garret hampton | vp, oncology biomarker development pharmaceuticals...
TRANSCRIPT
Garret Hampton | VP, Oncology Biomarker Development
Pharmaceuticals Division
Roche Pharma Day 2015
Molecular Information
Personalized healthcare
A cornerstone of the Genentech / Roche strategy
2
Diagnostics Pharma
60% of pipeline programs are being
developed with companion diagnostics
4 out of
9 BTDs
enabled by a Dx
that identified
patients most
likely to benefit
Molecule
Actemra (Systemic sclerosis)
Venetoclax (R/R CLL 17p)
Atezolizumab (NSCLC)
ACE 910 (Hemophilia)
Esbriet (IPF)
Lucentis (DR)
Atezolizumab (Bladder)
Alectinib (ALK+ NSCLC)
Gazyva (1L CLL)
Significant advances in cancer biology
Multiple molecular subsets of disease
Unknown
MET splice site MET
Amplification
KRAS NRAS
ROS1 Fusions
KIF5B-RET
EGFR
ALK Fusions
HER2 BRAF
PIK3CA AKT1
MAP2K1
PD-L1
Expression
3
4
Molecular Information in oncology
Combination of molecular and patient data will enable change in R&D and clinical practice
✓ ︎ ✗ ✓ ︎ ✗
Smarter, more
efficient R&D
Better
patient care Patients
matched to
clinical trials
Treatment plan
selected
Molecular understanding of cancer Patient outcomes
Database &
Analytics interface
Multiple capabilities required
Comprehensive tumor analysis and longitudinal assessment
mRNA-
expression
Cell signatures,
targets
RNA
sequencing
DNA-mutation
& CNVs
Ex: EGFR, BRAF
DNA
sequencing
Protein-
expression
PDL1, other CI
targets
Multiplex
IHC
Comprehensive tumor analysis Continuous monitoring over time
Cell free tumor
DNA
Blood DNA
sequencing
Imaging
Ex: ImmunoPet
Imaging
Ex: EGFR, BRAF
5
FMI R&D collaboration
Our partnership with FMI is key to informing R&D by leveraging molecular information
6
Molecular Information
from FMI database and
GNE/Roche clinical trials
(FM1 & FM1 heme)
mRNA-
expression
Cell signatures,
targets
RNA
sequencing
DNA-mutation
& CNVs
Ex: EGFR, BRAF
DNA
sequencing
Protein-
expression
PDL1, other CI
targets
Multiplex
IHC
Comprehensive tumor analysis Continuous monitoring over time
Cell free tumor
DNA
Blood DNA
sequencing
Imaging
Ex: ImmunoPet
Imaging
Ex: EGFR, BRAF
1 3
Development of a
blood-based
molecular assays
2
Immunotherapy panel
development (DNA & RNA)
2 2
Clinical trial data
Roche database FMI clinical database
50,000+ patient data in FMI database
1
Roche / FMI database queries
Example: PIK3CA mutations in multiple cancers
7
Implementation of FMI panels in development
Focus on high-value clinical samples
Clinical trial data
Roche database FMI clinical database
Current prioritization*:
1. Trials with post-progression biopsy (with archival baseline samples)
2. Phase 3 trial** n>300
3. Phase 2 trial* n>100
4. Phase 1b combos
** Positive trial, evidence of activity or potential identification of subset / high value for
informing our pipeline (i.e., importance of disease setting / indication / treatment)
50,000+ patient data in FMI database
1
8
FMI R&D collaboration
Immunotherapy R&D collaboration
9
2
Immunotherapy panel
development (DNA & RNA)
mRNA-
expression
Cell signatures,
targets
RNA
sequencing
DNA-mutation
& CNVs
