Bevacizumab In Epithelial Ovarian Cancer Research Articles

Correlation of imaging and plasma based biomarkers to predict response to bevacizumab in epithelial ovarian cancer (EOC)

PurposeIncreasing measures of adiposity have been correlated with poor oncologic outcomes and a lack of response to anti-angiogenic therapies. Limited data exists on the impact of subcutaneous fat density (SFD) and visceral fat density (VFD) on oncologic outcomes. This ancillary analysis of GOG-218, evaluates whether imaging markers of adiposity were predictive biomarkers for bevacizumab (bev) use in epithelial ovarian cancer (EOC). Patients and methodsThere were 1249 patients (67%) from GOG-218 with imaging measurements. SFD and VFD were calculated utilizing Hounsfield units (HU). Proportional hazards models were used to assess the association between SFD and VFD with overall survival (OS). ResultsIncreased SFD and VFD showed an increased HR for death (HR per 1-SD increase 1.12, 95% CI:1.05–1.19 p = 0.0009 and 1.13, 95% CI: 1.05–1.20 p = 0.0006 respectively). In the predictive analysis for response to bev, high VFD showed an increased hazard for death in the placebo group (HR per 1-SD increase 1.22, 95% CI: 1.09–1.37; p = 0.025). However, in the bev group there was no effect seen (HR per 1-SD increase: 1.01, 95% CI: 0.90–1.14) Median OS was 45 vs 47 months in the VFD low groups and 36 vs 42 months in the VFD high groups on placebo versus bev, respectively. ConclusionHigh VFD and SFD have a negative prognostic impact on patients with EOC. High VFD appears to be a predictive marker of bev response and patients with high VFD may be more likely to benefit from initial treatment with bev.

Recurrence patterns after bevacizumab in platinum-sensitive, recurrent epithelial ovarian cancer

ObjectiveEvidence on recurrence patterns after bevacizumab in epithelial ovarian cancer is still insufficient. The aim of this study was to evaluate recurrence patterns after treatment with bevacizumab as second-line treatment...

A phase I study of veliparib incorporated into front-line platinum based cheotherpy and bevacizumab in epithelial ovarian cancer (NCT00989651): A GOG/nrg trial.

5523 Background: Veliparib, a poly-(ADP-ribose)-polymerase inhibitor, increases anti-tumor activity when combined with platinum chemotherapy and has monotherapy activity in BRCA deficient tumors. This study was done to determine the recommended phase II dose (RP2D) of veliparib in combination with front line treatment for epithelial ovarian cancer (EOC). Methods: Eligible patients had newly diagnosed, stage II-IV EOC. Six regimens were evaluated, 3 variations of chemo delivery with either continuous (D1-21) or intermittent (days-2-5) veliparib BID. Chemo included 1: IV q3week carboplatin (C) (AUC 6) and paclitaxel(T) (175mg/m2); 2, IV q3week C (AUC 6) and weekly T(80mg/m2); and 3, IV T (135mg/m2, day 1), IP cisplatin (75mg/m2, day 1 or 2) and IP T (60mg/m2, day 8). Bevacizumab 15mg/kg started cycle 2 and continued as monotherapy cycles 7-22. A 3+3 dose escalation design evaluated dose-limiting toxicities (DLTs) in cycles 1 and 2. Once < 2/6 patients experienced a DLT, that dose level was expanded to evaluate feasibility over 4 cycles. Results: The study accrued 424 treated patients. For regimen 1, continuous (Reg1c) the maximum tolerated dose (MTD) was 250mg veliparib BID but the feasible dose was found to be 150mg BID. For regimen 1, intermittent (Reg1i) the MTD and feasible dose were 400 and 250mg BID respectively. For Reg2c the MTD and feasible dose were the same at 150mg BID. For Reg2i the MTD and feasible dose were 250 and 150mg BID respectively. For Reg3c the MTD and feasible dose are both 150mg BID and for Reg3i, the MTD was 400mg BID and the feasible dose felt to be 300mg BID. Median PFS by residual disease and BRCA status is: (Positive residual disease) 14.6, 19.1 and 16.9 months for BRCA+, BRCAwt and BRCA ukn respectively. For no gross residual disease the PFS is NR, 34.2 and 24.5 months respectively. Conclusions: Given the difficulty with toxicity not defined as a DLT, the RP2D for all regimens is veliparib 150mg BID. This data informed the dose that moved into the phase III trial GOG 3005/Velia: NCT02470585. Velia also incorporated maintenance veliparib instead of maintenance bevacizumab among all high grade serous patients (BRCA+ and wt). These results will determine utilization of veliparib in this space. Clinical trial information: NCT00989651.

