Biosimilars in the Evolving Cancer Care

Landscape: Experts Address Current Questions,

Controversies, and Impact on Clinical Practice

Supported by educational grants from Amgen, Pfizer,

and Sandoz Inc., a Novartis Division
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Program Director

Andrew D. Zelenetz, MD, PhD

Medical Director, Quality Informatics
Attending Physician, Lymphoma Service
Department of Medicine
Memorial Sloan Kettering Cancer Center
Professor of Medicine
Weill-Cornell Medical College
New York, New York
Faculty
Jeffrey Crawford, MD
George Barth Geller Professor of
Medicine
Duke University
Co-Director
Solid Tumor Therapeutics Program
Duke Cancer Institute
Durham, North Carolina
Lee S. Schwartzberg, MD, FACP
Executive Director
West Cancer Center
Chief
Division of Hematology/Oncology
The University of Tennessee Health
Science Center
Professor of Medicine
Division of Hematology/Oncology
The University of Tennessee Health
Science Center
Memphis, Tennessee
Faculty Disclosures
Jeffrey Crawford, MD, has disclosed that he has received consulting fees from
AstraZeneca, Beyond Spring, Celgene, Dova, G1 Therapeutics, Janssen, Merck,
Merrimack, Mylan, Pfizer, and Roche and funds for research support (principal
investigator) paid to his institution from Amgen, AstraZeneca, Bayer, and Genentech.
Lee S. Schwartzberg, MD, FACP, has disclosed that he has received consulting
fees from AbbVie, Amgen, Merck, Pfizer, and Spectrum, and funds for research
support from Helsinn and Tesaro.
Andrew D. Zelenetz, MD, PhD, has disclosed that he has received consulting fees
from Adaptive Biotechnology, Amgen, BeiGene, Celgene, Genentech/Roche, Gilead,
Janssen, and Novartis, and funds for research support from Gilead, MEI Pharma,
and Roche.
Agenda
Program Overview Latest Updates of Therapeutic
Andrew D. Zelenetz, MD, PhD Oncology Biosimilars and
Program Director Integration Into Practice
Lee S. Schwartzberg, MD, FACP
Development and Regulatory
Approval of Biosimilars Question and Answer Session
Andrew D. Zelenetz, MD, PhD and Closing Remarks
Andrew D. Zelenetz, MD, PhD
Latest Updates of Supportive
Oncology Biosimilars and
Integration Into Practice
Jeffrey Crawford, MD
Development and Regulatory Approval of
Biosimilars

Andrew D. Zelenetz, MD, PhD

Medical Director, Quality Informatics
Attending Physician, Lymphoma Service
Department of Medicine
Memorial Sloan Kettering Cancer Center
Professor of Medicine
Weill-Cornell Medical College
New York, New York
Topics to Be Addressed

• What is a biosimilar and why is it different than a generic

• Understanding biologics and manufacturing “drift”
– Regulatory guidance for minimizing drift
• Approval pathway for biosimilars
– The Biologics Price Competition and Innovation Act of 2009 directed the FDA to
establish guidelines for:
• Scientific considerations for efficacy and safety
• Meaningful endpoints for analytic, preclinical, and clinical studies
• Demonstrating biosimilarity to a reference product
• Interchangeability
– Evaluation for approval is based on “totality of the evidence” approach
Biosimilars Are Not Generics
 Regulatory Definitions of a Biosimilar

US Food and Drug Administration European Medicines Agency (EMA)

(FDA)
• Biosimilarity means “that the • “A biosimilar is a biological medicinal
biological product is highly similar to product that contains a version of the
the reference product active substance of an already
notwithstanding minor differences in authorised original biological medicinal
clinically inactive components . . . product (reference medicinal
there are no clinically meaningful product) . . . Similarity to the reference
differences between the biological medicinal product in terms of quality
characteristics, biological activity, safety,
product and the reference product in
and efficacy based on a comprehensive
terms of the safety, purity, and
comparability exercise needs to be
potency.”[1]
established.”[2]
1. FDA. Guidance for industry on biosimilars, part I. March 2016. 2. EMA. Guideline on similar biological medicinal products
containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. December 2014.
 Biologics: A Regulatory Perspective
Characteristic 351(a) 351(k) 351(k)(4) 351(a) 351(a)
Originator Biosimilar Interchangeable Non-originator Next-generation
Biosimilar Biologic “Biobetter”
Description First-to market biologic “Highly similar” to A biosimilar that can It is “another brand Biologic that has been
molecule; will likely be reference product; be substituted for the name” of an already altered to achieve
the reference product approved via reference without approved biologic improved clinical
biosimilars pathway permission from outcomes
prescriber
Depth of data “Standard” data Abbreviated data More extensive data “Standard” data “Standard” data
submitted to the FDA package: efficacy and package for package for package: efficacy and package: efficacy and
safety comparability comparability safety safety
supporting that the
interchangeable
biosimilar anticipated
to produce same
clinical effects for all
the reference product’s
licensed conditions
Compared to N/A Yes Yes Yes or no Likely (standard of
originator? care)

Lucio SD, et al. Am J Health Syst Pharm. 2013;70:2004-2017. FDA. Considerations in demonstrating
interchangeability with a reference product: guidance for industry. January 2017.
Manufacturing Drift: Originators Are
Biosimilars of Themselves
 What is Acceptable Variation? Lot-to-Lot Variation of Innovator Products: Rituximab

Cation Exchange Chromatography Cation Exchange Chromatography ADCC

Glycan Mapping

Significant change in ADCC likely related to the altered glycan map for unfucosylated G0 glycans

Schiestl M, et al. Nat Biotechnol. 2011;29:310-312.

