Safety and efficacy of bevacizumab biosimilar in recurrent/ progressive glioblastoma

Abstract

Background:
Multiple low-cost biosimilars of bevacizumab are now available but their clinical efficacy has never been compared against the original (innovator) molecule in glioblastoma. The aim of the current analysis is to compare the overall survival (OS) in recurrent/progressive glioblastoma patients between the biosimilar and innovator molecules.

Materials and methods:
Adult recurrent/progressive glioblastoma patients treated with bevacizumab from 1 July 2015 to 30 July 2019 were identified. These patients were either offered Bevacizumab innovator (Avastin, Roche) or biosimilar (BevaciRel: Reliance Life sciences or Bryxta: Zydus Oncosciences) depending upon the financial status and affordability of the patients. The primary endpoint of the study was OS, while progression-free survival (PFS) and adverse events were the secondary endpoints.

Results:
There were 82 patients, out of which 57 received innovator and 25 received biosimilar bevacizumab. At median follow-up of 26 months, the median PFS was 3.66 (95% confidence interval (CI) 2.08 to 5.25) and 3.3 months (95% CI 2.38 to 4.21) in innovator and biosimilar group, respectively (Log-rank test p-value = 0.072). The hazard ratio (HR) for progression was 0.61 (95% CI 0.35 to 1.05; p-value = 0.075). At the time of data cut-off, the median OS was 5.53 (95% CI, 5.07 to 5.99) versus 7.33 months (95% CI, 5.63 to 9.03) in innovator and biosimilar group, respectively (Log-rank test p-value = 0.51). The HR for death was 1.21 (95% CI, 0.67 to 2.17; p-value = 0.51). The adverse events and safety profiles were comparable between the two groups.

Conclusion:
In the recurrent/progressive glioblastoma patients, both innovator and biosimilar bevacizumab seem to have similar safety and clinical efficacy.

Full text

ecancer 2021, 15:1166; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2021.1166 1
Research
Safety and efficacy of bevacizumab biosimilar in recurrent/
progressive glioblastoma
Gunjesh Kumar1†, Hollis DSouza1†, Nandini Menon1, Sujay Srinivas1, Dilip Harindran Vallathol1, Mounika Boppana1, Annu Rajpurohit1,
Abhishek Mahajan2, Amit Janu2, Abhishek Chatterjee3, Rahul Krishnatry3, Tejpal Gupta3, Rakesh Jalali3 and Vijay M Patil1
1Department of Medical Oncology, Tata Memorial Hospital, Parel 400012 Mumbai, India
2Department of Radiodiagnosis, Tata Memorial Hospital, Parel 400012 Mumbai, India
3Department of Radiation Oncology, Tata Memorial Hospital, Parel 400012 Mumbai, India
†Co-first authorship
Correspondence to: Dr Vijay M Patil
Email: vijaypgi@gmail.com
ecancer 2021, 15:1166
https://doi.org/10.3332/ecancer.2021.1166
Published: 13/01/2021
Received: 05/09/2020
Publication costs for this article were supported by
ecancer (UK Charity number 1176307).
Copyright: © the authors; licensee
ecancermedicalscience. This is an Open Access
article distributed under the terms of the
Creative Commons Attribution License (http://
creativecommons.org/licenses/by/3.0), which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
work is properly cited.
Abstract
Background: Multiple low-cost biosimilars of bevacizumab are now available but their
clinical efficacy has never been compared against the original (innovator) molecule in glio-
blastoma. The aim of the current analysis is to compare the overall survival (OS) in recur-
rent/progressive glioblastoma patients between the biosimilar and innovator molecules.
Materials and methods: Adult recurrent/progressive glioblastoma patients treated with
bevacizumab from 1 July 2015 to 30 July 2019 were identified. These patients were
either offered Bevacizumab innovator (Avastin, Roche) or biosimilar (BevaciRel: Reliance
Life sciences or Bryxta: Zydus Oncosciences) depending upon the financial status and
affordability of the patients. The primary endpoint of the study was OS, while progres-
sion-free survival (PFS) and adverse events were the secondary endpoints.
Results: There were 82 patients, out of which 57 received innovator and 25 received bio-
similar bevacizumab. At median follow-up of 26 months, the median PFS was 3.66 (95%
confidence interval (CI) 2.08 to 5.25) and 3.3 months (95% CI 2.38 to 4.21) in innovator
and biosimilar group, respectively (Log-rank test p-value = 0.072). The hazard ratio (HR)
for progression was 0.61 (95% CI 0.35 to 1.05; p-value = 0.075). At the time of data cut-
off, the median OS was 5.53 (95% CI, 5.07 to 5.99) versus 7.33 months (95% CI, 5.63 to
9.03) in innovator and biosimilar group, respectively (Log-rank test p-value = 0.51). The
HR for death was 1.21 (95% CI, 0.67 to 2.17; p-value = 0.51). The adverse events and
safety profiles were comparable between the two groups.
Conclusion: In the recurrent/progressive glioblastoma patients, both innovator and bio-
similar bevacizumab seem to have similar safety and clinical efficacy.
Keywords: bevacizumab, biosimilar, innovator, glioma
Background
High grade gliomas are best treated with a multidisciplinary approach [1]. However, in
spite of adequate treatment, most of the patients show recurrence. The median time
to progression (TTP) for grade IV glioma/glioblastoma and grade 3 astrocytoma is 6.9

