Will bevacizumab biosimilars impact the value of systemic therapy in gynecologic cancers?
© The Author(s). 2017
Received: 20 January 2017
Accepted: 10 March 2017
Published: 21 March 2017
Bevacizumab is an important component in the treatment of various cancers, and despite guidelines recommending its use in both ovarian and cervical cancer, patient access to bevacizumab and other angiogenesis inhibitors is limited. Biosimilars are large, structurally complex molecules that are intended to be highly similar to, and treat the same condition(s) as, an existing licensed or approved (reference) biologic, with no clinically meaningful differences in purity, potency and safety. This article summarizes the role of bevacizumab in the treatment paradigm of ovarian and cervical cancer. We also discuss the potential role of biosimilars to bevacizumab, which may offer more affordable options in the future treatment of gynecologic cancers.
Literature searches of PubMed and ClinicalTrials.gov databases were conducted. Regulatory and individual pharmaceutical company web pages were also reviewed. Search terms included “biosimilar” and “bevacizumab,” and these were used to identify information regarding biosimilar development, reporting results of biosimilar studies or biosimilars in development.
At present, four bevacizumab biosimilar candidates are undergoing comparative clinical assessment, with the potential to increase access and offer efficiencies across healthcare systems.
It is anticipated that biologics such as bevacizumab will continue to play a key role in the treatment of an array of gynecologic cancers. Biosimilars to bevacizumab are currently in development and have the potential to increase access to medicines in a variety of settings, including gynecologic cancers.
KeywordsBevacizumab Biosimilar Ovarian cancer Cervical cancer
Bevacizumab: approved indications in the United States 
Metastatic colorectal cancer
Intravenous 5-fluorouracil–based chemotherapy
First- or second-line treatment
Metastatic colorectal cancer
Fluoropyrimidine-irinotecan– or fluoropyrimidine-oxaliplatin–based chemotherapy
Second-line treatment in patients who have progressed on a first-line bevacizumab-containing regimen
Non-squamous non-small-cell lung cancer
Carboplatin and paclitaxel
First-line treatment of unresectable, locally advanced, recurrent or metastatic disease
Adult patients with progressive disease following prior therapya
Metastatic renal cell carcinoma
Paclitaxel and cisplatin or paclitaxel and topotecan
Persistent, recurrent or metastatic disease
Platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer
Paclitaxel, pegylated liposomal doxorubicin or topotecan
Platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancerb
Carboplatin and paclitaxel or carboplatin and gemcitabine chemotherapy (followed by bevacizumab)
Adult patients who have relapsed ≥6 months following last treatment with platinum-based chemotherapy
It is expected that the use of bevacizumab in gynecologic cancers will increase, given the recent approval (in combination with carboplatin and gemcitabine) in platinum-sensitive ovarian cancer in the United States  and Canada . However, patient access to bevacizumab and other angiogenesis inhibitors is limited . This is due to several factors, including insurance coverage, drug availability, supply and manufacturing, and concerns regarding the cost-effectiveness of bevacizumab for some patients .
Biologics are large, structurally complex medicinal products. Their active ingredients are created by biological processes rather than chemical synthesis. Although biologics cannot be replicated, it is possible to create a version (termed “biosimilar”) that is highly similar to an already licensed or approved reference biologic in terms of purity, safety and efficacy [6, 7]. Biosimilars have the potential to increase patient access to biologic medicines, such as bevacizumab, and this may subsequently improve clinical outcomes.
This article reviews the role of bevacizumab in the treatment paradigm of ovarian and cervical cancer. We also discuss the potential role of biosimilars to bevacizumab, which may offer more affordable options in the future treatment of gynecologic cancers.
Literature searches of PubMed and ClinicalTrials.gov databases were conducted. Regulatory and individual pharmaceutical company web pages were also reviewed. Search terms included “biosimilar” and “bevacizumab,” and these were used to identify information pertaining to biosimilar development, reporting results of biosimilar studies, or biosimilars in development.
Bevacizumab in the treatment of gynecologic cancers: an overview
Bevacizumab, in combination with chemotherapy, is an important component of treatment of ovarian cancer. Approval of combination bevacizumab for the treatment of platinum-resistant recurrent epithelial ovarian or fallopian tube cancer was based on the results of an international, open-label, randomized study, AURELIA (Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer), in patients with measurable ovarian cancer that had progressed <6 months following platinum-based treatment . Median progression-free survival (PFS) was 6.7 months with bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) plus chemotherapy (weekly paclitaxel, pegylated liposomal doxorubicin or topotecan) vs 3.4 months with chemotherapy alone (P < 0.001). Objective response rate was 27.3% with bevacizumab plus chemotherapy vs 11.8% with chemotherapy alone (P = 0.001). No statistically significant difference in overall survival (OS) was observed between the two treatment regimens. Hypertension and proteinuria were common adverse events in patients treated with bevacizumab plus chemotherapy .