 ICH Q5E: Regulatory Guidance to Minimize the Impact of Manufacturing Drift of Biologics

• Over the life of a biopharmaceutical changes are invariably introduced into manufacturing
– Improve yield
– Changes in sourcing of components
– Changes in production scale
• Manufacturing changes are governed by ICH Q5E regulation recognized by both the FDA and EMA
– Guidance aims to minimize the drift inherent in a reference product
– The regulations provide guidance to conduct a comprehensive assessment on the impact to the
product
• Key requirements include:
– Analytics should be selected and optimized to maximize the likelihood of detecting potential
differences
– Apply more than 1 analytical procedure to evaluate the same quality to maximize the detection of
potential differences
– Evaluate critical control points in the manufacturing process that affect product characteristics

International Council on Harmonisation. Guidance for industry: Q5E comparability of biotechnological/biological products subject to change
in their manufacturing process. June 2005.
Foundations of Biosimilarity:
Preclinical Assessment
 Preclinical Assessment: Structure and Function

• Serve as the “foundation” of biosimilar development

• Useful in determining what future clinical studies are necessary
• Structure
– Amino acid sequence, higher-order structures, glycosylation, pegylation, etc.
– Analyze lot-to-lot variability
• Function
– Evaluate pharmacologic activity via in vitro and/or in vivo experiments
– Functional evaluation that compares candidate to reference

FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. April 2015.
 Preclinical Assessment: 4 Levels of Analytical Characterization

Studies of Structure &

Function: Residual
Uncertainty
Insufficient analytical similarity No further development through
High (not similar) 351(k)

Additional information needed:

Analytical similarity with
analytical, comparative PK/PD,
residual uncertainty (similar)
etc.

Tentative analytic similarity High confidence; appropriate for

(highly similar) targeted clinical studies

Fingerprint-like analytic similarity Very high confidence; appropriate

(highly similar with fingerprint-like for more targeted preclinical and
Low similarity) clinical studies

FDA. Clinical pharmacology data to support a demonstration of biosimilarity to a reference product: guidance for industry.
December 2016.
 Establishing Fingerprint-Like Similarity: Physiochemical Properties

Primary Sequence Impurities

Peptide Mapping Higher Order Structures Glycoforms

FDA. Clinical pharmacology data to support a demonstration of biosimilarity to a reference product: guidance for industry.
December 2016.
 Analytics for Characterization of Rituximab Biosimilar GP2013 and Originator Rituximab

Category Quality Attribute Methods

Physicochemical characterization
Primary structure Amino acid sequence Reduced reversed-phase high-performance liquid chromatography electrospray ionization mass
spectrometry (RP-HPLC–ESI–MS) peptide mapping, intact mass of whole monoclonal antibody, HC
and LC by RP-HPLC–ESI–MS, reduced RP-HPLC-ultraviolet (UV) peptide mapping

Higher-order structure Disulfide bridging Nonreduced RP-HPLC–ESI–MS peptide mapping

Free thiols Ellman’s assay

Secondary and tertiary structure Circular dichroism, Fourier transform infrared (FTIR) spectroscopy, hydrogen deuterium exchange
(HDX)-MS, x-ray

Thermodynamic stability Differential scanning calorimetry

General charge heterogeneity and amino 0K variant, acidic variants, basic variant, Gln-variant, Lys-variant, amidated proline Cation exchange chromatography digested/undigested
acid modifications

Glycation Boronate affinity

Oxidation/deamidation/C-terminal variants RP-HPLC-UV/MS peptide mapping

Glycosylation Galactosylation, sialylation, mannosylation, afucosylation, bisecting GlcNAc, NGNA, α-galactose, Normal-phase HPLC-fluorescence
qualitative glycosylation pattern

Size heterogeneity Monomer, low-molecular weight (LMW) and high molecular weight (HMW) variants (aggregates) Size exclusion chromatography, asymmetric flow field flow fractionation

Heavy chain (HC), light chain (LC), aglycosylated HC, clipped variants Reduced capillary electrophoresis with sodium dodecyl sulfate (CE-SDS)

Monomer, LMW (eg, half antibodies (HL) and HHL variant) and HMW variants Nonreduced CE-SDS

Subvisible particles Light obscuration (PhEur, ≥ 10 μm and > 25 μm)

Visible particles Visual inspection (PhEur)

Functional characterization
Target and receptor binding FcRn binding; FcγR binding (FcγRIa, FcγRIIa, FcγRIIb, FcγRIIIa[F158], FcγRIIIa[V158], FcγRIIIb) Surface plasmon resonance

Bioactivity CD20 target binding Cell-based binding assay

CDC potency Cell-based complement-dependent cytotoxicity assay

ADCC potency Cell-based antibody-dependent cell-mediated cytotoxicity assay

Apoptosis Cell-based apoptosis assay

Visser J, et al. BioDrugs. 2013;27:495-507.

 Characterization of Biosimilar Rituximab GP2013 and Originator Rituximab

UV Chromatography of Lys-C Digestion Glycosylation Pattern Cation Exchange Chromatography

1D 1H NMR Spectra

Originator drift complicates biosimilar

development
X-Ray Crystallography (1GP2013, Blue/Gold;
Rituximab, Grey)

Electrophoresis of Nonreduced
Proteins, Highlighting Ig Chains

Functional Assays
Parameter, % Target ADCC CDC Apoptosis
Binding
GP2013 97-108 86-105 99-111 88-97
Reference 96-110 70-132 95-127 88-102
range
2-sided P value < .0001 < .0001 < .0001 < .0001
Visser J, et al. BioDrugs. 2013;27:495-507.
 Animal Toxicity Studies

• Useful when there are unresolved questions about the safety of the candidate
biosimilar based on studies of structure/function
• Utilize comparative animal toxicology
• “The scope and extent of any animal toxicity studies will depend on information about
the reference product, information about the proposed product, and the extent of
known similarities or differences between the two.”

FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. April 2015.
Clinical Evaluation of Biosimilars
 Moving a Biosimilar Into the Clinic: Equivalent Pharmacokinetics is the First Critical Hurdle

• Molecules that have been demonstrated to be ‘highly similar’ in preclinical evaluation

need to be evaluated in the clinic
• Showing of biosimilar PK, within predefined equivalence margins, should be the first
clinical ‘go/no go’ step for biosimilars
• The biosimilar concept implies the same dose, strength, and route of administration
• PK is a critical measure in assessing bioavailability of ‘highly similar’ structure

Product class-specific PK equivalence margins will be

important to extrapolation decisions that occur later in
the development program

FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. April 2015.
Isakov L, et al. Am J Ther. 2016;23:e1903-e1910.
 Clinical Studies: FDA

• Specific clinical study design will depend on what residual questions remain
– Clinical evaluation should evaluate relevant and sensitive endpoints for PK (and PD, if possible)
• Trials do not need to establish primary efficacy and safety of the biosimilar
• Safety and efficacy have been established by the originator
– Clinical studies should be designed to demonstrate neither decreased nor increased activity
– The extent of study results will differ between ‘highly similar’ and ‘fingerprint similarity’
• Clinical immunogenicity
– Goal is to evaluate potential differences in incidence and severity of immune responses using
endpoints such as antibody formation (binding, neutralizing), cytokine levels, etc.
– FDA recommends a comparative parallel study in treatment-naive patients
• May also need to descriptively assess major risk of immunogenicity, hypersensitivity, or other
reactions following a single crossover from reference to biosimilar

FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. April
2015.
 Immunogenicity Concerns

• All biologics confer a risk of immunogenicity

– Related to patient, disease, and product factors
– Consequences include neutralizing antibodies or cytokine release
– Scientific tools for detecting immunogenicity exist, but they are not precise
• Changes to the structure of the protein increase variation in immunogenicity
– Lot-to-lot and between manufacturers
– Variations in manufacturing must be minimized
• Clinical consequences:
– Loss or diminished efficacy or safety
– Case reports of rare but serious adverse reactions

FDA. Guidance for industry: immunogenicity assessment for therapeutic protein products. August 2014.
Extrapolation and Interchangeability
 Extrapolation: Current Use and Role in Biosimilar Development

• Extrapolation: expansion of use to other approved indications based on clinical and safety data from
one indication
• Extrapolation is an established principle that has historically used by regulators
– Major process changes in manufacture of an originator typically requires a trial to confirm
equivalent clinical activity in a single indication
• Trial design is similar to that used in evaluation of biosimilars
• Extrapolation is provided to all approved indications
– Alteration in route of administration (eg, IV to SC)
• Typically one study demonstrates equivalent safety and efficacy
• Extrapolation is provided to other approved uses
• Extrapolation is key concept in the development of biosimilars
– Requires similar MOA, PK, PD, and patient populations
– Potentially provides substantial saving in drug development

Weise M, et al. Blood. 2014;124:3191-3196.

 Extrapolation: FDA Guidance

• Scientific justification for extrapolation should consider:

– The mechanism(s) of action (MoA) in each condition
• Target/receptor(s) for product’s relevant activity/function
• Binding, dose/concentration response, and pattern of molecular signaling when product
engages with target/receptor(s)
• Relationships between target/receptor interactions and product structure
• Target/receptor(s) location and expression
– PK, PD (if important for MoA), and biodistribution of product in different patient populations
– Immunogenicity of product in different patient populations
– Differences in expected toxicities for each condition and patient population
– “Any other factor that may affect the safety or efficacy of the product in each condition of use and
patient population for which licensure is sought”

FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. April 2015.
 Framework for Extrapolation

Patient Factors Disease Factors Endpoint Factors

• Similarity of biologic • Defined MoA • Differential efficacy and
disposition: PK/PD • Similarity in target toxicity
• Organ function distribution • Short term vs. long term
• Age, ethnicity, etc. • Single vs combo therapy • Sensitivity of surrogate
outcomes

Quantitative evidence
Disease progression: Disease models to characterize differences in progression between groups.
PK/PD: Modeling simulation with existing data to investigate the relationship between PK/PD, age, and other important
variables.
Clinical response: Quantitative synthesis or modeling of all existing data (in vitro, preclinical, and clinical) to predict degree of
similarity between source and target population in clinical response (efficacy, some safety aspects).

Determine appropriateness of indication extrapolation

No extrapolation; extrapolation to some indications; extrapolation to all indications

FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. April
2015. EMA. Concept paper on extrapolation of efficacy and safety in medicine development. September 2012.
Weise M, et al. Blood. 2014;124:3191-3196.
What a Clinician Wants Before They Feel Comfortable With Extrapolation

• PK analysis is essential to show equivalent drug exposure

– PK can differ by the clinical context (eg, rituximab for lymphoma vs rheumatoid
arthritis)
• Monitoring for anti-drug antibodies is a major safety measure
• Clinical efficacy should be demonstrated in appropriate patient populations
– Independent trials in NHL and non-malignant diseases (for rituximab)
– Single-agent activity in first-line follicular lymphoma as a sensitive indicator of
activity (for rituximab)
– Activity in the metastatic setting (for trastuzumab)
 Interchangeability

• Interchangeability is the use of a biosimilar without impacting on safety or efficacy if it

is alternated or switching between the biosimilar and the innovator compared to the
use of the innovator without alternation or switching
• Guidance has been issue by the FDA for the evaluation of interchangeability of a
biosimilar and a reference product
– There are no approved interchangeable biosimilars
• A drug must be designated to be interchangeable to permit drug substitution by a
pharmacist without prescriber permission
– Drug substitution rule and regulations are determined at the state level
– Designation of a biosimilar as interchangeable does not automatically allow drug
substitution

FDA. Considerations in demonstrating interchangeability with a reference product: guidance for industry. January 2017.
Barlas S. P T. 2017;42:509-512.
FDA. Prescribing biosimilar and interchangeable products. October 2017.
Summary

• Biologics are complex molecules and therefore identical ’generic’ copies are not possible
– Lot-to-lot variation of innovator drugs is inevitable and is closely regulated
• Regulations to enable the development of biosimilars were created to improve access to essential
medications
• Biosimilars are biological copies of an innovator with no meaningful differences in safety and efficacy
• The development of biosimilars is the inverse of innovator molecules, with the preclinical development
being the key to success
• Clinical trials to compare to the innovator are not aimed at establishing safety and efficacy in an
indication – this was accomplished by the innovator
– The goal is to establish equivalence in PK and PD endpoints and show clinical activity within an
accepted equivalence margin
• Major cost saving in the development of biosimilars comes from extrapolation to scientifically and
clinically justified indications already approved for the innovator
 Latest Updates of Supportive Oncology
Biosimilars and Integration Into Practice

