After a median follow-up of For patients who received bevacizumab upfront and as maintenance following chemotherapy, the hazard ratio dipped to 0. Despite the lack of survival benefit, the Gynecologic Oncology Group GOG trial did yield practice-informing and potentially practice-changing data, they noted in the Journal of Clinical Oncology. Concurrent plus maintenance bevacizumab led to significant improvement in progression-free survival PFS. To allow for unblinding at disease progression, investigators amended the protocol early on to make PFS the primary endpoint. The final results also showed a significant survival benefit for patients with stage IV disease treated with upfront and maintenance bevacizumab.
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Evaluation of candidate biomarkers was an exploratory objective. Methods Patients with stage III incompletely resected or IV ovarian cancer were randomly assigned to receive six chemotherapy cycles with placebo or bevacizumab followed by single-agent placebo or bevacizumab. Five candidate tumor biomarkers were assessed by immunohistochemistry.
The biomarker-evaluable population was categorized into high or low biomarker-expressing subgroups using median and quartile cutoffs. Associations between biomarker expression and efficacy were analyzed. All statistical tests were two-sided.
Conclusions These retrospective tumor biomarker analyses suggest a positive association between density of vascular endothelial cells the predominant cell type expressing VEGF receptors and tumor VEGF-A levels and magnitude of bevacizumab effect in ovarian cancer. Vascular endothelial growth factor VEGF —A, a dimeric glycoprotein, is a survival factor for endothelial cells, is considered to be a primary inducer of angiogenesis and vascular permeability, and is the molecular target of bevacizumab 1.
Although VEGF-A inhibition is lethal during embryonic development 3 , its neutralization is well tolerated in adults, consistent with postnatal vascular maturation and differentiation in various tissues 4. Following demonstration that VEGF-A signaling blockade inhibits angiogenesis and tumor growth in preclinical models 4 , the humanized VEGF-blocking antibody bevacizumab was evaluated in clinical trials and subsequently approved as treatment for several advanced cancers 5 , 6.
The Gynecologic Oncology Group GOG randomized phase III trial demonstrated statistically significantly improved progression-free survival PFS with bevacizumab added to standard frontline chemotherapy for epithelial ovarian cancer 7. These results, supported by findings from the randomized phase III ICON7 trial 8 , led to European approval of frontline bevacizumab combined with chemotherapy for epithelial ovarian cancer. However, neither trial demonstrated a statistically significant effect on overall survival OS.
In GOG, extensive crossover from the chemotherapy-alone arm to bevacizumab and further uncontrolled treatment lines may have masked a potential effect on OS 7 , 9. The present analyses explored whether candidate tumor biomarkers might define subsets of patients with epithelial ovarian cancer deriving differential clinical benefit from frontline bevacizumab.
Evaluation of potential biomarkers in prospectively collected specimens was an exploratory objective of GOG Retrospective biomarker analyses in metastatic breast cancer suggested that low levels of neuropilin-1 may predict increased PFS benefit from bevacizumab MET is biologically interesting as a candidate biomarker for bevacizumab efficacy because of its potential involvement in anti-VEGF-A resistance CD31 is an integral membrane glycoprotein expressed at high levels on endothelial cells, which form microvessels in normal tissue and tumors Microvessel density MVD quantified based on CDpositive endothelial cells in tumor samples assayed by IHC is often used as a surrogate for tumoral angiogenic activity Higher tumoral MVD is associated with worse prognosis in several tumor types, including ovarian cancer 14— New, immature blood vessels within the microvasculature require VEGF-A signaling for survival, and thus are among the direct targets of bevacizumab Retrospective analyses in colorectal cancer were consistent with this hypothesis 25 , but others failed to show a relationship between MVD and bevacizumab benefit 26 , Whether the lack of correlation reflects small patient numbers, tumor diversity, or other factors remains to be established.
In this biomarker substudy of the GOG trial evaluating bevacizumab in ovarian cancer, we sought to explore the potential prognostic and predictive effects of these five tumor markers. The study design details have been published previously 7. The protocol was approved by the relevant institutional review boards or ethics committees; all patients gave written informed consent.
