Cervical cancer - State of the science: From angiogenesis blockade to checkpoint inhibition.

Vascular endothelial growth factor (VEGF) has emerged as a therapeutic target in several malignancies, including cervical cancer. Chemotherapy doublets combined with the fully humanized monoclonal antibody, bevacizumab, now constitute first-line therapy for women struggling with recurrent/metastatic cervical carcinoma. Regulatory approval for this indication was based on the phase III randomized trial, GOG 240, which demonstrated a statistically significant and clinically meaningful improvement in overall survival when bevacizumab was added to chemotherapy: 17.0 vs 13.3 months; HR 0.71; 98% CI, 0.54-0.95; p = .004. Incorporation of bevacizumab resulted in significant improvements in progression-free survival and response. These benefits were not accompanied by deterioration in quality of life. GOG 240 identified vaginal fistula as a new adverse event associated with bevacizumab use. All fistulas occurred in women who had received prior pelvic radiotherapy, and none resulted in emergency surgery, sepsis, or death. Final protocol-specified analysis demonstrated continued separation of the survival curves favoring VEGF inhibition: 16.8 vs 13.3 months; HR 0.77; 95% CI, 0.62-9.95; p = .007. Post-progression survival was not significantly different between the arms in GOG 240. Moving forward, immunotherapy has now entered the clinical trial arena to address the high unmet clinical need for effective and tolerable second line therapies in this patient population. Targeting the programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) pathway using checkpoint inhibitors to break immunologic tolerance is promising. The immunologic landscape involving human papillomavirus-positive head and neck carcinoma and cutaneous squamous cell carcinoma can be informative when considering feasibility of checkpoint blockade in advanced cervical cancer. Phase II studies using anti-PD-1 molecules, nivolumab and pembrolizumab are ongoing, and GOG 3016, the first phase III randomized trial of a checkpoint inhibitor (cemiplimab) in cervical cancer, recently activated. Important considerations in attempts to inhibit the inhibitors include pseudoprogression and post-progression survival, abscopal effects, and immune-related adverse events, including endocrinopathies.

Endpoints in clinical trials: What do patients consider important? A survey of the Ovarian Cancer National Alliance.

OBJECTIVE: In order to understand the patient's perspective in regards to meaningful surrogate clinical trial endpoints and the impact of treatment-related toxicity, and quality of life, we surveyed women with gynecological cancers to ascertain their preferences. METHODS: A 28-question anonymous online survey was posted on the OCNA website (www.ovariancancer.org). Survey questions included demographic factors, tumor data, and patients' preference regarding side effects and therapy endpoints. Data was analyzed for frequency and percentage of each response. Student t-test, Fisher's exact test and Wilcoxon rank sums were preformed. RESULTS: There were 1413 survey responses. Participants reported that for a new agent to be meaningful, the minimum extension of progression-free survival (PFS) and overall survival (OS) should be five or more months, 77% and 85% of the time, respectively. Most subjects (55%, n=612) were interested in an agent that would keep tumor growth relatively static without change in OS. Addressing the impact of adverse aspects from a hypothetical new agent as a function of response, there was significant migration (p<0.0001) to acceptance of greater toxicity and cost under the scenario of a 5-6months OS gain, despite three-fold higher neurotoxicity, as compared to a PFS gain of 3-4months/no OS gain without toxicity. Response patterns weren't altered by recurrence status. CONCLUSIONS: Herein, we show that magnitude of outcome is a desired effect, even given the prospect of significant toxicity and cost. However, these preferences appear to differ between those with primary and recurrent disease.

Hereditary predisposition to ovarian cancer, looking beyond BRCA1/BRCA2.

OBJECTIVE: Genetic predisposition to ovarian cancer is well documented. With the advent of next generation sequencing, hereditary panel testing provides an efficient method for evaluating multiple genes simultaneously. Therefore, we sought to investigate the contribution of 19 genes identified in the literature as increasing the risk of hereditary breast and ovarian cancer (HBOC) in a BRCA1 and BRCA2 negative population of patients with a personal history of breast and/or ovarian cancer by means of a hereditary cancer panel. METHODS: Subjects were referred for multi-gene panel testing between February 2012 and March 2014. Clinical data was ascertained from requisition forms. The incidence of pathogenic mutations (including likely pathogenic), and variant of unknown significance were then calculated for each gene and/or patient cohort. RESULTS: In this cohort of 911 subjects, panel testing identified 67 mutations. With 7.4% of subjects harboring a mutation on this multi-gene panel, the diagnostic yield was increased, compared to testing for BRCA1 and BRCA2 mutations alone. In the ovarian cancer probands, the most frequently mutated genes were BRIP1 (n=8; 1.72%) and MSH6 (n=6; 1.29%). In the breast cancer probands, mutations were most commonly observed in CHEK2 (n=9; 2.54%), ATM (n=3; 0.85%), and TP53 (n=3; 0.85%). CONCLUSIONS: Although further studies are needed to clarify the exact management of patients with a mutation in each gene, this study highlights information that can be captured with panel testing and provides support for incorporation of panel testing into clinical practice.

