In the phase III KATHERINE trial reported in The New England Journal of Medicine,¹Gunter von Minckwitz, MD, of the German Breast Group, Neu-Isenburg, and colleagues found that adjuvant treatment with the antibody-drug conjugate trastuzumab emtansine (T-DM1) improved invasive disease–free survival vs standard trastuzumab in patients with early HER2-positive breast cancer with residual disease after neoadjuvant therapy containing a taxane and trastuzumab.

Study Details

In the open-label trial, 1,486 patients from 273 sites in 28 countries were randomly assigned between April 2013 and December 2015 to receive adjuvant T-DM1 at 3.6 mg/kg (n = 743) or standard trastuzumab at 6 mg/kg (n = 743) every 3 weeks for 14 cycles. Patients had to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane, with or without an anthracycline, and standard trastuzumab. Patients had to have completed at least 6 cycles (16 weeks) of a conventional neoadjuvant chemotherapy regimen containing a minimum of 9 weeks of taxane-based therapy and 9 weeks of standard trastuzumab therapy. Randomization was stratified by clinical stage

The risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant [T-DM1] than with standard trastuzumab alone.

— Gunter von Minckwitz, MD

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at presentation, hormone receptor status, preoperative HER2-directed therapy (ie, trastuzumab alone vs trastuzumab plus an additional HER2-directed agent), and pathologic nodal status after neoadjuvant therapy. Patients who discontinued T-DM1 during the study due to toxicity were permitted to complete 14 cycles of treatment with standard trastuzumab at the investigator’s discretion. The primary endpoint was invasive disease–free survival—defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause—in the intent-to-treat population.

For the T-DM1 vs standard trastuzumab groups, the median age of patients was 49 years in both; 74% vs 72% were white; 25% vs 26% had inoperable disease as clinical stage at presentation (tumor stage T4, nodal stage Nx, and metastasis stage M0 or tumor stage Tx, nodal stage N2 or N3, and metastasis stage M0); 72% vs 73% were estrogen receptor–positive or progesterone receptor–positive or both; 78% vs 76% had received an anthracycline in neoadjuvant treatment; and 81% vs 80% had received trastuzumab alone as HER2-targeted neoadjuvant therapy.

Invasive Disease–Free Survival

At a prespecified interim analysis, the early reporting efficacy boundary was crossed, triggering full trial analysis. The median follow-up was 40 months. Invasive disease or death had occurred in 12.2% of the T-DM1 group vs 22.2% of the trastuzumab group. At 3 years, invasive disease–free survival was 88.3% vs 77.0% (hazard ratio [HR] = 0.50, P < .001). Distant recurrence as the first invasive-disease event occurred in 10.5% of the T-DM1 group vs 15.9% of of the trastuzumab group (HR = 0.60, 95% confidence interval [CI] = 0.45–0.79). A subgroup analysis showed a consistent benefit of T-DM1 among stratification and other subgroups, including according to hormone receptor–positive (HR = 0.48, 95% CI = 0.35–0.67) or hormone receptor–negative disease (HR = 0.50, 95% CI = 0.33–0.74), positive (HR = 0.52, 95% CI = 0.38–0.71) or negative (HR = 0.44, 95% CI = 0.28–0.68) pathologic nodal status after neoadjuvant therapy, and receipt of neoadjuvant trastuzumab alone (HR = 0.49, 95% CI = 0.37–0.65) or with other HER2-directed agents (HR = 0.54, 95% CI = 0.27–1.06).

Death occurred in 42 patients in the T-DM1 group and in 56 patients in the standard trastuzumab group. The overall survival analysis did not cross the early reporting boundary (HR = 0.70, 95% CI = 0.47–1.05).

Among 133 patients who discontinued T-DM1 early, 71 switched to standard trastuzumab. A total of 63 completed 14 cycles of HER2-targeted treatment.

Adverse Events

Grade ≥ 3 adverse events occurred in 25.7% of patients in the T-DM1 group vs 15.4% of the standard trastuzumab group, with the most common adverse events in the T-DM1 group being decreased platelet count (5.7% vs 0.3% in the trastuzumab group) and hypertension (2.0% vs 1.2%). Hemorrhage of grade ≥ 3 occurred in 0.4% vs 0.3% of patients. Adjudicated cardiac events occurred in one patient treated with T-DM1 and four patients treated with standard trastuzumab. Peripheral sensory neuropathy of any grade occurred in 18.6% vs 6.9% of patients. Pneumonitis of any grade occurred in 2.6% vs 0.8%. Any-grade elevations of alanine transaminase (ALT; 23.1% vs 5.7%) and aspartate transaminase (AST; 28.4% vs 5.6%) were more common in the T-DM1 group.

Serious adverse events occurred in 12.7% vs 8.1% of patients. Adverse events led to discontinuation of the study drug in 18.0% vs 2.1% of patients, with the most common causes in the T-DM1 group being decreased platelet count (4.2%), elevated bilirubin (2.6%), elevated AST (1.6%), elevated ALT (1.5%), peripheral sensory neuropathy (1.5%), and decreased ejection fraction (1.2%). A patient in the T-DM1 group with decreased platelet count died of an intracranial hemorrhage after a fall.

The investigators concluded: “[I]n this randomized, phase III trial, among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy with a standard trastuzumab-containing regimen, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant [T-DM1] than with standard trastuzumab alone. The homogeneity of benefit was seen across all subgroups.” ■

DISCLOSURE: The study was funded by F. Hoffmann–La Roche/Genentech. Dr. von Minckwitz has received institutional research funding from AbbVie, Vifor Pharma, Pfizer, Amgen, Roche, Celgene, AstraZeneca, Myriad Genetics, and AbbVie; honoraria for consulting/advisory from Amgen and Roche; and has stock and other ownership interests in Cara GmbH.

REFERENCE

1. von Minckwitz G, Huang CS, Mano MS, et al: Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 380:617-628, 2019.