1. THERE ARE SO MANY
PROMISING AGENTS COMING
TO TREAT COLORECTAL
CANCER
Johanna Bendell, MD
Director, GI Oncology Trials
Sarah Cannon Research Institute
Nashville, TN

2. What is on the horizon?
• Biomarkers and molecular profiling to
guide treatment selection
• “Targeted therapies”
• Combination therapies
• Immunotherapy
• New ways of delivering chemotherapy
and targeted therapies

3. Why targeted therapy?
• Going after what makes the
cancer a cancer
• Our drug development is
catching up with the lab
• Identification of certain pathways
that are key in cancer
development and survival
• We are still learning
– One set of targets does not
fit all
– All of the pathways talk to
each other
– Side effect profiles are
different, but can be just as
toxic to the patient
– Chronic cancer treatment?

4. [TITLE]

5. Toward Personalized Care: Molecular
Profiling
Stricker et al. Semin Oncol. 2011

6. What biomarkers are we
already using in colorectal
cancers?
• Biomarkers can be prognostic or predictive
• Microsatellite instability (MSI)
• K-ras
• B-raf
• Rash
• And more to come…
• New drugs that are in early development
are looking at companion diagnostics and
specifying biomarker status early on

7. EGFR Pathway Signaling in CRC
P P Ras KRAS mutation (40%–50%)
EGFR Sos
P P Grb2 Mutually exclusive
Raf
BRAF mutation (10%)
MEK
ERK
Proliferation Metastasis
Survival Angiogenesis
MAPK: mitogen-activated protein kinase

8. KRAS as a Biomarker for Panitumumab
Response in Metastatic CRC
Patients With Wild-Type KRAS Patients With Mutant KRAS
1.0 Pmab + BSC
Median Mean 1.0
Proportion With PFS
BSC alone Events/N (%) Pmab + BSC
0.9 in Wks in Wks Mean
0.9 BSC alone Median
Proportion With PFS
0.8 12.3 19.0 Events/N (%) in Wks in Wks
115/124 (93) 0.8
0.7 114/119 (96) 7.3 9.3 9.9
0.7 76/84 (90) 7.4
0.6 95/100 (95) 7.3 10.2
HR: 0.45 (95% CI: 0.34–0.59) 0.6
0.5 Stratified log rank test: P < .0001 0.5
HR: 0.99 (95% CI: 0.73–1.36)
0.4 0.4
0.3 0.3
0.2 0.2
0.1 0.1
0 0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 3436 38 4042 44 46 48 50 52 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 3436 38 4042 44 46 48 50 52
Weeks Weeks
Amado et al., JCO 2008.

9. Amphiregulin/Epiregulin
• EGFR ligands:
– 1 in C. Elegans
– 4 in Drosophila
– 7 in mammals: EGF, TGF-α, HB-
EGF, amphiregulin
(AREG), betacellulin, epiregulin
(EREG) and epigen1
– EREG and AREG bind more
weakly to EGFR than EGF
but much more potently
and prolonged
– EREG preferentially activates
heterodimers2
• High gene expression levels of
EREG and AREG predict response to
cetuximab3
– High levels define tumors that are
EGFR-dependent?
1. Singh AB, et al. Cell Signal. 2005;17(10):1183-1193.
2. Shelly M, et al. J Biol Chem. 1998;273(17):10496-10505.
3. Khambata-Ford S, et al. J Clin Oncol. 2007;25(22):3230-3237,

10. EREG as a Predictive Marker for Cetuximab
Efficacy
• Combimarker: KRAS wildtype and high EREG
– The right predictive test
– High EREG predicts cetuximab benefit for OS
High EREG by minimum-P threshold Low EREG by minimum-P threshold
100
100
Cetuximab + BSC Cetuximab + BSC
80 80
Proportion Alive
Proportion Alive
60 60
40 40
BSC alone BSC alone
20 20
HR 0.46 [0.32-0.65], P<.0001 HR 0.93 [0.51-1.71], P = .81
0 0
0 2 4 6 8 10 12 14 0 2 4 6 8 10
84 80 76 66 43 28 18 8 30 25 16 13 8 5
85 73 54 26 19 14 10 5 26 18 15 10 5 3
Time From Randomization, months Time From Randomization, months
Jonker D, et al. J Clin Oncol. 2009;27(15S): Abstract 4016.

