Bevacizumab in ovarian cancer: Focus on clinical data and future perspectives

Accepted Manuscript Title: Bevacizumab in ovarian cancer: Focus on clinical data and future perspectives Author: Nicoletta Colombo Pier Franco Conte Sandro Pignata Francesco Raspagliesi Giovanni Scambia PII: DOI: Reference:

S1040-8428(15)30032-9 http://dx.doi.org/doi:10.1016/j.critrevonc.2015.08.017 ONCH 2034

To appear in:

Critical Reviews in Oncology/Hematology

Received date: Revised date: Accepted date:

3-3-2015 17-7-2015 6-8-2015

Please cite this article as: Colombo Nicoletta, Conte Pier Franco, Pignata Sandro, Raspagliesi Francesco, Scambia Giovanni.Bevacizumab in ovarian cancer: Focus on clinical data and future perspectives.Critical Reviews in Oncology and Hematology http://dx.doi.org/10.1016/j.critrevonc.2015.08.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Bevacizumab in ovarian cancer: Focus on clinical data and future perspectives

Nicoletta Colombo a,*, Pier Franco Conte b, Sandro Pignata c, Francesco Raspagliesi d, Giovanni Scambia e

a

University of Milan Bicocca and European Institute of Oncology, Milan, Italy; [email protected]

b

Department of Surgery, Oncology and Gastroenterology, University of Padova and Division of Medical Oncology 2, Oncology Institute of Veneto, Padova, Italy; [email protected]

c

Department of Urology and Gynecology, Istituto Nazionale Tumori Fondazione G. Pascale – IRCCS, Naples, Italy; [email protected]

d

Surgical Gynecology, Fondazione IRCCS, Istituo Nazionale dei Tumori di Milano, Milan, Italy; [email protected] e

Policlinico Universitario A. Gemelli, Rome, Italy; [email protected]

* Corresponding author at: University of Milan Bicocca and European Institute of Oncology, via Ripamonti 435, Milan, Italy. Tel.: +39 0257489543; fax: +39 0294379222 E-mail address: [email protected] (Nicoletta Colombo)

1

Vitae

Prof. Nicoletta Colombo graduated in Medicine in 1980 and in 1984 she completed the Specialty in Obstetrics and Gynecology from the University of Milan, Italy. After a training period at Charing Cross Hospital and the Royal Marsden Hospital in London, she became a clinical research associate at the Kaplan Cancer Center, New York University, USA, where she worked from 1984 until 1986. She was Junior and later Senior Faculty at the Department of Obstetrics and Gynecology at the University of Milan from 1986 to 1994. In September 1994 she became Deputy Director, and in July 2001 Director of the Gynecologic Oncology Unit, Division of Gynecology, European Institute of Oncology, Milan, Italy. Since October 2002 she has been Associate Professor of Obstetrics and Gynecology at the University of Milan-Bicocca. Prof. Colombo has authored several publications in the field of gynaecological oncology and is a member of various professional societies such as the American Society of Clinical Oncology (ASCO), the Society of Gynecologic Oncologists (SGO) and the International Gynecological Cancer Society (IGCS). She is also Past President of the European Society of Gynecologic Oncology (ESGO) and Senior Editor of the International Journal of Gynecological Cancer. Prof. PierFranco Conte is Chief of the Division of Medical Oncology 2 at the Istituto Oncologico Veneto, IRCCS I Padua, Italy. He received his MD in 1974, and a Specialty in Clinical Oncology in 1977, both from Turin University, Italy. He specialised further in Clinical Immunology in 1980 and Hematology in 1984 at Milan and Genoa Universities. Prof. Conte was Founder and Chairman of the Gruppo Oncologico Nord-Ovest, and is currently a member of the Steering Committee of the International Cancer Cooperative Group (ICCG), a Faculty Member of the European Society of Medical Oncology (ESMO), and Founder and Chairman of Association Translation Research Oncology (ASTRO) and Association Research Education Oncology (AREO). He has authored over 320 scientific papers and sits on the Editorial Boards of several journals, including the Journal of Clinical Oncology, Clinical Breast Cancer and The Oncologist. In 2007 Prof. Conte received the Claude Jacquillat Award for Achievement in Clinical Oncology. Prof. Sandro Pignata was born in Naples, Italy, in 1962. He took his MD degree in 1986 at Naples University and his PhD degree in Gastroenterological Science at the University of Rome in 1990. 2

Since 1993 he has been on the Staff at the National Cancer Institute in Naples, where he is now Head of the Uro-Gynecological Department. Prof. Pignata is the President of the Multicenter Italian Trial in Ovarian cancer (MITO) group, which is involved in several randomised trials of the treatment of gynaecological cancer with results published in important international journals. He is a member of the educational committee of European Society of Medical Oncology (ESMO) and of the executive board of the European Network of Gynaecological Oncological Trial Groups (ENGOT) and of the Gynecologic Cancer InterGroup (GCIG). Dr. Francesco Raspagliesi graduated in medicine in 1981 and is a specialist in obstetrics, gynaecology and oncology. Since 1999 he has been Director of the Gynecologic Oncology Unit at the Fondazione IRCCS Istituto Nazionale Tumori of Milan, Italy, and Professor at the School of Specialization in Obstetrics and Gynecology at the University of Milan. He was President of the Italian Society of Gynecologic Oncology and is a member of the European Board and Council of Obstetrics and Gynecology. He has authored several papers on gynaecological oncology and is a peer reviewer for journals including Gynecologic Oncology, the International Journal of Reproductive Medicine, Cancer, Oncology Topics, the European Journal of Obstetrics & Gynecology and Reproductive Biology. Prof. Giovanni Scambia received his degree in Medicine and Surgery in 1983 from the Catholic University of Rome. He did his residency at the Department of Obstetrics and Gynecology at the Catholic University of the Sacred Heart (UCSC) from 1983 to 1987, and then a Fellowship in Gynecologic Oncology at the Department of Obstetrics and Gynecology at the Catholic University of Rome from 1987 to 1990. Since 1992 he has been Head of the Research Laboratory, Department of Gynecology at UCSC, and in addition has been in charge of the management of clinical trials since 1997. He became a Full Professor of Gynaecology and Obstetrics at the Catholic University in 2007, and is currently Head of the Departments of Women’s and Children’s Health at UCSC, Director of Gynecology and Obstetrics Post Graduate School and Scientific Director of Cure and Research at Giovanni Paolo II in Campobasso, Italy. Prof. Scambia has authored over 730 scientific publications and is a member of the Italian Department of Health, on the Board of Directors of Multicenter Italian Trials in Ovarian Cancer (MITO), and a member of 3

various societies including the European Society of Gynecologic Oncology (ESGO), the Gynecologic Cancer Cooperative Group and the International Gynecological Cancer Society (IGCS).

