"Targeted Therapy in ovarian cancer: novel agents and predictive biomarkers"

Artigo de revisão bibliográfica Mestrado Integrado em Medicina Targeted therapy in ovarian cancer: novel agents and predictive biomarkers ´ Autor: Li Bei Orientador: Prof. Doutor Rui Henrique Co-Orientador: Dra. Deolinda Pereira Porto, Junho de 2011 2 Abstract Ovarian cancer is the second most common gynecological malignancy and the leading cause of death from gynecological cancer. Most women present with advanced stage disease, having a poor prognosis even with adequate treatment. Cure is unlikely for advanced disease. Despite the high rate of initial response to chemotherapy, the majority of women will develop recurrent disease, and, thus, new therapeutic options are required. Molecularly directed therapy has been developing rapidly for ovarian cancer, either as single therapy or in association with chemotherapy. Bevacizumab, an anti-VEGF antibody, is among the most promising agents as in phase III clinical trials it appeared to improve survival. PARP inhibitors may also have an important role for patients with BRCA1/BRCA2 mutations. This article will review the various targeted approaches under investigation in ovarian cancer, its current developments, clinical benefits, safety and also searching for predictive biomarkers of response to treatment. Introduction Ovarian cancer is the second most common gynecological malignancy and is by far the most lethal gynecological cancer. For the year 2010, it is estimated that 21,880 new cases will be diagnosed and that 13,850 patients will die from ovarian cancer [1]. The overall prognosis of this malignancy is poor, with a fiveyear overall survival of 45% for all stages [1]. Most ovarian cancers are of epithelial origin and its staging is performed according to the FIGO staging system, which differentiates early stage tumors (stage I-II) from advanced disease (III-IV). The later corresponds to 75% of patients and carries a poor prognosis. Most women present with advanced disease due to the unspecificity of symptoms and the often asymptomatic course in the early stages of this malignancy. The current therapeutic approach consists on the combination of maximal cytoreductive surgery followed by firstline chemotherapy based on platinum compounds (carboplatin or cisplatin) plus paclitaxel. Intraperitoneal drug administration and neoadjuvant chemotherapy are clinically acceptable variations of treatment regimens as they may benefit some patients, but it should be selected on an individualized basis. Managing recurrent ovarian cancer There are different criteria for defining relapse in ovarian cancer. These include 3 continuous rise in CA-125 level, CA-125>100 U/ml, and /or radiographic (usually CT) or symptomatic evidence of recurrence. Response rate is expected in over 70% of women who receive standard platinum and paclitaxel as first-line treatment [2]. However, the majority of patients treated for advanced disease will relapse, requiring a second and, possibly, more treatments [3, 4]. The most beneficial sequence of treatments has not been established. Recurrent patients can respond to platinum retreatment and the response rate is directly related to the length of time elapsed since the last course of platinum chemotherapy to the documented recurrence disease [5]. The second-line treatment has been studied on the basis of improved progression-free survival (PFS) or overall survival (OS). Given that recurrent disease is currently incurable, palliation of symptoms and extending survival with minimum drug toxicity are the goals of management. For platinumsensitive disease (relapse more than six months after completing first-line chemotherapy), a platinum based therapy continues to be the main regimen, often in combination with a drug like paclitaxel [6], gemcitabine [7] or pegylated liposomal doxorubicin (PLD) [8]. More recently, PLD in association with trabectedin has been approved for platinum-sensitive cases [9]. Expected response rates vary from 30% to 40% or even