published April 3, 2019. Accessed April 3, 2019.
  2. Geyer Jr CE, Huang C-S, Mano MS, et al. Phase III Study of Trastuzumab Emtansine(T-DM1) vs Trastuzumab as Adjuvant Therapy in Patients with HER2-Positive Early Breast Cancer with Residual Invasive Disease after Neoadjuvant Chemotherapy and HER2-Targeted Therapy Including Trastuzumab: Primary Results from KATHERINE (NSABP B-50-I, GBG 77 and Roche BO27938). Presented at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract GS1-10.
  3. von Minckwitz G, Huang C-S, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer [published online December 5, 2018].New Engl J Med. doi: 10.1056/NEJMoa1814017.