Long-term efficacy and safety of CT-P6 versus trastuzumab in patients with HER2-positive early breast cancer: final results from a randomized phase III trial.

PURPOSE: Equivalent efficacy was demonstrated for the biosimilar CT-P6 and trastuzumab following neoadjuvant therapy for patients with human epidermal growth factor receptor-2 (HER2)-positive early breast cancer. Following adjuvant treatment, efficacy and safety were comparable between treatments. We report updated safety and efficacy data after up to 3 years' follow-up. METHODS: Following neoadjuvant chemotherapy with CT-P6/trastuzumab, patients underwent surgery and continued receiving adjuvant CT-P6/trastuzumab. The primary endpoint (previously reported) was pathological complete response. Time-to-event analyses (disease-free survival [DFS], progression-free survival [PFS], and overall survival [OS]), study drug-related and cardiac adverse events, and immunogenicity were assessed during post-treatment follow-up. RESULTS: Most patients entered the follow-up period (CT-P6: 259 [95.6%]; trastuzumab: 269 [96.8%]). After a median follow-up of 38.7 (CT-P6) and 39.6 (trastuzumab) months, medians were not reached for time-to-event parameters; estimated hazard ratios (HRs) and 3-year survival rates were similar between groups. Estimated HRs (95% confidence intervals) for CT-P6 versus trastuzumab were 1.23 (0.78-1.93) for DFS, 1.31 (0.86-2.01) for PFS, and 1.10 (0.57-2.13) for OS (intention-to-treat population). Safety findings were comparable between groups for the overall study and follow-up period, including study drug-related cardiac disorders (CT-P6: 22 [8.1%] patients; trastuzumab: 24 [8.6%] patients [overall]) and decreases in left ventricular ejection fraction. Immunogenicity was similar between groups. CONCLUSION: The similarity of the time-to-event analyses between CT-P6 and trastuzumab supports the equivalence in terms of efficacy established for the primary endpoint. CT-P6 was well tolerated, with comparable safety and immunogenicity to trastuzumab. ClinicalTrials.gov: NCT02162667 (registered June 13, 2014).

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

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.

Clinical efficacy of plasmid encoding p62/SQSTM1 (Elenagen) in combination with gemcitabine in patients with platinum-resistant ovarian cancer: a randomized controlled trial.

Background: The purpose of this trial is to evaluate the safety and efficacy of ELENAGEN, a novel anticancer therapeutic DNA plasmid encoding p62/SQSTM1 protein, as an adjuvant to chemotherapy with gemcitabine (GEM) in patients with advanced platinum-resistant ovarian cancer. Methods: This open-label prospective randomized study with two arms. GEM (1000 mg/m2) on days 1 and 8 every 3 weeks was administered in both arms: in the Chemo arm (n = 20), GEM was the only treatment, and in the ELENAGEN arm (n = 20), GEM was supplemented with ELENAGEN (2.5 mg i.m. weekly). The primary endpoint was progression-free survival (PFS), and the secondary endpoint was safety. Antitumor activity was assessed by RECIST 1.1, and criteria safety was assessed according to NCI CTCAE version 5.0. Results: According to the cutoff data, the median follow-up was 13.8 months. There were no serious adverse events related to ELENAGEN treatment. The median PFS was 2.8 and 7.2 months in the Chemo and ELENAGEN arms, respectively (p Log-Rank = 0.03). Notably, at the time of cutoff, 9 patients (45%) in the ELENAGEN arm did not progress, with the longest PFS recorded thus far being 24 months. Subgroup analysis of patients in both arms demonstrated high efficacy of ELENAGEN in patients with worse prognostic factors: high pretreatment levels of CA125 and progression after platinum-free interval <3 months. Conclusions: The addition of ELENAGEN to gemcitabine is effective in patients with platinum-resistant ovarian cancer, including those with a worse prognosis. Clinical trial registration: https://www.clinicaltrials.gov/study/NCT05979298, identifier NCT05979298, 2023-08-07.

Six-Year Survival Outcomes for Patients with HER2-Positive Early Breast Cancer Treated with CT-P6 or Reference Trastuzumab: Observational Follow-Up Study of a Phase 3 Randomised Controlled Trial.

BACKGROUND: The Phase 3 CT-P6 3.2 study demonstrated equivalent efficacy and comparable safety between CT-P6 and reference trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive early breast cancer after up to 3 years' follow-up. OBJECTIVE: To investigate long-term survival with CT-P6 and reference trastuzumab. METHODS: In the CT-P6 3.2 study, patients with HER2-positive early breast cancer were randomised to neoadjuvant chemotherapy with CT-P6 or reference trastuzumab, surgery, and adjuvant CT-P6 or reference trastuzumab before a 3-year post-treatment follow-up. Patients who completed the study could enter a 3-year extension (CT-P6 4.2 study). Data were collected every 6 months to assess overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). RESULTS: Of 549 patients enrolled in the CT-P6 3.2 study, 216 (39.3%) patients continued in the CT-P6 4.2 study (CT-P6, 107; reference trastuzumab, 109) (intention-to-treat extension set). Median follow-up was 76.4 months for both groups. Medians were not reached for time-to-event parameters; estimated hazard ratios (95% confidence intervals) for CT-P6 versus reference trastuzumab were 0.59 (0.17-2.02) for OS, 1.07 (0.50-2.32) for DFS, and 1.08 (0.50-2.34) for PFS. Corresponding 6-year survival rates in the CT-P6 and reference trastuzumab groups, respectively, were 0.96 (0.90-0.99) and 0.94 (0.87-0.97), 0.87 (0.78-0.92) and 0.89 (0.81-0.94), and 0.87 (0.78-0.92) and 0.89 (0.82-0.94). CONCLUSIONS: Data from this extended follow-up of the CT-P6 3.2 study demonstrate the comparable long-term efficacy of CT-P6 and reference trastuzumab up to 6 years. EUDRACT NUMBER: 2019-003518-15 (retrospectively registered 10 March 2020).

Total pathological complete response versus breast pathological complete response in clinical trials of reference and biosimilar trastuzumab in the neoadjuvant treatment of breast cancer.

INTRODUCTION: Trastuzumab is a key drug in the neoadjuvant treatment of breast cancers that overexpress the human epidermal growth factor receptor 2 (HER2). Pathological complete response (pCR) is commonly used as an endpoint in neoadjuvant clinical trials of trastuzumab as evidence suggests it may be a surrogate for long-term survival. Several biosimilar candidates of originator or 'reference' trastuzumab are in development and have used pCR as a primary endpoint to assess therapeutic equivalence between treatments. The exact definition of pCR has varied across studies. Areas covered: Here we look at the clinical relevance of pCR and compare rates of total pCR (defined as ypT0/is ypN0) and breast pCR (defined as ypT0/is) in clinical trials of reference and biosimilar trastuzumab. Expert commentary: In order to evaluate the efficacy of neoadjuvant systemic therapies in a uniform way, standardization of trial endpoints is necessary. Future studies in HER2-positive breast cancer should include full assessment of the breast and lymph node basin before and after neoadjuvant systemic therapy, and the use of total pCR as the primary outcome.