Jeffrey Crawford, MD
George Barth Geller Professor for Research in Cancer
Co-Program Leader, Solid Tumor Therapeutics
Program
Duke Cancer Institute
Durham, North Carolina

Image: ALFRED PASIEKA/Copyright©2017 Science Source. All Rights Reserved

 Current Therapeutic Use of Myeloid Growth
Factors: Neutropenia
 Indications for myeloid growth factors  Myeloid growth factors used
to manage febrile neutropenia therapeutically until post-nadir ANC
– Sepsis syndrome recovery to near-normal levels
– Filgrastim or filgrastim-sndz: 5 μg/kg/day
– Age > 65 years
– Sargramostim: 250 μg/m2/day
– ANC < 100/μL
– Neutropenia likely to exceed 10 days
– Pneumonia or other infection(s)
– Invasive fungal infection
– Hospitalization with fever
– Prior febrile neutropenia
1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN
Guidelines®) for Myeloid Growth Factors. v1.2018. © National Comprehensive Cancer Network, Inc 2018.
All rights reserved. Accessed March 12, 2018. To view the most recent and complete version of the
guideline, go online to NCCN.org. Slide credit: clinicaloptions.com
 Biosimilars Represent Paradigm Shift in Product
Development
Originator Biologic[1] Biosimilar[2]
High Low
Postmarketing
Postmarketing Surveillance
Surveillance
Contribution to Clinical Predictability

Contribution to Clinical Predictability

Phase III Clinical Clinical

Phase II Clinical Immunogenicity

Phase I Clinical PK/PD

Preclinical Preclinical

Molecular
Molecular Characterization
Low Characterization High

1. FDA. Drug development overview. 2012. 2. FDA. Scientific considerations in

demonstrating biosimilarity to a reference product: guidance for industry. 2015. Slide credit: clinicaloptions.com
 Extrapolation to Additional Indications Possible
With Scientific Justification
Biosimilar
Postmarketing Extrapolation: extending conclusions from
Surveillance studies in one pt population to make inferences
in another population[1]
Clinical
y

Immunogenicity
a

Convincing evidence to

+
thw

support extrapolation to Extrapolated

an originator biologic’s indications
r Pa

PK/PD approved indications[2]

ila
sim

Preclinical
Bio

Molecular Characterization

Image adapted from Sherman RE. Biosimilar Guidance Webinar. February 15, 2012.
1. EMA. Concept paper on extrapolation of efficacy and safety in medicine development. 2012.
2. Weise M, et al. Blood. 2012;120:5111-5117. Slide credit: clinicaloptions.com
 First FDA-Approved Biosimilar:
Filgrastim-sndz—Analytics, PK/PD, Safety
 Approved March 6, 2015; first FDA-approved oncology-related biosimilar
 Structural and functional studies demonstrated same amino acid sequence
as US-licensed filgrastim
 Biological activity, receptor binding and physiochemical properties, product-
related substances and impurities, and stability profile are highly similar to
US-licensed filgrastim, notwithstanding minor differences in clinically inactive
components
 5 studies in healthy subjects evaluating ANC, Cmax, and CD34+ cell counts
demonstrated PK/PD similarity with US-licensed and EU-approved filgrastim
 Safety data in 204 healthy subjects and 214 pts with breast cancer were
similar to US-licensed and EU-approved filgrastim
37Drugs Advisory Committee Meeting. 2015.
FDA. Oncologic Slide credit: clinicaloptions.com
 Comparability of Biosimilar Filgrastim With
Originator Filgrastim: Protein Characterization
 Protein characterization by NMR spectroscopy

Biosimilar drug product (batch DP1)

Originator filgrastim US drug product (batch NUS1)

Originator filgrastim EU drug product (batch NEU1)

10 9 8 7 6 5 4 3 2 1 0 ppm
Sorgel F, et al. BioDrugs. 2015;29:123-131. Slide credit: clinicaloptions.com
 Comparability of Biosimilar Filgrastim With
Originator Filgrastim: Receptor-Binding Affinities
Biosimilar Filgrastim Originator Filgrastim
250 250

Relative Response (RU)

Relative Response (RU)

200 200

Batch DP1 Batch NEU2

150 150
Batch DP3 Batch DP5
Batch NUS2 Batch DP4
100 Batch DP2 100 Batch DP6
Batch NUS1 Batch NEU1
50 Buffer 50 Buffer
Batch NUS3 Batch NUS4
0 0

-50 -50
0 200 400 600 800 1000 1200 1400 0 200 400 600 800 1000 1200 1400
Time (Secs) Time (Secs)

Sorgel F, et al.39
BioDrugs. 2015;29:123-131. Slide credit: clinicaloptions.com
 Comparability of Biosimilar Filgrastim With
Originator Filgrastim: Pharmacokinetics
 Analysis: no significant differences between the biosimilar and originator product
100
Geometric Mean Filgrastim 90
80
Concentration (ng/mL)

70 Biosimilar filgrastim
60 US-licensed originator filgrastim
50
40
30
20
10
0
0 4 8 12 18 20 24 28 32 36 40 44 48
Hrs
Sorgel F, et al.40
BioDrugs. 2015;29:123-131. Slide credit: clinicaloptions.com
 Biosimilar Filgrastim (Filgrastim-sndz) vs
Reference Filgrastim: ANC Recovery
 N = 218 pts with breast cancer receiving myelosuppressive chemotherapy
 Filgrastim 5 µg/kg/day administered over 6 chemotherapy cycles
 Conclusion: biosimilar filgrastim noninferior to originator filgrastim at improving ANC counts
Time Course of ANC in Cycle 1 x Biosimilar (cycle 1):
30
biosimilar plus
biosimilar-originator
ANC (109/L)

