Novel antitumor agents are currently being evaluated in clinical trials for use in various gynecological cancers.
This article is part IV of a series. View parts I, II, and III:Evolving Paradigms in Gynecologic Cancer> >
Novel antitumor agents are currently being evaluated in clinical trials for use in various gynecological cancers. The majority of new agents in late-phase trials are antiangiogenic drugs that inhibit the formation of new blood vessels in the tumor microenvironment by targeting growth factors, tyrosine kinase receptors, and other molecular targets. Other promising strategies include poly(ADP-ribose) polymerase (PARP) inhibitors that exploit deficient DNA repair pathways in cancerous cells and immunotherapies that enhance the ability of the patient’s own immune system to target and eliminate malignant cells.Angiogenesis is a key component of a tumor’s microenvironment, and inhibiting pro-angiogenic signalling has been an effective strategy in treating a variety of solid tumors, including colon, lung, brain, and liver, among others. As antiangiogenic drugs have become approved for use in a greater number of different tumors, attention has turned to their potential for treating gynecologic cancers, and multiple abstracts have been presented at national and international meetings.54,55
Members of the VEGF protein family are key components of pro-angiogenic signaling and also play an important role in maintaining healthy functioning in the ovaries. Therefore, it has been hypothesized that controlling excessive VEGF and abnormal angiogenesis is of particular importance in ovarian cancer.56This expectation has been borne out by results obtained with the anti-VEGF antibody bevacizumab, which has generated a number of positive trial results in gynecologic cancers. In addition to the recent approval by the FDA for use of bevacizumab in advanced ovarian and cervical cancers (see current therapies section), several other anti-VEGF agents are in late-stage trials.
Other antiangiogenic agents with VEGF-independent mechanisms of action are also in late-stage trials for treatment of gynecologic cancers.Figure 2gives an overview of the various components of the angiogenic pathway in the cell and also depicts which steps of the cascade can be blocked with drugs.
Trebananib (AMG 386) is a peptide-antibody fusion protein that interferes with angiogenic signaling by binding to both angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) and preventing their interaction with the Tie2 receptor. Since the mechanism of trebananib is VEGF- independent, it has a different toxicity profile than anti-VEGF drugs, such as bevacizumab. The recently published results from the phase III TRINOVA-1 trial have shown that adding trebananib to paclitaxel chemotherapy in patients with recurrent EOC improved PFS while avoiding typical anti-VEGF adverse events.58As with bevacizumab, no improvement in OS has been shown with this agent.
Pazopanib is a tyrosine kinase inhibitor that blocks angiogenesis by targeting multiple tyrosine kinase receptors, including VEGFR-1, VEGFR-2, and VEGFR-3, as well as platelet-derived growth factor receptor and c-Kit. Results from a phase III trial investigating pazopanib as a maintenance therapy in patients with ovarian cancer after first-line therapy show that this drug is associated with increased PFS in these patients by a median of 5.6 months.59However, like other antiangiogenic agents, this trial found no effect on OS by pazopanib. Furthermore, post-hoc analysis of the trial data indicated that the increase in PFS was not observed in East Asian patients, suggesting that population stratification may be necessary to determine patient subgroups that experience the greatest benefit from pazopanib therapy.
Biomarkers for Antiangiogenic Therapy
Antiangiogenic therapy has shown potential in various gynecologic cancers, particularly cervical and ovarian; however, benefits such as OS have often been observed only in subsets of patient populations in trials. At the same time, trials have also reported significant toxicities, including diarrhea, nausea, fatigue, and hypertension.60Therefore, biomarkers to direct this type of treatment are likely to be key toward maximizing its potential.
The presence of malignant ascites is a potential clinical biomarker that has been associated with increased VEGF expression and is therefore hypothesized to be predictive of bevacizumab efficacy. Results released this year from the GOG 218 trial have indicated that patients with malignant ascites had poorer prognoses and derived greater benefit, including improved OS, from treatment with bevacizumab than those without them.61
Other biomarkers have been proposed as indicators of response to antiangiogenic treatment. Decreased expression of the microRNA miR-378 and the resulting upregulation of its downstream target genes,ALCAMandEHD1, were associated with improved PFS in patients treated with bevacizumab.62Conversely, low levels of Ang2 in circulating plasma have been associated with poor response to bevacizumab in pancreatic cancer.63 This association is thought to reflect the fact that antiangiogenic therapies are most effective in disease settings that are highly angiogenic.