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ecancer 2021, 15:1166; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2021.1166 2
(95% CI 5.8–8.2 months) and 42.8 months (95% CI 28.6–60.6), respectively [2]. The decision on the type of treatment in cases of disease
progression or recurrence depends upon the Eastern Cooperative Oncology Group-Performance Status (ECOG PS), TTP or relapse, site of
recurrence, size of recurrence and previous treatment [3]. Re-surgery and re-irradiation arguably are considered the treatments of choice
in such cases. However, very few patients qualify for these options and most of them end up receiving palliative systemic therapy including
Bevacizumab which is one of the important drugs in the oncologist’s armamentarium.
Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF) which has been implicated in the pathogenesis of
progressive glioblastoma [4]. Bevacizumab alone or in combination with chemotherapy is used routinely in the clinical practice for different
malignancies. It received an accelerated approval in 2009 for the treatment of progressive glioblastoma after the BRAIN trial [5]. Though it
failed to improve overall survival (OS) against lomustine (CCNU) in the EORTC 26101 study, the improvement in progression free survival
(PFS) was considered significant and the drug received final approval by the Food and Drug Association (FDA) in the year 2017 for progres-
sive glioblastoma [6, 7].
In spite of the approval, Bevacizumab is not very popular among the clinicians in the low- and middle-income countries and its widespread
utilisation still remains hampered owing to the high costs similar to any other monoclonal antibody. Bevacizumab (Avastin, Roche) lost its pat-
ent in 2016 and multiple biosimilars entered the Indian market the same year. These biosimilars were available at lower prices than the origi-
nal (innovator) molecule (Avastin, Roche). They soon took over the market and are now widely prescribed. Whether these biosimilars have
same efficacy as the original drug in the treatment of progressive glioblastoma remains an open question that still needs to be answered.
Methods
Selecon of paents
The neuro-medical oncology unit has maintained a prospective database of all the patients undergoing chemotherapy since 1 July 2015. This
database was used for the current analysis. Patients were selected from this database using the below mentioned criteria:
1. Adult patient aged > 18 years
2. Relapsed or progressive glioblastoma
3. Treated with bevacizumab
4. Time period from 1 July 2015 to 30 November 2019
Patients satisfying all four criteria were selected and the data with regard to the age, gender, category (private or general), diabetes, ischemic
heart disease (IHD) and smoking habit were extracted and entered in an excel sheet. Patients of both categories—general and private par-
ticipated in the study. The general category patients were either not charged or minimally charged for the consultation and investigations,
whereas private category ones were fully charged for the same.
Treatment
All the patients were discussed in the joint neuro-oncology meeting. These patients were ineligible for re-surgery or re-irradiation and were
offered bevacizumab either alone or in combination with cytotoxic therapy. The choice of single agent therapy or combination was based on
the ECOG PS and presence of co-morbidities. Bevacizumab was administered every 2–3 weeks. The fisrt dose was given with adequate sup-
portive medications over 90 minutes and the subsequent doses were administered in 30 minutes. The drug was continued till either disease
progression or intolerable side effects. The drug was also stopped if the financials of the patient were inadequate.
Data collecon
The detailed baseline characteristics, previous treatment, histopathology, molecular features, bevacizumab start date, brand of bevacizumab;
Avastin: Roche (innovator) or BevaciRel: Reliance Life sciences and Bryxta: Zydus Oncosciences (biosimilar), date of progression and date of
death were noted in the excel sheet.