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Contents 1.

Introduction

2.

Rationale for anti-angiogenic therapy in ovarian cancer 2.1.

Preclinical studies of bevacizumab

3.

Clinical evaluation of bevacizumab

4.

Bevacizumab as front-line treatment for ovarian cancer 4.1.

GOG-0218

4.2.

ICON7

5.

Bevacizumab in recurrent ovarian cancer

6.

Ongoing evaluation of bevacizumab in ovarian cancer

7.

6.1.

Treatment duration in the front-line setting

6.2.

Patient selection

6.3.

Rationale for the use of bevacizumab beyond progression in ovarian cancer

6.4.

Bevacizumab in the neoadjuvant setting

6.5.

Investigational anti-angiogenic strategies

Conclusions

5

Abstract

The past five years have yielded substantial developments in the management of advanced ovarian cancer. Initial promise shown by anti-angiogenic agents has translated into positive phase III trials in the front-line and recurrent settings. Nevertheless, several questions remain unanswered, including the most appropriate timing for initiation of anti-angiogenic therapy and patient selection for the various treatment approaches. This review article summarises the key results (including final overall survival data), from five pivotal phase III trials of bevacizumab, highlights emerging data with new maintenance strategies and considers unanswered questions and ongoing research to address uncertainties in treatment duration, re-exposure to bevacizumab in bevacizumab-pretreated patients and the potential integration of anti-angiogenic therapy into neoadjuvant treatment regimens.

Keywords: Anti-angiogenic; Bevacizumab; Front-line; Ovarian cancer; Phase III; Vascular endothelial growth factor

6

1.

Treatment landscape in ovarian cancer

The cornerstone of the management of ovarian cancer is primary cytoreductive surgery. After debulking surgery, patients receive front-line chemotherapy. For almost 15 years since the introduction of carboplatin–paclitaxel, most of the treatment strategies tested in the front-line setting yielded disappointing or controversial results. Substituting paclitaxel with other drugs in combination with carboplatin or adding a third drug to the carboplatin–paclitaxel regimen failed to improve outcomes [1–6]. Changes in the administration route (intraperitoneal application) or dose density (weekly paclitaxel) produced more encouraging results [7–10]. Nevertheless, until relatively recently, there had been little improvement in progression-free survival (PFS) with standard frontline chemotherapy and it was generally accepted that the maximal efficacy with paclitaxel– carboplatin alone had been reached. Improvements in overall survival (OS) were generally attributable to the broadening range of active treatment options at the time of relapse, which typically occurs in 70% of patients who receive front-line therapy. More recent research has explored the potential of novel targeted approaches to improve the outcomes in ovarian cancer [11]. In this article, we briefly discuss the rationale for one of the most advanced of these novel strategies, anti-angiogenesis, review the available phase III data with a particular focus on bevacizumab, and highlight some of the unanswered questions that are the focus of ongoing research.

2.

Rationale for anti-angiogenic therapy in ovarian cancer

At the 2010 Consensus Conference on ovarian cancer, it was agreed that angiogenesis represents one of the most promising targets in ovarian cancer [12]. One of the key mediators of angiogenesis is vascular endothelial growth factor (VEGF), a heparin-binding growth factor that selectively promotes proliferation and survival of vascular endothelial cells [13]. VEGF also induces vascular permeability and angiogenesis in a variety of in vivo models [14]. The VEGF gene family consists of VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor. VEGF-A binds two 7

closely related receptor tyrosine kinases, VEGFR-1 and VEGFR-2 [15]. VEGFR-2 is the major signalling receptor that mediates most of the biological activities of VEGF [16,17]. The role of VEGFR-1 is complex and varies according to the context [18]. VEGFR-3 is a member of the same family of receptor tyrosine kinases [19] and binds VEGF-C and VEGF-D [20], two molecules implicated in the regulation of lymphangiogenesis [21]. In addition to these receptor tyrosine kinases, VEGF-A interacts with neuropilin-1, a cell surface protein that binds heparin-binding VEGF-A isoforms, resulting in potentiation of VEGFR-2 signalling [22]. Although the process of growth and maturation of new blood vessels is highly complex and requires sequential activation of a series of signalling pathways, VEGF signalling often represents a rate-limiting step [17,23,24]. A key function of VEGF in adults is the regulation of the cyclical angiogenesis that takes place in the female reproductive tract. Expression of VEGF mRNA is temporally and spatially related to blood vessel growth in the ovaries [25–27]. VEGF inhibition results in suppression of corpus luteum and uterine angiogenesis in rodents and primates [28–30]. Many tumour cell lines secrete VEGF in vitro, suggesting that VEGF may be a mediator of tumour angiogenesis. In situ hybridisation studies have shown that VEGF mRNA is up-regulated in the majority of human tumours, including lung, kidney, bladder, ovary, cervix and endometrium carcinomas, as well as several intracranial tumours (reviewed in [14]). Approximately 97% of ovarian tumours overexpress the VEGF ligand [31], and this expression correlates with ascites formation, poor prognosis and reduced survival [31–34].

2.1.

Preclinical studies of bevacizumab

Subcutaneous and orthotopic models were used to test the effects of bevacizumab or its murine precursor, A4.6.1, on the growth of a variety of tumour cell lines. Collectively, these studies demonstrated reduction in tumour vessel density and suppression of primary tumour growth, even with single-agent treatment [35,36]. In addition, bevacizumab or A4.6.1 demonstrated inhibitory effects on metastasis [37,38] and was shown to abrogate ascites formation [39]. Additive and/or synergistic effects between bevacizumab and several commonly used chemotherapeutic agents, 8

including paclitaxel, were observed in a variety of human tumour xenografts [36,39,40]. The mechanism of the additive or synergistic interactions between VEGF inhibitors and cytotoxic agents is highly debated. As these therapeutic modalities have different mechanisms of action, the additivity may result from targeting both tumour and endothelial compartments [41]. Another possibility is that bevacizumab or other anti-angiogenic agents ‘normalise’ the abnormal and leaky tumour vessels, which typically result in increased interstitial fluid pressure, impaired flow and hypoxia [42]. The resulting improvement in flow would enhance delivery of chemotherapy to tumour cells.

3.

