THERE ARE SO MANY PROMISING AGENTS COMING TO TREAT

COLORECTAL CANCER

Johanna Bendell, MDDirector, GI Oncology Trials

Sarah Cannon Research InstituteNashville, TN

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

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?

[TITLE]

Toward Personalized Care: Molecular Profiling

Stricker et al. Semin Oncol. 2011

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

EGFR Pathway Signaling in CRC

P

P

P

P

Grb2

SosRas

Raf

MEK

ERK

KRAS mutation (40%–50%)

BRAF mutation (10%)

Mutually exclusiveEGFR

Survival

Proliferation

Angiogenesis

Metastasis

MAPK: mitogen-activated protein kinase

KRAS as a Biomarker for Panitumumab Response in Metastatic CRC

Patients With Mutant KRAS

Meanin Wks

Stratified log rank test: P < .0001

115/124 (93)

Patients With Wild-Type KRAS

1.0

0.9

Pro

po

rtio

n W

ith

PF

S

0.8

0.70.60.50.4

0.3

0.20.1

00 2 4 6 8 10

Events/N (%)Medianin Wks

Pmab + BSCBSC alone

114/119 (96)

12.37.3

19.09.3

HR: 0.45 (95% CI: 0.34–0.59)

12 14 16 18 20 22 24 26 2830 32 3436 38 4042 44 46 48 50 52

Weeks

Pro

po

rtio

n W

ith

PF

S

1.0

0.90.8

0.70.60.50.4

0.30.20.1

00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 3436 38 4042 44 46 48 50

Weeks

Pmab + BSCBSC alone Mean

in Wks

76/84 (90)

Events/N (%)Medianin Wks

95/100 (95)

7.47.3

9.910.2

HR: 0.99 (95% CI: 0.73–1.36)

52

Amado et al., JCO 2008.

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,

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?

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

Low EREG by minimum-P threshold

Cetuximab + BSC

BSC alone

HR 0.93 [0.51-1.71], P = .81

Prop

ortio

n Al

ive

0

20

40

60

80

100

Time From Randomization, months

03026

22518

41615

61310

885

1053

High EREG by minimum-P threshold

Prop

ortio

n Al

ive

20

40

60

80

100

Time From Randomization, months

08485

28073

47654

66626

84319

102814

121810

1485

Cetuximab + BSC

HR 0.46 [0.32-0.65], P<.0001

BSC alone

0

Jonker D, et al. J Clin Oncol. 2009;27(15S): Abstract 4016.

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.

BRAF Mutations in CRC• BRAF is primary effector of

KRAS signaling• BRAF mutations:

– Occur most frequently in exon 15 (V600E)

– Found in 4% to 14% of patients with CRC

– Mutually exclusive with KRAS mutations

Raf

MEK

Erk

P

P P

P

Tumor cellproliferationand survival

EGF

Tumor Cell

Ras

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..

HR, hazard ratio

32 25 16 12 8 5 2 2 2 038 24 14 6 6 3 3 1 0 0

00CT

CT + cetuximab

CRYSTAL plus OPUS: Pooled analysis of OS in patients with

KRAS wt/BRAF mt tumorsPr

obab

ility

of o

vera

ll su

rviv

al

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

180 6 12 24 6030 36 42 48 54Time (months)Number of patients

349 317 268 225 163 120 80 63 19 4381 350 283 212 149 107 63 46 17 2

00CT

CT + cetuximab

KRAS wt/BRAF wtHR [95% CI]: 0.840 [0.710–0.993]p=0.041 FOLFIRI / FOLFOX4 + cetuximab: (n=349) median 24.8 months FOLFIRI / FOLFOX4: (n=381) median 21.1 monthsKRAS wt/BRAF mtHR [95% CI]: 0.633 [0.378–1.060]p=0.079 FOLFIRI / FOLFOX4 + cetuximab: (n=32) median 14.1 months FOLFIRI / FOLFOX4: (n=38) median 9.9 months

