•Bevacizumab (Avastin®), a VEGF-A targeting monoclonal antibody, was the first approved angiogenesis inhibitor.•Approved in a range of solid tumor indications, bevacizumab is an important part of the ...standard of care in oncology.•The recently identified immune modulatory roles of VEGF provide a powerful rationale for combination therapies.•First clinical studies of the combination of bevacizumab with immune checkpoint inhibitors have shown efficacy.
When the VEGF-A-targeting monoclonal antibody bevacizumab (Avastin®) entered clinical practice more than 15 years ago, it was one of the first targeted therapies and the first approved angiogenesis inhibitor. Marking the beginning for a new line of anti-cancer treatments, bevacizumab remains the most extensively characterized anti-angiogenetic treatment. Initially approved for treatment of metastatic colorectal cancer in combination with chemotherapy, its indications now include metastatic breast cancer, non-small-cell lung cancer, glioblastoma, renal cell carcinoma, ovarian cancer and cervical cancer. This review provides an overview of the clinical experience and lessons learned since bevacizumab’s initial approval, and highlights how this knowledge has led to the investigation of novel combination therapies.
In the past 15 years, our understanding of VEGF’s role in the tumor microenvironment has evolved. We now know that VEGF not only plays a major role in controlling blood vessel formation, but also modulates tumor-induced immunosuppression. These immunomodulatory properties of bevacizumab have opened up new perspectives for combination therapy approaches, which are being investigated in clinical trials. Specifically, the combination of bevacizumab with cancer immunotherapy has recently been approved in non-small-cell lung cancer and clinical benefit was also demonstrated for treatment of hepatocellular carcinoma. However, despite intense investigation, reliable and validated biomarkers that would enable a more personalized use of bevacizumab remain elusive.
Overall, bevacizumab is expected to remain a key agent in cancer therapy, both due to its established efficacy in approved indications and its promise as a partner in novel targeted combination treatments.
Endometrial cancer is the most common gynecologic malignancy in the United States. Overactivation of the PI3K/AKT/mTOR pathway, a signaling pathway that plays an important role in cellular growth and ...survival, has recently been implicated in endometrial cancer pathogenesis, and as such, inhibition of the PI3K/AKT/mTOR pathway is of therapeutic interest. Preclinical and clinical studies are proving useful in elucidating the antitumor effects of different PI3K/AKT/mTOR pathway inhibitors, and in defining which patient populations these inhibitors might be most effective in. For example, an increasing amount of preclinical data suggest that loss of PTEN or genetic alteration of PIK3CA may be indicators of sensitivity to PI3K/AKT/mTOR pathway inhibition, while activating KRAS mutations may predict resistance. In the latter case, combined inhibition of the RAS/RAF/MEK and PI3K/AKT/mTOR pathways has been suggested as a therapeutic strategy. In addition, the PI3K/AKT/mTOR pathway has been implicated in conferring resistance to conventional therapies, and so PI3K/AKT/mTOR pathway inhibitors in combination with hormonal and/or cytotoxic agents are being evaluated. In conclusion, preclinical models are providing insights into the antitumor activity of PI3K/AKT/mTOR pathway inhibition, and are helping define patient populations most likely to benefit from these therapies. Clinical validation of these findings is ongoing.
There are limited data from retrospective studies regarding whether survival outcomes after laparoscopic or robot-assisted radical hysterectomy (minimally invasive surgery) are equivalent to those ...after open abdominal radical hysterectomy (open surgery) among women with early-stage cervical cancer.
In this trial involving patients with stage IA1 (lymphovascular invasion), IA2, or IB1 cervical cancer and a histologic subtype of squamous-cell carcinoma, adenocarcinoma, or adenosquamous carcinoma, we randomly assigned patients to undergo minimally invasive surgery or open surgery. The primary outcome was the rate of disease-free survival at 4.5 years, with noninferiority claimed if the lower boundary of the two-sided 95% confidence interval of the between-group difference (minimally invasive surgery minus open surgery) was greater than -7.2 percentage points (i.e., closer to zero).
