RESUMEN
BACKGROUND: BEVZ92 is a proposed biosimilar to bevacizumab. The two molecules have similar physicochemical and functional properties in in-vitro and preclinical studies. In this clinical study, we compared the pharmacokinetic profile, efficacy, safety, and immunogenicity of BEVZ92 with reference bevacizumab as a first-line treatment in patients with metastatic colorectal cancer. METHODS: We did a randomised, open-label trial at 15 centres in Argentina, Brazil, India, Spain, and Ukraine. Eligible patients were aged 18 years or older, had metastatic colorectal cancer with at least one measurable non-irradiated lesion for which first-line chemotherapy was indicated and Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, had not received previous treatment for advanced disease, and whose bone marrow, hepatic, renal, and coagulation markers were all within normal ranges. Patients were randomly assigned (1:1) to either BEVZ92 or reference bevacizumab (5 mg/kg on day 1 of each cycle every 2 weeks) in combination with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or fluorouracil, leucovorin, and irinotecan (FOLFIRI). Randomisation was done via a web service based on a stochastic minimisation algorithm and was stratified by chemotherapy regimen (FOLFOX vs FOLFIRI), previous adjuvant therapy (yes vs no), ECOG performance status (0-1 vs 2), and study site. The primary endpoint was the area under the concentration-versus-time curve after a single infusion (AUC0-336h) and at steady state (AUCss)-ie, at cycle 7-in the assessable population, which comprised all treated patients for whom serum concentration measurements were available during the first seven cycles. Bioequivalence was established if the 90% CIs for the ratio of BEVZ92 to reference bevacizumab of the geometric means for AUC0-336h and AUCss were within the acceptance interval of 80-125%. Secondary endpoints included objective response, clinical benefit, and progression-free survival in the intention-to-treat population and immunogenicity and safety profiles in all treated patients. This trial is registered with ClinicalTrials.gov, number NCT02069704, and is closed to new participants, with follow-up completed. FINDINGS: 142 patients were randomly assigned, 71 to the BEVZ92 group and 71 to the reference bevacizumab group. Two participants assigned to BEVZ92 did not receive treatment (one withdrew consent, the other had a serious intestinal obstruction before starting treatment); therefore, the treated population comprised 69 patients in the BEVZ92 group and 71 in the reference bevacizumab group. The geometric mean ratio of AUC0-336h in the BEVZ92 versus the control group was 99·4% (90% CI 90·5-109·0) and of AUCss was 100·0% (90·2-112·0). Objective response (35 [49%] of 71 vs 40 [56%] of 71), clinical benefit (62 [87%] vs 65 [92%]), and progression-free survival (median 10·8 months [95% CI 7·4-11·5] vs 11·1 months [95% CI 8·0-12·8]) were similar in the BEVZ92 and reference bevacizumab groups. No relevant differences were noted between the safety profiles of the two study treatments. Neutropenia was the most common grade 3 or 4 adverse event reported in the BEVZ92 (14 [20%] of 69 patients) and reference bevacizumab (19 [27%] of 71 patients) groups. Serious adverse events occurred in 19 (28%) patients in the BEVZ92 group and 21 (30%) in the reference bevacizumab group. Two patients died because of bevacizumab-related serious adverse events: a sudden death in the BEVZ92 group and a serious large intestinal perforation in the reference bevacizumab group. The occurrence of anti-drug antibodies was low and similar in both treatment groups (two patients in the BEVZ92 group and one in the reference bevacizumab group). INTERPRETATION: Our results suggest that BEVZ92 and reference bevacizumab are pharmacokinetically bioequivalent and have no appreciable differences in efficacy, immunogenicity, and safety profiles as first-line treatment in combination with FOLFOX or FOLFIRI in patients with metastatic colorectal cancer. FUNDING: mAbxience Research SL.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Biosimilares Farmacéuticos/uso terapéutico , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Anciano , Anticuerpos/sangre , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/inmunología , Área Bajo la Curva , Bevacizumab/efectos adversos , Bevacizumab/inmunología , Bevacizumab/farmacocinética , Biosimilares Farmacéuticos/efectos adversos , Biosimilares Farmacéuticos/farmacocinética , Camptotecina/uso terapéutico , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/uso terapéutico , Humanos , Análisis de Intención de Tratar , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Compuestos Organoplatinos/uso terapéutico , Supervivencia sin Progresión , Equivalencia TerapéuticaRESUMEN
Extrapulmonary poorly differentiated neuroendocrine carcinoma (PDNEC) is a rare and highly aggressive neoplasm for which the optimal chemotherapy remains unclear. The objective of this study was to evaluate the outcomes of patients with PDNEC treated with cisplatin and irinotecan (IP) and perform a review of the literature. From 2008 to 2012, patients with advanced PDNEC (Ki67≥20%) who received the IP combination were selected for analysis. Radiologic responses were determined through Response Evaluation Criteria In Solid Tumors criteria. Twenty-eight patients were included. The median age at diagnosis was 57 years and the most common presentation was pancreatic PDNEC. Twenty-five patients (89%) received chemotherapy with cisplatin and irinotecan and three received carboplatin and irinotecan. Forty-six percent of the patients achieved objective response and the median time to tumor progression was 3.7 months. The median overall survival was 11.7 months. Thirteen patients (46%) had treatment interruptions or dose reductions due to grade 3/4 toxicity. This retrospective cohort of advanced extrapulmonary PDNEC patients suggests that the IP combination is feasible and resulted in similar response rate and median survival to other treatments previously reported.