The United States Food and Drug Administration (FDA) recently granted approval of bevacizumab for the treatment of platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer . Approval was based on the results of two randomized Phase 3 studies. The Gynecologic Oncology Group (GOG) -0213 study showed that median OS was 42.6 months with bevacizumab plus chemotherapy vs 37.3 months with chemotherapy alone (P = 0.056). The GOG-0213 study also showed improvement in PFS with bevacizumab plus chemotherapy (13.8 months) compared with chemotherapy alone (10.4 months; P < 0.0001). In the OCEANS (Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Disease) study, median PFS was 12.4 months with bevacizumab plus chemotherapy vs 8.4 months with chemotherapy plus placebo (P < 0.0001). However, no statistically significant difference in OS was observed between the two treatment groups. The adverse events associated with bevacizumab in the GOG-0213 and OCEANS studies were consistent with those observed in previous studies, and included fatigue, low white blood cell count with fever, low sodium, pain in extremity, low platelet count, elevated protein in the urine, high blood pressure and headache . Bevacizumab, in combination with a chemotherapy backbone, is also a key component in the treatment of cervical cancer. Approval of combination bevacizumab for the treatment of persistent, recurrent or metastatic cervical cancer was granted on the results of an international Phase 2 randomized trial . Results from this study showed that bevacizumab plus chemotherapy (cisplatin plus paclitaxel or topotecan) was associated with increased OS (17.0 months) compared with chemotherapy alone (13.3 months) (P = 0.004). Significantly higher response rates were observed with bevacizumab plus chemotherapy (48%) compared with chemotherapy alone (36%) (P = 0.008). In addition, bevacizumab plus chemotherapy was associated with a higher frequency of hypertension, thromboembolic events and gastrointestinal fistulas, compared with chemotherapy alone . In summary, bevacizumab in combination with chemotherapy is the mainstay of treatment for a variety of gynecologic cancers.
Challenges and barriers to the use of bevacizumab in clinical practice
A recent retrospective population-based study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database of 9491 women with epithelial ovarian cancer showed that, despite strong evidence of improved survival associated with therapy recommended by National Comprehensive Cancer Network (NCCN) guidelines,  over 70% of women receiving initial treatment for epithelial ovarian cancer did not receive treatment consistent with NCCN recommendations . Ultimately, this may adversely affect patient care and is a serious global concern.
Despite the clinical success of bevacizumab in cancers with a large global incidence, such as lung and colorectal cancers, and clear guidelines recommending its use in both ovarian  and cervical cancer,  there is a notable lack of patient access to bevacizumab. Disparities in access to bevacizumab and other targeted therapies have been reported in Europe, with some countries reporting only occasional access to bevacizumab, or access for only 50% of patients with ovarian cancer . Therefore, it is important to identify areas of inefficiencies and to understand barriers to patient access.
Several factors, including healthcare system infrastructure, stage at diagnosis, population health and lifestyle and availability of anticancer agents, can influence access to cancer therapy. Issues related to insurance coverage, treatment cost, drug availability, supply and manufacturing may create barriers to the use of bevacizumab in many countries worldwide. A survey conducted by the European Society of Medical Oncology (ESMO) Consortium reported budget and affordability issues, and problems with the manufacture and supply of bevacizumab as the most common factors leading to suboptimal access to bevacizumab in a variety of cancers .
Cost-effectiveness of bevacizumab in the front-line treatment of ovarian cancer 
Total/Incremental costs (USD)
Cohn et al. 2011
PAC + CAR
Addition of BEV and maintenance BEV was not cost-effective
PAC + CAR + BEV
USD479,712 per PFLY gained
(PAC + CAR + BEV) + maintenance BEV
USD401,088 per PFLY gained
Barnett et al. 2013
PAC + CAR
PAC + CAR + BEV
PAC + CAR + BEV for high-risk patients
USD168,610 per QALY
Use of BEV with standard first-line taxane was not cost-effective in stage III/IV ovarian cancer. May be suitable in high-risk patients although ICER exceeded thresholds
Chan et al. 2014
PAC + CAR
For high-risk, advanced ovarian cancer patients, ICER was almost USD170,000 per life-year saved
PAC + CAR + BEV plus maintenance BEV
3760 (3225 for maintenance)e
USD167,771 per LYG
Bevacizumab will continue to remain an important component in the treatment of gynecologic cancers as well as other settings. In light of the limited access to bevacizumab worldwide, additional treatment options for gynecologic cancers are eagerly awaited.
Development of biosimilars and their potential benefits
Patents for bevacizumab will shortly expire in the United States and Europe . Biosimilars are large, structurally complex molecules that are intended to be highly similar to, and treat the same condition(s) as, an existing licensed or approved (reference) biologic [6, 7]. Biosimilars may offer increased treatment options for patients and physicians and have the potential to optimize efficiencies across healthcare systems worldwide. Additionally, biosimilars may provide lower cost alternatives and therefore increase access to biologics and allow greater use of biologic therapies, which may facilitate improved clinical outcomes.