higher, especially for those with a treatment free interval larger than 24 months [10, 11]. On the opposite, platinum-resistant disease (remission-free period less than six months) is typically treated with a single non–platinum agent, such as PLD, gemcitabine, paclitaxel, or topotecan and the reported response rate for each of these drugs is in the 10-20% range [12]. Thus, the current scenery of the treatment of ovarian epithelial cancer (EOC) demands new approaches which might contribute to improve patients‘ survival. Targeted therapies appear to be promising and several clinical trials are ongoing or have been published over the last few years. Among these, compounds targeting tumor-related angiogenesis have provided the more promising results and as such they constitute the main focus of this review. 4 Angiogenesis as therapeutic target The growth of malignant tumors and metastatic capacity are both highly dependent upon angiogenesis. Any increase in tumor burden must be accompanied by an increase in vessel formation to adequately supply the tumor mass. In addition, these new vessels are leaky because of the fragmented basement membranes, creating an easy access into circulation and, thus, facilitating metastization. Interestingly, studies evaluating the vessel count in EOC concluded that the degree of neovascularization is of prognostic significance in both early-stage and advanced disease [13, 14]. Ovarian tumors, like many other malignancies, overexpresses proangiogenic factors, including vascular endothelial growth factors (VEGFs), fibroblast growth factors (FGFs), angiopoietin, platelet-derived growth factors (PDGFs), and proangiogenic cytokines such as tumor necrosis factor alpha and interleukins 6 and 8 [15]. Among the markers of increased angiogenesis, VEGF is the most investigated in ovarian cancer. VEGFs constitute a family of growth factors that includes VEGF-A, -B, -C, -D and placental growth factor (PGF). VEGF-A is generally referred to as VEGF. VEGFs bind to a family of receptors (VEGFR-1, -2 and -3) with intrinsic tyrosine kinase activity. VEGFR-2 is believed to be the major mediator of the proangiogenic effects of VEGF-A [16]. VEGF activation promotes endothelial cell proliferation and migration for the formation of new blood vessels and increases permeability of existing blood vessels to allow for the leakage of multiple plasma proteins, including those playing a role in angiogenesis [17]. There is evidence that VEGF can recruit bone-marrow derived endothelial progenitor cell into sites of neovascularization [18]. Evidence based on measurement of serum VEGF levels suggests that VEGF may be a useful serological biomarker for clinical diagnosis, prognosis, followup of tumor metastasis and monitoring the efficacy of therapy [19, 20]. There is still some controversy about the concept of VEGF as an independent prognostic factor for EOC. Whereas some agree with this statement [21, 22], others believe that VEGF prognostic significance is related to its correlation with FIGO stage [23]. Based on VEGF pathway inhibition, it is possible do adopt different blocking strategies: inhibition of the VEGF ligand itself (e.g., Bevacizumab), inhibition of 5 the VEGF receptor (e.g., Tyrosine Kinase Inhibitors - TKIs) or neutralizing VEGF by administrating soluble receptors (e.g., VEGF Trap). In fact, angiogenic stimulation is not limited to VEGF. Endothelial cells express PDGF receptor (PDGFR) which is activated by its ligand – PDGF - for recruitment of pericytes and maturation of the microvasculature. PDGF secretion by tumor cells may also recruit stromal cells that further support angiogenesis through the release of VEGF [18]. FGF produced by tumor cells also promotes angiogenesis via endothelial cell proliferation, migration and differentiation [24]. PDGF and FGF are implicated in resistance to VEGF/VEGFR agents, explained by the fact that while an anti-VEGF agent is active, other proangiogenic factors that are overexpressed may restore angiogenesis [25]. Therefore, using a multi-target