Antiangiogenic agents as a maintenance strategy for advanced epithelial ovarian cancer

https://doi.org/10.1016/j.critrevonc.2012.09.012Get rights and content

Abstract

Bevacizumab is the first antiangiogenic agent to have demonstrated benefit as first-line and maintenance therapy in epithelial ovarian cancer (EOC), with the Gynecologic Oncology Group 218 and ICON 7 phase III trials revealing significantly prolonged progression-free survival (PFS) for carboplatin/paclitaxel plus bevacizumab followed by bevacizumab maintenance versus carboplatin/paclitaxel alone. Results are forthcoming from several phase III maintenance trials of investigational antiangiogenic agents, each evaluating PFS as the primary endpoint: AGO-OVAR12/LUME-Ovar1 (nintedanib [BIBF 1120]), AGO-OVAR16 (pazopanib), and TRINOVA-1, -2, and -3 (AMG 386). Here we review available data and ongoing clinical trials of investigational antiangiogenic agents as maintenance therapy for EOC. Current controversies, including uncertainties regarding the (1) most appropriate clinical trial endpoints, (2) optimal dosing, duration, and timing of therapy (e.g., with first-line chemotherapy and/or as maintenance monotherapy), and (3) feasibility, tolerability, and cost of adding these agents to platinum/taxane regimens are also highlighted.

Introduction

Since supplanting cisplatin/cyclophosphamide during the 1990s, platinum/taxane chemotherapy remains the international standard of care for the first-line treatment of advanced epithelial ovarian cancer (EOC). Despite initial chemosensitivity to platinum/taxane combinations, most patients with advanced EOC relapse after first-line therapy [1]. Thus, effective maintenance therapies are needed to extend these responses to delay or prevent recurrence. Currently, there is no established role for maintenance chemotherapy for EOC, as studies have been primarily negative due to uncertain clinical benefit and increased risk of cumulative toxicity [2], [3], [4], [5], [6], [7], [8]. The National Comprehensive Cancer Network guidelines list a 12-month course of single-agent paclitaxel 135 mg/m2 to 175 mg/m2 every 4 weeks for 12 cycles as a category 2B option (e.g., based on lower-level evidence and non-uniform consensus, but no major disagreement) for maintenance therapy for advanced EOC [9], stemming from results of Gynecologic Oncology Group (GOG) 178. This trial demonstrated prolonged progression-free survival (PFS) with maintenance paclitaxel 175 mg/m2 every 4 weeks for 12 months versus 3 months (28 vs 21 months; adjusted P = 0.0023) but with high toxicity and no overall survival (OS) benefit [3]. More recent results of After-6 Protocol 1, an Italian phase III trial of paclitaxel 175 mg/m2 every 3 weeks as 6-cycle maintenance therapy in patients achieving complete response (CR) from 6 cycles of platinum/paclitaxel, demonstrated no significant benefits for paclitaxel versus observation with respect to 2-year PFS (59% vs 54%) or 2-year OS (87% vs 90%) [8]. The lack of clear benefit observed to date for cytotoxic chemotherapeutic agents makes the suggestion of consolidative therapy using molecular agents more appealing.

Several ongoing clinical trials are evaluating molecularly targeted agents, including antiangiogenic agents, as maintenance therapy in EOC, with the hope that these agents will provide an optimized treatment strategy for these patients. Angiogenesis plays a fundamental role in normal ovarian physiology as well as in the pathogenesis of ovarian cancer, promoting tumor growth and progression through ascites formation and metastatic spread [10], [11], [12]. Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) are expressed in ovarian cancer [11], [13], [14], and increased VEGF expression has been associated with the development of malignant ascites [11]. Other angiogenesis pathways involved in ovarian cancer pathogenesis include platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF). Higher PDGF levels have been observed in ovarian carcinomas than in benign tissue and in malignant ascites, and have been linked to poor survival [15], [16], [17], [18], [19], [20], [21]. Additional evidence supports the involvement of the FGF pathway in angiogenesis, ovarian physiology [22], [23], [24], [25], [26], [27], and ascites [25]. Moreover, both PDGF [18], [28], [29] and FGF signaling pathways [30], [31], [32] appear to be involved in VEGF resistance described across various solid tumors, suggesting that combined inhibition of VEGF and PDGF and/or FGF may more completely block angiogenesis than VEGF inhibition alone [29], [33], [34], [35].

Herein, the current evidence (based on publications indexed on the U.S. National Library of Medicine PubMed.gov and abstracts/presentations at key oncology congresses) and ongoing clinical trials (indexed on the U.S. National Institutes of Health ClinicalTrials.gov) for the use of investigational antiangiogenic agents as maintenance therapy for EOC are reviewed, including a discussion of current controversies surrounding use of these agents in this treatment setting.

