Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial

BACKGROUND: HER2-targeted treatments have improved outcomes in patients with HER2-positive breast cancer in the neoadjuvant, adjuvant, and metastatic settings; however, some patients remain at risk of relapse or death for many years after treatment of early-stage disease. Therefore, new strategies are needed. We did a phase 3 trial to assess a neoadjuvant regimen for HER2-positive breast cancer that replaces traditional systemic chemotherapy with targeted treatment. METHODS: ; carboplatin area under the concentration-time curve 6 mg/mL × min; trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance doses) plus pertuzumab same dosing as in the other group). All treatments were administered intravenously. The primary objective was to compare the number of patients who achieved a pathological complete response (ypT0/is, ypN0), between groups in the intention-to-treat population (two-sided assessment), based on local evaluation of tumour samples taken at breast cancer surgery done between 14 days and 6 weeks after completion of neoadjuvant therapy. Safety was analysed in patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02131064, and follow-up of the adjuvant phase is ongoing. FINDINGS: Between June 25, 2014, and June 15, 2015, we randomly assigned 444 patients to neoadjuvant treatment with trastuzumab emtansine plus pertuzumab (n=223) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (n=221). A pathological complete response was achieved by 99 (44·4%) of 223 patients in the trastuzumab emtansine plus pertuzumab group and 123 (55·7%) of 221 patients in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group (absolute difference -11·3 percentage points, 95% CI -20·5 to -2·0; p=0·016). During neoadjuvant treatment, compared with patients receiving docetaxel, carboplatin, and trastuzumab plus pertuzumab, fewer patients receiving trastuzumab emtansine plus pertuzumab had a grade 3-4 adverse event (29 13% of 223 vs 141 64% of 219) or a serious adverse event (11 5% of 223 vs 63 29% of 219). The most common grade 3-4 adverse events in the trastuzumab emtansine plus pertuzumab group were decreased platelet count (three 1% of 223 patients vs 11 5% of 219 with docetaxel, carboplatin, and trastuzumab plus pertuzumab), fatigue (three 1% vs seven 3%), alanine aminotransferase increase (three 1% vs four 2%), and hypokalaemia (three 1% vs five 2%). The most common grade 3-4 adverse events in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group were neutropenia (55 25% of 219 vs one <1% of 223 with trastuzumab emtansine plus pertuzumab), diarrhoea (33 15% vs 2 <1%), and febrile neutropenia (33 15% vs 0). No deaths were reported during neoadjuvant treatment. INTERPRETATION: Traditional neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade (docetaxel, carboplatin, and trastuzumab plus pertuzumab) resulted in significantly more patients achieving a pathological complete response than HER2-targeted chemotherapy plus HER2-targeted blockade (trastuzumab emtansine plus pertuzumab); however, numerically more grade 3-4 and serious adverse events occurred in the chemotherapy plus trastuzumab and pertuzumab group. Further efforts to improve the efficacy of chemotherapy without imparting more toxicity are warranted. FUNDING: F Hoffmann-La Roche and Genentech.