From eligibility to CDx: developing and implementing .../media/q2labs/library/presentation… ·...
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Copyright ©2016 Q2 Solutions. All rights reserved.
From eligibility to CDx: developing and implementing
effective biomarker strategies for Immuno-oncology trials
Patrice Hugo, Ph.D., Chief Scientific Officer
Patrick Hurban, Ph.D., Senior Director and Global Head, Genomic Development/Esoteric Assays
Biomarker and Diagnostics World Congress May 18, 2016
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• Over 45 immuno-oncology drugs approved (US)*
• 57 immuno-oncology drugs in development*
• Over 250 studies registered/ongoing*
• Increasing number of relevant publications annually**
The Opportunity for Immuno-Oncology (IO): The Future of Cancer Treatment
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**PubMed; keywords ‘cancer immunotherapy’
*UBS Immuno-oncology Monthly Handbook (Jan 2015)
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Examples of Immuno-oncology therapies
• Immunomodulatory cytokines/receptors (ex: OX40,
CSF-1R)
• Bi-specific T cell engagers –BiTEs-
• Chimeric antigen receptors (CARs)
• Checkpoint inhibitors (ex: CTLA4, PD-1/PD-L1)
• Anti-cancer vaccines
• Adoptive cell transfer
• Immunosuppressive metabolism inhibitors (ex: IDO)
Novel Immunotherapies: Oncology’s “Breakthrough” Drugs From hypothesis to realization and refinement
www.researchcancerimmunotherapy.com
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Classification of Immuno-Oncology Therapies Immunomodulatory mAbs as Checkpoint Inhibitors: A Revolution
Source: Galluzi et al., Oncotarget, 5: www.impactjournals.com/oncotarget/
Checkpoint inhibitor posterchild:
Anti-PD-1/PD-L1 antibodies
Brahmer et al, N Engl J Med 2015; 373:123-135
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Expansion of PD-1/PL-L1 drugs into multiple indications and combinations adds complexity and opportunity
Mono therapy Combination
Phase I
Phase II
Phase III
BMS-936559
MEDI4736 (I/II)
Nivolumab + iliolumbar
Advanced Solid Tumors
MPDL3280A + vemurafenib (Phase Ib)
MEDI4736 + dabrafenib + trametinib or trametinib alone (I/II)
Nivolumab ± ipilimumab
Nivolumab + ipilimumab
Nivolumab + ipilimumab
Nivolumab sequentially with ipilimumab Nivolumab
Nivolumab + multiple class 1 peptides & montanide ISA 51 VG
Nivolumab
Pembrolizumab
Pembrolizumab
Melanoma
MPDL3280A + erlotinib (Phase Ib) MPDL3280A
MPDL3280A
MEDI4736 + tremelimumab (I/II)
Nivolumab ± gemcitabine/cisplatin, pemetrexed/cisplatin, carboplatin/paclitaxel, bevacizumab, erlotinib, ipilimumab Nivolumab
Pembrolizumab
Pembrolizumab (II/III) NSCLC
MPDL3280A ± bevacizumab vs sunitinib
Nivolumab + sunitinib, pazopanib, or ipilimumab
Nivolumab
Nivolumab
Pembrolizumab + pazopanib
Pidilizumab ± dendritic cell/RCC fusion cell vaccine
Renal Cell Carcinoma MPDL3280A
Solid or Hematological Malignancies
Pembrolizumab
Colon Cancer
Pembrolizumab
Nivolumab ± ipilimumab (I/II)
Gastric, SCLC, TNBC, HNC, Urothelial
Nivolumab ± ipilimumab
Glioblastoma
Nivolumab
Hepatocellular
Pembrolizumab Hodgkin Lymphoma,
Myeloma, MDS, NHL
Pidilizumab (I/II) Malignant Gliomas
Pembrolizumab Melanoma, NSCLC
Pidilizumab + gemcitabine
Pancreatic
Pidilizumab + sipuleucel-T + cyclophosphamide
Prostate Cancer
MPDL3280A + bevacizumab and/or chemotherapy
MPDL3280A + cobimetinib
MEDI4736 + tremelimumab MEDI4736
MSB0010718C
Anti-LAG3 (BMS-986016) ± nivolumab