An analysis of potential biomarkers has been included in various phase III trials of bevacizumab and produced promising candidates. Mutations ofVEGFAandVEGFreceptors, tumor expression levels of neuropilin-1, and circulating levels of all 3 have been identified as strong biomarker candidates.64More research is required, however, as these biomarkers have been shown to be prognostic of outcome, but not predictive of response to antiangiogenic therapy.The PARP1 enzyme is involved in the normal function of DNA repair pathways shown inFigure 3. By inhibiting the catalytic action of this protein, PARP inhibitors can cause PARP1 to be sequestered in complexes with damaged DNA, preventing damage repair and inducing double-stranded breaks.65 Although these agents were developed for use in cancers with defective homologous recombination function (eg,BRCA1-mutant andBRCA2- mutant tumors), recent data indicate that PARP inhibitors may have broader efficacy, including in combination with DNAdamaging agents in cancers with normal DNA repair function.
Development of PARP inhibitors for gynecologic cancers is most advanced in ovarian cancer, in which there is a high incidence of inherited or acquiredBRCAgene mutations, due to the demonstrated efficacy and specificity of PARP inhibitors for cancer cells with defectiveBRCAgenes.66A phase II study has shown responses to the PARP inhibitor olaparib (AZD2281) in patients with advanced, chemotherapy-resistant ovarian cancer,67and 2 phase III trials are ongoing to investigate the efficacy of olaparib inBRCA-mutation positive ovarian cancer.68,69In December, 2014, the FDA approved the use of olaparib in patients with advanced ovarian cancer who haveBRCAgene mutations and have progressed on at least 3 previous chemotherapies.36
Another phase III trial is testing the PARP inhibitor niraparib (MK-4827) as maintenance therapy in platinum-sensitive ovarian cancer.70 Additionally, data presented at the 2014 Society of Gynecologic Oncology 45th Annual Meeting on Women’s Cancer indicated that the PARP inhibitor veliparib (ABT-888) can produce responses even in patients with persistent or recurrent ovarian cancer,71providing patients with a possible alternative when other treatments have failed.
Olaparib in combination with carboplatin for refractory/recurrent gynecologic cancers
Veliparib in combination with topotecan in patients with relapsed epithelial ovarian cancer with negative or unknown BRCA status
Veliparib, topotecan, and filgrastim or pegfilgrastim in patients with persistent/recurrent cervical cancer
Veliparib with cisplatin and paclitaxel in patients with advanced, persistent, or recurrent cervical cancer
All clinical trials are found at www.clinicaltrials.gov and listed according to their NCT identifier.
Investigations using preclinical models have shown that cancers with decreased expression of phosphatase and tensin homolog (PTEN), including many endometrial cancers, are sensitive to PARP inhibitors.72Additionally, another preclinical study has shown that veliparib can potentiate the antitumor effects of DNA-damaging chemotherapy and radiation.73These results have led to growing interest in PARP inhibitors inBRCA-mutation negative gynecologic malignancies such as endometrial and cervical cancers, although these efforts have not yet reached phase III trials. A partial list of these trials is shown inTable 3.Biomarkers for PARP Inhibitor Therapy
Although interest in utilizing PARP inhibition clinically has primarily focused on patients with either germline or somatic BRCA mutations, several studies have identified other biomarkers that may predict responsiveness to PARP inhibition. Many of these candidates are also part of the cellular DNA-repair machinery, while others, such as PTEN, are not.
One such DNA-repair biomarker is the meiotic recombination 11 (MRE-11) gene. MRE-11 is part of the cellular mechanism that detects and repairs DNA double-strand breaks, and a recent paper reported that its protein is lost in over 30% of endometrial cancers.74Unsurprisingly, this group found that the absence of MRE-11 protein predicts sensitivity to PARP inhibition.