11. Combimarker: KRAS Wildtype
PLUS EREG High
–All comers n = 394 (100%) HR: 0.7
–KRAS wildtype n = 230 (58%) HR: 0.55
–Combimarker n = 169 (44%) HR: 0.46
Could use of the combimarker effectively “stack the
deck” to choose patients who would benefit from
cetuximab use in earlier lines of therapy?
Jonker D, et al. J Clin Oncol. 2009;27(15S): Abstract 4016.

12. BRAF Mutations in CRC
• BRAF is primary effector of EGF
KRAS signaling
Tumor Cell
• BRAF mutations:
– Occur most frequently in
exon 15 (V600E) P P Ras
– Found in 4% to 14% of
patients with CRC P P
Raf
– Mutually exclusive with
KRAS mutations MEK
Tumor cell
proliferation Erk
and survival
Yarden Y, et al. Nat Rev Mol Cell Biol. 2001; 2(2):127-137. Di Nicolantonio F, et al. J Clin Oncol. 2008; 26(35):5705-5712.
Artale S, et al. J Clin Oncol. 2008;26(25):4217-4219..

13. CRYSTAL plus OPUS: Pooled analysis of OS in
patients with
KRAS wt/BRAF mt tumors
1.0 KRAS wt/BRAF wt
HR [95% CI]: 0.840 [0.710–0.993]
0.9 p=0.041
FOLFIRI / FOLFOX4 + cetuximab: (n=349) median 24.8 months
0.8 FOLFIRI / FOLFOX4: (n=381) median 21.1 months
Probability of overall survival
KRAS wt/BRAF mt
0.7 HR [95% CI]: 0.633 [0.378–1.060]
p=0.079
0.6 FOLFIRI / FOLFOX4 + cetuximab: (n=32) median 14.1 months
FOLFIRI / FOLFOX4: (n=38) median 9.9 months
0.5
0.4
0.3
0.2
0.1
0.0
0 6 12 18 24 30 36 42 48 54 60
Number of patients Time (months)
CT + cetuximab 349 317 268 225 163 120 80 63 19 4 0
CT 381 350 283 212 149 107 63 46 17 2 0
CT + cetuximab
CT
32 25 16 12 8 5 2 2 2 0 0
38 24 14 6 6 3 3 1 0 0 0
Van Cutsem E, et al. N Engl J Med 2009;360:1408-17; Bokemeyer C, et al. J Clin Oncol 2009;27:663-71 HR, hazard ratio

14. Vemurafenib in V600E+ mCRC
100
75
1 PR and 4 MRs (≥10% shrinkage)
%Change From Baseline
50
(Sum of Lesion Size)
25
0
-25
(RECIST cutoff for PR, 30%)
-50
-75
-100
n=19 Evaluable Patients Interim - 12/31/09

15. Rationale for Combination
BRAF/MEK
RAS
BRAF RR ~60 %
GSK2118436
Key toxicity: SCC
MEK GSK1120212
RR ~40 %
Key toxicity: rash
1. Synergy in combination
2. Overcome/prevent potential BRAF resistance via activation
of MAPK pathway
pERK 3. Potentially decrease incidence of BRAFi-induced
hyperproliferative skin lesions
Proliferation, survival, Invasion, metastasis
Infante ASCO 2011

16. BRAF plus MEK inhibitors
Corcoran ASCO 2012

17. EGFRi+BRAFi has in vivo activity on
BRAFV600E mutant CRC xenografts
Corcoran RB et al, Cancer Discov 2012;2:227-35
Prahallad A et al, Nature 2012;483:100-3

18. Met Pathway and Targeted
Agents
Appleman (2011) JCO ePub 18

19. Activity of Tivantinib (ARQ197) +
cetuximab/irinotecan
Median # prior
therapies: 2 (range
1-4)
19
Eng et al. ASCOGI 2011