Biomarker Analyses Candidate biomarkers were measured after completion of the clinical trial using paraffin-embedded formalin-fixed sections taken from the pretreatment tumor samples. Membrane and cytoplasmic IHC staining were undertaken using validated, fit-for-purpose assays. JPEG image encoding with quality factor 80 and an interpolated focus distance of 15 with stitching in the scan options was chosen. For every slide, a specific scan profile was configured and holes in the scan area were filled to allow for correct detection of tissue and in-focus images of the tissue.
Microscopic analysis of the digitized slides was performed by a small number of highly experienced research pathologists and imaging scientists using rigorous research protocols. This included systematic, uniform, random sampling of at least three but generally 10 regions of interest ROIs from the whole-slide image to take into account potential tumor heterogeneity of the marker.
An unbiased, rectangular counting grid and optimized counting rules were used for MVD quantification Supplementary Figure 1 , available online 30 , The pathologists and imaging scientists were blinded to clinical outcomes in the study patients. Initially, the BEI population was dichotomized using the median value for each marker as the cutoff between low and high expression of each marker.
The median was prespecified as the cutoff before performing the present biomarker analyses but after unblinding of the clinical trial results. Biomarkers showing potential predictive effect using the median as the cutoff were evaluated further to explore the effect of choosing the first or third quartile instead of the median as the cutoff to define low vs high expression of each marker. Finally, sliding window analyses were performed to explore the effect of varying cutoffs for potentially predictive biomarkers.
In the biomarker analyses reported here, investigator-assessed PFS and OS were calculated from the date of random assignment. PFS was censored if nonstudy therapy was initiated for any reason before disease progression or if progression was defined by cancer antigen elevation alone without Response Evaluation Criteria in Solid Tumors-defined progression. Comparisons were based on the extended bevacizumab arm vs the chemotherapy-alone arm because PFS was improved only with extended bevacizumab in the primary analysis of the intent-to-treat ITT population.
Two-sided treatment-by-biomarker Pinteraction values were calculated using a Cox model including treatment, biomarker using first quartile, median, or third quartile cutoffs to define low and high biomarker expression levels , interaction of treatment by biomarker, FIGO stage and debulking status, and baseline GOG performance status.
Because of the exploratory nature of the analyses, no cutoff for statistical significance is specified and no adjustment for multiple testing was performed. The assumption of proportionality was not tested for the retrospective biomarker analyses. In the control arm, median PFS was In the extended bevacizumab arm, median PFS was The stratified hazard ratio for PFS was 0. A similar pattern was seen for OS: stratified hazard ratios were 0.
Three treatment arms were included in the trial known as GOG These included 1 standard intravenous paclitaxel and carboplatin 2 intravenous paclitaxel and carboplatin in conjunction with bevacizumab and 3 intravenous paclitaxel, carboplatin and bevacizumab with continuation of bevacizumab as a single agent for an additional 10 months maintenance. The Society of Gynecologic Oncology commends the Gynecologic Oncology Group, their investigators and the many patients who participated in this study for contributing valuable data advancing the evidence-based management of these diseases. The main finding was a significant improvement in progression free survival PFS with the addition of bevacizumab to upfront intravenous chemotherapy when the bevacizumab was continued as a maintenance regimen after chemotherapy.
GOG 0218 PDF
Overview of proposed MOA of Avastin. Avastin is not indicated for adjuvant treatment of colon cancer. The information contained in this section of the site is intended for U. Pregnancy warning Based on the mechanism of action and animal studies, Avastin may cause fetal harm Advise female patients that Avastin may cause fetal harm, and to inform their healthcare provider of a known bog suspected pregnancy Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose of Avastin Advise nursing women that breastfeeding is not recommended during treatment with Avastin and for 6 months following their last dose of Avastin may impair fertility. The Gof study included a diverse population of women [ 1 ]. Dosing and Usage Doses and Duration. The number of patients with measurable disease at baseline was in the Avastin plus chemotherapy arm and in the chemotherapy alone arm Median OS: Recommended dosing for approved cancer types.
No Overall Survival Benefit With Bevacizumab for Ovarian Cancer
The GOG study evaluated Avastin plus chemotherapy vs chemotherapy alone in platinum-sensitive ovarian cancer [ 1,3 ]. Bevacizumab Approved by FDA to Treat Ovarian Cancer Following Surgery These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study. Recurrent Glioblastoma GBM Avastin is indicated for the treatment of recurrent glioblastoma in adults. ORR by chemotherapy cohort.