Clinical evaluation of bevacizumab

These preclinical properties, together with the proven efficacy of bevacizumab in a range of other solid tumour types and the known poor prognosis of patients with ovarian cancer overexpressing VEGF, led to clinical evaluation of bevacizumab in patients with recurrent ovarian cancer. The Gynecologic Oncology Group (GOG) carried out a series of phase II studies evaluating targeted agents, including bevacizumab, in patients with ovarian cancer. The activity demonstrated by bevacizumab in GOG 170D in terms of objective response rate (ORR) and 6month PFS rate was substantially higher than that of all the other compounds evaluated in the GOG series of similarly designed phase II trials testing new agents [43] and was supported in subsequent phase II studies in more heavily pretreated populations in the recurrent setting [44,45]. These encouraging results triggered evaluation of bevacizumab as a component of front-line therapy. Two prospective randomised phase III trials, GOG-0218 and ICON7, were initiated to investigate the role of bevacizumab administered in combination with front-line chemotherapy and continued as single-agent maintenance therapy.

4.

Bevacizumab as front-line treatment for ovarian cancer

4.1.

GOG-0218 9

The double-blind, placebo-controlled randomised phase III GOG-0218 trial included 1873 patients with stage III (incompletely resected) or stage IV (any surgical outcome) epithelial ovarian, primary peritoneal or fallopian tube cancer [46] (Table 1). Patients were randomly assigned to one of three treatment groups: standard chemotherapy with carboplatin (AUC 6) and paclitaxel (175 mg/m2) every 3 weeks for 6 cycles plus placebo from cycle 2 to cycle 22; the same chemotherapy for 6 cycles plus bevacizumab (15 mg/kg) every 3 weeks in cycles 2 to 6 and placebo in cycles 7 to 22; or the same chemotherapy for 6 cycles plus bevacizumab from cycles 2 to 22. The primary endpoint of the trial was PFS evaluated by investigators according to RECIST and CA-125. The GOG-0218 trial met its primary objective, demonstrating significantly improved PFS with bevacizumab administered with and following chemotherapy (total duration 15 months) compared with chemotherapy alone (hazard ratio [HR] 0.72, P<0.001). Median PFS was 10.3, 11.2 and 14.1 months, respectively, in the control group, concomitant-only bevacizumab arm, and concomitant and maintenance bevacizumab arms [46]. PFS analyses according to the statistical analysis plan for regulatory purposes showed a HR of 0.70 and median PFS values of 10.6, 11.6 and 14.7 months, respectively (Fig. 1A) [47]. In the analysis of PFS based on RECIST only (censoring PFS events defined by CA-125 alone and for non-protocol therapy), as required by the regulatory authorities, the median PFS was 12.0 months in the chemotherapy-alone arm and 18.2 months in the concomitant and maintenance arm (HR 0.625, P<0.0001) [47]. PFS as assessed by an independent review committee confirmed the improvement in PFS with 15 months of bevacizumab therapy (HR 0.62, P<0.0001) [50]. Subgroup analyses showed that the PFS benefit was maintained in all subgroups evaluated (disease stage, residual disease, histological subtype, tumour grade, age and performance status) (Fig. 1B) [46]. In the final OS analysis, no statistically significant differences in OS were observed among the three arms: the median OS was 40.6, 38.8 and 43.8 months, respectively, for the control group, the concomitant-only bevacizumab group and the concomitant and maintenance bevacizumab group [48]. The higher crossover to bevacizumab in subsequent lines (28% in the control arm versus 15% in the bevacizumab maintenance arm [48]) could partially explain this lack of 10

difference [46]. Of note, in the subgroup of patients with stage IV disease, who have a poorer prognosis and thus shorter post-progression survival and reduced likelihood of multiple lines of therapy, an exploratory analysis showed a HR for OS of 0.72 (95% CI 0.53–0.97), favouring bevacizumab (Fig. 1C). Median OS was 32.8 months in the control arm, 32.9 months in the concomitant-only bevacizumab group and 40.6 months in the concomitant and maintenance bevacizumab group [48]. The tolerability profile was as expected for bevacizumab: grade ≥2 hypertension was significantly (P<0.001) more common with bevacizumab than with placebo but led to discontinuation of bevacizumab in only 2.4% of patients in the bevacizumab maintenance group. There were no significant differences between the three groups in the rates of other adverse events, including thromboembolic events, gastrointestinal perforation, fistulae or wound complications. Gastrointestinal perforation is a known side effect of bevacizumab but risk factors have been evaluated only retrospectively. Therefore the GOG-0218 trial included prospective analyses of potential risk factors for gastrointestinal adverse events (defined as grade ≥2 perforation, fistula, necrosis or haemorrhage occurring between the start of cycle 2 [when bevacizumab/placebo was initiated] and 30 days after last study treatment). The incidence of these adverse events with bevacizumab-containing therapy was double that observed with chemotherapy alone but was nevertheless quite low (3.4% with bevacizumab versus 1.7% with chemotherapy alone), particularly when taking into account that 8% of patients had undergone small bowel resection and 17% had undergone large bowel resection [51]. The majority of grade ≥2 gastrointestinal adverse events associated with bevacizumab occurred in earlier treatment cycles during the concurrent chemotherapy phase, particularly cycles 2 and 3. There was no difference in the incidence of grade ≥2 gastrointestinal adverse events between the two bevacizumab treatment arms. The medical history factors significantly associated with gastrointestinal adverse events were a history (or prior treatment) of inflammatory bowel disease and large or small bowel resection either at primary surgery or with anastomosis. However, risk of gastrointestinal events was not associated with age, baseline GOG performance status, disease stage/debulking or the interval between 11

surgery and systemic therapy. There was a non-significant trend towards increased risk of grade ≥2 gastrointestinal adverse events in patients who experienced febrile neutropenia. A multivariable logistic model adjusted for significant risk factors showed a two-fold increase in risk with bevacizumab and large bowel resection at primary surgery and a 13-fold increase in risk in patients who had received treatment for inflammatory bowel disease. However, there was no evidence of an additional increase in risk in patients with these risk factors who received treatment with bevacizumab [51]. Quality of life (QoL), measured using the Trial Outcome Index of the Functional Assessment of Cancer Therapy-Ovary (FACT-O TOI), was a prespecified endpoint of the GOG0218 trial. Patients completed QoL questionnaires during the concomitant chemotherapy and maintenance phases and 6 months after completing study therapy. Bevacizumab-containing therapy was associated with a statistically significant but small detriment to QoL during the chemotherapy phase but this did not persist during maintenance bevacizumab [52].

4.2.

