Hurvitz SA, et al. - Researchers undertook a phase 3 trial to evaluate neoadjuvant trastuzumab, pertuzumab, and chemotherapy vs trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE). In this trial, significantly more patients achieved a pathological complete response with traditional neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade (docetaxel, carboplatin, and trastuzumab plus pertuzumab) in comparison to HER2-targeted chemotherapy plus HER2-targeted blockade (trastuzumab emtansine plus pertuzumab). However, there appeared numerically more grade 3–4 and serious adverse events in the chemotherapy plus trastuzumab and pertuzumab group.

Methods

• A randomised, open-label phase 3 KRISTINE trial was undertaken in 68 Translational Research In Oncology centres (hospitals and specialty cancer centres in Asia, Europe, USA, and Canada).
• For this trial, eligible participants were aged 18 years or older with centrally confirmed HER2-positive stage II–III operable breast cancer (>2 cm tumour size), an Eastern Cooperative Oncology Group performance status of 0–1, and a baseline left ventricular ejection fraction of at least 55% (by echocardiogram or multiple-gated acquisition scan).
• Participants (1:1) were randomly assigned to receive either trastuzumab emtansine plus pertuzumab or docetaxel, carboplatin, and trastuzumab plus pertuzumab.
• Randomisation was performed via an interactive response system under a permuted block randomisation scheme (block size of four), stratified by hormone receptor status, stage at diagnosis, and geographical location.
• Patients were administered six cycles (every 3 weeks) of neoadjuvant trastuzumab emtansine plus pertuzumab (trastuzumab emtansine 3·6 mg/kg; pertuzumab 840 mg loading dose, 420 mg maintenance doses) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (docetaxel 75 mg/m²; 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]).
• Administration of all treatments was performed intravenously.
• Groups in the intention-to-treat population (two-sided assessment) were primarily compared regarding the number of patients who achieved a pathological complete response (ypT0/is, ypN0), based on local evaluation of tumour samples taken at breast cancer surgery done between 14 days and 6 weeks after completion of neoadjuvant therapy.
• In patients who received at least one dose of study medication, they analyzed safety.

Results

• Researchers randomly assigned 444 patients to neoadjuvant treatment with trastuzumab emtansine plus pertuzumab (n=223) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (n=221) from June 25, 2014, to June 15, 2015.
• Ninety-nine (44·4%) patients in the trastuzumab emtansine plus pertuzumab group and 123 (55·7%) 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) achieved a pathological complete response.
• Compared with patients receiving docetaxel, carboplatin, and trastuzumab plus pertuzumab, fewer patients receiving trastuzumab emtansine plus pertuzumab reported a grade 3–4 adverse event (29 [13%] of 223 vs141 [64%] of 219) or a serious adverse event (11 [5%] of 223 vs 63 [29%] of 219) during neoadjuvant treatment.
• In the trastuzumab emtansine plus pertuzumab group, the most common grade 3–4 adverse events 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%]).
• In the docetaxel, carboplatin, and trastuzumab plus pertuzumab group, the most common grade 3–4 adverse events 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).
• They recognized no deaths during neoadjuvant treatment.