Reference (cycle 1)
20 x originator plus
x originator-filgrastim-sndz
x
10 x x
ANC recovery x
x x x x
≥ 2 x 109/L 5 x x x
after ANC nadir 2 x
x x
0
Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 21
Biosimilar, n 97 97 100100101 99 98 97 98 83 51 16 6 5 4 99
Reference, n 102102103103102103103102102 97 43 15 7 4 2 102

Blackwell K, et al. Ann Oncol. 2015;26:1948-1953. Slide credit: clinicaloptions.com

 Biosimilar Filgrastim (Filgrastim-sndz) vs Reference
Filgrastim: Duration of Severe Neutropenia
 N = 218 pts with breast cancer receiving myelosuppressive chemotherapy
 Filgrastim 5 µg/kg/day administered over 6 chemotherapy cycles
 Conclusion: biosimilar filgrastim noninferior to originator filgrastim at improving neutropenia

X Biosimilar (cycle 1):

biosimilar plus 1.17 (95% CI: 0.95-1.39) (n = 101)
biosimilar-originator X

Reference (cycle 1): 1.20 (95% CI: 1.00-1.40) (n = 103)

originator plus
originator-biosimilar
0.5 1 1.5
Days
PP treatment difference: 0.04 days
(1-sided 97.5% CI: -0.26 to ∞)
Blackwell K, et al. Ann Oncol. 2015;26:1948-1953. Slide credit: clinicaloptions.com
 Alternating Biosimilar and Reference Filgrastim
to Manage Severe Neutropenia in Breast Cancer
Adverse Event, % Switched (alternating
Reference Only
biosimilar and originator)
(n = 51)
N = 107
Incidence of febrile 3.4 0
neutropenia (FN) 95% CI: -9.65 to 4.96
Infections 9.3 9.9
Hospitalization due to FN [1 patient in cycle 6] 0
Treatment-emergent AEs 42.1 39.2
Anti-drug antibodies 0 0

No evidence of clinically meaningful differences with switching

Blackwell K, et al. Ann Oncol. 2018;29:244-249. Slide credit: clinicaloptions.com

 Biosimilar Filgrastim in the US: Extrapolation to
Other Indications
 Oncologic Drugs Advisory Committee recommended the FDA
approve filgrastim-sndz for all current indications of filgrastim
– Patients with cancer receiving myelosuppressive chemotherapy
– Patients with acute myeloid leukemia receiving induction or
consolidation chemotherapy
– Patients with cancer receiving a bone marrow transplant
– Patients undergoing peripheral blood progenitor cell collection and
therapy
– Patients with severe chronic neutropenia
44 Review for Regulatory Action. 2014.
CDER Summary Slide credit: clinicaloptions.com
 Filgrastim-sndz: Best Practices
 NCCN recommendations:[1]
– Therapeutic use for the management of febrile neutropenia
– Prophylaxis of febrile neutropenia and adherence to schedule, dose
– Mobilization of hematopoietic progenitor cells for ASCT
– May be used with plerixafor in selected patients
– Mobilization of stem cells for allogeneic transplantation
– Supportive care following transplant
 ASCO recommends filgrastim-sndz at the same level of other G-CSF for prevention of
treatment-related febrile neutropenia (evidence quality: high, with strength of
recommendation: strong), with extrapolation to other indications for G-CSF [2]
1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for
Myeloid Growth Factors. v1.2018. © National Comprehensive Cancer Network, Inc 2018. All rights reserved.
Accessed March 12, 2018. To view the most recent and complete version of the guideline, go online to NCCN.org.
45
2. Smith TJ, et al. J Clin Oncol. 2015;33:3199-3212. Slide credit: clinicaloptions.com
 Extrapolating from Biosimilars: Key Principles

 Extrapolation across indications for a biosimilar will depend on

several factors, including:
– A common MOA and receptor/target/interaction
– Totality of the evidence showing comparability
– Acceptable safety profile without increased risks of immunogenicity
–May require ongoing pharmacovigilance
– Clinical experience with the originator product that can be used to
support the use of a biosimilar across indications

Weise M, et al.46
Blood. 2014;124:3191-3196. Slide credit: clinicaloptions.com
 ODAC Recommendation for FDA Approval of
Biosimilar Epoetin Alfa for Anemia
 On May 25, 2017, the FDA Oncologic Drugs Advisory Committee
(ODAC) recommended approval of an epoetin alfa biosimilar
across all indications of originator biologics for treatment of
anemia
– Preclinical data supported similarity to epoetin alfa in structure,
function, and mechanism of action
– Clinical PK/PD, immunogenicity similar to epoetin alfa
– 2 phase III trials showed comparable safety and efficacy in the
treatment of pts with chronic kidney disease and anemia
 Final FDA approval pending
47Drugs Advisory Committee briefing document. May 25, 2017.
FDA Oncologic Slide credit: clinicaloptions.com
 FDA-approved Biosimilars (Supportive, Non-Oncology)
Drug Approval Comparative Phase III Clinical Trial Data
Biosimilar Indications
Class Date Leading to Approval
 PIONEER: noninferiority to prevent
Filgrastim-sndz [1]
rG-CSF 2015 Prevention of severe neutropenia neutropenia in breast cancer pts on
myelosuppressive chemotherapy[2]
TNF-α Crohn’s, ulcerative colitis, RA,  PLANETRA: equivalent ACR20 in RA pts [5]
Infliximab-dyyb[3,4] 2016
inhibitor AS, PsA, plaque psoriasis  PLANETAS*: equivalent ASAS20 in AS pts [6]
TNF-α Crohn’s, ulcerative colitis, RA,  Equivalent ACR20 in RA pts[8,9]
Infliximab-abda[7] 2017
inhibitor AS, PsA, plaque psoriasis
TNF-α Crohn’s, ulcerative colitis, RA,  REFLECTIONS B537-02: Equivalent ACR20
Infliximab-qbtx[10] 2017
inhibitor AS, PsA, plaque psoriasis in RA pts[11]
TNF-α 2016; ongoing RA, AS, PsA,  EGALITY: equivalent PASI75 in pts with
Etanercept-szzs[3,4]
inhibitor patent litigation plaque psoriasis, polyarticular JIA plaque psoriasis[12]
Crohn’s, ulcerative colitis, RA,  Equivalent ACR20 in RA pts[14]
TNF-α 2016; ongoing
Adalimumab-atto[13] AS, PsA, plaque psoriasis, JIA  Equivalent PASI improvement in pts with
inhibitor patent litigation
psoriasis[15]
Crohn’s, ulcerative colitis, RA,  VOLTAIRE-RA: Equivalent efficacy, safety,
TNF-a 2017; ongoing
Adalimumab-adbm [16]
AS, PsA, plaque psoriasis, JIA and immunogenicity in mod-to-severe RA
inhibitor patent litigation
pts, including pts switching agents [17]