Of the antiangiogenic agents currently being evaluated as maintenance therapy for EOC (Table 1), bevacizumab (Avastin®, Genentech; South San Francisco, CA, USA), an anti-VEGF monoclonal antibody, is the most widely studied both across tumor types and specifically in EOC. Preclinical data suggest benefit with bevacizumab as maintenance therapy after cisplatin-based chemotherapy. Single-agent bevacizumab inhibited or delayed disease recurrence and prolonged survival in a murine ovarian cancer model [45]. Clinical study results in gynecologic malignancies collectively support the rationale for studying bevacizumab in EOC [46], [47], [48], [49], [50], [51], [52], [53], including as maintenance therapy. In a phase II study (N = 62) of carboplatin/paclitaxel plus bevacizumab 15 mg/kg (followed by bevacizumab maintenance therapy for 1 year), which enrolled patients with previously untreated stage ≥IC EOC, primary peritoneal cancer (PPC), fallopian tube cancer (FTC), or uterine papillary serous carcinoma, the overall response rate (RR) based on Response Evaluation Criteria in Solid Tumors (RECIST) was 75% (45/60 [95% confidence interval (CI), 62–85%]) with a median PFS of 29.8 months. Median OS had not yet been reached at the time of publication [54]. Two cases of gastrointestinal perforation (GIP) were reported, both during the chemotherapy phase, but no grade 4 toxicities were associated with bevacizumab during the maintenance phase. These results support the treatment strategy being evaluated in GOG 218.

Two completed, recently published phase III trials evaluated bevacizumab as first-line therapy in combination with chemotherapy and as maintenance therapy in previously untreated EOC, PPC, or FTC (Fig. 1A and IB). Fig. 1C compares the GOG 218 (NCT00262847) and ICON 7 (NCT00483782) study designs. Fig. 1D summarizes differences in duration of bevacizumab maintenance therapy between these trials and the phase III GOG 252 (NCT00951496) and GOG 262 (NCT01167712) studies. Other key studies of bevacizumab in EOC with implications for maintenance therapy are also described below.

GOG 218. GOG 218, a 3-arm, multicenter study in the United States, evaluated chemotherapy (carboplatin/paclitaxel) versus chemotherapy plus bevacizumab versus chemotherapy plus bevacizumab followed by bevacizumab maintenance (Fig. 1A). The primary endpoint was originally OS but was changed to PFS, as there were emergent issues during the trial regarding the unblinding of treatment assignment. Based on the primary efficacy results, median PFS was significantly prolonged with chemotherapy plus bevacizumab followed by bevacizumab maintenance versus chemotherapy alone (14.1 vs 10.3 months, respectively; hazard ratio [HR], 0.717; 95% CI, 0.625–0.824; P < 0.001) [55]. However, there was no significant difference in PFS between patients who received chemotherapy plus bevacizumab (no bevacizumab maintenance) versus chemotherapy alone (11.2 vs 10.3 months; HR, 0.908; 95% CI, 0.795–1.040; P = 0.16). At the time of this PFS analysis (median follow-up of 17.4 months), there was no significant difference in OS versus the control arm for use of bevacizumab with chemotherapy with (HR, 0.915; 95% CI, 0.727–1.152; P = 0.45) or without (HR, 1.036; 95% CI, 0.827–1.297; P = 0.76) maintenance. These PFS and OS results were consistent with those from an updated analysis, at which time 47% of patients had died. Adding bevacizumab to chemotherapy was generally well tolerated; adverse events (AEs; including GIP) were similar to previous bevacizumab studies and included increased rates of grade ≥2 hypertension (7.2% with chemotherapy alone vs 22.9% and 16.5% with chemotherapy plus bevacizumab with and without maintenance bevacizumab, respectively). Overall, bevacizumab represents the first molecularly targeted and first antiangiogenic agent to show significant benefit, in the form of prolonged PFS, as first-line and maintenance therapy of EOC.

ICON 7. ICON 7 was a 2-arm, multicenter Gynaecologic Cancer InterGroup (GCIG) study in the European Union, Norway, Canada, and Australasia that investigated chemotherapy versus chemotherapy plus bevacizumab followed by bevacizumab maintenance in advanced EOC, PPC, or FTC, which also enrolled patients (up to 10% of the population) with high-risk stage I/IA disease of grade 3 or clear-cell histology (Fig. 1B). At a median follow-up of 19.4 months, the primary endpoint of median PFS was significantly longer with chemotherapy plus bevacizumab followed by bevacizumab maintenance versus chemotherapy alone (19.0 vs 17.3 months, respectively; HR, 0.81; 95% CI, 0.70–0.94; P = 0.004) [56]. Final survival data are expected in 2013; after a median follow-up of 28 months, the survival data did not demonstrate a significant improvement in OS overall (HR, 0.85; 95% CI, 0.69–1.04; P = 0.11), but a post hoc exploratory OS analysis did show a significant improvement in the high risk for progression subgroup (FIGO stage III disease with debulking residuum > 1.0 cm or stage IV disease; HR, 0.64; 95% CI, 0.48–0.85; P = 0.002). Differences in toxicity included all-grade bleeding (40% with bevacizumab vs 12% with chemotherapy alone), grade ≥2 hypertension (18% vs 2%), grade ≥3 thromboembolic events (7% vs 3%), and GIP (1.3% [10 cases] vs 0.4% [3 cases]).