A total of 319 patients were assigned to minimally invasive surgery and 312 to open surgery. Of the patients who were assigned to and underwent minimally invasive surgery, 84.4% underwent laparoscopy and 15.6% robot-assisted surgery. Overall, the mean age of the patients was 46.0 years. Most patients (91.9%) had stage IB1 disease. The two groups were similar with respect to histologic subtypes, the rate of lymphovascular invasion, rates of parametrial and lymph-node involvement, tumor size, tumor grade, and the rate of use of adjuvant therapy. The rate of disease-free survival at 4.5 years was 86.0% with minimally invasive surgery and 96.5% with open surgery, a difference of -10.6 percentage points (95% confidence interval CI, -16.4 to -4.7). Minimally invasive surgery was associated with a lower rate of disease-free survival than open surgery (3-year rate, 91.2% vs. 97.1%; hazard ratio for disease recurrence or death from cervical cancer, 3.74; 95% CI, 1.63 to 8.58), a difference that remained after adjustment for age, body-mass index, stage of disease, lymphovascular invasion, and lymph-node involvement; minimally invasive surgery was also associated with a lower rate of overall survival (3-year rate, 93.8% vs. 99.0%; hazard ratio for death from any cause, 6.00; 95% CI, 1.77 to 20.30).
In this trial, minimally invasive radical hysterectomy was associated with lower rates of disease-free survival and overall survival than open abdominal radical hysterectomy among women with early-stage cervical cancer. (Funded by the University of Texas M.D. Anderson Cancer Center and Medtronic; LACC ClinicalTrials.gov number, NCT00614211 .).
The discovery of RNA interference, first in plants and Caenorhabditis elegans and later in mammalian cells, led to the emergence of a transformative view in biomedical research. Knowledge of the ...multiple actions of non-coding RNAs has truly allowed viewing DNA, RNA and proteins in novel ways. Small interfering RNAs (siRNAs) can be used as tools to study single gene function both in vitro and in vivo and are an attractive new class of therapeutics, especially against undruggable targets for the treatment of cancer and other diseases. Despite the potential of siRNAs in cancer therapy, many challenges remain, including rapid degradation, poor cellular uptake and off-target effects. Rational design strategies, selection algorithms, chemical modifications and nanocarriers offer significant opportunities to overcome these challenges. Here, we review the development of siRNAs as therapeutic agents from early design to clinical trial, with special emphasis on the development of EphA2-targeting siRNAs for ovarian cancer treatment.
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Summary Background Platinum-based chemotherapy doublets are a standard of care for women with ovarian cancer recurring 6 months after completion of initial therapy. In this study, we aimed to explore ...the roles of secondary surgical cytoreduction and bevacizumab in this population, and report the results of the bevacizumab component here. Methods The multicentre, open-label, randomised phase 3 GOG-0213 trial was done in 67 predominantly academic centres in the USA (65 centres), Japan (one centre), and South Korea (one centre). Eligible patients were adult women (aged ≥18 years) with recurrent measurable or evaluable epithelial ovarian, primary peritoneal, or fallopian tube cancer, and a clinical complete response to primary platinum-based chemotherapy, who had been disease-free for at least 6 months following last infused cycle of platinum. Patients were randomly assigned (1:1) to standard chemotherapy (six 3-weekly cycles of paclitaxel 175 mg/m2 of body surface area and carboplatin area under the curve 5) or the same chemotherapy regimen plus bevacizumab (15 mg/kg of bodyweight) every 3 weeks and continued as maintenance every 3 weeks until disease progression or unacceptable toxicity. Individuals who participated in both the bevacizumab objective and surgical objective (which is ongoing) were randomly assigned (1:1:1:1) to receive either of these two chemotherapy regimens with or without prior secondary cytoreductive surgery. Randomisation for the bevacizumab objective was stratified by treatment-free interval and participation in the surgical objective. The primary endpoint was overall survival, analysed