Search

Background Improvement in clinical outcomes of patients with platinum-resistant disease is an unmet medical need and trials in this population are urgently needed. Checkpoint-inhibitors have already shown activity in multiple other tumor entities and ovarian cancer, especially in the combination with anti-angiogenic treatment. Primary objective To test if the activity of nonplatinum-based chemotherapy and bevacizumab could be improved by the addition of atezolizumab. study hypothesis The addition of atezolizumab to standard non-platinum combination of chemotherapy and bevacizumab improves median overall survival from 15 to 20 months. Trial design Patients are randomized to chemotherapy (paclitaxel weekly or pegylated liposomal doxorubicin) + bevacizumab + placebo vs chemotherapy + bevacizumab + atezolizumab. Stratification factors are: number of prior lines, planned type of chemotherapy, prior use of bevacizumab, and tumor programmed death-ligand 1 (PDL1) status. Major inclusion/exclusion criteria Recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer with up to three prior therapies and a treatmentfree interval after platinum of less than 6 months. Patients with three prior lines of chemotherapy are eligible irrespective of the platinum free-interval. A de novo tumor tissue sample biopsy for determination of PD-L1 status prior to randomization for stratification is mandatory. Major exclusion criteria consider bevacizumab-specific and immunotherapy-specific criteria. Primary endpoint Overall survival and progression-free survival are co-primary endpoints. sample size It is planned to randomize 664 patients. Trial registration NCT03353831. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) is the fifth most common cause of cancer death in women. Although significant progress has been made in the treatment of OC, the majority of patients experience disease recurrence and receive second-line and sometimes several lines of treatment. Here we review the options available for the treatment of recurrent disease and discuss how different agents are selected, combined and offered in a rationale sequence in the context of multidisciplinary care. We reviewed published work between 1990 and 2013 and meeting abstracts related to the use of chemotherapy and surgery in patients with recurrent ovarian cancer. We discuss treatment regimens, efficacy endpoints and safety profiles of the different therapies. Platinum-based drugs are the most active agents and are selected on the basis of a probability of response to retreatment. Nonplatinum-based chemotherapy regimens are usually given in the ‘platinum-resistant’ setting and have a modest effect on outcome. Molecular targeted therapy of ovarian cancer given alone or integrated with chemotherapy is showing promising results. Many patients are now receiving more than one line of therapy for recurrent disease, usually platinum based until platinum resistance emerges. The sequential use of chemotherapy regimens and the incorporation of molecularly targeted treatments, either alone or in combination with chemotherapy, have over the last decade significantly extended the median survival of patients with ovarian cancer. [ABSTRACT FROM PUBLISHER]

Abstract: The last five years has seen a major expansion in the number of clinical trials with molecular targeted agents in ovarian cancer. Most of the studies are with anti-angiogenic agents. This review discusses the rationale for molecular targeted therapy in ovarian cancer and the current randomized trials. It focuses on anti-angiogenic agents, particularly bevacizumab and small molecule VEGFR tyrosine kinase inhibitors, and EGFR, α-folate receptor, PARP, src kinase and IGFR inhibitors. The results of first-line trials and studies in recurrent disease with bevacizumab will soon be available. Results of many other trials with molecular targeted therapy will follow over the next 2–3years. We highlight some of the complex issues about sequencing, duration of therapy and selection of agents to aid the debate about the best use of molecular targeted agents in the treatment of ovarian cancer. [Copyright &y& Elsevier]

Many women with ovarian cancer present with advanced disease, and although most respond to treatment, the majority relapse and eventually die of the disease. Therapy targeted against angiogenesis is a new strategy being investigated in ovarian cancer. We review current trials directed against vascular endothelial growth factor (VEGF), the dominant proangiogenic vascular growth factor in ovarian cancer. Two main groups of inhibitors are being investigated in randomized trials. In the first group is bevacizumab, a monoclonal antibody (MoAb) that targets VEGF and is being evaluated in the first-line treatment of ovarian cancer. In the second group are VEGF receptor tyrosine kinase inhibitors (TK; TKIs). Cediranib (AZD2171) is one agent now being studied in a randomized trial (ICON6) in women with platinumsensitive first relapse. ICON6 is a 3-arm study investigating cediranib in combination with platinum-paclitaxel and as maintenance after chemotherapy. The trial design is novel with 3 sequential phases assessing toxicity, activity, and survival combined within a single randomized, placebo-controlled trial to improve the speed of evaluation of the new compound, saving costs and using patient data efficiently. VEGF inhibitors are more cytostatic than cytotoxic, and stable disease (SD) rather than overall response is often the best "response." Novel trial designs to assess antiangiogenic agents are needed to unravel questions about dose and scheduling of the growing number of antiangiogenic agents in a rapid and efficient manner. International collaboration is essential as is a close partnership between academia and industry to make such trials feasible. [ABSTRACT FROM AUTHOR]

