Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial: The Lancet Oncology

S. Pignata, D. Lorusso, F. Joly, C. Gallo, N. Colombo, C. Sessa, A. Bamias, V. Salutari, F. Selle, S. Frezzini, U. De Giorgi, P. Pautier, A. Bologna, M. Orditura, C. Dubot, A. Gadducci, S. Mammoliti, I. Ray-Coquard, E. Zafarana, E. BredaL. Favier, A. Ardizzoia, S. Cinieri, R. Largillier, D. Sambataro, E. Guardiola, R. Lauria, C. Pisano, F. Raspagliesi, G. Scambia, G. Daniele, F. Perrone, MITO16b/MANGO-OV2/ENGOT-ov17 Investigators

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. Methods: In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB–IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0–2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin–carboplatin, or 15 mg/kg every 21 days combined with gemcitabine–carboplatin or paclitaxel–carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. Findings: Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4–9·3) in the standard chemotherapy group and 11·8 months (10·8–12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41–0·65; log-rank p<0·0001). Most common grade 3–4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related. Interpretation: Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice. Funding: Hoffmann–La Roche and Associazione Italiana per la Ricerca sul Cancro. © 2021 Elsevier Ltd
Original languageEnglish
Pages (from-to)267-276
Number of pages10
JournalLancet Oncol.
Volume22
Issue number2
DOIs
Publication statusPublished - 2021

Keywords

  • alanine aminotransferase
  • alkaline phosphatase
  • aspartate aminotransferase
  • bevacizumab
  • bilirubin
  • carboplatin
  • cholesterol
  • doxorubicin
  • gamma glutamyltransferase
  • gemcitabine
  • paclitaxel
  • platinum complex
  • antineoplastic agent
  • macrogol
  • abdominal pain
  • acne
  • adult
  • adult respiratory distress syndrome
  • aged
  • allergic reaction
  • anaphylaxis
  • anemia
  • anorexia
  • anus fistula
  • aphonia
  • area under the curve
  • arthralgia
  • Article
  • bilirubin blood level
  • cancer growth
  • cancer recurrence
  • cancer staging
  • catheter infection
  • cerebrovascular accident
  • cholesterol blood level
  • clinical outcome
  • clinical practice
  • colon fistula
  • colon obstruction
  • colon perforation
  • confusion
  • constipation
  • controlled study
  • dental caries
  • depression
  • device infection
  • diarrhea
  • doublet chemotherapy
  • drug dosage form comparison
  • drug response
  • drug safety
  • dysarthria
  • dyspnea
  • enzyme blood level
  • epistaxis
  • erythroderma
  • faintness
  • fatigue
  • febrile neutropenia
  • female
  • fever
  • follow up
  • fracture
  • functional status
  • gastrointestinal symptom
  • hand foot syndrome
  • headache
  • heart disease
  • heart failure
  • heart left ventricle ejection fraction
  • heart muscle ischemia
  • hemorrhoid
  • human
  • hyperglycemia
  • hyperkalemia
  • hypertension
  • hypokalemia
  • hyponatremia
  • hypotension
  • infection
  • intention to treat analysis
  • kidney colic
  • left ventricular systolic dysfunction
  • leukocyte count
  • leukocytosis
  • leukoencephalopathy
  • maculopapular rash
  • maintenance therapy
  • major clinical study
  • median survival time
  • mortality rate
  • mucosa inflammation
  • multicenter study
  • multiple cycle treatment
  • musculoskeletal disease
  • nausea
  • neutrophil count
  • open study
  • ovary cancer
  • overall survival
  • pain
  • pancreatitis
  • pelvic inflammatory disease
  • pericardial effusion
  • phase 3 clinical trial
  • platelet count
  • pleura effusion
  • priority journal
  • progression free survival
  • proteinuria
  • randomized controlled trial
  • rectum hemorrhage
  • respiratory tract disease
  • second cancer
  • seizure
  • sensory neuropathy
  • sepsis
  • side effect
  • skin disease
  • small intestine obstruction
  • small intestine perforation
  • stomach hemorrhage
  • thromboembolism
  • vasculitis
  • vertigo
  • vomiting
  • clinical trial
  • disease exacerbation
  • disease free survival
  • drug resistance
  • middle aged
  • ovary tumor
  • pathology
  • tumor recurrence
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols
  • Bevacizumab
  • Carboplatin
  • Disease Progression
  • Disease-Free Survival
  • Doxorubicin
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Middle Aged
  • Neoplasm Recurrence, Local
  • Ovarian Neoplasms
  • Paclitaxel
  • Polyethylene Glycols

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