The micro-RNA miR-182 regulates the expression of BRCA1, and thus can affect the sensitivity of some cancers to PARP inhibition. Increased expression of miR-182 decreases expression of BRCA1, and therefore sensitizes cells to PARP inhibitors, while decreased miR-182 expression has the opposite effect.75Treatments that induce the patient’s own immune system to target malignant cells (ie, immunotherapies) have become the subject of intense interest in many different tumor types in recent years. Although the development of immunotherapeutic agents for use in gynecologic cancers is less advanced than many antiangiogenic drugs, striking results have been reported in several early-stage trials, and rapid progress is expected in the near future.
Components of the immune checkpoint system are often aberrantly expressed by tumors or normal cells in the tumor microenvironment. In the healthy state, this system of receptors and ligands prevents immune T cells from attacking the body’s own cells. However, malignant cells or antigen-presenting cells in the microenvironment can use the expression of checkpoint ligands to evade immune surveillance. Several drugs have been developed to prevent the immune checkpoint system from being activated, which in turn increases immune targeting of tumor cells (Figure 4).
Nivolumab (Opdivo) is an antibody targeting the programmed cell death-1 (PD-1) receptor and prevents interaction with its ligand (PD-L1). By inhibiting this immune checkpoint, nivolumab and similar agents facilitate the activation of T cells against cancer cells that would otherwise evade immune detection. Data from a phase II trial presented at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting showed that nivolumab was able to produce responses in patients with advanced or relapsed, platinum-resistant ovarian cancer.77Other checkpoint inhibitors currently under development for use in ovarian cancer include ipilimumab, an antibody targeting cytotoxic T-lymphocyte antigen 4 (CTLA4),78and MDX-1105 (anti-PD-L1).79
Adoptive T-cell therapy (ACT) is an immunotherapeutic strategy in which patients are treated with autologous tumor-infiltrating lymphocytes (TILs) that target proteins expressed specifically by cancer cells. This type of approach is particularly amenable to cancers that are induced by viral infections and therefore express exogenous viral proteins. A study presented at the 2014 ASCO Annual Meeting reported that ACT with TILs selected for reactivity to 2 HPV oncoproteins, E6 and E7, was successful in producing responses in patients with metastatic cervical cancer.80Though this was a small study, it has shown the feasibility of this approach in a disease with few treatment options.
A novel agent to target cancerous cells that express HPV proteins is ADXS11-001, an attenuated strain of Listeria monocytogenes that has been genetically modified to express HPV proteins. This agent acts as a vaccine in that the bacteria induce a specific T-cell response targeting malignant cells expressing HPV antigens. Final data from a phase II study demonstrated activity by ADXS11-001 against recurrent cervical cancer.81
There is an effort to evaluate the anticancer effects of drugs that are FDA-approved for nononcology indications. This approach has the potential to quickly bring new therapies to the clinic in gynecologic cancers because the pharmacokinetic and safety profiles for these approved medications are already established, so preclinical and early-stage trials are largely unnecessary.
Metformin has been the main focus of drug repurposing research in gynecologic cancers.55 It is currently used in patients with diabetes and polycystic ovarian syndrome and has multiple metabolic effects at the cellular level. It is hypothesized that cancers are vulnerable to the activation of the AMP-activated protein kinase cascade by metformin, which results in decreased protein synthesis and proliferation, among other effects (Figure 5). There is a body of preclinical and clinical evidence that indicate that metformin has anticancer effects, and its use is associated with increased survival in uterine, ovarian, and cervical cancers.82
Several abstracts at the Society of Gynecologic Oncology’s 45th Annual Meeting on Women’s Cancers explored the possibility of using metformin clinically. Among the results presented, one group reported that metformin treatment in obese patients was most effective at reducing endometrial cancer cell proliferation in tumors with high Ki-67 expression.83However, another study did not find that metformin reduced the risk of developing endometrial cancer in a population-based cohort.84
Because the clinical data reported so far were obtained in patients who suffered from obesity and diabetes and the molecular mechanism mediating its anticancer effects remains uncertain, the utility of metformin for the prevention or treatment of gynecologic cancers in the general population continues to be investigated. At present, the phase II/III trial GOG 286B is evaluating whether or not the addition of metformin to paclitaxel-carboplatin chemotherapy in patients with advanced-stage or recurrent ovarian and endometrial cancer improves patient outcomes.85
Future Directions for Clinical Investigation
Targeted therapies, including antiangiogenic drugs, PARP inhibitors, and immunotherapies, are the subjects of intense development at this time. An improved understanding of both VEGF-dependent and VEGF-independent pathways of angiogenesis, DNA repair pathways, and immune surveillance have raised expectations that these drugs will be able to improve patient survival while avoiding toxicities associated with chemotherapies and radiation therapies. There are, however, many questions that remain to be answered regarding these emerging treatments including: what are the optimal duration and sequencing of these treatments; are they most effective as monotherapy or when combined with chemotherapeutic drugs; and how should clinicians identify patient populations that are most likely to benefit from these agents.