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ecancer 2021, 15:1166; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2021.1166 3
Endpoints
The primary endpoint of the study was OS. It was defined as time in months from start of bevacizumab to death. For the patients who were
still alive at the time of data censoring the OS was calculated up to the date of last follow-up. The secondary endpoints were PFS and adverse
events. PFS was defined as time in months from the start of bevacizumab to progression or death. For patients who were alive and had not
progressed at the time of data censoring, this time interval was calculated up to the date of last follow-up. The adverse events were graded
according to the common terminology criteria for adverse events version 4.02.
Stascal analysis
SPSS version 20 and R studio version 3.5.2 were used for the analysis. The time to event variables were estimated using the Kaplan–Meier
method. The median with its 95% CI was calculated using the Brookmeyer and Crowley method. The estimates were compared between
the original and biosimilar bevacizumab cohorts using the log rank test. The hazard ratio (HR) was calculated using Cox regression analysis.
The assumption for proportionality was tested before forming the Cox regression analysis and they were met. The continuous variables were
expressed in terms of median with 95% CI and compared between the two cohorts using the median test. The normal distribution of continu-
ous variables was confirmed using the Shapiro–Wilk test. The ordinal and nominal variables were expressed in the terms of percentage with
95% CI and were compared between the two cohorts using the Fisher’s test.
Results
Baseline characteriscs
The total enrolled patients were 82. Out of total, 57 received innovator (original) and 25 received biosimilar bevacizumab. 87.7% patients
from innovator and 80% from biosimilar cohort belonged to the younger age group (18–59 years).
Both sets in the study had predominantly males constituting 77.2% and 80% of the total patients in the innovator and biosimilar groups,
respectively. In the innovator group, 44 out of 57 (73.7%) were private patients, while 13 (26.3%) patients were from the general category
whereas in the biosimilar group, 13 out of 25 (52%) belonged to the private and 12 (48%) belonged to the general category and the differ-
ences between them were statistically significant (Fisher’s exact test, p-value = 0.028). Further details of baseline characteristics are men-
tioned in the Table 1.
Molecular characteriscs
The molecular analysis showed no significant difference between the two groups in terms of isocitrate dehydrogenase (IDH) mutation (Fish-
er’s exact test, p-value = 0.143), while the differences were statistically significant for O6-methylguanine-DNA methyl-transferase (MGMT)
methylation (Fisher’s exact test, p-value = 0.007), 1p19q deletion (Fisher’s exact test, p-value = 0.001) and telomerase reverse transcriptase
(TERT) promoter mutation (Fisher’s exact test, p-value = 0.000) (Table 2).
Outcome
At the median follow-up of 26 months, 76 patients had an event for progression. The median PFS was 3.66 (95% CI 2.08 to 5.25) and 3.3
months (95% CI 2.38 to 4.21) in the innovator and biosimilar group, respectively (Log-rank test p-value = 0.072). The HR for progression
was 0.61 (95% CI 0.35 to 1.05; p-value = 0.075). At the time of data cut-off, there were 69 deaths. The median OS was 5.53 (95% CI, 5.07
to 5.99) versus 7.33 months (95% CI, 5.63 to 9.03) in innovator and biosimilar group, respectively (Log-rank test p-value = 0.51). The HR for
death was 1.21 (95% CI, 0.67 to 2.17; p-value = 0.51) (Figure 1).