OCEANS. A multicenter, randomized, double-blind, phase III trial evaluated bevacizumab maintenance therapy in the relapsed setting (NCT00434642 [OCEANS]). Patients with platinum-sensitive recurrent EOC, PPC, or FTC were randomized to receive either carboplatin/gemcitabine/bevacizumab followed by maintenance bevacizumab or carboplatin/gemcitabine/placebo followed by maintenance placebo. Maintenance therapy was administered every 3 weeks until disease progression. PFS was the primary endpoint; 484 patients were enrolled with measurable disease, no prior chemotherapy for recurrent disease, and no history of receiving any VEGF/VEGFR targeted agent. Recently reported results (at which time the OS data were immature [29% event rate]) demonstrated significant improvement with bevacizumab in PFS (12.4 vs 8.4 months; HR, 0.484; 95% CI, 0.388–0.605; P < 0.0001) and overall RR (78.5% vs 57.4%; P < 0.0001) but not median OS (35.5 vs 29.9 months; HR, 0.751; 95% CI, 0.537–1.052; P = 0.094) compared with chemotherapy alone [57].

In terms of toxicity, hypertension is the most common drug-related AE associated with bevacizumab therapy in EOC, but it is medically manageable [58]. Evidence suggests that the risk of GIP is higher with bevacizumab in EOC than in other tumor types, with rates as high as 11.4% during individual clinical trials [47] and approximately 5% across trials [59] versus 0.9% (95% CI, 0.7–1.2%) in a meta-analysis of randomized, controlled phase II and III clinical trials in other tumor types [60]. The degree of pretreatment influences risk of GIP in EOC, with the 11.4% incidence consisting entirely of patients receiving 3 prior treatment regimens (0% [0/23] with 2 prior regimens, 24% [5/21] with 3 prior regimens; P < 0.01) [47]. Bevacizumab may heighten the propensity for GIP in EOC through necrotic effects on abdominal involvement (e.g., peritoneal carcinomatosis, bowel serosa spread) and/or impaired wound healing, ischemia, or both, as a consequence of inhibiting VEGF [59].

OCTAVIA. This single-arm, phase II study evaluated bevacizumab with chemotherapy (paclitaxel [weekly]/carboplatin [every 3 weeks]) followed by bevacizumab maintenance for up to 1 year as a front-line regimen for patients with stage I/IIA disease (grade 3 or clear-cell histology) or stage IIB/IV disease (any grade). The most common grade ≥3 hematological AEs included neutropenia (60%), anemia (8%), and thrombocytopenia (7%). Bevacizumab-related AEs (grade ≥3) that were described as of special interest included thromboembolic events (6.3%), hypertension (4.2%), and GIP (0.5%) [61]. Overall, the safety profile of weekly paclitaxel in combination with bevacizumab and carboplatin was comparable to that observed for ICON 7, where paclitaxel was administered once every 3 weeks.

AURELIA. AURELIA was a 2-arm, multicenter, randomized, phase III trial that evaluated chemotherapy alone versus chemotherapy plus bevacizumab in platinum-resistant EOC, PPC, or FTC. Patients with platinum-resistant (progression ≤6 months after ≥4 cycles of platinum-based therapy) disease were randomized to receive chemotherapy (pegylated liposomal doxorubicin [PLD], topotecan, or paclitaxel, as per the investigator's choice) alone or with bevacizumab until disease progression. At a median follow-up of ≥13 months (13.9 months in the chemotherapy arm; 13.0 months in the bevacizumab arm), median PFS was significantly prolonged with chemotherapy plus bevacizumab versus chemotherapy alone (6.7 vs 3.4 months, respectively; HR, 0.48; 95% CI, 0.38–0.60; P < 0.001) [62]. Similarly, chemotherapy plus bevacizumab was associated with a significant increase in overall RR (27.3% vs 11.8%; P = 0.001) relative to chemotherapy alone. The most common grade ≥3 AEs with bevacizumab that were described as of special interest were hypertension (7.3% vs 1.1% in the chemotherapy arm), thromboembolic events (5.0% vs 4.4%), proteinuria (1.7% vs 0%), and GIP (1.7% vs 0%). Of note, strict eligibility criteria, which excluded patients with > 2 previous anticancer treatments, a history of bowel obstruction/abdominal fistula, or clinical evidence of rectosigmoid involvement, may have minimized bevacizumab-associated AEs in this study. Although AURELIA did not include a maintenance phase due to a low RR, this trial speaks to the safety and efficacy of bevacizumab in the treatment of platinum-resistant EOC, PPC, and FTC.

GOG 213. This randomized, phase III trial is currently recruiting patients to evaluate adjuvant combination chemotherapy (paclitaxel or docetaxel, plus carboplatin) alone or with bevacizumab in platinum-sensitive, recurrent EOC, PPC, and FTC (NCT00565851) following cytoreductive surgery. Eligible patients must have had a CR to first-line platinum/taxane therapy (≥3 cycles) and a treatment-free interval ≥6 months without disease progression. Inclusion of bevacizumab or another biologic as a component of front-line therapy (with or without maintenance) is allowed if ≥6 months have elapsed since completion of therapy/identification of recurrent disease. All patients will be randomized to receive (1) chemotherapy alone or (2) chemotherapy/bevacizumab followed by bevacizumab maintenance until disease progression or unacceptable toxicity. Those eligible for surgery will undergo cytoreduction prior to treatment randomization. Primary endpoints include OS, PFS, and quality of life.

AGO-OVAR17. This randomized, phase III trial is currently recruiting patients to evaluate the optimal treatment duration of bevacizumab maintenance following front-line therapy (bevacizumab plus carboplatin/paclitaxel) in patients with primary EOC, PPC, or FTC (NCT01462890; BOOST). Patients will receive chemotherapy/bevacizumab once every 3 weeks for up to 6 cycles (until disease progression or unacceptable toxicity) followed by either 16 or 38 cycles of bevacizumab maintenance therapy. The primary endpoint is PFS, and secondary endpoints include objective RR, OS, and quality of life. This trial was initiated in late 2011, and the primary study completion is planned for November 2018.

