Keywords
colorectal cancer - bevacizumab - biosimilar - LMICS - Real-world evidence
Introduction
Bevacizumab is a humanized monoclonal antibody that binds to all circulating and soluble
vascular endothelial growth factor-A (VEGF-A) isoforms. By binding to VEGF-A, bevacizumab
prevents the interaction of VEGF-A with VEGF receptors, thereby inhibiting the activation
of VEGF signaling pathways that promote neovascularization and carcinogenesis.[1]
Bevacizumab is one of the mainstays in managing advanced/metastatic colorectal cancers
(mCRCs). It is used across scenarios in combination with chemotherapeutic agents and
rarely alone as maintenance.[2]
[3]
[4]
[5] While bevacizumab was developed by Roche (Avastin, Roche), it went off patent in
2016, after which multiple biosimilars became available for Indian patients being
treated with bevacizumab. These biosimilars were cheaper than the innovator molecule
(Avastin, Roche). Although these biosimilars went through the due regulatory process
before being available in the Indian market, there is limited real-world evidence
(RWE) to suggest equivalence or similar outcomes with the use of these molecules.
With this background, the investigators conducted a retrospective audit to compare
the survival outcomes between patients with mCRC receiving the innovator and biosimilar
molecules.
Materials and Methods
Patient Selection
The current retrospective study aimed to evaluate the survival of patients with mCRC
receiving a combination of chemotherapy with bevacizumab, whether innovator or biosimilar.
The innovator bevacizumab refers to Avastin (Roche), while the biosimilars used were
Bevacirel (manufactured by Reliance Life Sciences), Bryxta (manufactured by Zydus
Cadila), and Versavo (Dr. Reddy's Laboratories).[6]
[7]
[8] The investigators evaluated data from a prospectively maintained CRC database at
Tata Memorial Hospital (TMH) and included patients who had been treated between January
2017 and January 2022. Patients included in the study satisfied the following criteria:
histologically confirmed adenocarcinoma, radiologically confirmed unresectable or
metastatic cancer, started on chemotherapy plus bevacizumab and had at least one follow-up
visit documenting response postadministration, and had documented dates of starting
and cessation of chemotherapy plus bevacizumab.
Clinical Data Collection and Endpoints
Data collected were demographic and clinical variables, details of chemotherapy plus
bevacizumab administration in terms of first line, second line, or during later lines
of therapy, adverse events, and oncologic outcomes. The primary endpoint of the study
was a comparison of median progression-free survival (mPFS) between patients receiving
innovator bevacizumab and generic bevacizumab as first-line therapy (CT1). Secondary
endpoints included comparison of mPFS between patients receiving innovator bevacizumab
and generic bevacizumab as second-line therapy (CT2), comparison of mPFS between patients
receiving innovator bevacizumab and generic bevacizumab beyond second-line therapy
(CT3), and comparison of median overall survival (mOS) between patients receiving
innovator bevacizumab and generic bevacizumab as CT1.
Ethical Approval and Consent
The approval for the study was obtained from the Institutional Ethics Committee at
TMH (IEC418). The approval included the requirement of a short telephonic consent
for patient data accrued in TMH as part of ethics committee requirements. Data collection
and handling were conducted as per the ethical guidelines of the Declaration of Helsinki.
Statistics
Data were analyzed using IBM SPSS version 20 (Armonk, NY, United States). Descriptive
statistics such as median, frequency, and percentage were used to summarize the categorical
variables. The primary endpoint of the study was the mPFS of patients receiving chemotherapy
plus bevacizumab as CT1 and this was calculated from the date of diagnosis of starting
CT1 to the date of progression, loss to follow-up, or death, whichever was earlier.
mPFS during CT2 was similarly calculated. mOS during CT1 was calculated from the date
of starting CT1 to the date of death or loss to follow-up, whichever was earlier.
mOS during CT2 was similarly calculated. Survival analysis was performed using Kaplan–Meier
estimates, and the log-rank test was used for bivariate comparisons.
Results
Baseline Characteristics
A total of 944 patients received bevacizumab during the study period. This included
652 patients (69%) who received bevacizumab during CT1, 449 patients (48%) during
CT2, and 74 patients (8%) during CT3. A detailed report of the clinical characteristics
of patients in the study is presented in [Table 1], while the characteristics of systemic therapy received are presented in [Table 2]. Overall, 132 patients (14%) received the innovator, while 810 patients (86%) received
a biosimilar molecule.
Table 1
Baseline demographic and clinical characteristics (n = 944)
|
Characteristic
|
No. (percentage where applicable)
|
|
Median age (y)
|
|
|
ߦ Age <60
|
666 (70)
|
|
ߦ Age ≥60
|
278 (30)
|
|
Gender
|
|
|
ߦ Female
|
305 (32)
|
|
ߦ Male
|
639 (68)
|
|
Nature of metastatic CRC
|
|
|
ߦ De novo metastatic
|
627 (66)
|
|
ߦ Recurrent metastatic
|
317 (34)
|
|
Location of primary tumor
|
|
|
ߦ Right sided
|
308 (33)
|
|
ߦ Left sided
|
546 (58)
|
|
ߦ Transverse
|
69 (7)
|
|
ߦ Epicenter not identified
|
21 (2)
|
|
Prior local therapy
|
|
|
ߦ Resection of primary
|
317 (34)
|
|
ߦ Radiotherapy to primary
|
96 (10)
|
|
Signet ring histology
|
|
|
ߦ Yes
|
72 (8)
|
|
ߦ No
|
872 (92)
|
|
Mucinous histology
|
|
|
ߦ Yes
|
30 (3)
|
|
ߦ No
|
914 (97)
|
|
Sites of metastases
|
|
|
ߦ Hepatic
|
486 (52)
|
|
ߦ Peritoneal/omental
|
426 (45)
|
|
ߦ Pulmonary
|
223 (24)
|
|
ߦ Osseus
|
60 (6)
|
|
ߦ Brain
|
8 (1)
|
|
ߦ Leptomeningeal disease
|
0
|
|
ߦ Others
|
NA
|
|
ECOG PS
|
|
|
ߦ 0
|
72 (8)
|
|
ߦ 1
|
627 (66)
|
|
ߦ 2
|
218 (23)
|
|
ߦ > 2
|
27 (3)
|
Abbreviations: CRC, colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group
Performance Status.
