Elsevier

Gynecologic Oncology

Volume 139, Issue 1, October 2015, Pages 10-16
Gynecologic Oncology

Final overall survival and safety analysis of OCEANS, a phase 3 trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer

https://doi.org/10.1016/j.ygyno.2015.08.004Get rights and content

Highlights

  • Median follow-up for OS was 57.5 months in the updated analyses.

  • Results of the updated OS analyses were consistent with interim analyses.

  • Bevacizumab did not improve OS when added to GC therapy in this patient population.

Abstract

Objective

OCEANS is a randomized, placebo (PL)-controlled, phase 3 trial evaluating the efficacy and safety of bevacizumab combined with gemcitabine + carboplatin (GC) for patients with platinum-sensitive recurrent ovarian cancer (ROC). The study met its primary endpoint, demonstrating improved progression-free survival with GC + bevacizumab compared with GC + PL. Herein, we describe results of final overall survival (OS) and updated safety.

Methods

Patients with recurrent platinum-sensitive ROC (recurring ≥ 6 months after first-line platinum-based therapy) and measurable disease at baseline were randomized to receive GC + bevacizumab or GC + PL for 6–10 cycles; PL or bevacizumab was then continued until disease progression. In this updated analysis, a Cox proportional hazards model was used to compare OS between the 2 treatment arms.

Results

At the data cutoff date (July 19, 2013), 353 patients (72.9%) had died. Median follow-up for OS was 58.2 months in the experimental arm and 56.4 months in the control arm. Consistent with interim analyses, median OS was comparable between arms (GC + bevacizumab: 33.6 months; GC + PL: 32.9 months; hazard ratio = 0.95; log-rank p = 0.65), and was consistent across all examined patient subgroups. The frequency and severity of adverse events were consistent with previous analyses; no new safety concerns were identified.

Conclusions

Results from final OS analysis of the phase 3 OCEANS study showed no significant difference in OS for patients treated with GC + bevacizumab compared with GC + PL.

Introduction

Ovarian cancer, the fifth leading cause of cancer deaths among women, has the highest mortality rate among all gynecologic cancers [1]. Due to the biology of the disease and a lack of specific symptoms, the majority of cases are usually detected at an advanced stage [2]. While first-line therapy, which includes cytoreductive surgery and platinum- and taxane-based chemotherapy, usually elicits a good initial response, most patients eventually relapse [3], [4], [5]. Current treatment options for patients upon platinum-sensitive disease recurrence consist of re-treatment with a platinum doublet [5]. Almost all patients will subsequently go on to develop additional recurrences, requiring repeated courses of chemotherapy. Therefore, more effective treatments for recurrent ovarian cancer are needed.

Bevacizumab is currently approved in the United States for the treatment of a variety of solid tumors [6], and has been evaluated in ovarian cancer in both newly diagnosed and relapsed disease [7], [8], [9], [10]. The Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-angiogenic Therapy in Platinum-Sensitive Recurrent Disease (OCEANS) was initiated to study the addition of bevacizumab to gemcitabine and carboplatin (GC) combination treatment as a second-line therapy for patients with epithelial ovarian, primary peritoneal, or fallopian tube cancer [9]. The study met its primary endpoint, demonstrating that the addition of bevacizumab to GC conferred a significant improvement in progression-free survival (PFS) for patients compared with GC + placebo (PL) (median: 12.4 months for GC + bevacizumab vs. 8.4 months for GC + PL; hazard ratio [HR] = 0.484; 95% confidence interval [CI]: 0.388–0.605; log-rank p-value < 0.0001). Furthermore, GC + bevacizumab was associated with a higher objective response rate (78.5% vs. 57.4%, respectively; p < 0.001) and prolonged the duration of response (10.4 months vs. 7.4 months, respectively; HR = 0.534; 95% CI: 0.408–0.698) compared with GC + PL [9], [11]. Patients in the bevacizumab arm compared with those in the placebo arm experienced a higher incidence of grade ≥ 3 hypertension (17.4% vs. < 1%, respectively) and proteinuria (8.5% vs. < 1%, respectively), while the rate of neutropenia and febrile neutropenia was similar in both arms [9]. No gastrointestinal (GI) perforations occurred during the study treatment or safety assessment period, but 2 patients in the bevacizumab arm experienced GI perforations after discontinuation of study treatment [9].

The OCEANS study was not powered to detect a difference in overall survival (OS) between the arms, which was 1 of the secondary endpoints. At the time of the final PFS analysis, the interim OS analysis showed no difference between treatment groups (HR: 1.03; 95% CI: 0.79–1.33) [9]. The final OS analysis was pre-specified at 353 events, and these results are described herein.

Section snippets

Patients and study design

The patient eligibility criteria and study design for OCEANS (NCT00434642) have been previously described [9]. Briefly, all patients were required to have histologically confirmed recurrent ovarian cancer (i.e., epithelial ovarian, fallopian tube, or primary peritoneal carcinoma), disease progression after ≥ 6 months after completion of front-line platinum-based chemotherapy, and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. Patients were excluded if

Patient disposition and characteristics

Between April 2007 and January 2010, the OCEANS study enrolled a total of 484 patients with recurrent ovarian cancer (Fig. 1). As previously described, baseline patient and disease characteristics were similar between patients in each treatment group [9].

All patients had completed treatment by the data cutoff date of July 19, 2013. Patients in the GC + bevacizumab arm received a wider range of treatment cycles than those in the GC + PL arm (GC + bevacizumab: 1–88; GC + PL: 1–40), as well as a higher

Discussion

Results of the final OS analyses from OCEANS were consistent with those previously reported [9], [13]. The current analysis, performed following 353 deaths (72.9%), showed a median OS of 33.6 months for patients in the GC + bevacizumab arm compared with 32.9 months for those in the GC + PL arm. Notably, the median OS of 33.6 months in the experimental arm in the current study reflects a trend of increasing survival of patients with ovarian cancer concomitant with the development of novel treatment

Conflict of interest

A.H. and Y.V.W. are employees of Genentech, Inc. A.H. also has a patent pending with Genentech, Inc. S.V.B. has served on an advisory board for and received fees from Genentech, Inc.

Acknowledgment

Third-party medical writing support was provided by Ann Tang and assistance funded by Genentech, Inc. The study sponsor provided support for the conduct of the study and participated in the design of the study; in the collection, analysis, and interpretation of data; and in writing and reviewing the manuscript. All authors, including those employed by the sponsor, participated in the collection, analysis, and interpretation of data; participated in writing and reviewing the manuscript; had full

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