Ex: EGFR, BRAF
DNA
sequencing
Protein-
expression
PDL1, other CI
targets
Multiplex
IHC
Comprehensive tumor analysis Continuous monitoring over time
Cell free tumor
DNA
Blood DNA
sequencing
Imaging
Ex: ImmunoPet
Imaging
Ex: EGFR, BRAF
2
Checkpoint inhibitors
Most effective in “inflamed” tumors
Inflamed Non-inflamed
TILs
PD-L1 expression
CD8+ T cells
Genomic instability
Pre-existing immunity
2
10
PD-L1 IHC: Staining for TCs and ICs
Assay sensitivity critical in detecting both cell types
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Tumor cells
(TCs)
Tumor and immune cells
(TCs and ICs)
WCLC 2015
1IMvigor 210 ECC 2015, 2POPLAR ECC 2015
e.g. NSCLC e.g. bladder
Immune cells
(ICs)
2
Patient selection enriches for benefit
PD-L1 selected lung (TC & IC) and bladder cancer (IC)
Bladder cancer: Overall survival* Lung cancer: Survival hazard ratio*
* Monotherapy data
ECC 2015
Time (months)
100
80
60
40
20
0
5 6 7 8 9 10 11 1 2 3 4 0
– IC2/3
– IC0/1
+ Censored
12
Ove
rall
Su
rviv
al
Median OS 6.7 mo (95% CI, 5.7-8.0)
Median OS Not Reached (95% CI, 7.6-NE)
0.1 1
In favor of docetaxel
0.73
1.04
0.59
0.54
0.49
Hazard Ratio
In favor of atezolizumab
0.2 1 2
TC3 or IC3
TC2/3 or IC2/3
TC1/2/3 or IC1/2/3
TC0 and IC0
ITT N=287
2
12
Bladder cancer: Overall survival
Example: Atezolizumab phase 1 data
in urothelial bladder cancer patients
100
80
60
40
20
0
-20
-40
-60
-80
-100
0 21 42 63 84 105 126 147 168 189 210 231 252 273 294
Time on study (days)
Why do these patients progress?
Why do these patients respond? C
hange in s
um
of lo
ngest dia
mete
rs
(SLD
) fr
om
baselin
e (
%)
Time (months)
100
80
60
40
20
0
5 6 7 8 9 10 11 1 2 3 4 0
– IC2/3
– IC0/1
+ Censored
12
Ove
rall
Su
rviv
al
Median OS 6.7 mo (95% CI, 5.7-8.0)
Median OS Not Reached (95% CI, 7.6-NE)
Benefit is not the same for every patient
Some patients with high expression of PD-L1 do not benefit – why?
2
13
Many types of data will be needed to inform patient care including:
Biomarkers for cancer immunotherapy
Key platforms for discovery and development
mRNA-
expression
Cell signatures,
targets
RNA
sequencing
DNA-mutation
& CNVs
Ex: EGFR, BRAF
DNA
sequencing
Protein-
expression
PDL1, other CI
targets
IHC
Cell free tumor
DNA
Blood DNA
sequencing
Ex: EGFR, BRAF
Other Dx &
patient data
Ex: Imaging,
outcomes etc
EMRs
PDL-1 IHC and
multiplex IHC
Mutation burden
& neo-epitope
prediction
Immune cell
types and
signatures
1 2
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Gene expression & combination hypotheses
Understanding the biology of immune cells in tumors enables combination hypotheses
−2 −1.6 −0.67 0.22 1.1 1.6 2
2 1 0 -1 -2
cbind(1:nc)
Indication
Me
lan
om
a
SC
C
NS
CL
C
RC
C
Ade
no
NS
CL
C
Bla
dde
r
TN
BC
HE
R2
+B
C
CR
C
HR
+B
C
Th17 Signature
Treg Signature
Th2 Signature
Teff Signature
B cell Signature
IB Signature
IFNg Signature
NK cell Signature
APC Signature
Myeloid Signature
1
15
Gene expression & combination hypotheses
Understanding the biology of immune cells in tumors enables combination hypotheses
16
Myeloid signature (macrophages) associated with