by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00565851. Findings Between Dec 10, 2007, and Aug 26, 2011, 674 women were enrolled and randomly assigned to standard chemotherapy (n=337) or chemotherapy plus bevacizumab (n=377). Median follow-up at the end of the trial on Nov 5, 2014, was 49·6 months in each treatment group (IQR 41·5–62·2 for chemotherapy plus bevacizumab; IQR 40·8–59·3 for chemotherapy), at which point 415 patients had died (214 in the chemotherapy group and 201 in the chemotherapy plus bevacizumab group). Based on pretreatment stratification data, median overall survival in the chemotherapy plus bevacizumab group was 42·2 months (95% CI 37·7–46·2) versus 37·3 months (32·6–39·7) in the chemotherapy group (hazard ratio HR 0·829; 95% CI 0·683–1·005; p=0·056). We identified incorrect treatment-free interval stratification data for 45 (7%) patients (equally balanced between treatment groups); a sensitivity analysis of overall survival based on the audited treatment-free interval stratification data gave an adjusted HR of 0·823 (95% CI 0·680–0·996; p=0·0447). In the safety population (all patients who initiated treatment), 317 (96%) of 325 patients in the chemotherapy plus bevacizumab group had at least one grade 3 or worse adverse event compared with 282 (86%) of 332 in the chemotherapy group; the most frequently reported of these in the chemotherapy plus bevacizumab group compared with the chemotherapy group were hypertension (39 12% vs two 1%), fatigue (27 8% vs eight 2%), and proteinuria (27 8% vs none). Two (1%) treatment-related deaths occurred in the chemotherapy group (infection n=1 and myelodysplastic syndrome n=1) compared with nine (3%) in the chemotherapy plus bevacizumab group (infection n=1, febrile neutropenia n=1, myelodysplastic syndrome n=1, secondary malignancy n=1; deaths not classified with CTCAE terms: disease progression n=3, sudden death n=1, and not specified n=1). Interpretation The addition of bevacizumab to standard chemotherapy, followed by maintenance therapy until progression, improved the median overall survival in patients with platinum-sensitive recurrent ovarian cancer. Although the intention-to-treat analysis for overall survival was not significant, our sensitivity analysis based on corrected treatment-free interval stratification indicates that this strategy might be an important addition to the therapeutic armamentarium in these patients. Funding National Cancer Institute and Genentech.
Single-agent chemotherapies have limited activity and considerable toxicity in patients with platinum-resistant epithelial ovarian cancer (PROC). Mirvetuximab soravtansine (MIRV) is an antibody-drug ...conjugate targeting folate receptor α (FRα). SORAYA is a single-arm, phase II study evaluating efficacy and safety of MIRV in patients with PROC.
SORAYA enrolled FRα-high patients with PROC who had received one to three prior therapies, including required bevacizumab. The primary end point was confirmed objective response rate (ORR) by investigator; duration of response was the key secondary end point.
One hundred six patients were enrolled; 105 were evaluable for efficacy. All patients had received prior bevacizumab, 51% had three prior lines of therapy, and 48% received a prior poly ADP-ribose polymerase inhibitor. Median follow-up was 13.4 months. ORR was 32.4% (95% CI, 23.6 to 42.2), including five complete and 29 partial responses. The median duration of response was 6.9 months (95% CI, 5.6 to 9.7). In patients with one to two priors, the ORR by investigator was 35.3% (95% CI, 22.4 to 49.9) and in patients with three priors was 30.2% (95% CI, 18.3 to 44.3). The ORR by investigator was 38.0% (95% CI, 24.7 to 52.8) in patients with prior poly ADP-ribose polymerase inhibitor exposure and 27.5% (95% CI, 15.9 to 41.7) in those without. The most common treatment-related adverse events (all grade and grade 3-4) were blurred vision (41% and 6%), keratopathy (29% and 9%), and nausea (29% and 0%). Treatment-related adverse events led to dose delays, reductions, and discontinuations in 33%, 20%, and 9% of patients, respectively.
MIRV demonstrated consistent clinically meaningful antitumor activity and favorable tolerability and safety in patients with FRα-high PROC who had received up to three prior therapies, including bevacizumab, representing an important advance for this biomarker-selected population.