A Markov model to evaluate cost-effectiveness of antiangiogenesis therapy using bevacizumab in advanced cervical cancer.

OBJECTIVE: To evaluate the cost-effectiveness of bevacizumab in recurrent/persistent and metastatic cervical cancer using recently reported updated survival and toxicology data. METHODS: A Markov decision tree based on the Gynecologic Oncology Group 240 randomized trial was created. The 2013 MediCare Services Drug Payment Table and Physician Fee Schedule provided costs. In the 5-year model subjects transitioned through the following states: response, progression, minor complications, severe complications, and death. Patients experiencing a health utility per month according to treatment effectiveness were calculated. Because cervical cancer survival is measured in months rather than years, results were reported in both quality adjusted cervical cancer life months and years (QALmonth, QALY), adjusted from a baseline of having advanced cervical cancer during a month. RESULTS: The estimated total cost of therapy with bevacizumab is approximately 13.2 times that for chemotherapy alone, adding $73,791 per 3.5months (0.29year) of life gained, resulting in an incremental cost-effectiveness ratio (ICER) of $21.083 per month of added life. The ICER increased to $5775 per month of added life and $24,597/QALmonth ($295,164/QALY) due to the smaller difference in QALmonths. With 75% bevacizumab cost reduction, the ICER is $6737/QALmonth ($80,844/QALY), which translates to $23,580 for the 3.5month (0.29year) gain in OS. CONCLUSIONS: Increased costs are primarily related to the cost of drug and not the management of bevacizumab-induced complications. Cost reductions in bevacizumab result in dramatic declines in the ICER, suggesting that cost reconciliation in advanced cervical cancer may be possible through the availability of biosimilars, and/or less expensive, equally efficacious anti-angiogenesis agents.

The safety and efficacy of bevacizumab in the treatment of patients with recurrent or metastatic cervical cancer.

INTRODUCTION: Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF). (Avastin; Genetech, Inc, San Francisco, CA) Angiogenesis is blocked by the binding of bevacizumab to VEGF, inhibiting the binding of this ligand to the VEGF receptor. On 14 August 2014 the Food and Drug Administration (FDA) approved use of bevacizumab in persistent, recurrent, or metastatic cervical cancer. Areas covered: Herein we review pharmacodynamics and kinetics, clinical data and treatment-related toxicities of bevacizumab in the treatment of metastatic, recurrent or persistent cervical cancer. Additionally, future areas of development are reviewed. Expert commentary: Anti-angiogenesis therapy with bevacizumab is central to metastatic, persistent, and recurrent cervical cancer treatment. Additional anti-angiogenesis drugs are in development. Future studies will need to establish if the addition of multiple anti-angiogenesis agents or anti-angiogenesis in combination with immunotherapy is more effective than bevacizumab with chemotherapy.

Safety and efficacy of salvage nano-particle albumin bound paclitaxel in recurrent cervical cancer: a feasibility study.

BACKGROUND: After platinum and taxane chemotherapy, with or without bevacizumab, active regimens for advanced or recurrent cervical cancer are lacking. Our objective was to review a single institution experience in treating recurrent, refractory cervical cancer with nano-particle albumin bound (NAB) paclitaxel with or without bevacizumab. METHODS: This retrospective case series was conducted in accordance with the regulations set forth by the Institutional Review Board at St. Joseph's Hospital and Medical center. The chemotherapy log at the outpatient infusion center at the University of Arizona Cancer Center was reviewed to identify all advanced cervical cancer patients treated with NAB-paclitaxel from November 2011 until February 2015. The following data points were extracted from patient charts: demographic information, number of cycles, progression free survival (PFS), overall survival (OS), dose reductions and dose-limiting toxicities. In addition the average number of treatment cycles and age at recurrence were calculated. RESULTS: A total of 12 subjects were identified as receiving treatment with NAB-paclitaxel. Mean age at time of recurrence was 47.2 years (36-55). Nine subjects had squamous cell histology and three subjects had adenocarcinoma histology. All subjects had failed treatment with platinum and taxane, or platinum and topotecan chemotherapy. Two subjects were lost to follow up. The Median number of cycles of NAB-paclitaxel was 6.5 (2-19). The total number of cycles of NAB-paclitaxel in the study population was 65. Seven subjects were treated in combination with bevacizumab. Of these, three subjects are still alive and one subject is currently receiving active treatment with NAB-paclitaxel. The median PFS and OS for all subjects that met mortality endpoint was 4.8 months and 8.9 months (n = 7), respectively. One subject discontinued NAB-paclitaxel secondary to peripheral neuropathy, and one subject developed a vesicovaginal fistula while obtaining combination NAB-paclitaxel and bevacizumab therapy. CONCLUSIONS: NAB-paclitaxel with or without bevacizumab is tolerable and potentially active in treating recurrent cervical cancer after failing platinum-taxane or topotecan chemotherapy. This small case series deserves confirmation through prospective clinical trials.