antiangiogenic strategy is a desirable option to counteract this resistance. Targeting VEGF ligand – Bevacizumab Bevacizumab (Avastin®) is an intravenously administrated humanized monoclonal IgG antibody directed against human VEGF-A, and this drug acts by binding to VEGF-A isoforms preventing them to activate its receptors. It is currently approved for treating various advanced solid tumors: colorectal, breast, renal cell carcinoma, non-squamous non-small cell lung cancers, and glioblastoma. Phase II and III clinical trials results suggest that bevacizumab is a promising strategy in recurrent or persistent ovarian cancer, either as single agent or in combination with chemotherapy, as detailed below. Phase II clinical trials Two important studies, involving patients with relapsed ovarian cancer treated with bevacizumab as single agent (15 mg/kg every 21 days) were the first to demonstrate evidence of activity for a targeted agent in ovarian cancer. The Gynecology Oncology Group (GOG) 170 D study reported by Burger and colleagues [26] enrolled 62 patients with either platinum-sensitive or platinumresistant disease with no more than 2 prior chemotherapy regimens. Cannistra et al [27] recruited 44 patients only platinum-resistant who failed the topotecan 6 or liposomal doxorubicin therapy and could have received up to three prior chemotherapy regimens. Burger et al. [26] documented an objective response rate of 21% and 52% stable disease. At 6 months, 40% of patients were progression-free, median PFS was 4.7 months and OS 16.9 months. Cannistra et al. [27] demonstrated a response rate of 16% and 61.4% with stable disease as their best response. The median PFS was 4.4 months and the median OS 10.7 months. These results were encouraging since they were achieved by bevacizumab alone, contrasting with the lack of effectiveness in breast, colon or lung cancer. Regarding adverse events, Burger et al. reported two cases of deep vein thrombosis (3.2%), one case of grade 4 proteinuria (1.6%) and six cases of grade 3 hypertension (9.7%) [26]. The toxicity profile was different in Cannistra‘s study. They had five patients (11.4%) with gastrointestinal (GI) perforation, one of which was fatal, and other three patients developed arterial thromboembolic disease [27]. Three deaths (myocardial infarction, GI perforation and hypertensive encephalopathy) were suspected to be related with bevacizumab. Those who experienced GI perforation had receive three prior chemotherapy regimens compared with the rest of the group who had receive two prior chemotherapy regimens and none experienced perforation. Thus, higher GI perforation incidence in this study might be related with the fact that its population had more advanced disease [27]. Other trials suggested that bevacizumab in combination with chemotherapy (carboplatin, paclitaxel, cyclophosphamide or topotecan) is effective in advanced ovarian cancer. Two studies with chemotherapy-naïve patients with advanced ovarian carcinoma, concluded that carboplatin plus paclitaxel and bevacizumab (PCB) as first line therapy is safe and effective, with similar results [28, 29]. Micha et al. submitted 20 patients to six cycles of PCB and found 80% response rate; 23.3% and 25% of cycles were associated with grade 3 and 4 neutropenia, respectively. Two additional patients developed deep vein thrombosis that required hospitalization, although neither case appeared to be related to bevacizumab. No GI perforation, severe thrombocytopenia or anemia were reported [28]. Penson et al. recruited 62 patients. The study differs from the previous because patients maintained bevacizumab for a year after six to 7 eight cycles of PCB. Their results were the following: 76% of best overall response, median PFS duration of 29.8 months and 58% of patients were free from progression at 36 months. Treatment was associated with some important toxicities: two cases of pulmonary embolism, two GI perforation (grade 1 and 4), four cases of neuropathy and 14 patients developed neutropenia, all occurring