Nivolumab
Nivolumab + interleukin-21
AMP-554
Solid Tumors
Pembrolizumab (NSCLC)
Nivolumab ± ipilimumab (I/II)
AMP-514 + MEDI4736
MPDL3280A + radiation therapy MPDL3280A + carboplatin + paclitaxel / nab-paclitaxel
Pembrolizumab
Pembrolizumab
MPDL3280A
Pembrolizumab (I/II)
Pembrolizumab (I/II)
Pembrolizumab (I/II)2
Pembrolizumab + dabrafenib (I/II) + trametinib
Pembrolizumab + cisplatin + 5-FU3
Tremelimumab and / or MEDI4736 + radiation
MPDL3280A ± lenalidomide
MPDL3280A ± bevacizumab vs sunitinib
MPDL3280A + bevacizumab
MPDL3280A + RO6895882
MPDL3280A + carboplatin + nab-paclitaxel
MPDL3280A + RO5509554
MPDL3280A + RO7009789
MPDL3280A + obinutuzumab4
MPDL3280A + Interferon alfa-2b / ipilimumab
MPDL3280A
Avelumab
Skin Cancer
Avelumab
MPDL3280A + INCB024360
MPDL3280A + carboplatin + paclitaxel ± bevacizumab
Biomarker driven therapy
May 2015
Source: Quintiles Internal Analysis, Clinicaltrials.gov, BioPharm Clinical & ADIS Database,
Dolan, 2014, Cancer Control. 2014:231-237
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Novel Immuno-Oncology Drugs in the Pipeline
Source: Nature Biotech. 33:7 Page 673-67, 52015
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Current Challenges Turning a fatal disease into a chronic treatable disorder
Over 800 cancer drugs in clinical trials -
almost all are targeted at particular gene
products
Some Fundamental Problems in Cancer
Treatment
• Cancer is rarely detected early
• Cancer develops resistance rapidly to
targeted therapies and chemotherapies
due to the development/expansion of
resistance mutations
• Many patients do not respond to
immunotherapies. Immunotherapies are
changing the approach to treating cancer
by treating the immune system rather than
the cancer but not all patients respond
Source: Sharma, Allison: Cell, April 2015
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Immuno-oncology: A Comprehensive Biomarker Approach is Needed
Tumor – Immune Biology
• Target protein expression
• Serum soluble proteins
• Circulating tumor cells
• Circulating free DNA
• Tumor gene expression
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Immuno-oncology Research Requires Diverse Resources An integrated scientific approach can help drive a successful I-O clinical study
Flow Cytometry
Immunoassay
IHC
Genomics
Anatomic
Pathology
Target
Occupancy
Cytokine
Panels
ISH
Immune
Repertoire
Tumor
Antigens
Effector
Function
Immuno-
phenotyping
Immuno-
monitoring
Tumor
Lysates,
Cell Sorting
Digital
Pathology
Gene
Expression
Profile
Multiple Technologies and Methods Integrated Scientific Teams
Immunologists
Geneticists
Technical Experts
Pathologists
Clinical Scientists
Bioinformaticists
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The Overlooked Fundamentals: Sample Quality Methods and best practices to maximize integrity of clinical specimens
Pre-Analytics
Standardized collection
methods
Established guidelines (fixatives, fixation time,
etc.), collection device, biopsies versus blood,
etc.
Proper shipping/handling Logistics infrastructure, insulated shippers
Stabilization/Preservation PAXgene tubes, cfDNA tubes, ethanol fixation
Sample Processing
Cell Enrichment Cell purification, PBMC isolation, CTC isolation,
FFPET macrodissection
Ex vivo assays Cell stimulation, drug treatment, co-culture
Sample QC Pathology review (% tumor), tissue quantity,
viability assessment
Nucleic Acid Preparation
FFPET-specific protocols (e.g.