ICON7

The open-label randomised phase III ICON7 trial also evaluated the addition of bevacizumab to front-line chemotherapy for ovarian cancer. The study population included patients with stage I or IIA grade 3 or clear-cell disease as well as those with advanced (stage IIB–IV) ovarian cancer. A total of 1528 patients were randomly assigned to one of two treatment groups: standard chemotherapy with carboplatin (AUC 5 or 6) and paclitaxel (175 mg/m2) every 3 weeks for 6 cycles or the same chemotherapy regimen for 6 cycles plus bevacizumab 7.5 mg/kg every 3 weeks for a total duration of 12 months [49]. If chemotherapy was initiated <28 days after surgery or the surgical wound had not fully healed, bevacizumab was not administered with the first cycle. The primary endpoint, as in GOG-0218, was PFS. Median PFS was 17.3 months in patients treated with chemotherapy alone and 19.0 months in those treated with bevacizumab and chemotherapy (HR 0.81, 95% confidence interval [CI] 0.70–0.94, P=0.004). Bevacizumab treatment effect varied over time and the difference 12

between the two treatment arms was greatest (15%) at 12 months, coinciding with the discontinuation of bevacizumab [49]. The complete or partial response rate in patients with measurable disease was 48% in the chemotherapy-alone group versus 67% in the bevacizumab group (difference of 19 percentage points [95% CI 11–28]; P<0.0001). At the final OS analysis, there was no difference in OS between treatment arms. The HR was 0.99 (95% CI 0.85–1.14), with median OS of 58.6 months in the chemotherapy-alone group and 58.0 months in the bevacizumab arm [53]. As the ICON7 trial included patients with early-stage ovarian cancer (stage I and II; 18% of the population), a subgroup analysis of PFS was undertaken focusing on patients considered to be at high risk of progression, predefined in this study as FIGO stage III with residual disease >1 cm or stage IV with any surgical debulking. The PFS difference between the two treatment arms was larger in this subgroup (HR 0.68, P<0.001; median PFS 10.5 months with chemotherapy alone versus 15.9 months with bevacizumab) than in the overall population (Fig. 2A) [49]. Importantly, in exploratory analyses in a similar subgroup (but also including an additional 30 patients with no initial surgery), an OS benefit was also observed with bevacizumab. Median OS was 30.2 months in patients treated with standard therapy and 39.7 months in those treated with bevacizumab (HR 0.78, P=0.03) (Fig. 2B) [53]. QoL was a prespecified endpoint of the ICON7 trial and was measured until progression using the European Organisation for Research and Treatment of Cancer QoL questionnaireovarian cancer module (EORTC QLQ-OV28) and core 30 (C30). Continued bevacizumab therapy was associated with a clinically small but statistically significant decrement in QoL at week 54 compared with observation alone [54]. These two large prospective randomised phase III trials both met their primary objective, demonstrating a significant PFS benefit from the incorporation of bevacizumab into standard chemotherapy for advanced ovarian cancer. Exploratory analyses in the ICON7 trial suggested more pronounced benefit in a subgroup of patients defined by stage and residual disease after surgical debulking. In December 2011, bevacizumab received European regulatory approval for

13

use in combination with front-line carboplatin–paclitaxel for stage IIIB–IV newly diagnosed ovarian cancer, based on the results of these two trials. Neither of the trials demonstrated a significant improvement in OS (secondary endpoint) in the overall study population. However, at the 2010 Consensus Conference in Vancouver, it was unanimously agreed that PFS is the preferred endpoint both in maintenance and non-maintenance first-line trials because of the confounding effect of post-recurrence/progression therapy on OS [55]. From a methodological viewpoint, in tumour types with long post-progression survival, defined as the interval between the first disease progression and death, it is difficult to detect a significant OS benefit, even when the difference in PFS is significant [56]. There are several reasons why prolonging PFS may be clinically important for women with ovarian cancer, providing that quality of life is maintained. Firstly, increasing PFS delays the onset of physical symptoms associated with progressive disease. Secondly, it delays the need to start new therapies, which may introduce new toxicities. Thirdly, it delays the psychological burden of disease progression. Fourthly, increasing the time from the last platinum therapy to disease recurrence may improve a patient’s treatment options, especially if the PFS interval can be extended beyond 6 months. Following the results of the GOG-0218 and ICON7 trials, the 2010 Consensus Conference stated that bevacizumab can be incorporated into the control arm of future clinical trials in ovarian cancer.

5.

Bevacizumab in recurrent ovarian cancer

Three further randomised phase III clinical trials have evaluated the efficacy and safety of bevacizumab in recurrent ovarian cancer: OCEANS (Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Disease) [57], GOG-0213 [58] and AURELIA (Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer) [59]. In the placebo-controlled double-blind randomised phase III OCEANS trial, 484 patients with platinum-sensitive ovarian cancer were randomly assigned to either standard chemotherapy with carboplatin (AUC 4) and gemcitabine (1000 mg/m2 on days 1 and 8) every 3 weeks for 6 14

cycles (maximum 10 cycles) plus placebo or the same chemotherapy regimen plus bevacizumab 15 mg/kg every 3 weeks, continued until disease progression or unacceptable toxicity [57]. The primary endpoint was PFS as evaluated by the investigators; secondary endpoints included ORR, OS and duration of response. The baseline characteristics of the two groups were well balanced. Median age was approximately 60 years, almost 60% of patients had a platinum-free interval >1 year and approximately 10% had undergone cytoreductive salvage surgery. Chemotherapy was administered for a median of 6 cycles in both arms. The median number of placebo cycles was 10 (range 1–36) and the median number of bevacizumab cycles was 12 (range 1–43). At the time of the primary PFS analysis, the median duration of follow-up was 24 months. There was a significant improvement in PFS with the addition of bevacizumab to chemotherapy (HR 0.484, P<0.0001; Fig. 3). Median PFS was 8.4 months in the group treated with chemotherapy alone and 12.4 months in patients treated with bevacizumab, representing a 4-month improvement in the median. The significant PFS benefit was observed in all of the subgroups analysed (age > or ≤65 years, baseline Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, platinum-free interval <12 months, 12–24 months or >24 months and cytoreductive surgery). The improvement in PFS was confirmed by the independent review committee-assessed PFS results (HR 0.45, P<0.0001; median PFS 8.6 months with chemotherapy alone versus 12.3 months with bevacizumab) [60]. Bevacizumab also increased the activity of chemotherapy in terms of ORR. The ORR was significantly higher in patients treated with bevacizumab (79%) than in those receiving placebo (57%), with an absolute difference of 21% (P<0.0001). Unlike some other tumour settings, in ovarian cancer this endpoint is clinically very relevant due to the burdensome nature of symptoms for patients. The median duration of response was 7.4 months with placebo compared with 10.4 months with bevacizumab (HR 0.534, P<0.0001). Surprisingly for the second-line setting, almost one-third of patients (30%) treated with bevacizumab and chemotherapy were free of disease progression after 12 months, compared with only 9% in the chemotherapy-alone arm [61]. This result has important implications for patients and 15