Biosimilars must have an identical primary amino acid sequence and the same route of administration, strength and type of administration as the reference biologic [6, 7]. Biosimilars are manufactured through a process of reverse engineering and must undergo extensive comparative structural and functional characterization using state-of-the-art technology and highly specialized techniques to identify any differences between the proposed biosimilar and the reference biologic, particularly those that may alter the mechanism of action .
A series of analytical similarity assessments are conducted to confirm identical amino acid sequences, similar post-translational modifications and highly similar biologic activity between the proposed biosimilar and the reference biologic. Analytical similarity forms the foundation for similarity in safety and efficacy. In addition, a comprehensive assessment of the structural and functional similarity of the potential biosimilar and the reference biologic is conducted using state-of-the-art techniques, physicochemical methods and functional assays .
Regulatory agencies do not typically require extensive nonclinical studies for the approval of biosimilars, although this is assessed on a case-by-case basis [6, 7]. A comparative clinical study is generally conducted in one therapeutic indication to demonstrate that there are no clinically meaningful differences in PK, pharmacodynamics (PD), efficacy or safety, including immunogenicity, between the potential biosimilar and the reference biologic. The goal of a comparative clinical study is to address any residual uncertainty between the proposed biosimilar and the reference biologic [6, 7]. Because all biologics, including biosimilars, have the potential to trigger an immunogenic response, which may alter the PK, efficacy or safety properties,  the formation of antidrug antibodies is carefully monitored throughout development and during postmarketing surveillance.
Biosimilars and the scientific basis of extrapolation across indications
Extrapolation is a scientific and regulatory principle that describes the approval of a biosimilar for use in an indication held by the reference biologic, which is not directly studied in a comparative clinical trial with a biosimilar. Extrapolation is key to the concept of biosimilarity and is based on establishing a similar mechanism of action for the biosimilar in various disease indications . As well as reducing or eliminating the need for studies in multiple indications, extrapolation can potentially allow greater access to biosimilars, with minimal delays in treatment. The concept of extrapolation is supported by the US FDA and the European Medicines Agency (EMA) regulatory guidelines [6, 7]. However, the decision to extrapolate data from one indication to another is made on a case-by-case basis, with strong scientific justification and the totality of evidence.
The mechanism of action of bevacizumab involves the inhibition of vascular endothelial growth factor (VEGF), which has an important role in tumor angiogenesis and vascularization [1, 2]. Bevacizumab is an effective treatment for a number of tumors and its mechanism of action is independent of tumor site . This forms the basis of the scientific rationale for extrapolation of similarity data across indications and may support the approval of bevacizumab biosimilars in indications held by the reference biologic without clinical studies in gynecologic indications.
Bevacizumab biosimilar candidates in development
Bevacizumab biosimilars in late-stage clinical development
Functional similarity and PK equivalence
•Similar functional characteristics
•Equivalent PK 
Clinical equivalence of objective response rate
•Similar safety and immunogenic profiles to bevacizumab 
PK and safety
•Similar PK and safety 
Overall response rate
•Similar efficacy, safety and immunogenicity 
Efficacy and safety
Efficacy and safety
•Similar structure and in vitro biological activity 
•Similar in vivo toxicology 
PK and safety
•PK similarity 
•Comparable safety profile 
Comparative efficacy and safety
It is anticipated that biologics such as bevacizumab will continue to play a key role in the treatment of an array of gynecologic cancers. Limited access to bevacizumab and the lack of cost-effectiveness in some patients has driven the need to develop safe and effective biosimilars to bevacizumab, which have the potential to increase access to medicines and offer efficiencies across healthcare systems.
Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer
European Medicines Agency
European Society of Medical Oncology
Food and Drug Administration
Gynecologic Oncology Group
National Comprehensive Cancer Network
non-small-cell lung cancer
Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Disease
Surveillance, Epidemiology, and End Results
Vascular endothelial growth factor.
Medical writing support was provided by Neel Misra, MSc, of Engage Scientific Solutions and was funded by Pfizer.
This report is supported by Pfizer Inc.
Availability of data and materials
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication.
Dr Monk discloses that St. Joseph’s Hospital institution has received research grants from Novartis, Amgen, Lilly, Genentech, Janssen/Johnson & Johnson, Array, TESARO and Morphotek. He has received honoraria for speaker bureaus from Roche/Genentech, AstraZeneca, Janssen/Johnson & Johnson, and Myriad. Additionally, Dr Monk has been a consultant for Roche/Genentech, Merck, TESARO, AstraZeneca, Gradalis, Advaxis, Cerulean, Amgen, Vemillion, ImmunoGen, Pfizer, Bayer, NuCana, Insys, GlaxoSmithKline, Verastem, Mateon (formerly OxiGENE), PPD and Clovis. Dr Warner K. Huh declared no conflicts of interest. Dr Julie Ann Rosenberg and Dr Ira Jacobs are full-time employees of Pfizer Inc.
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