PracticeUpdate Oncology February 2019

EDITOR’S PICKS 10

Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer The New England Journal of Medicine Take-home message • This phase III, open-label trial evaluated 1486 patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 (n=743) or trastuzumab (n=743) for 14 cycles. • The risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone. Jeffrey Wiisanen MD

COMMENT By Lee S. Schwartzberg MD, FACP

T he consequences of HER2-positive breast cancer patients receiving neoadjuvant chemotherapy and anti-HER2 therapy without achieving a pathologic complete response (pCR) are potentially serious: a significant risk of developing recurrent disease over the next 5 years despite receiving adjuvant trastuzumab +/− pertuzumab. In the KATHERINE trial, patients were randomized to receive the antibody–drug conjugate T-DM1 or trastuzumab for close to 1 year of therapy after less than a pCR to neoadjuvant treatment. Many of the patients in this trial had locally advanced, “nonoperable” breast cancer, and about one-fifth received chemotherapy with both trastuzumab and pertuzumab as neoadjuvant treatment. The results were striking, with a 50% improvement in DFS and a 40% reduction in distant recurrence rate. At 3 years, the absolute invasive DFS was 88.3% for T-DM1 post surgery compared with 77.0% for trastuzumab. All subgroups benefited from this approach, including those with little residual tumor in the breast, those with node-negative disease at surgery, and those with hormone receptor-positive disease. These impressive results are practice-changing, with the large improvement in outcome balanced by little in the way of increased toxicity for patients except for decreases in platelet count, and slight increases in grade 3 hypertension and sensory neuropathy. Notably, compared with the commonly used adjuvant treatment of trastuzumab and pertuzumab in this setting, the substitution of T-DM1 should be comparably or less expensive. Therefore, this is one of those rare situations where tangible improvements in patient outcome are not associated with a rise in cost for the benefit. A win all around!

Abstract BACKGROUND Patients who have residual inva- sive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastu- zumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhib- itor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy. METHODS We conducted a phase 3, open-label trial involving patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned

interval, 0.39 to 0.64; P<0.001). Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group. The safety data were consistent with the known safety profile of T-DM1, with more adverse events associated with T-DM1 than with trastuzumab alone. CONCLUSIONS Among patients with HER2-pos- itive early breast cancer who had residual invasive disease after completion of neoadju- vant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adju- vant T-DM1 than with trastuzumab alone. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med 2018 Dec 05;[EPub Ahead of Print], G von Minck-

to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point 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). RESULTS At the interim analysis, among 1486 ran- domly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive dis- ease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastu- zumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease-free sur- vival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence

witz, CS Huang, MS Mano, et al. www.practiceupdate.com/c/77143

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