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Pathways and Targets:How do these affect my treatment

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Dr. Gail Eckhardt, MD Professor and Division Head

University of Colorado Division of Medical Oncology

Pathways and Targets: How do these affect my treatment

options?

S. Gail Eckhardt, M.D.University of Colorado Cancer Center

CRC: What Have We Learned?

• Patient selective trials are needed earlier in order to avoid thousands of patients being treated with ineffective agents (EGFR Ab/KRAS)

• Indiscriminant addition of biological agents to adjuvant therapy is not warranted (bevacizumab/cetuximab)

• Dual biological combinations in unselected patients may lead to more toxicity with little benefit (bevacizumab + cetuximab)

Treatment for colorectal cancer has improved, but . . .

Courtesy of Wells Messersmith, MD

• Solid tumors cannot grow beyond 1-2 mm3 without an increase in blood supply via new vessel formation

• Angiogenesis is thus required for tumor growth and metastasis• Inhibition of tumor angiogenesis leads to tumor cell growth arrest, death

of tumor cells, and in some cases, tumor regression

Tumor angiogenesis is stimulated…

New vessels then facilitate tumor growth

Slide Courtesy of Novartis Oncology

Targeting Angiogenesis in CRC

VEGF: A Central Mediator of Angiogenesis

Binding and activation of VEGF receptor

Environmental factors(hypoxia, pH)

Growth factors,hormones

(EGF, bFGF, PDGF, IGF-1, IL-1, IL-6, estrogen)

Genes involved in tumorigenesis

(p53, p73, src, ras, vHL, bcr-abl)

PP

PP

ANGIOGENESIS

ProliferationSurvival Migration

Endothelial cellactivation

VEGF

1. Dvorak. J Clin Oncol. 2002;20:4368.2. Ferrara et al. Nat Med. 2003;9:669.3. Ebos et al. Mol Cancer Res. 2002;1:89.

VEGF

Small-molecule TKIs

Antibodies

VEGFR-2(KDR/flk-1)

VEGFR-1(flt-1)

VEGFR-1/2 heterodimer

P

P

P

P

P

P

P

P

P

P

P

P

Soluble, truncated receptors

Targeting VEGF and its receptorsSeveral Approaches

Courtesy of Herb Hurwitz

Pivotal Randomized Phase III Trial of 813 Advanced CRC Patients Comparing IFL Regimen +/- Bevacizumab

Primary Endpoint: Survival

Previously untreated pts with metastatic colorectal cancer

Arm A: IFL + Bevacizumab

Arm B: IFL + Placebo

IFL = Irinotecan / 5-FU / Leucovorin

Hurwitz et al, N Engl J Med. 2004 Jun 3;350(23):2335-42.

p<.001

Results: Bevacizumab added to IFL significantly improved overall survival by > 4 months

Hurwitz et al, N Engl J Med. 2004 Jun 3;350(23):2335-42.Copyright Mass Med Soc

VEGFR Tyrosine Kinase Inhibitors in CRC:Over 10,000 CRC Patients Treated on Negative Trials!

Agent AKA mCRC Trials CRC Patients

Cediranib AZD2171 2 Phase III 3,194

Semaxinib SU5416 2 Phase III 2,084

Vatalanib PTK787 2 Phase III 2,050

Sunitinib SU11248 Phase III 1,623

Brivanib BMS-582664 Phase III 926

Sorafenib BAY 43-9006 Phase IIB 814

Vandetanib ZD6474 Phase IIB 356

Axitinib AG-013736 Phase IIB 299

Linifanib ABT-869 Phase IIB 147

Vargateg BIBF 1120 Phase II 166

Tivozanib AV-951 Phase II 80

Motesanib AMG-706 Phase IB 148

Pazopanib GW786034 Phase IB 94

Clinicaltrials.gov; Slide courtesy of Scott Kopetz

Mode of Action of Regorafenib• Regorafenib inhibits multiple cell-

signaling kinases:– Angiogenic

• VEGFR1–3, TIE2– Stromal

• PDGFR-β, FGFR– Oncogenic

• KIT, PDGFR, RET• T1/2 in man: approx. 26-28 hrs

– Two major metabolites (M2, M5) are pharmacologically active

Wilhelm SM et al. Int J Cancer 2011

Toxicity (>10% patients, any grade, related)Patients D/C treatment due to AEs: 8.2% (R) versus 1.2%(P)

