Progression-free survival by local investigator versus independent central review: Comparative analysis of the AGO-OVAR16 Trial☆,☆☆
Introduction
Ovarian cancer is among the most common cancers in women, and has the highest mortality among all gynecologic cancers [1]. First-line treatment includes debulking surgery followed by platinum-taxane–based chemotherapy [2]. Although the initial response rate is high, most patients experience recurrence and eventually die from the disease [3]. Recent studies have demonstrated that addition of the angiogenesis inhibitor bevacizumab to the chemotherapy regimen can delay recurrence of advanced ovarian cancer [4], [5]. Pazopanib, an oral angiogenesis inhibitor targeting VEGF receptors, platelet-derived grown factor receptors, and c-kit, has demonstrated promising activity in ovarian cancer [6], [7]. The phase 3, randomized, placebo-controlled trial AGO-OVAR16 (OVAR16; NCT00866697) evaluated pazopanib monotherapy as maintenance therapy in patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (AEOC) whose disease had not progressed following first-line treatment [8].
The primary endpoint of OVAR16 was progression-free survival (PFS), and the primary analysis was based on radiologic progression per Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST) as assessed by the local investigator (INV).
In ovarian cancer, PFS is considered to be an appropriate primary endpoint because disease progression is associated with recurrence of symptoms and relatively short survival, and further treatment is usually initiated, which brings additional toxicities [5], [9], [10]. However, assessment of PFS is sensitive to timing of evaluations and requires consistent interpretation of radiologic progression; variability in timing and interpretation between the control and treatment arms can introduce bias to the analysis [11]. In addition, in ovarian cancer the radiologic assessment of progression is particularly difficult because: 1) upfront standard surgery and chemotherapy are generally able to remove most, if not all, of the tumor, so most patients are disease-free at the end of their initial therapy; 2) surgical scarring is often difficult to distinguish from actual tumor lesions; and 3) in many patients progression may be characterized by diffuse peritoneal implantation and the prevalence of non-target lesions, such as ascites. To avoid investigator bias, regulatory agencies commonly require an additional analysis by blinded independent central review (BICR) to confirm the reliability of results obtained by INV evaluation of disease progression. Recent studies have suggested that independent review of all scans, which is associated with increased cost and complexity, may not be necessary. A meta-analysis of 27 phase 3 oncology trials revealed good concordance between INV and BICR assessments of PFS, and little evidence of investigator bias [12]. The United States Food and Drug Administration (US FDA) has discussed the use of an independent audit of random sample assessments rather than a complete review of all patients [13]. In this report we compare the primary endpoint of OVAR16 as assessed by INV and BICR, and explore the use of a subset of patient evaluations to confirm the primary analysis.
Section snippets
Patients and study design
Detailed descriptions of the eligibility criteria and study design have been published previously [8]. Briefly, eligible patients were ≥ 18 years of age, with histologically confirmed, FIGO stage II–IV AEOC that had been treated with surgical debulking and at least 5 cycles of platinum-taxane–based chemotherapy. Eligibility included no evidence of disease progression following first-line treatment, Eastern Cooperative Oncology Group performance status 0–2, and adequate hematologic, hepatic, and
Patients
Overall, 940 eligible patients were enrolled in OVAR16; 472 patients were randomized to receive pazopanib and 468 were randomized to receive placebo [8]. Demographic and baseline clinical characteristics were well balanced between treatment groups. All patients were evaluated for disease progression by both INV and BICR. Radiologic scans were performed at 3513 time points, and scans were available for BICR at 3425 (97%) of those times.
Analysis of PFS
By INV assessment, there were 237 PFS events in the
Discussion
The primary analysis of OVAR16 demonstrated that maintenance therapy with pazopanib led to a prolongation of PFS in women with AEOC. However, despite the increase in PFS, there was no increase in overall survival for pazopanib-treated patients in OVAR16 compared with placebo-treated patients, based on an interim survival analysis after 36% of events had occurred in the overall study population [8]. These results are consistent with those of GOG-0218 and ICON7, which evaluated the incorporation
Conflict of interest statement
du Bois has received grants from Roche and AstraZeneca, lecture honoraria from AstraZeneca, and advisory board reimbursement from Boehringer Ingelheim (all unrelated to the submitted work). Floquet has received honoraria from Roche and non-financial support from Roche, GlaxoSmithKline, PharmaMar, and Merck Sharp & Dohme (all unrelated to the submitted work). Friedlander reports honoraria from Roche for lectures and non-financial support from AstraZeneca (all unrelated to the submitted work).
Funding and authorship
GlaxoSmithKline Pharmaceuticals provided support for this study and for medical editorial assistance with the manuscript. The academic authors and authors Crescenzo, Barrett, Wang, and Mitrica (who are employed by the study sponsor GlaxoSmithKline) participated in study design, data collection/analysis/interpretation, and writing of the manuscript. Final decisions regarding the content of the manuscript and the decision to submit the manuscript for publication were made by the first and
Acknowledgments
We thank all the patients and their families who participated in this study. Furthermore, we thank all investigators and supporters at the study sites. We thank William Sinkins, PhD, of ProEd Communications, Inc., Beachwood, Ohio, for his medical editorial assistance with this manuscript. Financial support for this study and for medical editorial assistance was provided by GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania.
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Clinical Trials Registration Number: NCT00866697 [http://clinicaltrials.gov/ct2/show/NCT00866697].
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Previous Publication: Portions of the data were presented by Floquet A, et al. (oral presentation) at ESGO 2013; the abstract appeared in Int J Gynecol Cancer 2013;23(8 suppl 1):182–3.