1. Rugo HS, et al. Cancer Treat Rev. 2016;46:73-79. 2. Blackwell K, et al. Ann Oncol. 2015;26:1948-1953. 3. Rutherford AI, et
al. Expert Rev Clin Immunol. 2016;12:697-699. 4. Ianculescu I, et al. Curr Opin Rheumatol. 2016;28:303-309. 5. Yoo DH, et al.
Ann Rheum Dis. 2013;72:1613-1620. 6. Park W, et al. Ann Rheum Dis. 2013;72:1605-1612. 7. Infliximab-abda PI. 2017. 8.
Choe JY, et al. ACR/ARHP 2015. Abstract 2056. 9. Choe JY, et al. Ann Rheum Dis. 2017;76:58-64. 10. Infliximab-qbtx PI. 11.
Cohen SB, et al. Arthritis Rheumatol. 2017; 69 (suppl 10). 12. Griffiths CE, et al. Br J Dermatol. 2017;176:928-938.13. Kaur P, et
al. Ann Rheum Dis. 2017;76:526-533. 14. Cohen S, et al. Ann Rheum Dis. 2017;76:1679-1687. 15. Papp K, et al. J Am Acad Slide credit: clinicaloptions.com
Dermatol. 2017;76:1093-1102. 16. Adalimumab-adbm PI. 17. Thatcher N, et al. ASCO 2016. Abstract 9095.
 Selected Supportive Care Biosimilars in the
Pipeline
Originator Drug Paten
Indication Biosimilars with Phase III Clinical Trials
Biologic Class t Exp.
 EMA-approved epoetin alfa biosimilar
Epoetin alfa[1,2] r-EPO 2013 Anemia recommended by FDA panel but not
approved; others registered/ongoing
 EMA-approved filgrastim biosimilar accepted
rG-
Filgrastim[1,2] 2013 Neutropenia for FDA review
CSF
 Registered trial for MK-4214 ongoing
rG-  2 pegfilgrastim biosimilars accepted for FDA
Pegfilgrastim[1,2] 2015 Neutropenia
CSF review, including CHS-1701

1. Stevenson JG, et al. Ann Pharmacother. 2017;51:590-602.2. Butteri E, et al. Eur J Cancer. 2018;89:49-55. Slide credit: clinicaloptions.com
 Myeloid Growth Factors for Neutropenia:
Best Practices

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN
Guidelines®) for Myeloid Growth Factors. v1.2018. © National Comprehensive Cancer Network,
Inc 2018. All rights reserved. Accessed March 12, 2018. To view the most recent and complete
version of the guideline, go online to NCCN.org.
 Biosimilars: Issues in Practical Use

 Formulary analysis
 Therapeutic substitution
 Pharmacovigilance
 Economics of biosimilars
 Provider and pt education

Lucio SD, et al. Am J Health Syst Pharm. 2013;70:2004-2017. Slide credit: clinicaloptions.com
Latest Updates of Therapeutic Oncology
Biosimilars and Integration Into Practice

Lee Schwartzberg, MD, FACP

Executive Director, West Cancer Center
Chief, Division of Hematology/Oncology
University of Tennessee Health Science Center
Memphis, Tennessee
The Costs of Cancer Treatment
 Growth in Cost of Oncology Therapeutics, US
50
45 5.8 -4.8 2.6
40 3.4
Costs and Growth

35
30 13.6

25 44.1
20
15
23.4
10
5
0
2011 New Branded Branded LOE Generics 2016
Therapies Volume Price
Since 2011
IQVIA, MIDAS Q4 2016; IQVIA Institute for Human Data Science, March 2017. Slide credit: clinicaloptions.com
Cost of Biologic Anticancer Agents

 Trastuzumab global sales (2016): $6.6 billion

 Average cost of trastuzumab in US: $70,000-$80,000/year
 Bevacizumab global sales (2016): $6.7 billion
 US accounts for about half of global sales

Slide credit: clinicaloptions.com

 Cost of Biologic Oncology Agents Over Time
110 Bevacizumab Rituximab  Trastuzumab increased
100
Change From Baseline Cost (%)

Bortezomib Temsirolimus
90 Brentuximab Trastuzumab 78% over 10 years[1]
80 Cetuximab Ziv-aflibercept
70 Denosumab Inflation  Cost of biologics[2]
60 Ipilimumab Health-related
Ofatumumab inflation
50
Panitumumab
‒ 2005: 32% of $9.5B,
40
30 Pertuzumab Medicare Part B
20
10 ‒ 2014: 62% of $18.5B,
0 Medicare Part B
-10
-20
-30
0 05 006 007 008 009 010 011 012 013 014 015 016 018
2 2 2 2 2 2 2 2 2 2 2 2 2
Yr
1. Gordon N, et al. J Clin Oncol. 2017;36:319-325. 2. Nabhan C, et al. JAMA Oncol. 2018;4:241-247. Slide credit: clinicaloptions.com
 Where Will Cost Control Come From?
 Which of the Clinical standardization 63%

