ABSTRACT: Standard therapy for platinum-resistant ovarian cancer (OC) is single-agent chemotherapy. The most active single agents are pegylated liposomal doxorubicin, paclitaxel, and topotecan. Use of these single agents has limited benefit, and their use in combination increases toxicity without improving efficacy. Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor, inhibiting development of new blood vessels and cancer growth. This agent has shown activity in OC both as monotherapy and when combined with chemotherapy.
AURELIA (Avastin Use in Platinum-Resistant Epithelial OC) is an open-label randomized phase III trial designed to evaluate the efficacy and safety of the combination of bevacizumab and chemotherapy in patients with platinum-resistant OC. Eligible participants had measurable/assessable OC that had progressed within 6 months after completing platinum-based therapy. Patients were excluded who had refractory disease or had received more than 2 prior anticancer regimens, as were those with a history of bowel obstruction related to the underlying disease. The single-agent chemotherapy selected by the investigators was pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan. Subjects were randomly assigned to receive the selected single-agent chemotherapy alone (CT, n = 182) or bevacizumab plus CT (BEV-CT, n = 179), 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks. This regimen was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Patients receiving CT could cross over to single-agent bevacizumab if there was clear evidence of progression. The primary study end point was progression-free survival (PFS) according to RECIST (Response Evaluation Criteria in Solid Tumors). Secondary end points included objective response rate (ORR) by RECIST, overall survival (OS), and safety, as well as patient-reported tolerability and quality of life.
Addition of bevacizumab significantly improved PFS; median PFS increased from 3.4 months with CT alone to 6.7 months with BEV-CT; the hazard ratio was 0.48, with a 95% confidence interval of 0.38 to 0.60; unstratified log-rank test, P < 0.001. RECIST ORR was 11.8% with CT and 27.3% with BEV-CT (P = 0.001). Median OS increased from 13.3 months with CT to 16.6 months with BEV-CT, but the difference was not statistically significant (hazard ratio, 0.85; 95% confidence interval, 0.66–1.08; P < 0.174). Addition of bevacizumab increased the incidence of grade ≥2 hypertension and proteinuria. Grade ≥2 gastrointestinal perforation occurred in 2.2% of patients receiving BEV-CT and none of those receiving CT alone.
This open-label study is the first randomized trial showing that adding bevacizumab to chemotherapy significantly improves PFS and ORR in patients with platinum-resistant OC. No significant improvement in OS was observed. The safety profile with BEV-CT was acceptable and consistent with that reported in previous studies.
Group d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO) and Université Paris Descartes, Assistance Publique–Hôpitaux de Paris, Paris, France (E.P.-L.); Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) and Klinik für Gynäkologie und Geburtshilfe, Kiel, Germany (F.H.); GINECO and Centre Alexis Vautrin, Vandoeuvre-les-Nancy, France (B.W.); AGO and Coordinating Center for Clinical Trials, Marburg, Germany (A.R.); Grupo Español de Investigación en Cáncer de Ovario (GEICO) and Instituto Valenciano de Oncologia, Valencia, Spain (A.P.); Nordic Society of Gynaecological Oncology (NSGO) and Norwegian Radium Hospital, Oslo, Norway (G.K.); Multicenter Italian Trials in Ovarian Cancer and Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy (R.S.); Belgian Gynaecological Oncology Group and University Hospital Leuven, Leuven, Belgium (I.V.); Dutch Gynecological Oncology Group and University Medical Center Utrecht, Utrecht, the Netherlands (P.W.); Hellenic Cooperative Oncology Group and University of Athens, Athens, Greece (A.B.); GINECO and Instituto Português de Oncologia do Porto, Porto, Portugal (D.P.); AGO and University of Duisburg-Essen, Essen, Germany (P.W.); GEICO and Vall d’Hebron University Hospital, Barcelona, Spain (A.O.); NSGO and Rigshospitalet, Copenhagen, Denmark (M.R.M.); GINECO and Centre Antoine-Lacassagne, Nice (P.F.); F. Hoffmann-La Roche, Basel, Switzerland (D.B.); and GINECO and Centre Léon Bérard, Lyon, France (I.R.-C.)