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PURPOSE We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma. METHODS A total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration v time curve 6) and paclitaxel (175 mg/m2) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for BRCA1/2 and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry. RESULTS Median follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8 v 32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for BRCA1/2 mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non- BRCA1/2 HRR, the HR was 0.65 (95% CI, 0.51 to 0.85). BRCA1/2, HRR, and CD31 were not predictive of bevacizumab activity. CONCLUSION No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for BRCA1/2 mutations and homologous recombination deficiency is essential.

Purpose To evaluate risk factors for GI adverse events (AEs) within a phase III trial of bevacizumab in first-line ovarian cancer therapy. Patients and Methods Women with previously untreated advanced disease after surgery were randomly allocated to six cycles of platinum-taxane chemotherapy plus placebo cycles (C)2 to C22 (R1); chemotherapy plus bevacizumab C2 to C6 plus placebo C7 to C22 (R2); or chemotherapy plus bevacizumab C2 to C22 (R3). Patients were evaluated for history or on-study development of potential risk factors for GI AEs defined as grade ≥ 2 perforation, fistula, necrosis, or hemorrhage. Results Of 1,873 patients enrolled, 1,759 (94%) were evaluable, and 2.8% (50 of 1,759) experienced a GI AE: 10 of 587 (1.7%, R1), 20 of 587 (3.4%, R2), and 20 of 585 (3.4%, R3). Univariable analyses indicated that previous treatment of inflammatory bowel disease (IBD; P = .005) and small bowel resection (SBR; P = .032) or large bowel resection (LBR; P = .012) at primary surgery were significantly associated with a GI AE. The multivariable estimated relative odds of a GI AE were 13.4 (95% CI, 3.44 to 52.3; P < .001) for IBD; 2.05 (95% CI, 1.09 to 3.88; P = .026) for LBR; 1.95 (95% CI, 0.894 to 4.25; P = .093) for SBR; and 2.15 for bevacizumab exposure (aggregated 95% CI, 1.05 to 4.40; P = .036). Conclusion History of treatment for IBD, and bowel resection at primary surgery, increase the odds of GI AEs in patients receiving first-line platinum-taxane chemotherapy for advanced ovarian cancer. After accounting for these risk factors, concurrent bevacizumab doubles the odds of a GI AE, but is not appreciably increased by continuation beyond chemotherapy.

e17070Background: MicroRNAs (miRNA) have been established as key regulators of tumor gene expression as well as prime biomarker candidates for clinical phenotypes. We analyzed the regulatory structure of miRNAs and their colocalized gene targets in EOC tissue to construct a regulatory signature for clinical prognosis. Methods: FFPE blocks of primary EOC tumor tissue with > 80% tumor cells were selected for 20 patients (stage ≥ IIc) for whom follow up data was available. Expression levels of mRNA and miRNA were assayed separately. An integrated analysis was performed to identify miRNA/mRNA regulatory clusters. Gene set enrichment analysis (GSEA) was carried out on the coexpression of putative miRNA target genes, from the miRTarBase database, with their respective miRNAs, to identify enriched categories for each miRNA. MiRNAs with at least one significantly enriched category from the MSigDB C2 dataset at a false discovery rate of 0.05 were chosen. For each enriched category of each miRNA, a regulon was defi...

LBA1 Background: BEV, a humanized anti-VEGF monoclonal antibody, has demonstrated single-agent activity in patients with recurrent EOC, or PPC. The therapeutic impact of concurrent ± maintenance BEV with standard chemotherapy (CT) was evaluated in an international, double-blind, placebo-controlled phase III trial. Methods: Eligible patients had newly diagnosed, previously untreated EOC, PPC or FTC following abdominal surgery for staging and maximal effort at tumor debulking; stage III (macroscopic residual disease) or stage IV disease. The randomly allocated regimens were (1) CT (IV paclitaxel 175 mg/m2 + carboplatin AUC 6 cycles 1-6) + placebo cycles (C)2-22 (R1) (2) CT + concurrent BEV (15 mg/kg) C2-6 + placebo C7-22 (R2) (3) CT + concurrent BEV C2-6 + maintenance BEV C7-22 (R3) Infusions were administered d1 of a 21d cycle. The primary endpoint is progression-free survival (PFS) (radiographic, CA125, clinical criteria or death); secondary endpoints include overall survival, safety, and QoL. Results: 1,873 patients, median age 60, were enrolled from 9/05 - 6/09. Stage III optimally debulked (34%), stage III sub-optimally debulked (40%), and stage IV (26%) patients were similarly distributed in each treatment group. Grade 3 - 4 hypertension was reported in 1.6% (R1), 5.4% (R2), and 10.0% (R3). Grade ≥ 3 GI perforation, hemorrhage or fistula occurred in 0.8% (R1), 2.6% (R2) and 2.3% (R3). Relative to R1, the hazard of first progression or death for R2 was 0.908 (95% CI: 0.795 – 1.04, p=0.16) and for R3 was 0.717 (95% CI: 0.625 – 0.824, p Conclusions: This study demonstrates that front-line treatment of EOC, PPC, and FTC patients with CT plus concurrent and maintenance BEV prolongs PFS. This is the first anti-angiogenic agent to demonstrate benefit in this population. [Table: see text]