Blocking multiple targets involved in angiogenesis may be an effective treatment approach as maintenance therapy for advanced EOC.

Nintedanib (BIBF 1120; Boehringer Ingelheim; Ingelheim, Germany) targets VEGFR-1, -2, and -3, PDGFR-α/β, FGFR-1, -2, and -3, members of the v-src sarcoma viral oncogene homolog (Src) family, and fms-like tyrosine kinase 3 (Flt-3) (Table 1) [63]. In a phase II randomized trial comparing nintedanib 250 mg twice daily with placebo as maintenance therapy in 84 patients with recurrent EOC, PPC, or FTC who responded to their last (second-line or higher) chemotherapy, the primary endpoint of 36-week PFS was 16.3% with nintedanib versus 5.0% with placebo (HR, 0.65; 95% CI, 0.42–1.02; P = 0.06) [64]. The incidence of grade 3/4 AEs was similar with nintedanib and placebo (34.9% vs 27.5%; P = 0.49), and the most common grade 3/4 AEs with nintedanib were hepatic enzyme elevations (51.2% vs 7.5%, respectively; P < 0.001).

Safety results from a phase I study of standard carboplatin/paclitaxel plus twice-daily nintedanib (100 mg to 250 mg) in 22 patients with advanced or recurrent gynecologic malignancies support the tolerability of nintedanib, with 200 mg twice daily as the maximum tolerated dose (MTD) [65]. All patients experienced gastrointestinal AEs (primarily grade 1/2). In patients treated with nintedanib 200 or 250 mg twice daily, diarrhea and alanine aminotransferase (ALT) elevations were the most common grade 3/4 AEs (n = 4 each, all grade 3) followed by leukopenia, neutropenia, and aspartate aminotransferase (AST) elevation (n = 3 each). Across all dose levels, of 7 patients evaluable for RECIST-assessed response, 1 had a CR (MTD-treated EOC patient) and 4 had partial response (PR; of whom 2 had EOC); all 10 CA-125–evalauable EOC patients achieved a CA-125 response. Patients who did not progress during the combination phase were eligible to receive nintedanib maintenance monotherapy; among 16 patients who received nintedanib monotherapy, 1 dose-limiting toxicity was reported (ALT elevation).

An ongoing placebo-controlled phase III trial is investigating the combination of nintedanib with carboplatin/paclitaxel in the first-line setting followed by nintedanib maintenance therapy until disease progression or for a maximum of 120 weeks after randomization in EOC, PPC, or FTC (NCT01015118 [AGO-OVAR12/LUME-Ovar1]; Fig. 2). Eligibility requirements for AGO-OVAR12/LUME-Ovar1 include stage IIB to IV disease; Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; prior surgery (e.g., debulking surgery) or either biopsy or limited surgery for stage IV disease (if surgical debulking not appropriate) provided that the diagnosis is histologically confirmed and no surgery is planned prior to progression; and no prior chemotherapy, antiangiogenic therapy, or radiotherapy. Data collection for the primary endpoint of PFS is expected to occur in 2016.

Sorafenib (Nexavar®, Bayer; Leverkusen, Germany) targets VEGFR-2 and -3, PDGFR-β, stem cell factor receptor (c-kit), Flt-3, and v-raf 1 murine leukemia viral oncogene homolog 1 (Raf) (Table 1) [66]. A German phase II trial found that adding sorafenib 400 mg twice daily to carboplatin/paclitaxel as neoadjuvant therapy for patients with advanced stage IIIC/IV EOC and large-volume ascites was not feasible; however, grade 3/4 toxicity necessitated the withdrawal of the first 4 enrolled patients and early closure of the trial [67]. Sorafenib also has been evaluated as a single agent [68] and in combination with chemotherapy [69], [70] in recurrent EOC. A Princess Margaret Hospital phase II Consortium trial of sorafenib 400 mg twice daily plus weekly gemcitabine in pretreated EOC failed to meet its primary endpoint of an overall RR ≥35% [70]. Regarding grade 3/4 toxicity, hematologic AEs were most common and manageable (primarily lymphopenia [28%] and neutropenia [26%]), but high rates of dose delays and reductions support studying an alternative dosing schedule. In the recently published GOG trial (GOG 170F) of sorafenib 400 mg twice daily as second-line or third-line therapy for recurrent EOC or PPC (n = 71), the primary endpoint of 6-month PFS rate was 24% (90% CI, 15–35%), with median PFS and OS of 2.1 months and 16.3 months, respectively [68]. The most common grade 3/4 AEs were metabolic toxicities (n = 10), hand-foot syndrome (n = 9), and rash (n = 7) with no reports of GIP. Preliminary results from an ongoing phase II study of intermittent sorafenib and bevacizumab in bevacizumab-naive patients with recurrent EOC showed PR in 6 of 25 evaluable patients and clinical benefit rate of 88% [71]. Grade 3/4 AEs included hypertension (47%), thrombosis (13%), and elevated liver enzymes (7%); grade 2 hand-foot syndrome occurred in 80% of patients.