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ecancer 2021, 15:1166; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2021.1166 4
Table 1. Baseline characteristics.
Characteristics Innovator Biosimilar Fisher’s exact test (p-value)
Non-elderly (up to 59 years)
Elderly (≥60 years)
50 (87.7%)
7 (12.3%)
20 (80%)
5 (20%)
0.498
ECOG-PS
1
2
3
4
Not recorded
21 (38.8%)
7 (12.3%)
13 (22.8%)
4 (7%)
12 (21.1%)
8 (32%)
8 (32%)
6 (24%)
1 (4%)
2 (8%)
0.241
GenderMaleFemale
44 (77.2%)
13 (22.8%)
20 (80%)
5 (20%)
0.791
CategoryPrivateGeneral
42 (73.7%)
15 (26.3%)
13 (52%)
12 (48%)
0.028
HypertensionNo
Yes 47 (82.5%)
10 (17.5)
23 (92%)
2 (8%)
0.328
DiabetesNo
Yes 50 (87.7%)
7 (12.3%)
22 (88%)
3 (12%)
1.0
IHD
NoYes 56 (98.2%)
1 (1.8%)
25 (100%)
0 (0%)
1.0
Smoker
NoYes 57 (100%)
0(0%)
24 (96%)
1 (4%)
0.305
ECOG-PS, Eastern Cooperative Oncology Group-Performance Status
IHD, Ischemic heart disease
Table 2. Molecular markers comparison between biosimilar and innovator bevacizumab.
Absent Present Not done Equivocal Un-interpretable
IDH mutation (p-value = 0.143)
Biosimilar 14 (56%) 7 (28%) 3 (12%) 1 (4%) 0
Innovator 21 (36.8%) 16 (28.1%) 19 (33.3%) 1 (1.8) 0
MGMT methylation (p-value = 0.007)
Biosimilar 15 (60%) 7 (28%) 3 (12%) 0 0
Innovator 18 (31.6%) 10 (17.5%) 26 45.6%) 3 (5.3%) 0
1p19q deletion (p-value = 0.001)
Biosimilar 15 (60%) 0 10 (40%) 0 0
Innovator 11 (19.3%) 2 (3.5%) 44 (77.2%) 0 0
TERT promoter mutation (p-value = 0.000)
Biosimilar 15 (60%) 0 10 (40%) 0 0
Innovator 4 (7%) 0 53 (93%) 0 0