during the chemotherapy phase of treatment. No grade 4 toxicities were seen during maintenance therapy with bevacizumab [29]. Metronomic chemotherapy (MC), which is intended to prevent tumor angiogenesis, is based on more frequent and low-dose drug administrations compared with conventional chemotherapy. This model of treatment suppresses tumor growth in experimental models [30, 31] and was encouraged by studies in metastatic breast cancer where MC was associated with clinical improvement and drop in VEGF levels with minimal toxicity [32]. To assess the efficacy of MC in ovarian cancer, two phase II trial were developed. Combination of bevacizumab and metronomic chemotherapy with cyclophosphamide was applied by Chura et al. [33], which conducted a trial of 15 heavily pre-treated patients with bevacizumab in a lower dose than the previous trials (10 mg/kg) plus cyclophosphamide. A response rate of 53.3% and a median duration of progression free survival of 3.9 months were found. Despite being heavily pre-treated and having confirmed intra-abdominal cancer, no GI perforations were reported. In another study, Garcia et al. [34] enrolled 70 patients with platinum-sensitive and platinum-resistant disease and administered the same treatment regimen. They reported a 24% response rate, 63% stable disease and 56% of patients were free from disease at 6 months. The median time to progression and median survival time were 7.2 months and 16.9 months, respectively. However, GI perforation and thromboembolism occurred (4% of cases each), along with three treatment-related deaths. The levels of angiogenesis markers (VEGF, E-selectin, and thrombospondin-1) of less than half of participants were measured and were not associated with clinical outcome. Table 1 summarizes all phase II trials mentioned above. 8 Phase III clinical trials The first two phase III studies designed to study addition of bevacizumab to standard chemotherapy (carboplatin/paclitaxel) in front-line treatment, GOG-218 and ICON-7, have already reported their preliminary results. Both have PFS as the primary endpoint. GOG-218 [35] is a three-arm, placebo-controlled, randomized trial involving 1,873 stage III or IV patients. The 3 treatment arms are: placebo plus chemotherapy followed by placebo maintenance (Arm 1), bevacizumab plus chemotherapy followed by placebo maintenance (Arm 2), and bevacizumab plus chemotherapy followed by bevacizumab maintenance (Arm 3). Dosage of bevacizumab used was 15 mg/kg. PFS was defined according to either Response Evaluation Criteria in Solid Tumors (RECIST), or CA-125 levels defining progressive disease according to Gynecologic Cancer Intergroup (GCIG) criteria. Using both criteria simultaneously, a significant improvement in PFS for maintenance bevacizumab group compared with control group was detected (PFS 14.1 months vs. 10.3 months for Arm III vs. Arm I, p<0.0001), but no significant benefit of bevacizumab plus chemotherapy without maintenance (p=0.08). The PFS difference censoring CA-125 was 18 vs. 12 months for Arm III vs. Arm I (p<0.0001), allowing for the same conclusion about the benefit of bevacizumab maintenance. The toxicity profile was favorable, with 23% of grade 2 or greater hypertension. Across the 3 arms, GI perforation/fistula events were observed in less than 3% of patients. The low rate of GI perforation may be explained by the fact that patients with a history of small bowel obstruction were excluded. On the other hand, the ICON-7 [36] study is an open-label randomized trial which recruited 1,528 patients with highrisk stage I-II or stage IIb to IV disease. It allocated patients into two different arms: standard carboplatin/paclitaxel (Arm 1) and carboplatin/paclitaxel plus low dose bevacizumab (7.5 mg/kg) followed by bevacizumab (Arm 2). Their PFS was measured according to RECIST criteria and the results differed significantly (18.3 months vs. 16 months for Arm 2 vs. Arm 1, p=0.001). The toxicity profile was similar to that of GOG-218 with 1.3% GI perforation (compared with 0.4% in the control arm) and 18.3% grade 3 or greater hypertension. Table 2 compares the results of GOG-218 and ICON-7. 