A randomized phase II study is evaluating sorafenib versus placebo as maintenance therapy in patients with stage III/IV EOC or PPC who have achieved clinical CR (confirmed by standard computed tomography [CT] or magnetic resonance imaging [MRI]) after surgical debulking and 4–6 cycles of standard platinum/taxane chemotherapy (NCT00791778 [Study 12007]). An ECOG performance status of 0 or 1 and normal serum CA-125 level within 7 days of receiving the initial sorafenib dose are required. PFS is the primary endpoint, with complete data expected in June 2011.

Pazopanib (GlaxoSmithKline; London, UK) targets VEGFR-1, -2, and -3, PDGFR-α/β, FGFR-1 and -3, and c-kit (Table 1) [72]. A phase II open-label study evaluated pazopanib 800 mg/day in patients with pretreated recurrent EOC or PPC (no prior antiangiogenic therapy) with complete CA-125 response to initial platinum-based chemotherapy and subsequent CA-125 elevation to ≥42 U/mL [73]. The primary endpoint of CA-125 response (≥50% decrease from baseline, confirmed after ≥21 days) was seen in 11 of 36 patients (31%; 95% CI, 16–48%), with median duration of 113 days, and an additional 20 patients (56%) had SD with median duration of 80 days. In patients with measurable disease at baseline, the overall CA-125–assessed RR was 18% (3/17; 95% CI, 3.8–43.4%). The most common grade 3 AEs were fatigue and γ-glutamyl transpeptidase elevation (11% for each) followed by diarrhea and ALT elevation (8% for each). One patient developed grade 4 peripheral edema.

In light of antitumor activity and acceptable tolerability for pazopanib in recurrent EOC or PPC, an ongoing phase III trial is investigating pazopanib versus placebo for 24 months as maintenance therapy in patients with non-bulky stage II–IV EOC, PPC, or FTC with a CR, PR, or SD after surgical debulking and at least 5 cycles of first-line platinum/taxane chemotherapy (NCT00866697 [AGO-OVAR16]; Fig. 3). The inclusion criteria included an ECOG performance status of 0 or 1 and ability for randomization between 3 and 12 weeks from the last dose of first-line chemotherapy, with resolution of all major toxicities. Documented residual disease in need of imminent second-line therapy or history of prior anti-VEGF therapy precluded participation in the study. Enrollment is complete, whereas full data collection for the PFS primary endpoint is expected in 2012.

Cediranib (Recentin™, AstraZeneca; Wilmington, DE, USA) targets VEGFR-1, -2, and -3, PDGFR-α/β, FGFR-1, and c-kit (Table 1) [43]. Cediranib 45 mg/day or 30 mg/day has been evaluated in 2 phase II studies in patients with either platinum-resistant or -sensitive recurrent EOC, PPC, or FTC [74], [75]. In the first, which required no prior VEGF/VEGFR-targeted therapy, the primary endpoint of clinical benefit was observed in 30% of patients (PR, 17% [95% CI, 7.6–30.8]; SD, 13% [95% CI, 4.8–25.7]) with a mean duration of response of 3.9 months. The most common drug-related grade ≥3 AEs were hypertension (46%), fatigue (24%), and diarrhea (13%) [74]. In the second study, for which the primary endpoints were objective RR and PFS, RRs were 41% for platinum-sensitive and 29% for platinum-resistant patients; median survival was 11.9 months, with no significant difference between platinum-sensitive and -resistant patients. The most common grade ≥3 AEs were hypertension (33%) and fatigue (20%) [75].

A multi-stage phase III trial is assessing the safety and efficacy of platinum-based chemotherapy alone versus chemotherapy with concurrent cediranib versus chemotherapy with concurrent and maintenance cediranib in platinum-sensitive relapsed EOC, PPC, or FTC (NCT00532194 [ICON 6]; Fig. 4). The inclusion criteria include an ECOG performance status of 0 to 1 and more than 6 months since the completion of first-line chemotherapy. Primary endpoints include safety, PFS, and OS, and trial completion is expected in October 2013. Based on blinded safety data available for 60 treated patients during stage I, enrollment has expanded into stage II [76].

AMG 386 (Amgen; Thousand Oaks, CA, USA) is a peptide-Fc fusion protein (or peptibody) that targets angiogenesis by inhibiting binding of both angiopoietin 1 and 2 to the Tie2 receptor [77]. In a phase I trial of AMG 386, 1 patient with advanced refractory ovarian cancer achieved a PR and durable CA-125 response [78]. A phase II randomized trial has since evaluated weekly paclitaxel 80 mg (3 weeks on/1 week off) plus weekly AMG 386 10 mg/kg, AMG 386 3 mg/kg, or placebo in 161 patients with recurrent EOC, PPC, or FTC, with PFS as the primary endpoint [44]. Median PFS with AMG 386 10 mg/kg and 3 mg/kg was 7.2 months and 5.7 months, respectively, versus 4.6 months with placebo (HR for AMG 386 arms combined, 0.76; 95% CI, 0.52–1.12; P = 0.165), with evidence of a significant dose–response effect (P = 0.037). The most common grade ≥3 AE was hypokalemia with both doses of AMG 386 (12% and 11% for 10 mg/kg and 3 mg/kg, respectively, vs 4% for placebo).