is of considerable clinical significance, because it represents an increase in the time without chemotherapy, which may be expected to have a positive psychological benefit. Similar to the front-line trials, the significant PFS benefit did not translate into a significant improvement in OS, which at the time of the final OS analysis (after events in 73% of patients) was similar in the two treatment arms (HR 0.95, P=0.65; median OS 32.9 months with placebo versus 33.6 months with bevacizumab) [62]. However, these data demonstrate that stopping antiangiogenic therapy does not increase tumour invasiveness or select more aggressive phenotypes, contrary to hypotheses based on preclinical data from other anti-angiogenic agents. The lack of a significant OS benefit may be explained in part by subsequent lines of active treatment, administered in almost all patients, and including bevacizumab in 38% of patients in the placebo arm versus 23% of those in the bevacizumab arm. There were no unexpected toxicities with bevacizumab-containing therapy in the OCEANS trial. The only grade ≥3 adverse events observed more frequently in the bevacizumab than the placebo arm were hypertension, proteinuria and non-CNS bleeding [57]. Hypertension is generally easily managed but patients must be monitored carefully for both hypertension and proteinuria, particularly because the frequent presence of ascites in these patients entails significant protein loss. Recently, results of a second randomised phase III trial of bevacizumab in platinumsensitive recurrent ovarian cancer were reported [58]. In this open-label trial conducted predominantly in US centres but including some sites in Japan and Korea, patients with recurrence of ovarian cancer at least 6 months after completing platinum therapy were randomised to receive six cycles of carboplatin and paclitaxel either alone or in combination with bevacizumab 15 mg/kg every 3 weeks and followed by single-agent bevacizumab until disease progression. The study also included randomisation before systemic therapy to surgery or no surgery in patients who were eligible for surgery; however, results for the surgical question of the trial are not yet available. The primary endpoint was OS. PFS and quality of life were secondary endpoints. The baseline characteristics of the two groups were well balanced. In both arms, 10% of patients had received prior bevacizumab and 69% had a platinum-free interval of >12 months. 16

Analysis of OS, the primary endpoint, showed a HR of 0.83 (95% CI 0.68-1.01) favouring bevacizumab but this did not reach statistical significance (p=0.056). Median OS was 42.2 months in the bevacizumab-containing arm versus 37.3 months in the chemotherapy-alone arm. The curves separated before month 24 and then remained clearly separated. PFS (secondary endpoint) was significantly improved with bevacizumab (HR 0.61, 95% CI 0.52-0.72; p<0.0001). Median PFS was 13.8 months with bevacizumab versus 10.4 months with chemotherapy alone. ORR also favoured bevacizumab (79% vs 59%, respectively). Analysis of treatment immediately after study therapy showed that 16% of patients randomised to chemotherapy alone crossed over to bevacizumab vs 8% of those in the bevacizumab arm. Bevacizumab was associated with increased grade ≥3 incidences of hypertension, proteinuria, infection, joint pain and thromboembolism. However, no new safety signals were observed. There was no significant difference in patient-reported quality of life, as measured by the FACT-O TOI, with the addition of bevacizumab to carboplatin and paclitaxel for platinum-sensitive recurrent ovarian cancer. Finally, the randomised phase III AURELIA trial assessed the efficacy and tolerability of chemotherapy with or without bevacizumab in a more difficult setting, platinum-resistant recurrent ovarian cancer (defined as relapse <6 months after platinum-containing therapy) [59]. Before randomisation of each patient, the investigator chose one of three single-agent chemotherapy options: paclitaxel (80 mg/m2, days 1, 8, 15 and 22 every 4 weeks); topotecan (4 mg/m2, days 1, 8 and 15 every 4 weeks or 1.25 mg/m2, days 1–5 every 3 weeks); or pegylated liposomal doxorubicin (40 mg/m2, day 1 every 4 weeks). Patients were then randomly assigned to either chemotherapy alone or chemotherapy plus bevacizumab 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks (depending on the chosen chemotherapy regimen) until disease progression or unacceptable toxicity. At the time of disease progression, patients initially assigned to chemotherapy alone could receive bevacizumab monotherapy, whereas those initially treated with bevacizumab could receive only standard-of-care treatment (without bevacizumab). The primary endpoint was PFS.

17

The baseline characteristics of the two groups were well balanced. Of note, only 7% of patients had previously received anti-angiogenic therapy. The addition of bevacizumab to chemotherapy doubled PFS (HR 0.48, P <0.001; median PFS 3.4 months with chemotherapy alone versus 6.7 months with bevacizumab; Fig. 4). A significant increase was also observed in ORR with bevacizumab, a particularly important finding in ovarian cancer because the reduction in symptoms improves patients’ QoL. Of additional note, in the subgroup of 113 patients with ascites at baseline, nine (17%) of the 54 patients treated with chemotherapy alone underwent paracentesis after starting study treatment compared with one patient (2%) of the 59 receiving bevacizumab-containing therapy. The OS difference between the treatment arms at the time of the final OS analysis did not reach statistical significance (HR 0.85, P=0.174; median 13.3 months with chemotherapy alone versus 16.6 months with bevacizumab plus chemotherapy). At this time, 72 of the 182 patients (40%) initially randomised to chemotherapy alone had received single-agent bevacizumab after progression. As in previous trials of bevacizumab in ovarian cancer and other tumour types, the most frequent adverse events associated with the use of bevacizumab were hypertension and proteinuria [59]. Patient-reported outcomes objectives were prespecified before database lock. The primary patient-reported outcome objective was met: a significantly larger proportion of patients receiving bevacizumab-containing therapy than chemotherapy alone achieved a ≥15% improvement in the gastrointestinal/abdominal symptom subscale (EORTC QLQ-OV28) at week 8/9 (22% versus 9%, respectively; P=0.002) [63].

6.

Ongoing evaluation of bevacizumab in ovarian cancer

A number of questions on the optimal use of bevacizumab in ovarian cancer remain unanswered, including the dose and the duration of bevacizumab treatment, the role and feasibility of combining bevacizumab with intraperitoneal chemotherapy, the selection of patients who can benefit most from bevacizumab, the optimal timing of bevacizumab initiation (front-line or at the time of relapse), strategies for patients previously treated with bevacizumab in the front-line setting 18

and the most appropriate chemotherapy partner in the recurrent setting. Key completed and ongoing trials are summarised in Table 2 and below.

6.1.