following are your Drugs 62%

cancer program’s Supplies 28%

biggest opportunities Capital expenses (eg, LINAC, imaging technology) 24%

for cost savings? Nonclinical staff (eg, financial counselor,

billing and coding specialist, schedulers)
22%

Technology maintenance 20%

‒ 62% identified
Clinical staff 16%
drugs as the
biggest Retail pharmacy 14%

opportunity Clinical research 10%

Support services (eg, yoga, acupuncture,
9%
nutrition services)
Other 4%

ACCC. 2017 Trending Now in Cancer Care Survey. Slide credit: clinicaloptions.com
FDA-Approved Therapeutic
Oncology Biosimilars
 FDA-approved Therapeutic Oncology
Biosimilars
Drug Approval Comparative Phase III Clinical
Biosimilar Indications
Class Date Trial Data Leading to Approval
mCRC, NSCLC,  Comparable ORR, grade ≥3
Bevacizumab- VEGF Sept.
glioblastoma, mRCC, AEs, and TEAEs[1]
awwb[1] inhibitor 2017
cervical
Breast, met  HERiTAge: equivalent ORR and
Trastuzumab- HER2 Dec.
gastric/GEJ cancer PFS, and comparable safety to
dkst[2] inhibitor 2017
trastuzumab[2]

1. Stevenson JG, et al. Ann Pharmacother. 2017;[Epub ahead of print]. 2. Trastuzumab-dkst PI. Slide credit: clinicaloptions.com
 Regulatory Status of Bevacizumab and
Trastuzumab: Originators and Biosimilars
 Patent for branded bevacizumab expires in 2020
 Bevacizumab biosimilar: bevacizumab-awwb (ABP-215)
– FDA approval in September 2017
 Patent for branded trastuzumab expires in 2019
 Trastuzumab biosimilar: trastuzumab-dkst (MYL-14010)
– FDA approval in December 2017

Trastuzumab-dkst PI, 2017.

Bevacizumab-awwb PI, 2017. Slide credit: clinicaloptions.com
 Bevacizumab-awwb vs Bevacizumab in Normal
Volunteers: Pharmacokinetics
Mean
Mean Cmax Mean AUCinf Median tmax(h) Mean t1/2 (days)
Agent AUClastμg
μg/mL (n) μg h/mL (n) (n) (range) (n) (SD)
h/mL (n)
Bev-awwb 1.50 (67)
87.2 (67) 28,200 (62) 29,400 (66) 17.77 (66) (3.68)
(1.47-24.0)
Bev (US) 1.50 (66)
89.1 (66) 28,500 (62) 29,600 (66) 17.5 (66) (3.39)
(1.48-24.0)
Bev (EU) 3.94 (64)
84.7 (64) 29,400 (64) 30,600 (66) 18.5 (66) (3.28)
(1.47-8.00)

Markus R, et al. Cancer Chemother Pharmacol. 2017;80:755-763. Slide credit: clinicaloptions.com

 Phase III Trial: Bevacizumab-awwb vs
Bevacizumab in Advanced NSCLC
Bevacizumab-awwb 15 mg/kg IV +
Patients with Carboplatin/paclitaxel Q3W x 18 wks
advanced (n = 328)
NSCLC
(N = 642) Bevacizumab 15 mg/kg IV +
Carboplatin/paclitaxel Q3W x 18 wks
(n = 314)

42.9 44.3

26.2 23.0
Median
Agent ORR, %
DoR, Mos
4.0 3.6
Bevacizumab-awwb (n = 324) 39 5.8
Bevacizumab (n = 314) 41.5 5.6 AE SAE Fatal AE
Grade ≥ 3

FDA Advisory Committee document. ABP 215 – Bevacizumab biosimilar candidate. Slide credit: clinicaloptions.com
 Bevacizumab-awwb: Indications
 Metastatic colorectal cancer
– First- or second-line treatment combined with IV 5-FU-based chemotherapy
– Second-line treatment with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy after
progression with first-line bevacizumab regimen
– Not indicated for the adjuvant treatment of surgically resected colorectal cancer

 Non-squamous NSCLC
– First-line treatment of unresectable, locally advanced, recurrent, or metastatic NSCLC in combination with
carboplatin/paclitaxel
 Glioblastoma
– Second-line treatment in progressive disease following prior therapy, based on improvement in ORR

 Metastatic renal cell carcinoma

– In combination with interferon alfa

 Cervical cancer
– In patients with recurrent, persistent, or metastatic disease, in combination with paclitaxel/cisplatin or paclitaxel/topotecan
FDA. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm576112.htm.
Trastuzumab in Breast Cancer
Trastuzumab Biosimilars: Considerations

 Do the data support equal efficacy in HER2+ breast cancer?

 Do the data support equal efficacy in the neoadjuvant setting?
 Do the data support equal efficacy in the neoadjuvant setting
when combined with pertuzumab?
 Do the data support equal efficacy in the adjuvant setting?

Slide credit: clinicaloptions.com

 Phase III HERITAGE: Responses w/Trastuzumab
vs Trastuzumab-dkst in HER2+ MBC
Trastuzumab-dkst + Trastuzumab
Response taxane, n (%) + taxane, n (%) Difference, % Rate Ratio
(n = 230) (n = 228)
Response type
 Complete 3 (1.3) 0
 Partial 157 (68.3) 146 (64.0)
 Stable disease 48 (20.9) 49 (21.5)
 Progressive disease 9 (3.9) 20 (8.8)
 Not evaluable 13 (5.7) 13 (5.7)