Correlation of imaging and plasma-based biomarkers to predict response to bevacizumab in epithelial ovarian cancer (EOC): A GOG 218 ancillary data analysis.

5507Background: Increasing measures of adiposity can correlate with poor oncologic outcomes and lack of response to antiangiogenic therapies. Limited data exists on the impact of subcutaneous fat a...

Time for a level playing field: inequalities in regulatory/approval processes—the example of bevacizumab in epithelial ovarian cancer.

As outsiders, we do not have access to the deliberations of the regulatory bodies. The NICE reasons are in the public domain. The Health Canada queries that led to Roche withdrawing their application are not known. Therefore, the following are possible explanations for this inconsistency. One possible reason that might be given for nonapproval: The clinical benefit is too small (Fig 1). This statement is incorrect. The PFS benefit that was obtained, as demonstrated by hazard ratios, ranged from 0.48 to 0.73 in EOC (superior in the recurrent setting). In comparison, hazard ratios for colorectal cancer were 0.50 to 0.89 and for lung cancer were 0.66 to 0.75. More relevantly, the absolute differences in median PFS were 3.3 to 5.5 months, 2 to 4.4 months, and 0.4 to 1.7 months, respectively, in these three cancer types. Is it that regulatory bodies need more than improvements in medians alone? This would be ideal but, unfortunately, is rarely the case because financial imperatives usually result in relatively immature data being submitted, leading to reliance on the medians. Even if longer term outcomes had been used as part of the decision making, they would not have had an adverse impact, given that the increases in survival at 1 and 2 years were clinically meaningful. Overall survival (OS) benefits were much less impressive. Hazard ratios again were 0.64 to 0.88, 0.66 to 0.94, and 0.79 to 0.93 in ovary, colorectal, and lung cancers. Absolute OS differences were 3.2 to 7.8 months, 0.4 to 4.4 months, and 0.5 to 2 months, respectively. These ovarian and colorectal outcomes are similar. Oncologists are convinced of bevacizumab’s utility. Bevacizumab is part of standard therapy in metastatic colorectal cancer. These outcomes in EOC are also regarded as worthwhile by Canadian oncologists. Support for use of bevacizumab was unanimous at a recent meeting of Gynecologic Oncology Canada (a pan-Canadian not-for-profit organization that represents physicians and nurses who specialize in gynecologic malignancies). Bevacizumab’s use is included in the National Comprehensive Cancer Network ovary guidelines in the platinum resistant/refractory setting in combination or as monotherapy. 21 The EMA, who approved it, found that there was “robust evidence for clinically significant effect.” 22(p47) However, some agencies were less enthusiastic. Documented reasons are available from NICE in the United Kingdom. 23,24 Lack of clinical benefit was not the only reason. The reasoning in the first-line setting was that,

Bevacizumab in the treatment of epithelial ovarian carcinoma

In recent years, inhibitors of angiogenesis have become a focus of clinical trials aimed at expanding treatment options for women afflicted with epithelial ovarian cancer (EOC). Bevacizumab, a VEGF inhibitor, has been well studied in multiple solid tumors, suggesting progression-free and overall survival benefits. In EOC, bevacizumab has been the subject of many trials with results indicating a progression-free survival benefit in a variety of settings. The addition of bevacizumab to the EOC armamentarium, however, is not without risk. This article provides a rationale for targeting angiogenesis and discusses pivotal trials evaluating the utility of bevacizumab in EOC. Current research is evaluating optimal dosing duration, benefit of bevacizumab beyond progression, biomarkers to direct anti-angiogenic therapy and patient reported outcomes.

Integrating bevacizumab into the management of epithelial ovarian cancer: the controversy of front-line versus recurrent disease

Angiogenesis plays a fundamental role in the pathogenesis of ovarian cancer. Vascular endothelial growth factor (VEGF) expression has been associated with the development of malignant ascites and tumor progression. Bevacizumab (Avastin®; Genentech, South San Francisco, CA, USA), a humanized anti-VEGF monoclonal antibody, is the most widely studied antiangiogenesis agent across tumor types and specifically in epithelial ovarian cancer (EOC). With the recent reporting of four consecutive positive randomized trials adding bevacizumab to chemotherapy in the treatment of both front-line (GOG 218 and ICON7) and recurrent EOC [‘platinum-resistant’ (AURELIA Trial) or ‘platinum-sensitive’ (OCEANS Trial)], the most debatable question today is thus not IF we should treat ovarian cancer patients with bevacizumab, but WHEN. As bevacizumab is active in both settings, it seems appropriate to carefully consider this clinical controversy: ‘what is the optimal setting for bevacizumab treatment?’ A fine balance of efficacy, toxicity, quality of life, and symptom control is the main crux of this controversy. The cost effectiveness of bevacizumab in EOC is also controversial

