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China’s State Administration of Drug Administration has approved ado-trastuzumab emtansine for the adjuvant treatment of patients with HER2-positive early breast cancer who have residual disease following a neoadjuvant trastuzumab-based regimen.
Zhimin Shao, MD
China’s State Administration of Drug Administration has approved ado-trastuzumab emtansine (T-DM1; Kadcyla), for the adjuvant treatment of patients with HER2-positive early breast cancer who have residual disease following a neoadjuvant trastuzumab (Herceptin)-based regimen, according to an announcement by Roche China, the developer of the antibody-drug conjugate.1
The approval is based on findings from the phase III KATHERINE study, in which T-DM1, known by the trade name Hersele in China, led to a 50% reduction in the risk of invasive disease recurrence or death versus trastuzumab in this setting (HR, 0.50; 95% CI, 0.39-0.64; P <.001).2 Additionally, the 3-year invasive disease-free survival (iDFS) rate with T-DM1 was 88.3% compared with 77.0% with trastuzumab, leading to an absolute improvement of 11.3%.
“The KATHERINE study adds new milestones to the optimal treatment of HER2-positive breast cancer patients, and opens a new path for clinical choice of patients with poor outcomes after receiving neoadjuvant anti-HER2 targeted therapy,” Zhimin Shao, MD, director of the Institute of Oncology, Fudan University, director of the Breast Cancer Institute, director of Department of General Surgery, and director of Breast Surgery at the Affiliated Tumor Hospital of Fudan University, stated in a press release.
In the open-label KATHERINE trial, 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 were enrolled. Neoadjuvant chemotherapy had to consist of ≥6 cycles of chemotherapy containing a taxane (with or without anthracycline) and ≥9 weeks of trastuzumab.
Patients were randomized within 12 weeks of surgery to either T-DM1 at 3.6 mg/kg intravenously (IV; n = 743) or trastuzumab at 6 mg/kg IV (n = 743). Both agents were administered every 3 weeks for 14 cycles.
Patient characteristics were well balanced between the 2 arms. Across the entire population, the median age was 49 years, three-fourths of patients were white, and 75% of patients had operable breast cancer at presentation. Three-fourths of patients in both arms were estrogen receptor—positive, progesterone receptor–positive, or both.
Over 76% 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 approximately 18%, and trastuzumab plus other HER2-targeted therapy—including neratinib (Nerlynx), dacomitinib (Vizimpro), afatinib (Gilotrif), and lapatinib (Tykerb) for 1%.
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 18.0% 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) and hypertension (2.0% vs 1.2%, respectively).
Subgroup analyses of the KATHERINE study were presented at the 2019 San Antonio Breast Cancer Symposium.3 Results showed that iDFS benefit was observed with T-DM1 regardless of the type of neoadjuvant chemotherapy (NACT) that was used, and was also seen across several high-risk patient populations.
In a comparison of patients who received anthracycline (AC)-based NACT versus those who received non-AC­—based NACT, the HR for iDFS was 0.51 (95% CI, 0.38-0.67) and 0.43 (95% CI, 0.22-0.82) with T-DM1 and trastuzumab, respectively. In the AC arm, the 3-year iDFS rates were 87.4% with T-DM1 versus 75.7% with trastuzumab. In the non-AC arm, the 3-year iDFS rates were 91.7% versus 81.4%, respectively.
Moreover, researchers identified 4 mutually exclusive high-risk subgroups; while small subsets, there was an improvement in the 3-year iDFS rate with T-DM1 across all 4 subgroups.
Among 375 patients who were inoperable at presentation irrespective of hormone receptor and ypN status, the 3-year iDFS rates were 76% and 60.2% with T-DM1 and trastuzumab, respectively (HR, 0.54; 95% CI, 0.37-0.80). The corresponding rates were 76% and 69.5% (HR, 0.72; 95% CI, 0.35-1.50), respectively, among 110 patients who were operable at presentation with ypN-positive nodes and hormone receptor—negative disease.
In 335 patients who were operable at presentation with ypN-positive nodes and hormone receptor—positive disease, the 3-year iDFS rates were 91.4% and 77.2% with T-DM1 and trastuzumab, respectively (HR, 0.43; 95% CI, 0.25-0.75). The corresponding rates were 91.1% and 77.2% (HR, 0.43; 95% CI, 0.17-1.06), respectively, among 137 patients who were operable at presentation with ypN-negative nodes and hormone receptor–negative disease.
Outcomes were also assessed in 77 lower-risk patients with small tumors (cT1 cN0) at presentation—45 patients in the T-DM1 arm and 32 in the trastuzumab arm. Overall, patient characteristics were well balanced between the 2 arms. Results showed that there were 6 iDFS events in the trastuzumab group and none in the T-DM1 group.
In May 2019, the FDA approved ado-trastuzumab emtansine for use as an adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease following neoadjuvant trastuzumab and chemotherapy. T-DM1 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.
“The KATHERINE study confirms that intensive adjuvant therapy with [trastuzumab] has further reduced the risk of recurrence or death by 50% of patients,” Yongsheng Wang, MD, director of the KATHERINE study participating unit, director of the Breast Disease Center of Shandong Cancer Hospital, stated in the press release. “This is a revolutionary progress in the treatment of HER2-positive breast cancer, and will lead patients in clinical treatment.”