ORR 160 (69.6) 146 (64.0) 5.53 1.09

 90% CI 64.57-74.56 58.81-69.26 -1.70 to 12.69 0.974-1.211
 95% CI 63.62-75.51 57.81-70.26 -3.08 to 14.04 0.954-1.237
Equivalence demonstrated clinically and statistically!
Rugo HS, et al. JAMA. 2017;317:37-47. Slide credit: clinicaloptions.com
 Trastuzumab vs Trastuzumab-dkst in HER2+
MBC: Secondary Outcomes, Safety
Trastuzumab-dkst + Trastuzumab + taxane, Stratified HR
Outcome
taxane, n (%) (n = 230) n (%) (n = 228) (95% CI)
Time to tumor progression
 Events, n (%) 95 (41.3) 98 (43.0) 0.92 (0.69-1.23)
 Median TTP, mo (95% CI) 11.1 (8.83-11.20) 11.1 (8.88-11.20)
Progression-free survival
 Events, n (%) 102 (44.3) 102 (44.7) 0.95 (0.71-1.25)
 Median PFS, mo (95% CI) 11.1 (8.88-11.20) 11.1 (8.60-11.20)
Overall survival
 Events, n (%) 25 (10.9) 34 (14.9) 0.61 (0.36-1.04)
 Median OS, mo (95% CI) Not estimable Not estimable
TEAEs, % 96.8 94.7
 SAEs 38.1 36.9
 Antidrug antibodies* 5.9 8.9
*No neutralizing antibodies
Rugo HS, et al. JAMA. 2017;317:37-47. Slide credit: clinicaloptions.com
 Selected Therapeutic Oncology Biosimilars in
the Pipeline
Reference Drug Patent
Indication Biosimilars with Phase III Clinical Trials
Biologic Class Exp.
CD20  PF-05280586, ABP 798, BCD-020, CT-P10, RTXM83,
Rituximab[1,3,4] 2016 Lymphoma
inhibitor others registered/ongoing
CRC, head
EGFR
Cetuximab [4]
2016 and neck  ABP 494 in preclinical study
inhibitor
cancer
VEGF CRC, lung,  PF-06439535, BCD-021, BI 695502, others
Bevacizumab[1,3,4] 2019
inhibitor renal cancer registered/ongoing
HER2 Breast  PF-05280014, ABP 980, CT-P6, SB3, others
Trastuzumab[1,3,4] 2019
inhibitor cancer registered/ongoing

1. Stevenson JG, et al. Ann Pharmacother. 2017;51:590-602.2. Butteri E, et al. Eur J Cancer. 2018;89:49-55.
3. Rugo HS, et al. Cancer Treat Rev. 2016;46:73-79. 4. Panesar K. US Pharm. 2016;41:26-29. Slide credit: clinicaloptions.com
 Selected Trastuzumab Biosimilars in 1:1
Randomized Phase III Trials
Agent Study Design Endpoints Results Researcher
Conclusions
ABP 980 ABP 980 vs OriT (both + paclitaxel q3w x 4 1st: RD, RR of pCR in ABP 980 vs ABP 980 and OriT
(LILAC)[1] cycles neoadjuvant, then w/out paclitaxel pCR in breast OriT: 48.0% vs 40.5%; clinically equivalent
q3w to 1 yr adjuvant) on pCR in patients with tissue + axillary RD: 7.3%; RR: 1.19%. in neoadjuvant
HER2+ EBC (N=725; n = 696 in pCR lymph nodes. 2nd: Grade ≥3 TEAEs: setting for these
evaluable pop.). safety 14.8% vs 14.1%. patients.
PF-05280014 PF-05280014 vs T-EU (8 mg/kg→6 mg/kg 1st: steady state Ctrough >20 µg/mL in PF- PF-05280014
(REFLECTIONS q3w x 6 cycles w/docetaxel + carboplatin) in drug concentration 05280014 vs T-EU: showed similarity to
B327-04)[2] patients with HER2+ EBC (N=226), stratified Ctrough >20 µg/mL 92.1% vs 93.3%. pCR, T-EU in safety and
by hormone receptor status, primary tumor at Cycle 5; 2nd: 47% vs 50%; ORR, immunogenicity, and
size. ORR, pCR 88.1% vs 82.0%. noninferiority in PK
PF-05280014 First-line PF-05280014 vs T-EU (first dose 4  1st: ORR. 2nd: PF-05280014 vs T-EU: PF-05280014 similar
(REFLECTIONS mg/kg; then 2 mg/kg weekly until at least safety, tumor ORR = 0.940; Safety, to T-EU for efficacy,
B327-02)[3] week 33 (both + paclitaxel) in patients with control, PK, PK, immunogenicity immunogenicity,
HER2+ MBC (N=707). immunogenicity equivalent. safety, and PK.
SB3[4] SB3 vs OriT (8→6 mg/kg q3w x 8 cycles) + 1st: pCR in breast bpCR in SB3 vs OriT: SB3 comparable to
DOC and FEC (4 cycles) neoadjuvant in pts tumor. 2nd: safety, 51.7% vs 42.0%.PK, OriT for safety, PK,
w/HER2+ EBC or LABC, LVEF ≥ 55% (N = immunogenicity, safety, immunogenicity immunogenicity, and
875)*, then 10 cycles adjuvant SB3 vs OriT. EFS, OS equivalent. efficacy.

*Stratified by hormone receptor status, disease stage.

1. Von Minkwitz G, et al. ESMO 2017. Abstract 151PD. 2. Lammers P, et al. ESMO 2017. Abstract 154PD. Slide credit: clinicaloptions.com
3. Pegram M, et al. ESMO 2017. Abstract 238PD. 4. Pivot X, et al. J Clin Oncol. 2018;Jan 26:[E-pub ahead of print].
Remaining Questions

 Extrapolation  Long-term outcomes

– From one setting to another – Cardiac effects
– From one drug to another – DFS and OS
 Immunogenicity  Effect on cost
– Neutralizing antibodies – To practice
– To patient

Slide credit: clinicaloptions.com

 FDA Commissioner's Position on Biosimilars
“Bringing new biosimilars to patients, especially for diseases where
the cost of existing treatments can be high, is an important way to
help spur competition that can lower health-care costs and increase
access to important therapies.”
“We’ll continue to work hard to ensure that biosimilar medications are
brought to the market quickly, through a process that makes certain
that these new medicines meet the FDA’s rigorous gold standard for
safety and effectiveness.”
-- FDA Commissioner Scott Gottlieb, MD

FDA News Release; September 14, 2017.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm576112.htm Slide credit: clinicaloptions.com
 Go Online for More NCCN and CCO
Coverage of Oncology Biosimilars!

CME-certified Webcast and downloadable slidesets from this symposium

Additional archived Webcasts, slidesets, and white papers
addressing the development, regulatory approval, and
integration of oncology biosimilars in clinical practice

https://education.nccn.org
clinicaloptions.com/oncology