Several phase III clinical trials (TRINOVA-1 [NCT01204749; Fig. 5A], TRINOVA-2 [NCT01281254; Fig. 5B], and TRINOVA-3 [NCT01493505; Fig. 5C]) are evaluating AMG 386 in EOC, PPC, or FTC. TRINOVA-1 is evaluating paclitaxel in combination with either AMG 386 or placebo in previously treated patients with EOC, PPC, or FTC (Fig. 5A). Eligible patients must have ECOG performance status of 0 or 1 and either received ≤3 prior platinum-based chemotherapy regimen(s) or had a platinum-free interval < 12 months from first platinum-based therapy. The initiation date was October 2010 and the estimated primary completion date is July 2013. TRINOVA-2 is evaluating pegylated liposomal doxorubicin in combination with either placebo or AMG 386 in previously treated patients with EOC, PPC, or FTC (Fig. 5B). To be eligible for the TRINOVA-2 trial, patients also must have ECOG performance status of 0 or 1 and have received ≤3 prior platinum-based chemotherapy regimen(s) or had a platinum-free interval of < 12 months from the first platinum-based therapy. The study was initiated in March of 2011 and the primary study completion is planned for April 2014; of note, TRINOVA-2 was suspended in 2012 due to the global shortage of PLD, and further updates are awaited. In TRINOVA-3, AMG 386 is being combined with first-line carboplatin/paclitaxel for EOC, PPC, or FTC, followed by AMG 386 maintenance therapy for 18 months or until disease progression (Fig. 5C). To be eligible for the TRINOVA-3 trial, patients are required to have stage III or IV disease; ECOG performance status of 0 or 1; prior primary debulking surgery within 12 weeks of randomization (alternatively, patients with stage IIIC or IV disease may undergo interval debulking surgery after the first 3 cycles of study treatment); and no prior anticancer or experimental therapy for EOC, PPC, or FTC. The study was initiated in December 2011, with final data collection for the primary endpoint of PFS expected in 2016.

While antiangiogenic agents are currently the most promising molecularly targeted agents for EOC treatment, their optimal role has yet to be determined. Although there is no established role for maintenance chemotherapy for EOC, early clinical data with antiangiogenic agents in the maintenance setting appear promising. However, there are many controversies that must be considered with respect to using antiangiogenic agents as maintenance therapy for EOC.

One overarching question surrounding clinical research efforts to evaluate maintenance therapy for EOC and related gynecologic malignancies, regardless of modality, pertains to the appropriate endpoint. According to a recent report from the GCIG Fourth Ovarian Cancer Consensus Conference, endpoints for front-line/maintenance clinical trials need to specifically define and measure clinical benefit, which may include PFS, OS, toxicity, and/or patient-reported outcomes [79]. The recommended primary endpoints for future front-line/maintenance clinical trials for EOC were PFS, PFS at defined time point, or response for phase II studies screening for activity, recurrence-free survival for phase III studies in early EOC, and PFS and OS for phase III studies in advanced EOC. While both PFS and OS are important, PFS is often the preferred primary endpoint, owing to the confounding effect of subsequent therapy upon progression on OS. Of note, the observed PFS benefit with bevacizumab plus chemotherapy followed by maintenance bevacizumab led to approval of bevacizumab for advanced ovarian cancer in Europe in December 2011 [80].

Second, the appropriate dose of bevacizumab as maintenance therapy has not been established in clinical trials to date, and GOG 218 and ICON 7 evaluated different doses of bevacizumab (15 mg/kg vs 7.5 mg/kg, respectively). Of greater clinical importance than dose, the optimal duration of maintenance therapy remains an unanswered question that will persist following the completion of ongoing trials. In addition to the differences in number of maintenance bevacizumab cycles between GOG 218 and ICON 7, maintenance bevacizumab is being used differently within other ongoing GOG trials (GOG 252, GOG 213, and GOG 262, which are not designed to determine the benefits of bevacizumab vs no bevacizumab) (Fig. 1D). Administering bevacizumab until progression (as in GOG 262 but not GOG 252 or GOG 213, for which bevacizumab is being given for a defined period) is an intriguing strategy, particularly when the risk of recurrence is high (e.g., cases of bulky residual disease after primary surgery), as data for both GOG 218 and ICON 7 have shown convergence of the PFS curves subsequent to the end of bevacizumab maintenance therapy. Of note, further evidence that bevacizumab prevents progression or recurrence specifically during active treatment is provided by the National Surgical Adjuvant Breast and Bowel Project C-08 experience in stage II/III colorectal cancer, in which a 1-year course of bevacizumab (concurrent with 26 weeks of adjuvant chemotherapy followed by 26 weeks of monotherapy) did not improve 3-year disease-free survival (DFS) but improved DFS during bevacizumab exposure [81]. In ongoing trials of other agents in EOC, the duration of maintenance therapy is 2 years with pazopanib (AGO-OVAR16), approximately 60 weeks with cediranib (ICON 6), 18 months with AMG 386 (TRINOVA-3), and approximately 2 years with nintedanib (AGO-OVAR12/LUME-Ovar1).