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ecancer 2021, 15:1166; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2021.1166 5
Figure 1. Comparison of OS between innovator and biosimilar bevacizumab.
Adverse events
A summary of adverse events is shown in Table 3. The observed adverse events were mostly anti-VEGF toxicities including hypertension,
thrombosis, bleeding, proteinuria and dyslipidaemia, along with others such as febrile neutropenia, diarrhoea, myelosuppression, transamini-
tis, hypersensitivity and fatigue. These events were comparable between the two treatment groups. Also, there was no difference in grade 3
and grade 4 toxicities between the two groups (Fischer’s exact test, p-value = 0.373).
Discussion
Glioblastoma Multiforme (GBM) is one of the deadliest tumours and accounts for 0.5% of all malignancies in India [8]. Due to its aggressive
nature and short TTP, bevacizumab has an important place in the treatment of GBM especially in the recurrent setting. It is not the first time
when biosimilar of an original molecule has been tried and documented in the literature. Filgrastim (2015) and Infliximab (April 2016) were
the first biosimilars approved by the United States (US) FDA. Later, biosimilars for etanercept (August 2016) and adalimumab (September
2016) were also approved [9]. Trastuzumab and rituximab biosimilars have also been tried, found to be clinically efficient and hence have
been approved by the FDA including four of trastuzumab (Herceptin, Genentech), namely Ogivri (trastuzumab, dkst); Herzuma (trastuzumab,
pkrb); Ontruzant (trastuzumab, dttb) and Trazimera (trastuzumab, qyyp) and two of rituximab, viz., Ruxience (rituximab, Pfizer) and Truxima
(rituximab, Teva and Celltrion) [10, 11]. Also, more than 20 biosimilars have been approved by the European Medicines Agency, including
those of monoclonal antibodies like infliximab, etanercept and adalimumab [12, 13]
Biosimilars of bevacizumab (Avastin: Roche Pharma AG) have also been studied extensively including bevacizumab-awwb (Mvasi, Amgen and
Allergan) and bevacizumab-bvzr (Zirabev, Pfizer) and have already been approved by the FDA for treatment of recurrent GBM [14, 15]. In
countries like India, where high cost and hence affordability is the prime issue with use of original molecule, biosimilars play a pivotal role in
the disease management. The brands of bevacizumab currently available at our centre are—Avastin: Roche Pharma AG (original/innovator),
BevaciRel: Reliance Life sciences and Bryxta: Zydus Oncosciences (biosimilar). The costs of 100 mg and 400 mg vials of Avastin are approxi-
mately 20,000 Indian rupees (260 $), 82,000 Indian rupees (1100 $), whereas of BevaciRel are 8,500 Indian rupees (110 $), 35,000 Indian
rupees (460 $) and of Bryxta are 8,500 Indian rupees (110 $), 26,000 Indian rupees (340 $), respectively. Innovator bevacizumab was offered
only to those patients who had either medical or employer insurance, who could afford on the basis of their income, social status and physi-
cal judgement. Non-affording patients were not given option of innovator bevacizumab. Hence, none of our patients receiving innovator
changed to biosimilar bevacizumab and also no one has discontinued biosimilar bevacizumab due to non-affordability.

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This huge difference in the cost gets reflected on the affordability and the same was also noted in our observational study. Here, we found a
statistically significant difference between the two groups in terms of patients in the two categories (private and general), Fisher’s exact test
(p value)—0.028. Forty-two out of total 57 patients (73.7%) in the innovator group belonged to the private category while for the biosimilar
group, this figure was 13 out of 25 patients (52%) clearly indicating that mostly the private category patients could afford the innovator drug.
Table 3. Toxicities comparison between biosimilar and innovator bevacizumab.
Toxicities Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
Febrile neutropenia
Biosimilar 25 (100%) 0 0 0 0
Innovator 54 (94.7%) 0 2 (3.55) 1 (1.8%) 0
Diarrhoea
Biosimilar 24 (96%) 1 (4%) 0 0 0
Innovator 50 (87.7%) 1 (1.8%) 5 (8.8%) 1 (1.8%) 0
Myelosuppression
Biosimilar 25 (100%) 0 0 0 0
Innovator 51 (91.2%) 2 (3.5%) 2 (3.5%) 1 (1.8%) 0
Transaminitis
Biosimilar 23 (92%) 2 (8%) 0 0 0
Innovator 49 (85.9%) 4 (7%) 3 (5.3%) 1 (1.8%) 0
Dyslipidaemia
Biosimilar 24 (96%) 1 (4%) 0 0 0
Innovator 48 (84.2%) 7 (12.3%) 2 (3.5%) 0 0
Bleeding
Biosimilar 25 (100%) 0 0 0 0
Innovator 51 (89.5%) 4 (7%) 2 (3.5%) 0 0
Thrombosis
Biosimilar 25 (100%) 0 0 0 0
Innovator 54 (94.7%) 1 (1.8%) 2 (3.5%) 0 0
Proteinuria
Biosimilar 25 (100%) 0 0 0 0
Innovator 53 (93%) 2 (3.5%) 2 (3.5%) 0 0
Hypersensitivity
Biosimilar 25 (100%) 0 0 0 0
Innovator 54 (94.7%) 1 (1.8%) 2 (3.5%) 0 0
Hypertension
Biosimilar 25 (100%) 0 0 0 0
Innovator 49 (86%) 3 (5.3%) 5 (8.8%) 0 0
Fatigue
Biosimilar 25 (100%) 0 0 0 0
Innovator 54 (94.7%) 0 2 (3.5%) 1 (1.8%) 0