Van Cutsem E, et al. N Engl J Med 2009;360:1408-17; Bokemeyer C, et al. J Clin Oncol 2009;27:663-71

Vemurafenib in V600E+ mCRC

-100

-75

-50

-25

0

25

50

75

100

%C

ha

ng

e F

rom

Ba

se

line

(S

um

of

Le

sio

n S

ize

)

(RECIST cutoff for PR, 30%)

n=19 Evaluable Patients

1 PR and 4 MRs (≥10% shrinkage)

Interim - 12/31/09

Rationale for CombinationBRAF/MEK

Infante ASCO 2011

1. Synergy in combination

2. Overcome/prevent potential BRAF resistance via activation of MAPK pathway

3. Potentially decrease incidence of BRAFi-induced hyperproliferative skin lesions

pERK

BRAF

MEK

Proliferation, survival, Invasion, metastasis

GSK2118436

GSK1120212

RAS

RR ~60 %

Key toxicity: SCC

RR ~40 %

Key toxicity: rash

BRAF plus MEK inhibitors

Corcoran ASCO 2012

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

Median # prior therapies: 2 (range 1-4)

Activity of Tivantinib (ARQ197) + cetuximab/irinotecan

19Eng et al. ASCOGI 2011

Drug Induction Regimen Maintenance Regimen

MetMAb (or placebo) 10 mg/kg IV Day 1 10 mg/kg IV Day 1

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

5-FU400 mg/m2 IV bolus then 2400 mg/m2 over 46 hours starting Day 1

400 mg/m2 IV bolus then 2400 mg/m2 over 46 hours starting Day 1

Schema Regimen

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.

GI155 - ACCOMPLISH Schema & Regimen

Immune-Modulating Therapies

Infection-fighting Autoimmunity

• Immune system contains receptor-ligand pairs that inhibit or stimulate immune response

• Balance necessary to fight infections but not develop autoimmunity

PD-1 and PD-1-Like Inhibitors

CD27TNFR/ligand family

B7-CD28 family

B7H3

B7H1/B7DC

B7-1/B7-2

CD27L

Tumor cell

4.

5.

?

PD1

CTLA-4

1.

2.

3.

6.

T cell

1. FDA-approved Ipilimumab2. Monoclonal antibody that targets PD1 (receptor)3. Recombinant fusion protein of B7DC (PD-L2 ligand), targets PD14. Monoclonal antibody that targets B7H1 (PD-L1 ligand)5. Monoclonal antibody that targets B7H3 ligand6. Agonist anti-CD27 monoclonal antibody

Immunotherapy: PD-1 Inhibitor

Tumor

Suppressive/dysfunctional T cells are 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?

Genomic Landscape of CRC… 2006

FBXW7

KRAS

PIK3CA

APC

TP53

Wood L et al, Science (2007); Sjoblom T et al, Science (2006)

Facts:11 colorectal tumorsFirst Generation Sequencing13,023 genes21 Mb target sequence135,483 primer pairs~90 mutated genes/tumor11 recurrent mutations/tumor

The List of Candidate Genes: Total 142Usual suspects APC, KRAS, PIK3CA, PTEN, SMAD4, TGFBR2, TP53…

Genomic Landscape of CRC… 2012

Cancer Genome Atlas Network, Nature (2012)

Facts:224 T/N pairsNext-Generation Sequencing – Whole Exome Seq >20X coverage32 somatic recurrent mutations per tumor

16% 84%

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)

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 -

CRC subtypes – dMMR/EMT… 2013

PI3K pathway inhPIK3CA mut or PTEN low

42

11

11Second-generationanti-EGFR mAbKRAS wt refractory to cetuximab/panitumumab

anti-HGF mAbpMET high

mTOR inh + anti-IGFR1 mAbPTEN low

BRAF inh BRAF mut

10

53

Molecular Profiling and Matched Targeted Agents in Colorectal Cancer Patients enrolled in Phase I trials

Dienstmann et al. Mol Cancer Ther. 2012;11:2062-71.

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