Treatment duration in the front-line setting

Results of the GOG-218 trial clearly show that bevacizumab should be continued as a single agent after completion of front-line chemotherapy. The improvement in PFS compared with chemotherapy alone was statistically significant in the group of patients treated with bevacizumab concurrently and then continued as a single agent for up to 15 months, but not in those who received bevacizumab only concurrently with chemotherapy (cycles 2–6) [46]. This finding implies that bevacizumab treatment duration is critical, and bevacizumab should be continued beyond chemotherapy to delay disease progression. Furthermore, in the group that received bevacizumab as a single agent after combination with chemotherapy, maximal separation of the PFS curves occurred at 15 months, at the end of the bevacizumab administration period. Likewise, in ICON7, there was a significant improvement in median PFS in the bevacizumab group and the effect of bevacizumab was greatest at 12 months. These observations are consistent with earlier preclinical findings in a variety of tumours, including ovarian cancer models, suggesting that long-term VEGF blockade is required to achieve maximal therapeutic benefit [70–72]. Furthermore, the findings raise the question whether a greater benefit could potentially be achieved by continuing bevacizumab therapy until progression? The ongoing AGO-OVAR17 trial (BOOST; ClinicalTrials.gov Identifier: NCT01462890) is designed to determine whether bevacizumab for up to 30 months is more effective than bevacizumab given for up to only 15 months (as in GOG-0218). The trial has completed accrual. In addition, the single-arm ROSiA (Research in Ovarian cancer: Safety with Avastin) study (ClinicalTrials.gov Identifier: NCT01239732) [69] is assessing the safety of front-line bevacizumabbased therapy given until disease progression or for up to 36 cycles (24 months). The study has completed accrual of more than 1000 patients and results will be presented in 2015.

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6.2.

Patient selection

With respect to patient selection, results of exploratory subgroup analyses of both ICON7 and GOG-0218 described above generate intriguing hypotheses about patient selection for bevacizumab-containing therapy, and raise important questions about the definition of high risk of progression in this setting. However, these hypotheses based on exploratory analyses require validation and it is important to note that PFS benefit is seen across almost all subgroups evaluated. Ultimately, treatment decisions for each individual patient are guided by evaluation of the relative risk/benefit of treatment and, of course, regulatory approval and reimbursement considerations within each country. Another important avenue of investigation is the search for biomarkers that may predict bevacizumab efficacy and enable identification of those patients who may derive the most substantial benefit from bevacizumab. There have been extensive translational research efforts in many of the bevacizumab trials, including those in ovarian cancer. The initial focus in ovarian cancer was on plasma markers, particularly VEGF-A and VEGFR-2 [73], which showed promise in other tumour settings [74–77]. More recently, exploratory analyses evaluating gene expression profiles, tumour markers and other plasma markers in the ICON7 and GOG-0218 trials have been reported [78–81], generating interesting hypotheses requiring further exploration and validation. Several of the ongoing trials summarised in Table 2 also include biomarker evaluation but as yet, no robust biomarker predicting bevacizumab efficacy has been identified. The need for a biomarker(s) for bevacizumab efficacy is becoming even more urgent with the availability of PARP inihibitors. Increasingly, patients with high-grade serous ovarian cancers are being tested for BRCA status and a proportion of these patients will be found to have BRCA mutations (either germline or somatic). The efficacy of bevacizumab in this patient population is largely unknown.

6.3.

Rationale for the use of bevacizumab beyond progression in ovarian cancer 20

All five phase III trials described above have demonstrated that bevacizumab improves PFS when given in combination with first- or second-line chemotherapy. Based on results of the first four of these trials to report, bevacizumab-containing regimens are now approved in Europe in the front-line, the platinum-sensitive recurrent and the platinum-resistant recurrent settings [47] and in the USA in the platinum-resistant recurrent setting [82]. Nevertheless, there are no data available to answer the important question of whether bevacizumab can be used in combination with chemotherapy in both the front-line and recurrent setting in the same patient. In the OCEANS trial, patients previously treated with bevacizumab were not eligible [57]. In the AURELIA trial, such patients were allowed to enrol, but represented only 7% of the study population [59]. In the GOG0213 trial, 10% of patients had previously received bevacizumab and subgroup analyses of OS according to prior bevacizumab (a stratification factor) suggested at least similar OS benefit (HR 0.66) [58]. Nevertheless, the subgroup included only 67 patients and no firm conclusions can be drawn about the effect of bevacizumab in bevacizumab-pretreated ovarian cancer. Bevacizumab continued beyond disease progression is an intriguing clinical hypothesis with a compelling biological rationale. VEGF is expressed throughout the tumour life cycle and preclinical data suggest that continuous suppression of VEGF is required to achieve and maintain tumour control [83]. In malignancies where VEGF plays a role in progression, the development of resistance to cytotoxic chemotherapy does not necessarily mean that the tumour is no longer partially or significantly dependent on VEGF-mediated angiogenesis. The timing and mechanisms of resistance to bevacizumab are likely to be different from those for chemotherapy [84]. AntiVEGF therapy may sensitise tumour vasculature, resulting in anti-angiogenic and anti-tumour effects through multiple lines of chemotherapy [41,85]. Several completed or ongoing clinical trials have been designed to investigate the concept of bevacizumab beyond progression in a range of disease settings. In metastatic colorectal cancer, a prospective randomised phase III trial evaluated continued use of bevacizumab in 820 patients whose disease had progressed after standard first-line bevacizumab-based therapy [86]. Patients were randomised to receive second-line chemotherapy (oxaliplatin-based or irinotecan-based) with 21

or without bevacizumab (5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks). OS, the primary endpoint, was significantly improved in patients treated with bevacizumab beyond progression (HR 0.81, P=0.0062). Median OS was 11.2 months with continued bevacizumab versus 9.8 months in patients treated with chemotherapy alone. The results in metastatic colorectal cancer demonstrate that continuing bevacizumab beyond progression improves efficacy, even when PFS after first-line therapy is long (>9 months). Similarly, in metastatic breast cancer, patients randomised to receive bevacizumab with their second-line chemotherapy after progression on first-line bevacizumab-containing therapy had significantly improved PFS, the primary endpoint [87]. These data cannot be directly extrapolated to other malignancies. However, ongoing prospective phase III trials are exploring this strategy in non-small-cell lung cancer (AvaALL; ClinicalTrials.gov Identifier: NCT01351415) [88] and recurrent ovarian cancer (MITO-16/MaNGO OV-2, ClinicalTrials.gov Identifier: NCT01802749) and results are eagerly awaited. The MITO-16/MaNGO OV-2 trial in ovarian cancer recently started recruiting patients with platinum-sensitive recurrent ovarian cancer after first-line bevacizumab-containing therapy. Patients are randomised to receive second-line chemotherapy with or without bevacizumab (Fig. 5). First results are expected in 2016.

6.4.