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Monk et al [16] conducted a survey to identify the barriers to bevacizumab access in the US, European countries and emerging markets (EM:
Brazil, Mexico and Turkey). Bevacizumab was indicated as a second line drug in the treatment of GBM in the US and EM. Most of the physi-
cians from EM reasoned the lack of reimbursement and high costs for its limited use. Also nearly 50% of the physicians admitted that they
would ‘definitely’ or ‘probably’ prescribe biosimilar of bevacizumab, if available [16].
This highlights the importance and need of introducing low cost biosimilars to address this problem area with intent to cause greatest impact
on the patient outcomes.
IDH mutation, 1p/19q co-deletion, MGMT methylation and TERT promoter mutations are considered prognostic markers in diffuse glioma [17,
18]. In our study, there was significant difference between the innovator and biosimilar groups with regard to the above-mentioned mutations
except IDH mutation; however, there was non-significant difference in OS and PFS between the two groups with HR of 1.21 (95% CI, 0.67 to
2.17; p-value = 0.51) and 0.61 (95% CI 0.35 to 1.05; p-value = 0.075), respectively. Likewise, Thatcher et al [19] in MAPLE study found similar
PFS and OS with both ABP 215 (U.S.: MVASI (bevacizumab-awwb); European Union (EU):MVASI (bevacizumab)) and bevacizumab reference
product in advanced non-small cell lung cancer patients, with estimated HR of 1.03 (90% CI, 0.83–1.29) for PFS [19]. Apsangikar et al [20] also
found biosimilar bevacizumab (BevaciRel: Reliance Life sciences) to be non-inferior to the reference bevacizumab in metastatic colorectal cancer
[20].
Additionally, these biosimilar drugs also have proved their worth in terms of safety and toxicities when compared to the original molecule. In
the MAPLE study, the frequency, type and severity of adverse events were comparable between biosimilar and reference bevacizumab and
were same as expected of the latter [19]. Apsangikar et al [20] also observed similar adverse events with both the biosimilar bevacizumab
and the reference drug. [20]. Similarly, in our study, we observed the common anti-VEGF associated toxicities with both the drugs including
similar grade 3 and 4 toxicities. Also, the difference in the safety profiles between the two groups was statistically non-significant. There was
no death due to adverse events of the drug in either group.
First study to analyse the efficacy of bevacizumab biosimilars in recurrent or progressive glioblastoma patients makes it distinctive. How-
ever, retrospective nature of the study limits the study. In future, phase 3 randomised controlled trials can be planned to more appropriately
explore this important research area.
Conclusion
In brain tumour patients, both the innovator and biosimilar bevacizumab seem to have similar clinical efficacy and safety. Prospective studies
in this direction may provide greater insight into the subject.
List of abbreviaons
TTP, Time to progression; OS, Overall survival; PFS, Progression free survival; ECOG-PS, Eastern Cooperative Oncology Group-Performance
Status; VEGF, Vascular endothelial growth factor; FDA, Food and Drug Association; GCP, Good clinical practice; ICH, International Council for
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. IDH, Isocitrate dehydrogenase; MGMT, O6-methylguanine-
DNA methyl-transferase; GBM, Glioblastoma Multiforme.
Declaraons
Ethics approval and consent to parcipate
The study methodology was approved by Institutional Ethics Committee-III, Advanced Centre for Treatment, Research and Education in Can-
cer (ACTREC), Mumbai-410210, India. Waiver of consent was obtained. Principle of declaration of GCP and International Council for Har-
monisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) was obtained. All patients were provided written informed
consent prior to chemotherapy.

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ecancer 2021, 15:1166; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2021.1166 8
Consent for publicaon
We are giving consent for publication.
Availability of data and material
The authors confirm that the data supporting the findings of this study are available within the article.
Conicts of interests
The authors declare that they have no competing interests.
Funding
None.
Authors’ contribuons
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by all. The
first draft of the manuscript was written by Vijay Maruti Patil and all authors commented on previous versions of the manuscript. All authors
read and approved the final manuscript.
Acknowledgement
None.
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