9 When comparing patients‘ profiles, several characteristics distinguish these two phase III trials (see figure 1). GOG-218 enrolled poorer-prognosis patients (only advanced disease was accepted) and only 34% had optimal debulking stage III disease (compared with 73% in ICON7). The dosage of bevacizumab in ICON-7 was half of that of GOG-218 and the duration of exposure was shorter. Both trials suggest an advantage of bevacizumab maintenance in ovarian cancer, but the absolute benefit in terms of PFS is modest, and neither trial showed an overall survival benefit. Thus, more phase III trials using bevacizumab are required and those that are ongoing are depicted in Tables 3 and 4, concerning first-line or relapsed ovarian cancer treatment, respectively. Toxicity The adverse events associated with bevacizumab in ovarian cancer trials are similar to those described in other solid tumors, mainly comprising hypertension, proteinuria, thrombosis and GI perforation [37]. Gastrointestinal perforation is a potentially life-threatening complication of major concern. It is estimated to occur in up to 2.4% of patients treated with bevacizumab in colorectal cancer [38]. Cannistra‘s study was stopped prematurely due to the higher than expected incidence of GI perforation [27]. The recent GOG-218 and ICON-7 trials provided relevant information in this regard because the rate of potentially fatal GI perforation was lower than suggested by earlier phase II trials. The confirmation of safety of bevacizumab is obviously critical for any further investigation on this drug. Retrospective reviews of small studies prior to GOG- 218 and ICON-7 trials results indicated that incidence of GI perforation may be slightly higher in pretreated patients and when a history of bowel obstruction exists [39, 40]. VEGF Trap VEGF trap (Aflibercept) is a fusion protein containing the VEGF binding domains of both VEGFR-1 and 2 linked through the Fc region of a human IgG1. Aflibercept binds VEGF-A and neutralizes all VEGF-A isoforms plus PGF. The clinical applicability of this drug in age-related macular degeneration is already in phase III trials. Experiments in ovarian models suggested that VEGF Trap 16 Erlotinib has also been tested in combination with bevacizumab. The objective response rates were 15% (2/13 patients) and 54% (7/13 patients) had stable disease. Due to lack of improvement over bevacizumab therapy alone and two incidents of fatal gastric perforation, the erlotinib plus bevacizumab study was stopped [85]. Estrogen Receptor Since ovarian cancers commonly express estrogen receptors (ER), trials have been carried out to whether they might constitute therapeutic targets. The hormonal agent tamoxifen is routinely used to treat breast cancer in women whose tumors express ER. The recent Cochrane review of tamoxifen in ovarian cancer was unable to provide evidence-based recommendations as comparative studies assessing the effectiveness of tamoxifen are not available. The small phase II trials that were reported thus far showed an overall objective response rate of 9.6% (range: 0-52%), whereas 31.9% (range: 0-83%) of patients achieved disease stabilization [86]. Thus, questions such tamoxifen improving survival and symptom control or whether hormone receptor status is useful in selecting patients for tamoxifen treatment remain unanswered. Concerning the aromatase inhibitor letrozole (Femara®), phase II trials results indicated disease stabilization rather than improvement [87-90]. In a study comprising 42 patients with ER+ relapsed ovarian cancer, Smyth et al. reported 9% partial remission and 42% stable disease, according to radiological response criteria. Using CA-125 levels as a response marker, they observed 17% of responders (decrease > 50%) and 26% of patients had stable disease (no doubling of CA-125) at 6 months. In addition, the CA-125 response was more likely in cancers with the highest level of ER