Bevacizumab in the neoadjuvant setting

An ongoing controversy in ovarian cancer is the timing of chemotherapy in relation to surgery. The randomised EORTC-55971 clinical trial, which compared primary debulking surgery with neoadjuvant chemotherapy followed by interval debulking surgery, demonstrated similar PFS and OS with the two approaches [89]. The selection of patients most suitably treated with primary debulking surgery or neoadjuvant chemotherapy continues to be intensely debated. The safety and efficacy of integrating bevacizumab into front-line therapy after surgery (observing the recommended 28 days between surgery and initiation of bevacizumab) has been established in the GOG-0218 and ICON7 trials described above. The global single-arm ROSiA study provides additional data in the context of routine oncology practice. In an interim analysis of 22

ROSiA (n=912), the median time from surgery to start of bevacizumab-based therapy was 6.1 weeks (range 5.1–7.1 weeks) [90]. In 148 patients, chemotherapy (without bevacizumab) was given in the neoadjuvant setting. Incidences of selected adverse events of particular surgical relevance (wound-healing complications/infections, abdominal/pelvic pain, abscess/fistula, intestinal perforation/obstruction and bleeding) were not markedly different between subgroups of patients with versus without bowel resection, with interval versus primary debulking, according to surgical outcome, and according to the interval between surgery and bevacizumab. Overall, incidences of surgical complications (including gastrointestinal perforations) were within ranges reported in the two phase III bevacizumab trials in the front-line setting. As well as the robust data for post-operative bevacizumab in ovarian cancer, efficacy and safety data are beginning to emerge for bevacizumab as a component of neoadjuvant carboplatin and paclitaxel therapy in ovarian cancer. First results were recently reported from the NOVA study, undertaken in Spain by the Grupo Español de Investigación en Cáncer de Ovario [66]. In this randomised phase II trial, patients receive carboplatin and paclitaxel either alone or with bevacizumab followed by post-operative bevacizumab given for up to a total of 22 cycles. No significant improvement was seen with bevacizumab for the primary endpoint of complete macroscopic response rate at the time of interval debulking surgery. However, per-protocol analysis showed that patients completing neoadjuvant bevacizumab had higher rates of complete and optimal surgeries compared with those receiving chemotherapy alone. The neoadjuvant bevacizumab regimen was feasible and tolerable. In a second ongoing randomised phase II trial, ANTHALYA (ClinicalTrials.gov Identifier: NCT01739218), conducted by French investigators, bevacizumab is combined with neoadjuvant carboplatin and paclitaxel and then continued after surgery for up to a total of 26 cycles [65]. The primary endpoint is the percentage of patients achieving complete resection after interval debulking. Secondary endpoints include safety, ORR (before surgery and at treatment completion) and PFS.

6.5.

Investigational anti-angiogenic strategies

23

Recently, results of phase III trials exploring other anti-angiogenic therapies (pazopanib, nintedanib) in the front-line setting have been reported. Both trials indicated a significant improvement in PFS when these drugs were given either as maintenance therapy alone after frontline chemotherapy (pazopanib) or concurrently with front-line chemotherapy and then continued as a single agent (nintedanib) [91,92], supporting the pivotal role of anti-angiogenic strategies in the management of ovarian cancer. Phase III results are also available for investigational agents in the recurrent setting. In the three-arm randomised phase III ICON6 trial in platinum-sensitive recurrent ovarian cancer, cediranib given in combination with platinum-based chemotherapy and then continued as a single agent resulted in significantly improved PFS and OS compared with chemotherapy alone [93]. Significantly improved PFS has also been reported with the addition of cediranib to the PARP inhibitor olaparib in a recently presented randomised phase II trial [94]. Also in the recurrent setting, the angiopoietin-1 and -2 inhibitor trebananib was shown to significantly improve PFS (but not OS) when combined with weekly paclitaxel in the TRINOVA-1 trial [95,96]. Currently all these agents remain investigational, but the future landscape may include a range of biological agents and further studies evaluating sequential strategies are warranted.

7.

Conclusions

Bevacizumab combined with chemotherapy provides a statistically and clinically significant improvement in PFS in the primary and recurrent advanced ovarian cancer settings. Exploratory analyses suggest an OS benefit in subgroups of patients defined according to residual disease and/or disease stage and have led to provocative hypotheses relating to patient selection, which need further evaluation and validation. Ongoing clinical trials are aiming to address currently unanswered questions, such as the potential of bevacizumab given until disease progression in the front-line setting, the role of bevacizumab in patients previously exposed to bevacizumab in the front-line setting, the combination of bevacizumab with different paclitaxel schedules, and the incorporation of bevacizumab into neoadjuvant chemotherapy regimens. In the meantime, consistent efficacy benefits in randomised phase III trials support a pivotal role of anti-angiogenic 24

strategies in ovarian cancer, and initial promise has translated into positive phase III results. As treatment options expand, the outlook for women with ovarian cancer is at last slowly but steadily improving.

Conflict of interest statement

NC received research support and honoraria for lecturing and advisory boards from Roche, AstraZeneca, GSK, Clovis, MSD, Pharmamar and AMGEN. SP has received research grants from Roche, GSK and AstraZeneca, and honoraria from Roche and AstraZeneca. FR has received research support and honoraria for advisory boards from Roche, Pharmamar and AMGEN. PFC and GS declare that they have no conflict of interest.

Author contributions

NC contributed in writing and revising the article. PFC, FR and GS contributed to drafting the manuscript. SP contributed to the conception and writing of the paper. All authors approved the final version for submission.

Acknowledgements

Medical writing and editorial support was funded by Roche Italy.

Role of the funding source

The sponsor was not involved in analysis and interpretation of the data.

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37

Table 1 Overview of GOG-0218 and ICON7 trial designs and results. GOG-0218 [46–48] Design

ICON7 [49]

Double-blind, placebo-



Open-label

controlled



2 arms



3 arms



Bevacizumab 7.5 mg/kg for



Bevacizumab 15 mg/kg every



12 months

3 weeks for 15 months Primary endpoint



PFS (RECIST and/or CA-125)



Regulatory-required PFS

only progression not

(censored for CA-125 and non-

permitted)



PFS (RECIST, CA-125-

protocol therapy) Independent review

Yes (exploratory analysis of PFS)

No

Advanced stage with macroscopic

Early and advanced stages,

residual disease

including patients without

committee Patient population

residual disease Crossover to anti-

31% (chemotherapy-alone arm)

4%* (chemotherapy-alone arm)

angiogenic therapy in

17% (chemotherapy + extended

2%* (chemotherapy +

subsequent lines, % of

bevacizumab arm)

bevacizumab arm)

PFS hazard ratio

0.70 (P <0.0001)

0.86 (P=0.0185)

Median PFS

10.6 months (chemotherapy alone,

16.9 months (chemotherapy

n=625)

alone, n=764)

14.7 months (chemotherapy +

19.3 months (chemotherapy +

extended bevacizumab, n=623)

bevacizumab, n=764)

patients Primary efficacy outcome

38

*Maximum numbers of patients that may have received further anti-angiogenic treatment at the time of data cut-off (exact numbers not known, as many enrolled in blinded studies). PFS, progression-free survival.