Abstract Objective In the randomized phase 3 ICON7 trial (ISRCTN91273375), adding bevacizumab to chemotherapy for newly diagnosed ovarian cancer significantly improved progression-free survival (PFS; primary endpoint) but not overall survival (OS; secondary endpoint) in the intent-to-treat (ITT) population. We explored treatment effect according to stage and extent of residual disease. Methods Patients with stage IIB–IV or high-risk (grade 3/clear-cell) stage I–IIA ovarian cancer were randomized to receive six cycles of carboplatin and paclitaxel either alone or with bevacizumab 7.5 mg/kg every 3 weeks followed by single-agent bevacizumab for 12 further cycles (total duration 12 months). Post hoc exploratory analyses of subgroups defined by stage and extent of residual disease at diagnosis within the stage IIIB–IV population (European indication) was performed. Results The PFS benefit from bevacizumab was seen consistently in all subgroups explored. The PFS hazard ratio was 0.77 (95% confidence interval [CI], 0.59–0.99) in 411 patients with stage IIIB–IV ovarian cancer with no visible residuum and 0.81 (95% CI, 0.69–0.95) in 749 patients with stage IIIB–IV disease and visible residuum. As in the ITT population, no OS difference was detected in any subgroup except the previously described 'high-risk' subgroup. Safety results in analyzed subgroups were consistent with the overall population. Conclusions Adding bevacizumab to front-line chemotherapy improves PFS irrespective of stage/residual disease. In patients with stage III with >1 cm residuum, stage IV or inoperable disease, this translates into an OS benefit. No OS benefit or detriment was seen in other subgroups explored. Highlights • Post hoc analyses of ICON7 explored bevacizumab by stage and extent of residual disease after upfront surgery for OC. • The progression-free survival (PFS) benefit from bevacizumab was seen consistently in all subgroups explored. • The PFS hazard ratio was 0.77 (95% CI, 0.59–0.99) in 411 patients with stage IIIB–IV disease and no visible residuum. • No OS difference was detected overall or in any subgroup except the previously reported 'high-risk' subgroup. • Adding bevacizumab to front-line chemotherapy improves PFS irrespective of stage/residual disease. [ABSTRACT FROM AUTHOR]