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•Patients with advanced/recurrent gynecologic cancers have few treatment options (82/85).•ADCs are of interest as targeted, biomarker-driven therapies in this space (85/85).•Tisotumab ...vedotin is approved for recurrent cervical cancer (60/85).•Mirvetuximab soravtansine is approved for FRɑ+ platinum-resistant ovarian cancer (82/85).•Ongoing studies are evaluating more than 10 ADCs in gynecologic malignancies (78/85).
Despite significant advances in the treatment of cervical, ovarian, and uterine cancers with the approvals of checkpoint and PARP inhibitors into standard treatment, patients with recurrent metastatic gynecologic malignancies still experience poor outcomes, and most of these patients will experience disease relapse. Once standard preferred treatments are exhausted, options have historically been limited to treatments associated with poor outcomes and notable toxicities. Consequently, novel therapies that are effective and well-tolerated are needed for patients with recurrent and metastatic gynecologic malignancies. Antibody-drug conjugates (ADCs) are a class of targeted therapies that are well established in several cancers including hematologic malignancies and some solid tumors. Significant strides in ADC technology and design have led to improvements in efficacy and safety with newer-generation ADCs. Consequently, ADCs are gaining traction in gynecologic cancers with the recent US Food and Drug Administration approvals of tisotumab vedotin in cervical cancer and mirvetuximab soravtansine in ovarian cancer. Many additional ADCs against various targets are being explored in patients with metastatic or recurrent gynecologic malignancies.
The purpose of this review is to summarize the nuanced structural and functional properties of ADCs, while outlining opportunities for innovation. Further, we highlight the ADCs in clinical development for gynecologic malignancies, exploring how ADCs may be able to address the clinical care gap for patients with gynecologic cancers.
Ovarian cancer remains one of the most challenging malignancies to treat. Targeted therapies such as poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as one of the most exciting new ...treatments for ovarian cancer, particularly in women with BRCA1 or BRCA2 mutations or those without a functional homologous recombination repair pathway. Perhaps the most advantageous characteristic of PARP inhibitors is their mechanism of action, which targets cancer cells on the basis of their inherent deficiencies while seemingly avoiding normally functioning cells. Although health-care providers might assume a low toxicity profile because of their specific mechanism of action, PARP inhibitors are not completely benign and overall show a class effect adverse-event profile. Further complicating this situation, three different PARP inhibitors have been approved by the US Food and Drug Administration since 2014, each with their own specific indications and individual toxicity profiles. The diversity of adverse events seen both within and across this class of drug underscores the importance of having a comprehensive reference to help guide clinical decision making when treating patients. This Review characterises and compares all toxicities associated with each PARP inhibitor, both in monotherapy and in novel combinations with other drugs, with a particular focus on potential management strategies to help mitigate toxic effects. Although the excitement surrounding PARP inhibitors might certainly be warranted, a thorough understanding of all associated toxicities is imperative to ensure that patients can achieve maximal clinical benefit.
The natural history of ovarian cancer continues to be characterized by late-stage presentation, metastatic bulky disease burden and stagnant mortality statistics, despite prolific drug development. ...Robust clinical investigation, particularly with modifications to primary treatment surgical goals and adjuvant therapy are increasing median progression-free survival and overall survival, although the cure rates have been affected only modestly. Maintenance therapy holds promise, but studies have yet to identify an agent and/or strategy that can affect survival. Recurrent disease is largely an incurable state; however, current intervention with selected surgery, combination and targeted therapy and investigational protocols are impacting progression-free survival. Ovarian cancer is a diverse and genomically complex disease, which commands global attention. Rational investigation must balance the high rate of discovery with lagging clinical investigation and limited patient resources. Nevertheless, growth in our armamentarium offers unprecedented opportunities for patients suffering with this disease. This Review presents and reviews the contemporary management of the disease spectrum termed epithelial 'ovarian' cancer and describes the direction and early results of clinical investigation.
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