A third controversy pertains to the optimal timing of the antiangiogenic regimen: combination with first-line chemotherapy only, combination with first-line chemotherapy and as maintenance therapy, or as maintenance therapy alone. Given the distinct pathophysiology of ovarian cancer, which confers recurrence in the majority of patients despite initial CRs, it is imperative to determine which treatment strategy will successfully prolong PFS beyond that of front-line combination therapy. While GOG 218 and ICON 7 both evaluated bevacizumab in combination with first-line chemotherapy followed by bevacizumab maintenance therapy, neither trial compared this strategy with chemotherapy alone followed by bevacizumab maintenance therapy. Similarly, the AGO-OVAR12/LUME-Ovar1 study is evaluating nintedanib in combination with carboplatin/paclitaxel and as maintenance therapy thereafter, the TRINOVA-3 study is evaluating AMG 386 in combination with carboplatin/paclitaxel followed by AMG 386 maintenance, and ICON 6 also includes concurrent cediranib in the chemotherapy phase. In contrast, clinical trials with sorafenib and pazopanib are evaluating these agents as maintenance therapy only after response to first-line platinum/taxane chemotherapy. Of note, although the HR associated with bevacizumab use is greater when used in treating recurrent ovarian cancer (AURELIA and OCEANS), the absolute benefit of bevacizumab as measured in months is greater when used in the front-line setting (GOG 218 and ICON 7).

Because of the potentially higher costs associated with newer targeted therapies compared with traditional chemotherapies, the cost-effectiveness of antiangiogenic therapies, especially bevacizumab, has also been a major point of debate in EOC. One analysis based on efficacy and safety results from the GOG 218 study found that bevacizumab was not cost-effective [82]. However, until the optimal dosing and scheduling of antiangiogenic therapies are established, a true evaluation of cost-effectiveness remains a challenge. In addition, the validation of predictive markers that could be used to select patients based on likelihood of response may further impact cost-effectiveness analyses of antiangiogenic therapy in EOC [83], [84].

Another important consideration for designing clinical trials of antiangiogenic therapy is the potential for increased toxicity when these agents are added to first-line chemotherapy. For example, the tolerability of pazopanib when combined with platinum/taxane regimens for EOC is unknown, while the combination of other antiangiogenic agents (e.g., nintedanib) with standard carboplatin/paclitaxel has already demonstrated feasibility. As discussed above, results from a phase II trial of sorafenib in combination with carboplatin/paclitaxel as neoadjuvant therapy in advanced EOC showed severe toxicities that required termination of the study after enrolling only 4 patients, suggesting that addition of sorafenib to carboplatin/paclitaxel is not feasible [67].

Finally, when maintenance chemotherapy is added subsequent to front-line therapy for EOC in routine clinical practice, some patients may not be in true clinical remission when maintenance therapy begins. This real-world use may therefore be very different than the scenario in GOG 178 [3], in which all patients were in complete remission (absence of cancer symptoms plus normal imaging [including CT scan of the abdomen and pelvis and chest X-ray], physical examination, and CA-125 level). Whereas the sorafenib Study 12007 requires that patients be in CT-confirmed or MRI-confirmed complete remission prior to commencing maintenance therapy, the AGO-OVAR16 trial of pazopanib permits the enrollment of patients with PR or even SD following first-line platinum/taxane. One recent study showed that CA-125 levels can increase in response to bevacizumab treatment prior to radiographic evidence of disease progression [85]. Therefore, recurrence should be confirmed by CT or MRI in order to limit premature discontinuation of therapy. Toward this end, the ongoing AGO-OVAR12/LUME-Ovar1 and TRINOVA-3 trials will discontinue treatment only after disease progression is confirmed by RECIST. Additional cross-trial differences pertain to stage of disease, with enrollment of GOG 218 restricted to patients with advanced stage III/IV disease whereas up to 10% of the ICON 7 population was allowed to have high-risk early disease (Fig. 1C). Based on these various differences between study populations, extrapolating available and forthcoming clinical trial results to guide decision-making regarding the risk and benefit of maintenance therapy with a specific agent for a given patient will prove challenging for clinicians.

Although results from ongoing trials may begin to resolve some of these controversial issues, additional studies will be needed to provide more definitive resolution to the question of how antiangiogenic agents can be optimally used as a maintenance strategy for advanced EOC. Until clear evidence of improved clinical outcomes surfaces, maintenance therapy will remain investigational in this population for which effective and tolerable treatments for prolonging long-term outcomes are so urgently needed.

Section snippets

Conclusion

Angiogenesis is a validated target in EOC and, when inhibited, has been shown to prolong tumor control in the maintenance setting. Controversy exists regarding when to start and end antiangiogenesis therapy as well as the choice of the optimal agent. Longer durations of maintenance therapy may improve efficacy because the benefit of therapy may be lost when angiogenesis inhibition ends.

Conflict of interest statement

Dr. Bradley Monk has received honoraria for speaker bureaus from Roche and consultation fees from Roche, GlaxoSmithKline, and Boehringer Ingelheim. Dr. Ivor Benjamin, Dr. John Farley, Dr. Dana Chase, and Dr. Heather Dalton have no financial relationships and/or potential conflicts of interest to disclose.

Role of the funding source

Financial support for writing and editorial assistance was provided by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). The authors meet criteria for authorship as recommended by the ICMJE, were fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development. The authors received no compensation related to the development of the manuscript.

Reviewers

Kwan-Hwa Chi, Shin-Kong Memorial Hospital, Department of Radiation Therapy & Oncology, Taipei, Taiwan.

Franz Rödel, University of Frankfurt, Department of Radiation Therapy and Oncology, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.