degraded material)
FFPET extraction and purification methods,
optimized target capture protocols, increased
depth of coverage, specialized bioinformatics
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Routinely collected clinical samples
Data can be mined for immune-oncology characterization
Anatomic Pathology and Immuno-Oncology Predicting and assessing a patient’s response to checkpoint inhibitors
Samples Central AP testing Potential Application How these characterizations can be used in drug studies
Tissue
PD-L1 or related immuno-
modulatory proteins
Tumor-infiltrating
lymphocytes (TILs)
Image Analysis for
multiplex IHC assays
CDx Registrational trial
Predictive Biomarkers for
Optimized Patient Selection
Predictive Biomarkers for
Optimized Patient Selection
CDx Registrational Trial
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• PD-1/PD-L1 expression by
Immunohistochemistry (IHC) in multiple
indications
• Numerous assays and scoring methodologies
• Expression on tumor cells vs. non-malignant cells
• Cutoffs
• Standardization of assay and scoring will be key
• Companion diagnostic (CDx) assay for PD-1
/PD-L1 inhibitors
• Central lab acts as investigative sites (PI and
regulatory support)
• Tumor-infiltrating lymphocytes: Assay
development for CD8, FoxP3 IHC
Anatomic Pathology and Immuno-Oncology Clinical Trials Ongoing biomarker assessments across all phases of development
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Situation: Pharma requires pathologist expertise and central testing for
large CDx program
Solution:
– Pathologist familiar with drug MOA engaged to score and refine protocols for multiple
indications in collaboration with Rx pathologist and support from Dx
– Global laboratories trained with expanded pathologist team led by lead pathologist
Result: Global assay deployment, cost and time-savings for pharma, central lab
pathologist support for regulatory discussions
Case Study: Pathologist Expertise for IHC CDx Development of scoring methodology for Rx-sponsored study using Dx-provided assay
Protein
Biomarker
Scoring
Development
Lab
Pharma
Global
Deployment
Dx
Pharma
Dx
Ongoing CDx
Support
Lab
Pharma
Dx
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Routinely collected clinical samples
Data can be mined for immune-oncology characterization
Flow Cytometry in Immuno-Oncology New opportunities for immune characterization
Samples Central Flow Analysis Potential Application How these characterizations can be used in drug studies
Blood
Immune Status
• T, B, NK, Monocyte, DC
Cell Subset Activation
Profile
Receptor Occupancy
ExVivo Predictive Assay
Retrospective Data Analysis
Correlation of Activation Profile
to Response
Predictive Biomarkers for
Optimized Patient Selection
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Cancer Immunotherapy Monitoring Flow Cytometry Assays
• Antigen Specific T Cells (Dimers,
Tetramers, Pentamers)
• B Cell Bcl-2 Family Assay
• Bispecific Antibody Assays
• CAR T Cell Assays
• Cell Culture/Predictive Bioassays
• Cytotoxic T Cells (Functional Assays)
• Dendritic Cell Assays (pDC, m1DC, m2DC)
• Leukemia/Lymphoma Assays (EuroFlow)
• Magnetic Bead Separation (RNA, DNA)
• Minimal Residual Disease Assay (CLL, ML,
MM, AML, ALL, NHL)
•
• Myeloid/Fibrocyte Derived Suppressor
Cell Assays
• Phosphorylated Protein Assays (pSMAD,
pCCR5, Whole Blood & PBMC)
• Receptor Occupancy Assays
• T Cell Homing/Activation (ICOS, CD38,
HLA-DR, CD28, CD25, CD69, CD71, CD134)
• T Cell Checkpoint/Exhaustion Assays
(CTLA-4, PD-1, PD-L1, TIM3)
• TIL Assays(Tumor Infiltrating T Cells)
• T Regulatory Cell Assays (surface, FoxP3,
activated)
•
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Q2 Solutions Flow Panels Identify Dose Dependent PD Effect of Checkpoint Inhibitor Combination Therapy MEDI4736 (anti-PD-L1) & Tremelimumab (anti-CTLA-4)
Activation & Memory T Cell Panel
Combined data from flow panels running in US, Europe and Asia
Proliferating T Cell Panel
Source: Safety and antitumour activity of durvalumab plus Tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study
Scott Antonia, Sarah B Goldberg, Ani Balmanoukian, Jamie E Chaft, Rachel E Sanborn, Ashok Gupta, Rajesh Narwal, Keith Steele, Yu Gu,
Joyson J Karakunnel, Naiyer A Rizvi
Lancet Oncology 2016. Published February 5, 2016
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Beyond IHC and flow cytometry:
Incorporation of genomics due to limitations of other methodologies
(e.g. subjectivity, quantitative ability, low capacity for multiplex, sensitivity, etc.)