Table 2 Summary of key ongoing or completed trials evaluating bevacizumab. Treatme

Chemothe

nt setting rapy partner

Bevacizu

Control

Primary

Patient

mab

arm

endpoint

populatio

dose and

Status

n

treatment duration Randomi sed phase III GOG-

Front-

Carboplati

0218

line

n + q3w IV q3w for paclitaxel

ICON7

15 mg/kg

Stage III

Complete,

in + q3w

(macrosc

published/pres

15

IV

opic) or

ented [46,48]

months

paclitaxel

stage IV

7.5

Carboplat

Front-

Carboplati

line

n + q3w IV mg/kg paclitaxel

Carboplat

PFS

PFS

Stage I–

Complete,

in + q3w

IIA grade

published/pres

q3w for

IV

3 or clear-

ented [49,53]

12

paclitaxel

cell or

months

stage IIB– IV

GOG262

Front-

Carboplati

Optional

Carboplat

line

n + weekly 15 mg/kg

in + q3w

dose-

q3w until

IV

dense IV

progressi

paclitaxel 39

PFS

Stage II–

Primary

IV

endpoint reported [64]

paclitaxel GOG252

Front-



line



on

IP

15 mg/kg

Carboplat

PFS

Optimally

carbop

q3w for

in + q3w

or

latin +

15

IV

suboptim

weekly

months

paclitaxel

ally

IV

+

debulked

paclita

bevacizu

stage III–

xel

mab

IV

Fully recruited

IP cisplati n+ weekly IV and IP paclita xel

AGO-

Front-

Carboplati

OVAR

line

n + q3w IV q3w for

in + q3w

paclitaxel

30

IV

months

paclitaxel

17 (BOOST

15 mg/kg

)

Carboplat

PFS

Stage

Fully recruited

IIB–IV

+ bevacizu mab (15 months)

OCEAN

Platinum

Carboplati

15 mg/kg

Carboplat

S

-

n+

q3w until

sensitive

gemcitabi

PD

Measurab

Complete,

in +

le, one

published/pres

gemcitabi

prior

ented [57,62]

40

PFS

recurrent

ne +

ne

chemothe

bevacizu

rapy

mab

regimen

MITO-

Platinum

Carboplati

10 mg/kg

Carboplat

PFS

Stage

16/MaN

-

n + either

q2w or

in + either

IIIB–IV

GO OV-

sensitive

PLD or

15 mg/kg

PLD or

progressi

2 (BBP)

recurrent

gemcitabi

q3w until

gemcitabi

ng/

ne or

PD

ne or

recurring

paclitaxel

paclitaxel

≥6

(investigat

(investiga

months

or’s

tor’s

after

choice)

choice)

front-line

Recruiting

bevacizu mab + chemothe rapy GOG-

Platinum

Carboplati

15 mg/kg

0213

-

n + q3w IV q3w until

in + q3w

sensitive

paclitaxel

IV

PD

recurrent

Carboplat

OS

Platinum-

Accrual

sensitive

complete, presented [58]

paclitaxel

AGO-

Platinum

Carboplati

10 mg/kg

Carboplat

OVAR2.

-

n + PLD +

q2w until

in +

21

sensitive

bevacizu

PD

gemcitabi

recurrent

mab

PFS

Platinum-

Recruiting

sensitive

ne + bevacizu mab

AURELI

Platinum

Weekly

15 mg/kg

Weekly

A

-

paclitaxel

q3w or

paclitaxel 41

PFS

Platinum-

Complete,

resistant

published/pres

resistant

or PLD or

10 mg/kg

or PLD or

recurrent

topotecan

q2w until

topotecan

ented [59]

PD ANTHAL

Neoadju

Carboplati

15 mg/kg

Carboplat

Complet

Unresecta

Fully recruited

YA

vant

n+

q3w

in +

e

ble stage

[65]

paclitaxel

cycles 1–

paclitaxel

resectio

IIIC/IV

NOVA

3 before

n rate

surgery

after

and 2–26

interval

after

debulkin

surgery

g

Neoadju

Carboplati

15 mg/kg

Carboplat

Complet

Inoperabl

Fully

vant

n+

q3w

in +

e

e but with

recruited,

paclitaxel

cycles 1–

paclitaxel

respons

interval

primary

3 before

e rate

debulking

endpoint

surgery

after

planned

presented [66]

and 2–22

neoadju

after

vant

surgery

therapy

Singlearm studies OCTAVI

Front-

Carboplati

7.5

NA

PFS

Complete,

A

line

n + weekly mg/kg

published

IV

q3w for

[67,68]

paclitaxel

12 months

ROSiA

Front-

Carboplati

15 mg/kg

NA 42

Safety

Newly

Fully recruited

line

n + IV

q3w for

diagnose

paclitaxel

24+

d stage

(q3w or

months

IIB-IV or

weekly,

or until

clear cell

investigat

PD if

or grade 3

or’s

earlier

stage I-IIa

[69]

choice)

IP, intraperitoneal; IV, intravenous; NA, not applicable; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin

Figure captions:

Fig. 1. GOG-0218: A) investigator-assessed PFS, all patients [Roche data on file]; B) subgroup analyses of PFS [46]; C) final OS, stage IV subgroup [49]. B15, bevacizumab 15 mg/kg; CI, confidence interval; CP, carboplatin and paclitaxel; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; Pl, placebo.

Fig. 2. ICON7 subgroup of patients at high risk of progression: A) PFS [52]; B) OS [53]. B7.5, bevacizumab 7.5 mg/kg; CP, carboplatin and paclitaxel.

Fig. 3. OCEANS: Investigator-assessed PFS (primary endpoint) [57]. B15, bevacizumab 15 mg/kg; CI, confidence interval; GC, gemcitabine; HR, hazard ratio; PFS, progression-free survival; Pl, placebo.

Fig. 4. AURELIA: PFS [59]. B15, bevacizumab 15 mg/kg; CI, confidence interval; CT, chemotherapy; HR, hazard ratio; PFS, progression-free survival. 43

Fig. 5. Design of the MITO-16/MaNGO OV-2 trial. PLD, pegylated liposomal doxorubicin; R, randomisation.

44

Fig. 1

45

Fig. 2

Fig. 3

46

Fig. 4

Fig. 5

47