Elsevier

The Lancet Oncology

Volume 22, Issue 2, February 2021, Pages 267-276
The Lancet Oncology

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

https://doi.org/10.1016/S1470-2045(20)30637-9Get rights and content

Summary

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.

Introduction

The addition of bevacizumab to chemotherapy is one of the most recent advances in treatment of advanced ovarian cancer. When this study was designed in 2012, bevacizumab was known to improve progression-free survival not only in the first-line setting, concomitantly with platinum-based chemotherapy and then as maintenance,1, 2 but also in recurrent disease.3, 4 Regulatory approval of bevacizumab in Europe for patients with recurrent advanced ovarian cancer at least 6 months after platinum-based chemotherapy stemmed from the OCEANS trial,3 in which a significant progression-free survival benefit was observed when bevacizumab was added to carboplatin and gemcitabine in patients not previously treated with bevacizumab. However, evidence in patients with colorectal cancer suggested that continuing anti-angiogenic therapy beyond progression could be efficacious.5 This trial aimed to test if the addition of bevacizumab to chemotherapy, at the first platinum-sensitive recurrence of ovarian cancer, prolonged progression-free survival of patients who had already received bevacizumab during first-line treatment.

Section snippets

Study design and participants

MITO16b/MANGO–OV2/ENGOT–ov17 is an academic, multicentre, open-label, randomised phase 3 trial of carboplatin-based doublet plus or minus bevacizumab for patients with recurrent advanced ovarian cancer. The trial was sponsored by Istituto Nazionale per lo Studio e la Cura dei Tumori–IRCCS Fondazione Pascale (Naples, Italy) and done within the European Network for Gynaecological Oncological Trial (ENGOT) collaboration in Italy (Multicenter Italian Trials in Ovarian cancer and gynecologic

Results

Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited. 203 patients (50%) were randomly assigned to receive either a carboplatin-based doublet plus bevacizumab (bevacizumab group) and 203 (50%) were randomly assigned to receive a carboplatin-based doublet alone (standard chemotherapy group). One patient in the bevacizumab group was subsequently found to be ineligible at histology revision, because of a colon cancer (figure 1).

Baseline characteristics are shown in table 1. 130

Discussion

Results from this study show that adding bevacizumab to a platinum-based doublet is safe and improves progression-free survival in patients with platinum-sensitive recurrent ovarian cancer already treated with bevacizumab during first-line therapy.

To date, two randomised controlled trials have investigated bevacizumab plus platinum-based regimens in patients with platinum-sensitive recurrence of ovarian cancer. In the OCEANS study,3 484 patients not previously treated with bevacizumab were

Data sharing

Data for this study will be shared with publication on reasonable and motivated request to the Principal Investigator of the study ([email protected]). The following individual patient data will be available for sharing: baseline characteristics of patients, treatment data, safety data, and follow-up data. There will be no time limit for data sharing.

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For a full list of the MITO16b/MANGO–OV2/ENGOT–ov17 Investigators, see appendix (pp 9–13)

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