European Regulators Approve Adjuvant T-DM1 for Treatment of Patients With HER2+ Breast Cancer

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%.

&ldquo;Optimal treatment is vital for every patient with early-stage breast cancer, a setting where cures are possible,&rdquo; 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. &ldquo;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 &ge;6 cycles of chemotherapy containing a taxane (with or without anthracycline) and &ge;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 &ge;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 &ge;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 &ge;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.

References

1. European Commission approves Roche&rsquo;s Kadcyla for the adjuvant treatment of people with HER2-positive early breast cancer with residual invasive disease after neoadjuvant treatment [news release]. Roche. Published December 19, 2019. https://bit.ly/36P5TqA. Accessed December 19, 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. New Engl J Med. 2019;380:617-628. doi: 10.1056/NEJMoa1814017.