Late-phase clinical trials clearly need to incorporate the most appropriate endpoints into their design to be informative; however, in the case of ovarian cancer, there has been significant debate regarding which endpoints are the most relevant and useful. Improvement in OS is generally considered the gold-standard endpoint for cancer studies; however, several unique factors in the setting of ovarian cancer have made it very challenging to adequately measure OS. Longer survival times overall make it more likely that patients will receive subsequent lines of therapy after the conclusion of a trial, and there is a high rate of treatment arm crossover during trials themselves. These factors both contribute to making accurate determination of OS difficult, lengthy, and costly.86These obstacles have led to the acceptance of PFS and other endpoints in trials, and the FDA approval of bevacizumab for recurrent ovarian cancer was based, in part, on the increased PFS observed in the AURELIA trial.34
In early 2014, the Society of Gynecologic Oncology (SGO) issued guidance for the design of trials in ovarian cancer in consultation with the National Cancer Institute’s Clinical Therapy Evaluation Program, the FDA, representatives of the pharmaceutical industry, and patient advocacy groups.87The guidance reiterates the superiority of OS as an endpoint, while also acknowledging the pragmatic difficulties associated with its use, and notes the increasing acceptance of surrogate endpoints in ovarian cancer trials. Other recommendations made in the SGO guidance include the enrollment of smaller, more histologically and molecularly homogenous patients in trials, and the deployment and validation of composite endpoints to integrate multiple traditional endpoints into a single metric.Gynecologic cancers are devastating to the women who are diagnosed with them by threatening not only their current health but also their ability to conceive and give birth in the future. While significant progress has been made in reducing the incidence of cervical carcinoma with widespread screening and HPV vaccination, the rates of the other gynecologic cancers have remained steady in recent decades. The small numbers of patients affected, relative to other malignancies, and the heterogeneity of these cancers have slowed progress on large clinical trials, hampering efforts to develop new treatments.
Survival rates for ovarian cancer have improved incrementally since the 1990s, but the disease continues to pose a significant mortality threat to patients. Improved understanding of the importance of the tumor microenvironment has led to the development of potent antiangiogenic agents that are effective in a range of solid tumors, and these drugs have become a compelling new option in advanced and recurrent ovarian cancer. Though questions remain regarding the benefit of antiangiogenic therapy to OS, emerging biomarkers that can stratify patient populations may soon allow clinicians to administer this new treatment modality to those who are most likely to benefit.
In addition to antiangiogenic drugs, promising results from trials with PARP inhibitors, immunotherapies, and repurposed drugs offer the potential for improved treatment on several fronts for patients. The shift away from systemic cytotoxic chemotherapy and radiation toward more targeted strategies in other malignancies has resulted in improved survival with fewer toxic side effects, and it is hoped that the same will be observed in gynecologic cancers.
The “omics” revolution in DNA sequencing and RNA detection technologies has produced an extensive list of new candidate biomarkers and the possibility of routinely using profiles of multiple biomarkers that have the potential to improve prognostic power and allow clinicians to match patients to therapies that are most likely to produce positive results. The convergence of new diagnostic tools and new therapeutic agents has raised the prospect that a major improvement in the incidence and care of gynecologic malignancies is imminent.
This article is part IV of a series. View parts I, II, and III:Evolving Paradigms in Gynecologic Cancer> >
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87. Herzog TJ, Alvarez RD, Secord A, et al. SGO guidance document for clinical trial designs in ovarian cancer: A changing paradigm.Gynecol Oncol. 2014;135(1):3-7.This article is part IV of a series. View parts I, II, and III:Evolving Paradigms in Gynecologic Cancer> >