Acknowledgements

This work was supported by BIPI. Writing and editorial assistance was provided by Lisa Shannon, PharmD, of MedErgy, which was contracted by BIPI for these services. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE), were fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development. The authors received no compensation related to development or writing of the manuscript.

Bradley J. Monk, M.D. After graduating first in his class with a medical degree from the University of Arizona College of Medicine in 1988, Dr. Monk completed a residency in obstetrics and gynecology at the University of California, Los Angeles, in 1992 and a fellowship in gynecologic oncology at the University of California, Irvine, also in 1992. Dr. Monk was appointed director of gynecologic oncology at Texas Tech University Health Services Center in 1995, and in 1996 he became associate

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  • Cited by (0)

    Bradley J. Monk, M.D. After graduating first in his class with a medical degree from the University of Arizona College of Medicine in 1988, Dr. Monk completed a residency in obstetrics and gynecology at the University of California, Los Angeles, in 1992 and a fellowship in gynecologic oncology at the University of California, Irvine, also in 1992. Dr. Monk was appointed director of gynecologic oncology at Texas Tech University Health Services Center in 1995, and in 1996 he became associate medical director of the Southwest Cancer Center, both in Lubbock, Texas. From 1998 to 2010, Dr. Monk was at the University of California, Irvine, where in 2004 he was appointed a tenured Associate Professor of Obstetrics and Gynecology in the Department of Obstetrics and Gynecology. Dr. Monk is a fellow or full active member of numerous professional societies and organizations, and he also serves as a reviewer and sits on the editorial board for several peer-reviewed journals. He has authored or co-authored numerous textbook chapters and more than 165 articles in peer-reviewed journals, and his research interests span a wide variety of topics relevant to gynecological malignancies. Since 1995, Dr. Monk has been an investigator for the Gynecologic Oncology Group, where he serves as the Group's Cervical and Vulvar Committee Chair and also as a member of the Tissue Utilization, Publications, and Protocol Development committees. Since 2010, Dr. Monk has served as a Professor in the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology at Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, a Dignity Health Member. Dr. Monk currently holds the title of Director of the Division of Gynecologic Oncology.

    Heather Dalton, M.D. In 2008, Dr. Dalton graduated from the University of South Carolina School of Medicine in Columbia, South Carolina. Dr. Dalton worked as a chief obstetrics and gynecology resident at Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, a Dignity Health Member. Dr. Dalton started a fellowship in gynecological oncology in July 2012 at MD Anderson Cancer Center in Houston, Texas.

    John H. Farley, M.D., COL(ret), FACOG, FACS. In 1990, Dr. Farley graduated from the Uniformed Services University of the Health Sciences and then completed a residency in obstetrics and gynecology at Walter Reed National Military Medical Center, both in Bethesda, Maryland. Dr. Farley has been stationed in Georgia, Virginia, and Hawaii, and was deployed to Afghanistan from April 2004 until June 2005, where he was awarded the Bronze Star for his service. From 2006 to 2011, he was assigned to the Uniformed Services University of the Health Sciences where he achieved the academic rank of Professor. Dr. Farley has been an active participant in the Gynecologic Oncology Group, where he has held numerous committee appointments and developed and executed numerous multi-institutional clinical trials. He has also authored or co-authored more than 50 peer-reviewed works and invited book chapters, and received numerous awards and honors. Currently, Dr. Farley is a staff physician and Professor of Obstetrics and Gynecology at Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, a Dignity Health Member.

    Dr. Chase. earned a medical degree at the University of California, Irvine, where she subsequently completed her residency and fellowship training. She then completed a four-year fellowship in gynecologic oncology at the University of California, Irvine. Dr. Chase's expertise includes quality of life during cancer treatment and survivorship, supportive and palliative care, and imaging of gynecologic cancers. She is a member of a number of oncology societies, including the Gynecologic Oncology Group, and a fellow of the American College of Obstetrics and Gynecology. She has authored or co-authored over 20 peer-reviewed publications and over 24 abstracts presented at organizational meetings and congresses. Currently Dr. Chase is a gynecologic oncologist in the Division of Gynecologic Oncology and the Department of Obstetrics and Gynecology at the Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, a Dignity Health Member.

    Dr. Benjamin. received a medical degree from Columbia University in New York, New York in 1987, and subsequently completed a residency program at the Hospital of the University of Pennsylvania in Philadelphia, Pennsylvania and fellowships at Memorial Sloan Kettering Cancer Center in New York, New York, and at St. Joseph's Hospital and Medical Center in Phoenix, Arizona. Dr. Benjamin has given several invited lectures throughout the country, and has authored or co-authored more than 40 peer-reviewed works and 18 abstracts with a focus in gynecologic cancer research. Currently, Dr. Benjamin is a gynecologic oncologist in the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology at Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, a Dignity Health Member. He also serves as the Medical Director of the Robotic Surgery Program, Vice Chair of the Obstetrics and Gynecology Committee, and as a robotic surgery proctor for training and skill certification of other surgeons throughout the country.

    1

    Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, 500 W Thomas Road, Suite 660, Phoenix, AZ 85013, United States. Tel.: +1 803 316 7402; fax: +1 602 798 0807.

    2

    Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, 500 W Thomas Road, Suite 800, Phoenix, AZ 85013, United States. Tel.: +1 602 406 7730; fax: +1 602 798 0807.

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