Immuno-Oncology is Genomics Solutions Oriented Molecular methods provide an advantage for complex biomarker analysis
Mutational Load
Gene Expression Signature
Immune Repertoire
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Routinely collected clinical samples
Data can be mined for molecular immune-oncology characterization
Genomics in Immuno-Oncology Innovation New opportunities for molecular characterization
Samples Analysis Potential Application How these characterizations can be used in drug studies
Saliva
Blood
Biopsy
Slides
Self-recognition HLA and KIR genotyping
Immune activation B and T-cell repertoire,
Immune gene signature
Tumor
characterization DNA and RNA
Cancer Vaccines and Tumor-
Specific Immune Responses
Optimized Patient Selection
Refinement of Immuno-
modulatory Therapies
Exploitation of Innate and
Adaptive Immune Response to
Tumors
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Novel Antigen Determination Can Kick-Start Immunity
Source: Van Allen et. al. (2015) Science 350(6257):207
• In most cases, somatic mutation calling
from Exomes provides early evidence of
malformed antigens
• Coupling with RNA-Seq is essential to
confer expression of that variant allele
• Clinical group groups by mutation burden
within antigens
• Creating custom antibodies to restore
recognition has increased survivability
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Immune Repertoire
• TCR (/, /) and BCR
receptor sequencing to
assess clonal diversity*
• IgVH mutation analysis
(RNA-based)
• Whole-exome deep sequencing to quantify mutational burden
• Identification of ‘neo-antigens’
– Coupled with RNAseq to confirm tumor antigen expression
• BFX and predictive algorithms to generate ‘immunogenicity score’
• DNA damage and mismatch repair:
– MSI instability (PCR and IHC)
– BRCA1 mutation analysis
Genomics Capabilities for Immuno-Oncology Analyzing the tumor: immune system interface
*In development; planned for 2016
HLA and KIR Genotyping
• HLA allele calling from:
–Microarray
–RNAseq
–Targeted DNA sequencing
• KIR genotyping and expression (from PAXgene) using commercial kit (Miltenyi)
http://www.innovations-report.com
Source: Draper et al, Clinical Cancer Research.
October 1, 2015
Mutation Analysis HLA and KIR
Genotyping Immune Repertoire
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Checkpoint Inhibitor
Expression
Mutational Load
Gene Expression Signature
Immune Repertoire
Immuno-oncology is Genomics Solutions Oriented Molecular methods provide an advantage for complex biomarker analysis
Assessment Genomics Application
Somatic Mutation Analysis Identify Neo-Antigens
Tumor Exome Sequencing, Breakpoint analysis and Fusion Detection
Gene Expression Profiling Confirm Neo-Antigen Expression, Identify Immune Activation
Pan-Cancer Immune Panel, RNA-Seq, Arrays
Germ Line Variant Analysis Confirm Somatic Mutations and Heritable Lesions
CNV, Structural and Small Variant Detection
HLA Characterization Identify Mutations in HLA
HLA Analysis (DNA, RNA, Arrays)
Antigen-Specific Immune Response Characterize Immune Activation
B/T Cell Repertoire (DNA/RNA), VDJ mutation (DNA/RNA)
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Potential Roadmap for Immuno-Oncology Biomarker Strategy Multiple parallel and synergistic pathways maximizing immediate lab opportunities
as well as long term clinical differentiation
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Reagent kit production capabilities
& GMP consulting
Companion Diagnostic Development Partner of Choice Extensive expertise to accelerate your tandem development pathway
Clinical Development Preclinical FDA Filing Launch Rx
IVD Feasibility Development IVD Registration Commercialization
& Modification Lab Validation
Clinical
Validation
Marker selection & study design
Deep experience in 3-4 way CDx development relationships
Strategic consulting including regulatory & reimbursement
Global clinical trial wraparound services including Central Lab
Commercial, diagnostic &
market analytics capabilities
Assay development, validation &
scale up
Registration & market access
expertise (510(k); PMA; CE Mark)
Pre-launch medical communications & proficiency training
Q2 Solutions helped develop
≈60% of all FDA approved
oncology
pharmacogenomics drugs as of April 2015
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Thanks
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