expression [87]. Other potencial targets Oregovomab, a monoclonal antibody against CA-125, was tested in a phase III trial. This monoimmunotherapy after front-line therapy did not demonstrate clinical benefit compared to the placebo group [91]. The folate receptor α-FR is overexpressed in 90% of ovarian cancers [92]. Farletuzumab (MORAb-003) is in a phase III trial comparing the efficacy and safety of intravenous carboplatin 17 and taxanes with and without farletuzumab in individuals with first platinumsensitive relapse. Angiopoietin is involved in an angiogenic pathway parallel to VEGF pathway. AMG 386 is a peptide-Fc fusion protein that inhibits angiogenesis by neutralizing the interaction between the Tie2 receptor and angiopoietin 1 and 2. A recent phase II showed increased PFS with the AMG 386 and paclitaxel association compared to paclitaxel alone [93]. Conclusions Contrarily to other common malignancies (e.g., breast, colon, and lung cancers), targeted therapy in epithelial ovarian cancer is still at its inception. Most phase II trials testing bevacizumab indicated that VEGF targeting might be an efficient strategy for ovarian cancer treatment. The results from the latest phase III trials GOG-218 and ICON-7, however, showed only a modest benefit in progressionfree survival. Importantly, the potentially fatal GI perforation events observed in previous studies were lower in phase III trials (<3%), although we should be aware that the eventual risk factor for perforation (bowel obstruction) was an exclusion criteria in GOG-218 trial. This study revealed that treatment of ovarian cancer with carboplatin, paclitaxel and bevacizumab followed by bevacizumab maintenance may be an effective first-line treatment option. However, the optimal dosage of bevacizumab and its duration is still unclear. More consistent judgments about bevacizumab use can be made when OS results are matured and other phase III trials report their preliminary results. Moreover, the RECIST criteria traditionally used to evaluate objective response rate might not be the best for assessing antiangiogenic agents, as these agents appear to slow tumor growth and do not cause tumor shrinkage. The search for adequate response biomarkers is also a critical issue as current studies only rely on the unspecific CA-125 measurement. Notwithstanding, even before assessing therapeutic response, physicians need biomarkers that will identify which patients will or will not benefit from the addition of the novel agent. This requires a better understanding of ovarian cancer tumorigenesis and a broad search for key genetic and epigenetic alterations. In this regard, BRCA1/BRCA2 mutations or the ―BRCAness‖ status might constitute an example of this effort if further 18 studies are able to prove the efficacy of PARP inhibitors in defined subgroups of patients. Given the multiplicity and redundancy of aberrant pathways involved in ovarian cancer, it is unlikely that inhibition of a single cascade will be highly effective, thus contributing to resistance to VEGF-targeted therapy. Combining multiple antiangiogenic agents may be, then, a solution. An additional question needs to be answered, i.e., whether it is most effective to inhibit different signaling pathways (horizontal blockade) or different molecules within the same pathway (vertical blockade). Finally, the cost-effectiveness of adding targeted therapy to ovarian cancer treatment has to be thoroughly analyzed but only when a significant impact on survival has been proven and when more definite answers to the questions raised above are provided by additional research in this field. 19 Study Patients characteristics Intervention Results Common grade ≥ 3 adverse effects Burger et al. (2007) [26] 62 patients with persistent or recurrent of EOC or PPC 1-2 CT regimens 42% were platinum resistent Single agent bevacizumab (15 mg/kg q21) CR: 3% PR: 18% SD: 52% PFS: 4.7 mos 6mPFS: 40% OS: 16.9 mos Hypertension: 9.7% GI events: 6.5% TED: 3.2% Proteinuria: 1.6% Cannistra et al. (2007) [27]a 44 patients with recurrent platinum-resistant EOC or PPC after discontinuing topotecan or liposomal doxorubicin. 