Table 2
Details of bevacizumab administration (n = 944)
|
Characteristic
|
No. (percentage where applicable)
|
|
Receipt of bevacizumab (overall)
First line
Second line
Third line
Beyond third line
|
944 (100)
652 (69)
449 (48)
74 (8)
7 (<1)
|
|
Receipt of innovator bevacizumab
ߦ First line
ߦ Second line
ߦ Third line
ߦ Beyond third line
|
132 (14)
83 (9)
63 (7)
10 (1)
4 (<1)
|
|
Receipt of generic bevacizumab
ߦ First line
ߦ Second line
ߦ Third line
ߦ Beyond third line
|
812 (86)
569 (60)
386 (41)
64 (7)
3 (<1)
|
Survival Endpoints
With a median follow-up of 18 months, among the 652 patients who received bevacizumab
during CT1, 83 patients (13%) received the innovator bevacizumab, while 569 patients
(87%) received a biosimilar bevacizumab. There was no difference in mPFS between patients
receiving the innovator or biosimilar (10 vs. 9.3 months, p = 0.62; [Fig. 1]). Similarly, there was no difference in mOS between patients receiving the innovator
or biosimilar during CT1 (17.8 vs. 18 months, p = 0.85).
Fig. 1 Progression-free survival (PFS; first line) with the originator versus generic.
Among the 449 patients who received bevacizumab during CT2, 63 patients (14%) received
the innovator bevacizumab, while 386 patients (86%) received a biosimilar bevacizumab.
There was no statistically significant difference in mPFS between patients receiving
the innovator and biosimilar (5.5 vs. 5.8 months, p = 0.97), and there was no difference in mOS between patients receiving the innovator
or biosimilar during CT2 (8.15 vs. 8.58 months, p = 0.16).
The complications related to bevacizumab were similar in both the groups and are described
in [Supplementary Table S1] (available in the online version only). Even though perforations were numerically
more in biosimilars, tumor perforations were also included in this, and separate data
are not available. The data on the bleeding complications cannot be captured separately
as tumoral bleeds are very common especially in the left-sided tumors.
Discussion
The current study of more than 900 patients with mCRC provides RWE to suggest that
there is similar efficacy between innovator and biosimilar bevacizumab across treatment
lines. The results provide greater confidence to clinicians in using these biosimilars
in patients in whom use of the innovator is not feasible.
The management of patients with cancers in India has its challenges and mCRC is no
exception. Some of the major challenges include logistic and financial constraints.
While the number of successful therapeutic options in mCRC has increased over the
last two decades, access to these newer medications is limited in India, primarily
due to cost constraints. This has been shown in studies from governmental tertiary
cancer centers in India wherein the use of targeted therapy as part of first-line
therapy has been only around 15%.[9]
[10] In such a scenario, the availability of efficacious and cost-effective biosimilars
is of major benefit to patients in their treatment journey. The biosimilars used in
our institute are available at approximately 8 to 12% of the cost of the innovator
bevacizumab.
However, it is important to ensure that logistics and cost alone are not determinants
of the kind of therapy available to patients who can afford relatively little.[11] The overriding aim would be to provide appropriate and efficacious treatment options,
and the current study throws light on the same in the space of mCRC. Hard endpoints
such as PFS and OS have been examined in the current analysis and suggest similar
outcomes among patients using the innovator and generic versions of bevacizumab. The
above results, along with a smaller study previously published by our institute, suggest
that the use of generic bevacizumab should be strongly considered given their efficacy
as well as the financial advantages they offer.[12]
The current study, while offering RWE, has several caveats to be considered. Several
factors such as chemotherapy backbone, biomarker status, patient performance status,
and ability to receive multiple lines of therapy, besides the use of targeted therapy,
affect outcomes in the management of mCRCs in the current era. These are variables
that may have played a role in the current study in determining survival outcomes.
We have not differentiated between the various generic molecules and outcomes associated
with them as this was not part of the study plan. We have provided limited data on
bevacizumab-related class side effects, which have an important bearing on the use
of these molecules in clinical practice. The OS seen in the study would appear lesser
than those published from current studies but are similar to previously published
Indian data. There are multiple reasons for these decreased survivals, which are beyond
the scope of the current analysis.
In conclusion, the current study offers RWE to suggest similar outcomes with innovator
and generic bevacizumab when combined with chemotherapy in advanced colorectal cancers.
This provides strong clinical evidence to back published pharmacokinetic and pharmacodynamic
studies to suggest the efficacy of commonly used bevacizumab generics in Indian scenarios
and provides oncologists with greater confidence to use these molecules in their clinical
practice.