The Role of Bevacizumab in Advanced Epithelial Ovarian Cancer

There is a strong rationale for usage of anti-angiogenic agents in epithelial ovarian cancer. Bevacizumab is the most widely investigated anti-VEGF agent and has shown promising results in recent clinical trials. To review the rationale and usage of bevacizumab in advanced epithelial ovarian cancer; as mono-therapy, in combination with chemotherapy both as first line and for recurrent ovarian cancer as well as in combination with other targeted therapies. In epithelial ovarian cancer, angiogenesis promotes tumor growth, ascites formation and metastasis. Targeting VEGF in ovarian cancer patients may have indirect and direct cytotoxic effects. Results of placebo controlled phase III trials, the GOG-218 and ICON7, of carboplatin-paclitaxel alone or combined with bevacizumab in chemo-naive patients and the OCEAN trial comparing carboplatin-gemcitabine with or without bevacizumab in women with recurrent platinum-sensitive epithelial ovarian cancer all suggest a benefit for the addition of bevacizumab on progression free survival. Additionally, bevacizumab in combination with other targeted therapies, such as sorafenib and everolimus are under investigation in phase II trials and the current knowledge of molecular predictors is discussed. Until now no survival benefit has been observed, but bevacizumab is the first anti-angiogenic agent demonstrating a progression free survival benefit in addition to standard chemotherapy regimens in advanced epithelial ovarian cancer, both in the upfront and recurrent setting. Mature overall survival data and the search for predictive biomarkers are important for the future role of bevacizumab in epithelial ovarian cancer.

A case series of low dose bevacizumab and chemotherapy in heavily pretreated patients with epithelial ovarian cancer.

BackgroundThe addition of bevacizumab to standard chemotherapy prolongs progression free survival in the first line treatment of epithelial ovarian cancer (EOC), but its cost/effectiveness is debated. We assessed the safety and activity of a lower dose of bevacizumab in pretreated advanced stage EOC.MethodsWe treated 15 patients, mostly with platinum resistant EOC, who had received a median of four prior cytotoxic regimens, with bevacizumab 5–7.5 mg/kg q21 days in combination with either carboplatin (n = 8), oral cyclofosfamide (n = 5) or weekly paclitaxel (n = 2). Bevacizumab was administered until disease progression. Tumor response was assessed by CA125 and fusion 18 F-FDG PET/contrast enhanced CT.ResultsThe median number of bevacizumab cycles was 21 (range 3–59). The median baseline CA125 was 272 U/ml and decreased to 15.2 U/ml at nadir. Tumor response was 4 complete response (CR) (26.7%) and 7 partial response (PR) (46.7%) by chemotherapy (CT), with an overall response rate of 73.4% (95% CI, 51.0 – 95.8) according to Response Evaluation Criteria In Solid Tumors (RECIST), and 6 CR (40%) and 4 PR (26.7%) by PET, for an overall metabolic response rate of 67% (95%CI, 42.8 – 90.6) according to PET Response Criteria in Solid Tumors (PERCIST). Median progression free survival (PFS) was 21 months and median overall survival (OS) was 24 months. Grade 3 adverse events related to bevacizumab were hypertension (n = 2), proteinuria (n = 1) and epistaxis (n = 5). Treatment was delayed in five patients for nasal bleeding or uncontrolled hypertension.ConclusionsLow-dose bevacizumab and chemotherapy was well tolerated and active in a heavily pretreated population of advanced EOC. Further studies should assess the activity of low dose bevacizumab in EOC.

Bevacizumab and ovarian cancer

Vascular endothelial growth factor (VEGF), one of the major pathways involved in tumor angiogenesis, is often overexpressed in epithelial ovarian cancer (EOC), and therefore an attractive target for therapy. This review aims to evaluate the rationale for targeting angiogenic pathways by the usage of the anti-VEGF agent bevacizumab in EOC. Bevacizumab monotherapy has been shown to be effective in the treatment of EOC with response rate of 16-21% in phase II trials. In phase III trials, patients with advanced EOC who received combination chemotherapy (paclitaxel + carboplatin) plus bevacizumab with maintenance bevacizumab had significantly longer progression-free survival than those who received chemotherapy alone, but did not prolong overall survival. The most common grade 3/4 adverse events of bevacizumab monotherapy include hypertension and proteinuria, while heavily pretreated patients were at increased risk of bowel perforation. The addition of bevacizumab to the standard chemotherapy in patients with advanced EOC may not be cost-effective. Bevacizumab has significant activity and is the most promising drug in EOC. However, understanding of its unique adverse events and identification of predictive biomarkers of bevacizumab response are necessary in order to select patients most likely to benefit from this therapy.