2-3 CT regimens Single agent bevacizumab (15 mg/kg q21) CR: 0% PR: 16% SD: 61.4% PFS: 4.4 mos 6mPFS: 27.8% OS: 10.7 mos GIP: 11.4% Small intestinal obstruction: 9.1% Hypertension: 9.1% TED: 6.8% Micha et al. (2007) [28] 20 patients with Stage III or IV EOC, PPC and FTC 85% optimally cytoreducted First line carboplatin + paclitaxel + bevacizumab (15 mg/kg q21) CR: 30% PR: 50% SD: 5% Neutropenia:18 pts TED: 2 ptsb Hypertension: 2 pts Neuropathy: 1pt Penson et al. (2010) [29] 62 patients with advanced EOC, PPC, FTC and UC 82% optimally cytoreducted First line carboplatin + paclitaxel + bevacizumab (15 mg/kg q21) with maintenance of bevacizumab for a year CR:21% PR:55% SD:21% PFS: 29.8 mos 36mPFS: 58% OS: NR CT phase Neutropenia: 14 pts Metabolic: 8 pts Hypertension: 6 pts Thrombocytopenia: 4pts Neuropathy: 4pts TED: 2 pts GIP: 2 pts (grade 1,4) Maintenace phase Hypertension: 5 pts Chura et al. (2007) [33] 15 patients with recurrent ovarian cancer Median number of previous chemotherapy regimens = 8 Bevacizumab (10 mg/kg q14) + cyclophosphamide CR: 13.3% PR: 40% SD: 20% PFS: 3.9 Pancreatitis: 1 pt Diarrhea: 1 pt Garcia et al. (2008) [34] 70 patients with recurrent EOC and PPC 1-3 prior CT regimens 40% were platinumresistant Bevacizumab (10 mg/kg q14) + cyclophosphamide CR: 0% PR: 24% SD: 63% OS: 16.9 mos TTP: 7.2 mos 6mPFS: 56% Lymphopenia: 14 pts Hypertension:11 pts GI obstruction: 6 pts Proteinuria: 3 pts GIP: 3 pts (grade 2,4,5) TED: 3 pts Table 1. Reported phase II trials of bevacizumab in ovarian cancer a Study stopped prematurely due to high rate of GIP bTED cases were not directly attributed to bevacizumab Abbreviations: CR, complete response; CT, chemotherapy; EOC, epithelial ovarian cancer; FTC, fallopian tube cancer; GIP, gastrointestinal perforation; mos, months; NR, not reported; PFS, progression-free survival (6m, 6 months; 36m, 36 months); PPC, primary peritoneal cancer; PR, partial response; pt(s), patient(s); q14, every 14 days; q21, every 21 days; SD, stable disease; TED, thromboembolic disease (either arterial or venous); TTP, time to progression; UC, uterine carcinoma. 20 GOG 218 ICON-7 Characteristics Arm 1 CP Arm 2 CP+Bev Arm 3 CP+Bev →Bev maintenance Arm 1 CP maintenance Arm 2 CP+Bev →Bev maintenance Median PFS RECIST or CA-125 RECIST only 10.3 mos 12.0 mos 11.2 mos NR 14.1 mos 18.0 mos NA 16 mos NA 18.3 mos Select adverse events Hypertension GIP/fistula Venous thromboembolism Arterial thromboembolism Proteinuria 7.2%a 1.2% 5.8% 0.8% 0.7% 16.5%a 2.8% 5.3% 0.7% 0.7% 22.9%a 2.6% 6.7% 0.7% 1.6% 2.1%b 1.3% 1.7% 1.3% 0.1% 18.3%b 2.1% 4.3% 2.7% 0.5% Figure 1. Differences between two phase III trials of first line treatment with chemotherapy alone or in combination with bevacizumab: GOG 128 and ICON – 7 (see table 2 for results). Abbreviations: EOC, epithelial ovarian cancer; FTC, fallopian tube cancer; PPC, primary peritoneal cancer; q21, every 21 days; RECIST, Response Evaluation Criteria in Solid Tumors. Table 2. Results of two phase III trials of first line treatment with chemotherapy alone or in combination with bevacizumab: GOG 218 and ICON-7 a grade ≥ 2 b grade ≥ 3 Abbreviations: Bev, Bevacizumab; CP, carboplatin plus paclitaxel; GIP, gastrointestinal perforation; NA, not applicable; NR, not reported; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors. 21 Trial Type No. patients Patients characteristics Design End point GOG-262 Open label, randomized 625 Stage III or IV, suboptimal debulking Carboplatin + paclitaxel q21 ± (optional) Bev→Bev maintenance vs carboplatin q21 + paclitaxel q7 ± (optional) Bev→Bev maintenance PFS GOG-252 Open label, randomized 1500 Stage II-IV, optimal or suboptimal debulking Paclitaxel IV + carboplatin IV + Bev→Bev maintenance vs paclitaxel IV + carboplatin IP + Bev→Bev maintenance vs paclitaxel IV and IP + cisplatin IP + Bev→Bev maintenance PFS Trial Type No. patients Patients characteristics Design End point GOG 213 Open label, randomized 