CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial

• Published in: The lancet oncology Vol. 18; no. 7; pp. 917 - 928
• Main Authors: Stebbing, Justin, Prof, Baranau, Yauheni, MD, Baryash, Valeriy, MD, Manikhas, Alexey, MD, Moiseyenko, Vladimir, Prof, Dzagnidze, Giorgi, MD, Zhavrid, Edvard, Prof, Boliukh, Dmytro, MD, Stroyakovskii, Daniil, MD, Pikiel, Joanna, MD, Eniu, Alexandru, MD, Komov, Dmitry, MD, Morar-Bolba, Gabriela, MD, Li, Rubi K, MD, Rusyn, Andriy, Prof, Lee, Sang Joon, PhD, Lee, Sung Young, MS, Esteva, Francisco J, Prof
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2017; Elsevier Limited
• Subjects: 5-Fluorouracil; Adenocarcinoma - chemistry; Adenocarcinoma - drug therapy; Adenocarcinoma - pathology; Adenocarcinoma - surgery; Adult; Aged; Anthracycline; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological products; Biosimilar Pharmaceuticals - administration & dosage; Biosimilar Pharmaceuticals - adverse effects; Biosimilar Pharmaceuticals - therapeutic use; Bone marrow; Breast; Breast cancer; Breast Neoplasms - chemistry; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Breast Neoplasms - surgery; Cancer therapies; Chemotherapy; Chemotherapy, Adjuvant; Clinical trials; Cyclophosphamide; Cyclophosphamide - administration & dosage; Docetaxel; Double-Blind Method; Double-blind studies; Epirubicin; Epirubicin - administration & dosage; ErbB-2 protein; Estrogens; FDA approval; Febrile Neutropenia - chemically induced; Female; Fluorouracil - administration & dosage; Heart; Hematology, Oncology and Palliative Medicine; Humans; Immunotherapy; Lactation; Mastectomy; Metastasis; Middle Aged; Monoclonal antibodies; Neoadjuvant Therapy; Neoplasm Staging; Neutropenia; Oncology; Pregnancy; Progesterone; Receptor, ErbB-2 - analysis; Renal function; Studies; Surgery; Targeted cancer therapy; Taxoids - administration & dosage; Trastuzumab; Trastuzumab - administration & dosage; Trastuzumab - adverse effects; Ventricle; United States > US
• ISSN: 1470-2045; 1474-5488
• DOI: 10.1016/S1470-2045(17)30434-5

Summary Background CT-P6 is a proposed biosimilar to reference trastuzumab. In this study, we aimed to establish equivalence of CT-P6 to reference trastuzumab in neoadjuvant treatment of HER2-positive early-stage breast cancer. Methods In this randomised, double-blind, active-controlled, phase 3 equivalence trial, we recruited women aged 18 years or older with stage I–IIIa operable HER2-positive breast cancer from 112 centres in 23 countries. Inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 0 or 1; a normal left ventricular ejection fraction of at least 55%; adequate bone marrow, hepatic, and renal function; at least one measureable lesion; and known oestrogen and progesterone receptor status. Exclusion criteria included bilateral breast cancer, previous breast cancer treatment, previous anthracycline treatment, and pregnancy or lactation. We randomly allocated patients 1:1 to receive neoadjuvant CT-P6 or reference trastuzumab intravenously (eight cycles, each lasting 3 weeks, for 24 weeks; 8 mg/kg on day 1 of cycle 1 and 6 mg/kg on day 1 of cycles 2–8) in conjunction with neoadjuvant docetaxel (75 mg/m2 on day 1 of cycles 1–4) and FEC (fluorouracil [500 mg/m2 ], epirubicin [75 mg/m2 ], and cyclophosphamide [500 mg/m2 ]; day 1 of cycles 5–8) therapy. We stratified randomisation by clinical stage, receptor status, and country and used permuted blocks. We did surgery within 3–6 weeks of the final neoadjuvant study drug dose, followed by an adjuvant treatment period of up to 1 year. We monitored long-term safety and efficacy for 3 years after the last patient was enrolled. Participants and investigators were masked to treatment until study completion. The primary efficacy endpoint, analysed in the per-protocol population, was pathological complete response, assessed via specimens obtained during surgery, analysed by masked central review of local histopathology reports. The equivalence margin was −0·15 to 0·15. This trial is registered with ClinicalTrials.gov , number NCT02162667 , and is ongoing, but no longer recruiting. Findings Between Aug 7, 2014, and May 6, 2016, we randomly allocated 549 patients (271 [49%] to CT-P6 vs 278 [51%] to reference trastuzumab). A similar proportion of patients achieved pathological complete response with CT-P6 (116 [46·8%; 95% CI 40·4–53·2] of 248 patients) and reference trastuzumab (129 [50·4%; 44·1–56·7] of 256 patients). The 95% CI of the estimated treatment outcome difference (−0·04% [95% CI −0·12 to 0·05]) was within the equivalence margin. 19 (7%) of 271 patients in the CT-P6 group reported serious treatment-emergent adverse events versus 22 (8%) of 278 in the reference trastuzumab group; frequent (occurring in more than one patient) serious adverse events were febrile neutropenia (four [1%] vs one [<1%]) and neutropenia (one [<1%] vs two [1%]). Grade 3 or worse treatment-related adverse events occurred in 17 (6%) of 271 patients in the CT-P6 group versus 23 (8%) of 278 in the reference trastuzumab group; the most frequently reported adverse event was neutropenia in ten (4%) versus 14 (5%). Interpretation CT-P6 showed equivalent efficacy to reference trastuzumab and adverse events were similar. Availability of trastuzumab biosimilars could increase access to this targeted therapy for HER2-positive early-stage cancer. Funding Celltrion Inc.