lack of response to atezolizumab in bladder cancer
−2 −1.6 −0.67 0.22 1.1 1.6 2
2 1 0 -1 -2
cbind(1:nc)
Indication
Me
lan
om
a
SC
C
NS
CL
C
RC
C
Ade
no
NS
CL
C
Bla
dde
r
TN
BC
HE
R2
+B
C
CR
C
HR
+B
C
Th17 Signature
Treg Signature
Th2 Signature
Teff Signature
B cell Signature
IB Signature
IFNg Signature
NK cell Signature
APC Signature
Myeloid Signature
Anti-CSF-1R
Anti-PD-L1
Tumor associated macrophages
Hypothesis: Anti-CSF-1R removes macrophages
which may enable atezolizumab activity
Myeloid signature:
IL1B, IL8, CCL2
P=0.01
PD = Progressive disease
SD = Stable disease
CR/PR = Complete/partial response
1
T cell infiltration
Cancer T cell recognition
anti-CEA/CD3 TCB
anti-CD20/CD3 TCB
anti-HER2/CD3 TCB
ImmTAC* (Immunocore)
anti-VEGF (Avastin)
anti-Ang2/VEGF (vanucizumab)
Chen and Mellman. Immunity 2013; CI=cancer immunotherapy
T cell killing
anti-PDL1 (atezolizumab)
anti-CSF-1R (emactuzumab)
anti-OX40
IDOi
IDOi* (Incyte)
CPI-444* (Corvus)
anti-TIGIT
IDO1/TDOi* (Curadev)
EGFRi (Tarceva)
ALKi (Alectinib)
BRAFi (Zelboraf)
MEKi (Cotellic)
anti-CD20 (Gazyva)
anti-HER2 (Herceptin; Kadcyla; Perjeta)
various chemotherapies
lenalidomide
rociletinib* (Clovis)
Antigen presentation
T-Vec oncolytic viruses* (Amgen)
INFa
anti-CD40
CMB305 vaccine* (Immune Design)
Priming & activation
anti-CEA-IL2v FP
anti-OX40
anti-CD27* (Celldex)
entinostat* (Syndax)
Antigen release
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Unlocking full value of CI through combinations
Broadest industry portfolio in oncology
1
Clinical development Preclinical development
* Partnered or external
Established therapies
Schmid et al ECC 2015
Patients with a high tumor IFNg-associated gene signature derive OS
benefit from atezolizumab in NSCLC (POPLAR)
PD-L1 expression
IFN-g producing CD8+ T cells
Genomic instability
Pre-existing immunity INFLAMMED
Gene expression as a predictive biomarker
Presence of INFg-producing CD8 T-cells predicts benefit in NSCLC treated with atezolizumab
1
18
Many types of data will be needed to inform patient care including:
Biomarkers for cancer immunotherapy
Key platforms for discovery and development
mRNA-
expression
Cell signatures,
targets
RNA
sequencing
DNA-mutation
& CNVs
Ex: EGFR, BRAF
DNA
sequencing
Protein-
expression
PDL1, other CI
targets
IHC
Cell free tumor
DNA
Blood DNA
sequencing
Ex: EGFR, BRAF
Other Dx &
patient data
Ex: Imaging,
outcomes etc
EMRs
Mutation burden
& neo-epitope
prediction
Immune cell
types and
signatures
1 2
19
PFS
/ O
S
Time
High
Low
Mutation burden
# o
f m
uta
tio
ns
e.g. Lung tumors
Low
High
1
2
Tumor cell
1
Tumor cell
2
Mutation burden is clinically important
Tumors with higher numbers of mutation tend to be more sensitive to anti-PDL1 / anti-PD1
Hypothetical – partly based on: Rivzi et a l Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer,
Science, 2015; Snyder et al Genetic basis for clinical response to CTLA-4 blockade in melanoma, NEJM 2014
2
20
Conclusions
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Personalised
healthcare
Molecular
Information
Transformational
time
Diagnostics Pharma
R&D insights
✓ ︎ ✗