660 CR to first-line platinumtaxane therapy and DFI≥ 6 months; previous Bev allowed Carboplatin + paclitaxel ± Bev→Bev maintenance in surgical and non-surgical candidates OS OCEANS Placebocontrolled, double-blind randomized 487 Platinum-sensitive Carboplatin + gemcitabine ± Bev→Bev maintenance PFS AURELIA Open label, randomized 300 Platinum-resistant Liposomal doxorubicin or paclitaxel or Topotecan ± Bev→Bev maintenance PFS Abbreviations: Bev, bevacizumab; IP, intraperitoneal; IV, intravenous; PFS, progression-free survival; q7, every week; q21, every 21 days; vs, versus. Table 4. Ongoing phase III trials with bevacizumab in relapsed ovarian cancer Table 3. Ongoing first-line phase III trials with bevacizumab in ovarian cancer Abbreviations: Bev, bevacizumab; CR, complete response; DFI, disease-free interval; OS, overall survival; PFS, progression-free survival; vs, versus. 22 Study No. Patients Target Treatment Response Rate (RECIST) SD Outcomes (months) OS (months) Tew et al. (2007) [43] 162 VEGF-Trap Aflibercept 11% NR NR NR Hirte et al. (2008) [45] 60 VEGFR1,-2,-3, PDGFR Cediranib Pl-s: 2 pts confir. Pl-r: 1pt unconfir. NR TTP: 4.1 11.9 Matulonis et al. (2009) [46] 46 VEGFR1,-2,-3, PDGFR Cediranib Pl-s: 2 pts Pl-r: 6 pts 6 pts PFS 5.2 Not reached Matei et al. (2010) [48] 71 VEGFR,PDGFR, FLT3, c-KIT, Raf Sorafenib 3.4% 34% 6mPFS: 24% NR Welch et al. (2010] [47] 43 VEGFR,PDGFR, FLT3, c-KIT Sorafenib + gemcitabine 4.7% 27.9% (CA-125) 23.3 TTP: 5.4 13.3 Biagi et al. (2011) [50] 30 VEGFR, PDGFR, c-KIT Sunitinib 3.3% 10% (CA-125) 53% PFS: 4.1 NR Friedlander et al. (2010) [51] 36 VEGFR, PDGFR, c-KIT Pazopanib 31% (CA-125) NR MDR: 113 days NR Ledermann et al. (2009) [53] 84 VEGFR, PDGFR, FGFR BIBF-1120 NR NR 9mPFS: 15.6 vs 2.9* NR *placebo Abbreviations: conf., confirmed; unconf, unconfirmed; FGFR, fibroblast growth factor receptor; MDR, median duration of response; NR, not reported; MDR, median duration of response; OS, overall survival; PDGFR, platelet-derived growth factor receptors; PFS, progression-free survival (6m, 6 months; 9m, 9 months); Pl-r, platinum resistant; Pl-s, platinum-sensitive; pt(s), patient(s); pt(s), patient(s); RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; TTP, time to progression; VEGF, vascular endothelial growth factor ; VEGFR, vascular endothelial growth factor receptor; vs, versus. Table 5. Published phase II trials of non-bevacizumab VEGF pathway inhbitors 23 Trial No. patients Target Treatment Response SD PFS Schielder et al. (2009) [75] 25 EGFR Cetuximab 1 pt 9 pts 2.1 mos Gordon et al. (2006) [78] 61 HER-2 dimerization Pertuzumab 4.3% 6.8% 6.6 wks Makhija et al. (2010) [79] 130 HER-2 dimerization Pertuzumab+ gemcitabine 13.8% vs 4.6%* NR NR Bookman et al. (2003) – GOG 160 [80] 41 HER-2 Trastuzumab 7.3% NR NR Posadas et al. (2007) [81] 24 EGFR Gefitinib 0% 37% NR Schielder et al. (2005) – GOG 170 C [82] 27 EGFR Gefitinib 1 pt NR 6mPFS: 15% Wagner et al. (2007) [83] 56 EGFR, ER Gefitinib + tamoxifeno 0% 29% NR Gordon et al. (2005) [84] 34 EGFR Erlotinib 6% 4% NR Nimeri et al. (2008) [85] 13 EGFR, VEGF Erlotinib + bevacizumab 2 pt 7 pts NR Table 6. Published phase II trials of human epidermal growth factor receptor (HER) inhibitors *gemcitabine and placebo Abbreviations: HER, human epidermal growth factor receptor, EGFR, epidermal growth factor receptor; ER, estrogen receptor; NR, non reported; PFS, progression-free survival (6m, 6 months); pt(s), patient(s); SD, stable disease; vs, versus. 24 REFERENCES 1 Jemal A, Siegel R, Xu J et al. Cancer Statistics, 2010. CA Cancer J Clin 2010;60:277-300. 2 McGuire WP, Hoskins WJ, Brady MF et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1-6. 3 Armstrong DK. Relapsed ovarian cancer: challenges and management strategies for a chronic disease. The Oncologist 2002;7(suppl 5):20-28. 4 Markman M, Bookman MA. Second-line treatment of ovarian cancer. The Oncologist 2000;5:26-35. 5 Spriggs D. Optimal sequencing in the treatment of recurrent ovarian cancer. 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