Grothey, GI Symposium 2012, J Clin Oncol 30, 2012 (suppl 4; abstr LBA385)

Adverse event, % RegorafenibN=500

PlaceboN=253

All grades

Grade 3 Grade 4 Grade 5 All grades

Grade 3 Grade 4 Grade 5

Hand–foot skin reaction 46.6 16.6 0 0 7.5 0.4 0 0

Fatigue 47.4 9.2 0.4 0 28.1 4.7 0.4 0

Hypertension 27.8 7.2 0 0 5.9 0.8 0 0

Diarrhea 33.8 7.0 0.2 0 8.3 0.8 0 0

Rash/desquamation 26.0 5.8 0 0 4.0 0 0 0

Anorexia 30.4 3.2 0 0 15.4 2.8 0 0

Mucositis, oral 27.2 3.0 0 0 3.6 0 0 0

Thrombocytopenia 12.6 2.6 0.2 0 2.0 0.4 0 0

Fever 10.4 0.8 0 0 2.8 0 0 0

Nausea 14.4 0.4 0 0 11.1 0 0 0

Bleeding 11.4 0.4 0 0.4 2.8 0 0 0

Voice changes 29.4 0.2 0 0 5.5 0 0 0

Weight loss 13.8 0 0 0 2.4 0 0 0

Regorafenib: Overall survival (primary endpoint)

Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p<0.009279 at approximately 74% of events required for final

analysis)

1.00

0.50

0.25

0

0.75

200100500 150 300250 400350 450

Days from randomization

Sur

viva

l dis

trib

utio

n fu

nctio

n

Placebo N=255Regorafenib N=505

Median 6.4 mos 5.0 mos95% CI 5.9–7.3 4.4–5.8

Hazard ratio: 0.77 (95% CI: 0.64–0.94)

1-sided p-value: 0.0052

Regorafenib Placebo

Grothey et al, ASCO GI 2012

42 days!

AfliberceptAnother Approach to Targeting Angiogenesis

• Soluble fusion protein• Consists of portions of the extracellular domains of

human VEGFR1 and VEGFR2 fused to a human IgG1 Fc portion

• Binds all VEGF-A isoforms, VEGF-B, and PlGF• High affinity: Binds VEGF-A and PlGF more tightly

than native receptors• Half-life ~ 17 days

Van Cutsem et al, 2011.

Aflibercept: MOA Comparison

Courtesy of Philip Philip.

Cell membrane

VEGF-A

VEGF-R1(Flt-1)

MigrationInvasionSurvival

VEGF-R3(Flt-4)

Lymphangio-genesis

VEGF-R2(KDR/Flk-1)Proliferation

SurvivalPermeability

PlGF VEGF-B

VEGF-C VEGF-D

Func

tions

Y

Bevacizumab

YVGX-100

YRamucirumab

II

CT-322

Y

IMC-18F1

Aflibercept

Y

TB403

XXX VEGFRTKIs

“VELOUR” trialSimilar Combination Approach as Bev

- Aflibercept (VEGF Trap) in colorectal cancer- Multiple centers in Australia, China, Europe, Japan, and

North America

mCRC afterfailure of an

oxaliplatin-based regimenN=1200

Placebo + FOLFIRI

(n=605)

R

Aflibercept 4 mg/kg IV+ FOLFIRI

(n=611)

Primary Endpoint: Overall Survival (OS)

1:1

Note: 30% had received prior bevacizumab

Van Cutsem et al, 2011.

(FOLFIRI= infusional 5FU/IRI/LV)

VELOUR trialSafety Population, % of patients Placebo, N = 605 Aflibercept N = 611

PT, SOC, HLT* All Grades Grade 3/4 All Grades Grade 3/4

Diarrhea 56.5 7.8 69.2 19.3

Neutropenia** Complicated neutropenia

56.3 29.52.8

67.8 36.75.7

Asthenic conditions (HLT) 50.2 10.6 60.4 16.9

Stomatitis & ulceration (HLT) 34.9 5.0 54.8 13.7

Thrombocytopenia** 33.8 1.7 47.4 3.3

Infections (SOC) 32.7 6.9 46.2 12.3

Decrease appetite 23.8 1.8 31.9 3.4

Weight decreased 14.4 0.8 31.9 2.6

Palmar plantar erythrodysaesthesia 4.3 0.5 11.0 2.8

Skin hyperpigmentation 2.8 0 8.2 0

Dehydration 3.0 1.3 9.0 4.3

PL: 12.1% AFL: 26.6%

AEs leading to treatment discontinuation

Van Cutsem et al, 2011.