20. GI155 - ACCOMPLISH Schema &
Regimen
Schema Regimen
Drug Induction Regimen Maintenance Regimen
MetMAb (or
10 mg/kg IV Day 1 10 mg/kg IV Day 1
placebo)
Bevacizumab 5 mg/kg IV Day 1 5 mg/kg IV Day 1
Oxaliplatin 85 mg/m2 IV Day 1 Discontinued
Leucovorin 400 mg/m2 IV Day 1 400 mg/m2 IV Day 1
400 mg/m2 IV bolus 400 mg/m2 IV bolus then
5-FU then 2400 mg/m2 over 2400 mg/m2 over 46 hours
46 hours starting Day 1 starting Day 1
a Objective response or stable SD after 4 cycles – mFOLFOX-6 continued
for a further 4 cycles;
b Patients with measurable disease in lesions between cycles 4 and 8
may elect to continue treatment for a maximum of 12 cycles prior to
commencing maintenance treatment if in the best interests of the
patient and after consultation with the Study Chair;
c Objective response or SD at cycle 8 – commence maintenance
treatment.

21. Immune-Modulating Therapies
• Immune system contains receptor-ligand pairs that
inhibit or stimulate immune response
• Balance necessary to fight infections but not
develop autoimmunity
Infection-fighting Autoimmunity

22. PD-1 and PD-1-Like Inhibitors
Tumor cell T cell
B7H1/B7DC PD1
3.
4. 2.
B7-CD28 family
B7-1/B7-2 CTLA-4
1.
B7H3 ?
5.
TNFR/ligand family
CD27L CD27
6.
1. FDA-approved Ipilimumab
2. Monoclonal antibody that targets PD1 (receptor)
3. Recombinant fusion protein of B7DC (PD-L2 ligand), targets PD1
4. Monoclonal antibody that targets B7H1 (PD-L1 ligand)
5. Monoclonal antibody that targets B7H3 ligand
6. Agonist anti-CD27 monoclonal antibody

23. Immunotherapy: PD-1 Inhibitor
Suppressive/dysfunctional T cells are
Tumor present in tumors
CD8+PD-1+ PD-1 inhibitor
CD8+PD-1-
1. Functional anti-tumor response with
CD8+PD-1- T cells infiltrate and kill tumor
cells.
2. T cell memory is established
What about combinations? Bevacizumab?

24. Genomic Landscape of CRC… 2006
PIK3CA FBXW7
TP53
Facts:
11 colorectal tumors
First Generation Sequencing
KRAS 13,023 genes
APC 21 Mb target sequence
135,483 primer pairs
~90 mutated genes/tumor
11 recurrent mutations/tumor
The List of Candidate Genes: Total 142
Usual suspects APC, KRAS, PIK3CA, PTEN, SMAD4, TGFBR2, TP53…
Wood L et al, Science (2007); Sjoblom T et al, Science (2006)

25. Genomic Landscape of CRC… 2012
16% 84%
Facts:
224 T/N pairs
Next-Generation Sequencing – Whole Exome Seq >20X
coverage
32 somatic recurrent mutations per tumor
Cancer Genome Atlas Network, Nature (2012)

26. Molecular Classification of CRC… 2012
Right-sided, MSI-H, Hypermethylated, BRAF mut, Chromosomal stability
Left-sided, Rectal, MSS, KRAS mut, CIN +ve
Cancer Genome Atlas Network, Nature (2012)

27. CRC subtypes – dMMR/EMT… 2013
A-type B-type C-type
22% 62% 17%
BRAFmt 39% BRAFmt 2% BRAFmt 13%
MSI 49% MSS 87% MSI 13%
dMMR 68% dMMR 1% dMMR 36%
Adj Rx + Adj Rx + Adj Rx -

28. Molecular Profiling and Matched Targeted Agents
in Colorectal Cancer Patients enrolled in Phase I
trials
BRAF inh
BRAF mut
mTOR inh + anti-IGFR1 mAb
PTEN low 3
5
anti-HGF mAb
pMET high 10
42 PI3K pathway inh
Second-generation 11 PIK3CA mut or PTEN low
anti-EGFR mAb
KRAS wt refractory to
cetuximab/panitumumab
11
Dienstmann et al. Mol Cancer Ther. 2012;11:2062-71.

29. There is so much more to
come…
• We are learning at an exponential rate
• We finally have drugs to hit the right
targets
• And the targets may change over time
• We are learning more about specific
colorectal tumors
– Are there people more at risk?
– Location of the tumor, etc
• Clinical trials are essential to ending this
disease