Summary Background The ICON7 trial previously reported improved progression-free survival in women with ovarian cancer with the addition of bevacizumab to standard chemotherapy, with the greatest effect in patients at high risk of disease progression. We report the final overall survival results of the trial. Methods ICON7 was an international, phase 3, open-label, randomised trial undertaken at 263 centres in 11 countries across Europe, Canada, Australia and New Zealand. Eligible adult women with newly diagnosed ovarian cancer that was either high-risk early-stage disease (International Federation of Gynecology and Obstetrics [FIGO] stage I–IIa, grade 3 or clear cell histology) or more advanced disease (FIGO stage IIb–IV), with an Eastern Cooperative Oncology Group performance status of 0–2, were enrolled and randomly assigned in a 1:1 ratio to standard chemotherapy (six 3-weekly cycles of intravenous carboplatin [AUC 5 or 6] and paclitaxel 175 mg/m 2 of body surface area) or the same chemotherapy regimen plus bevacizumab 7·5 mg per kg bodyweight intravenously every 3 weeks, given concurrently and continued with up to 12 further 3-weekly cycles of maintenance therapy. Randomisation was done by a minimisation algorithm stratified by FIGO stage, residual disease, interval between surgery and chemotherapy, and Gynecologic Cancer InterGroup group. The primary endpoint was progression-free survival; the study was also powered to detect a difference in overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN91273375. Findings Between Dec 18, 2006, and Feb 16, 2009, 1528 women were enrolled and randomly assigned to receive chemotherapy (n=764) or chemotherapy plus bevacizumab (n=764). Median follow-up at the end of the trial on March 31, 2013, was 48·9 months (IQR 26·6–56·2), at which point 714 patients had died (352 in the chemotherapy group and 362 in the bevacizumab group). Our results showed evidence of non-proportional hazards, so we used the difference in restricted mean survival time as the primary estimate of effect. No overall survival benefit of bevacizumab was recorded (restricted mean survival time 44·6 months [95% CI 43·2–45·9] in the standard chemotherapy group vs 45·5 months [44·2–46·7] in the bevacizumab group; log-rank p=0·85). In an exploratory analysis of a predefined subgroup of 502 patients with poor prognosis disease, 332 (66%) died (174 in the standard chemotherapy group and 158 in the bevacizumab group), and a significant difference in overall survival was noted between women who received bevacizumab plus chemotherapy and those who received chemotherapy alone (restricted mean survival time 34·5 months [95% CI 32·0–37·0] with standard chemotherapy vs 39·3 months [37·0–41·7] with bevacizumab; log-rank p=0·03). However, in non-high-risk patients, the restricted mean survival time did not differ significantly between the two treatment groups (49·7 months [95% CI 48·3–51·1]) in the standard chemotherapy group vs 48·4 months [47·0–49·9] in the bevacizumab group; p=0·20). An updated analysis of progression-free survival showed no difference between treatment groups. During extended follow-up, one further treatment-related grade 3 event (gastrointestinal fistula in a bevacizumab-treated patient), three grade 2 treatment-related events (cardiac failure, sarcoidosis, and foot fracture, all in bevacizumab-treated patients), and one grade 1 treatment-related event (vaginal haemorrhage, in a patient treated with standard chemotherapy) were reported. Interpretation Bevacizumab, added to platinum-based chemotherapy, did not increase overall survival in the study population as a whole. However, an overall survival benefit was recorded in poor-prognosis patients, which is concordant with the progression-free survival results from ICON7 and GOG-218, and provides further evidence towards the optimum use of bevacizumab in the treatment of ovarian cancer. Funding The National Institute for Health Research through the UK National Cancer Research Network, the Medical Research Council, and Roche. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis plays a role in the biology of ovarian cancer. We examined the effect of bevacizumab, the vascular endothelial growth factor inhibitor, on survival in women with this disease. Methods: We randomly assigned women with ovarian cancer to carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease. Outcome measures included progression-free survival, first analyzed per protocol and then updated, and interim overall survival. Results: A total of 1528 women from 11 countries were randomly assigned to one of the two treatment regimens. Their median age was 57 years; 90% had epithelial ovarian cancer, 69% had a serous histologic type, 9% had high-risk early-stage disease, 30% were at high risk for progression, and 70% had stage IIIC or IV ovarian cancer. Progression-free survival (restricted mean) at 36 months was 20.3 months with standard therapy, as compared with 21.8 months with standard therapy plus bevacizumab (hazard ratio for progression or death with bevacizumab added, 0.81; 95% confidence interval, 0.70 to 0.94; P=0.004 by the log-rank test). Nonproportional hazards were detected (i.e., the treatment effect was not consistent over time on the hazard function scale) (P<0.001), with a maximum effect at 12 months, coinciding with the end of planned bevacizumab treatment and diminishing by 24 months. Bevacizumab was associated with more toxic effects (most often hypertension of grade 2 or higher) (18%, vs. 2% with chemotherapy alone). In the updated analyses, progression-free survival (restricted mean) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab (P=0.04 by log-rank test); in patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months with standard therapy alone and 18.1 months with bevacizumab added, with respective median overall survival of 28.8 and 36.6 months. Conclusions: Bevacizumab improved progression-free survival in women with ovarian cancer. The benefits with respect to both progression-free and overall survival were greater among those at high risk for disease progression. (Funded by Roche and others; ICON7 Controlled-Trials.com number, ISRCTN91273375.) [ABSTRACT FROM PUBLISHER]