Establishing a molecular taxonomy for epithelial ovarian cancer (EOC) from 363 formalin-fixed paraffin embedded (FFPE) specimens.

5000 Background: Despite histological heterogeneity and evidence of some molecular subtypes (e.g. BRCA1/2-deficient) EOC continues to be treated as a single disease. Using unsupervised hierarchical clustering of DNA microarray expression data we aimed to identify molecular subgroups with a view to personalized therapy. Methods: Microarray expression analysis was performed on 363 FFPE EOC samples (by far the largest dataset to date) with linked prospectively collected clinical data. Unsupervised clustering was applied to the most variable genes. This was followed by computational classification in the serous samples only. Results: Unsupervised analysis of all samples identified 6 subgroups which were most significantly related to histology (p=3.65 x 10-27) and had different overall survival (OS; p<0.0001). Clear cell tumors were present in one group, mucinous in another, serous and endometrioid were spread across 4 groups each. When a similar approach was applied to pure serous samples (no mixed tumors; n=199) three subgroups were identified with different OS (p<0.0001). Intriguingly, the dominant discriminatory biology within the serous cohort was related to vasculature development (FDR p.vasc.dev.=7.31 x 10-7) and more specifically to angiogenic processes (FDR p.Angiogenesis= 8.59 x 10-5). Up-regulation of these angiogenesis-related genes predominated in only one of the 3 serous subgroups (58 out of 199 tumours). Class labels were assigned to these samples based upon expression of these angiogenesis-related genes and a gene expression signature was developed which could identify the novel angiogenesis molecular subgroup. Conclusions: 1) It is possible to consistently perform transcriptomic analysis from small FFPE ovarian tumor sections and cluster similar tumors. 2) We have identified 6 main clusters of EOC, strongly associated with histology and survival. 3) In the pure serous subgroup, 3 clusters were identified with significantly differing survival; one of these subgroups was defined by upregulation of multiple angiogenesis genes. In light of the recently reported activity of bevacizumab in EOC (GOG 218 and ICON7) this subgroup may explain the observed response.

Predictive and prognostic angiogenic markers in a gynecologic oncology group phase II trial of bevacizumab in recurrent and persistent ovarian or peritoneal cancer

Objective Potential predictive/prognostic angiogenic markers were prospectively examined in a phase II trial of bevacizumab in epithelial ovarian cancer (EOC)/primary peritoneal cancer (PPC). Methods Recurrent/persistent EOC/PPC patients were treated with bevacizumab (15 mg/kg IV q21days) until disease progression. Validated-immunohistochemistry (IHC) assays were performed on pre-cycle 1/4 tumor biopsies for CD31-microvessel density (MVD), VEGF-histoscore (HS), p53-HS, and TSP1 image analysis score (IA). Pre-cycle 1/4 serum and plasma VEGF were quantified using a validated-ELISA. Results CD31-MVD and serum VEGF, evaluated pre-cycle 1 in 41/61 and 51/61 eligible patients, respectively, did not appear to be correlated. High CD31-MVD, categorized at the median, appeared to be associated with tumor response, a 13-month shorter median survival, and an increased risk of death (unadjusted hazard ratio [HR] = 2.2, 95% confidence interval [CI] = 1.067–4.467). In addition, each standard deviation (SD) increase in CD31-MVD appeared to be associated with worse survival in unadjusted and adjusted analyses. IHC and plasma biomarkers did not change with bevacizumab treatment except for serum VEGF, which appeared to decrease during bevacizumab treatment. This decrease was not associated with response. High pre-cycle 1 serum VEGF, categorized at the median, was associated with 22-month shorter median survival and an increased risk of death (unadjusted HR = 2.7, 95% CI = 1.369–5.191). Categorized p53 appeared to be associated with unadjusted survival and each SD increase in TSP1-IA appeared to be associated with a decreased risk of progression in unadjusted and adjusted analyses. Conclusions Despite the limitations in sample size and exploratory nature of the study, angiogenic markers in tumor and serum may provide prognostic value in recurrent/persistent EOC/PPC, and are being prospectively evaluated in the GOG phase III trial of carboplatin, paclitaxel and bevacizumab/placebo in previously untreated EOC/PPC.