“VELOUR” trial: Overall Survival

Cut-off date = February 7, 2011; Median follow-up = 22.28 mos

Van Cutsem et al, 2011.

6 weeks longer OSNot compared to bevacizumab

Issues Regarding Angiogenesis Inhibitors– Most medical oncologists believe that utilization of AIs

is relevant throughout the course of advanced CRC (when risks are acceptable)

– Bevacizumab can be used with chemotherapy and the reason aflibercept is not being routinely used is related to unfamiliarity and concerns regarding the toxicity data

– For some reason, although regorafenib was active in refractory patients, drugs that are similar have not worked with chemotherapy

– Among those involved in clinical research (like me), we are worried that patients will get regorafenib rather than be offered a clinical trial

Can Biomarkers Help Us Select the Patients Most Likely to Benefit from

Targeted Therapies ?

Biomarker = Toxicity (mechanism based) Biological effect Efficacy

Pharmacodynamic biomarker: Associated with drug effect Example: skin rash with EGFR inhibitor, or inhibition of p-ERK with MEK inhibitor

Predictive biomarker: Predicts outcome to therapyExample: Her2/Neu amplification by FISH for trastuzumab

Prognostic biomarker: Associated with outcome, independent of therapy Example: VEGF expression

Biomarkers: Introduction

Biomarkers for Bevacizumab in CRC

• Although there are biomarkers associated with the PD effects of bevacizumab, to date to no predictive biomarkers have been identified

• This is likely due to the complex interaction of the tumor and microenvironment

• Studies are ongoing to determine whether the PD biomarkers such as high blood pressure and MRI can be used to identify patients deriving clinical benefit

Slide courtesy of Axel Grothey

Targeting the EGFR in CRC

Cetuximab +/- IrinotecanPFS

p<0.001

Cunningham, NEJM 2004

Note: overall survival curves were nearly identical (likely due to crossover)

What About Biomarkers and EGFR Antibodies in CRC?

Did staining for EGFR matter? NO!

Courtesy of DakoCytomation, 2004

21% 25%

23%

Response Rates

EGFR Signaling Cascade and KRAS

Akt

SOS

FOS Myc

P13K

FKHRmTOR

PTEN

MEK 1/2

MAPK

BADGSK-3

Shc

Grb-2

Ras

Raf

Junp27

Cyclin D-1

Ligand

SignalAdaptersand Enzymes

SignalCascade

EGFR dimer

TranscriptionFactors

STAT

Inhibitors upstream may be

ineffective

Karapetis WGIC 2008

Randomized Trial ResultsMedian PFS (Cetux- or Pmab- containing arms)

Study Treatment Total Pts MT WT

Amado2008

P versus BSC (3rd line) 427 7.4 wks

HR 0.99 12.3 wks HR 0.45

Karapetis2008

C versus BSC(no X-over) 394 1.9 mos 3.7 mos

HR 0.40

Van Cutsem2008

FOLFIRI +/- C (1st line) 540

7.6 mos HR 1.07

9.9 mos HR 0.68

Bokemeyer2008 FOLFOX +/- C

(1st line) 233 5.5 mos HR 1.83

7.7 mos HR 0.57

C = cetuximab; P = panitumumab; BSC = best supportive care

Amgen “408” TrialThis trial was important because it had a

placebo arm

Patients had to be “EGFR positive,” defined as >1% tumor cells staining by IHC Pretreated with 5-FU, oxaliplatin, irinotecan

Previously treated metastatic colorectal cancer

N=463

Panitumumab 6 mg/kgQ2 weeks

Best Supportive Care

Opti

onal

Cro

ssov

er

Van Cutsem et al. J Clin Oncol; 25(13):1658-1664 2007

PFS by treatment overall

Van Cutsem et al. J Clin Oncol; 25(13):1658-1664 2007

Resulted in FDA approval of

panitumumab for use in 3rd line setting

Amado, R. G. et al. J Clin Oncol; 26:1626-1634 2008

PFS by treatment within KRAS groupsNote: The BSC arms look similar indicating lack of impact on prognosis

KRAS MT

KRAS WT

BSC

BSC

KRAS and Panitumumab

Waterfall plot shows responses (tumor shrinkage) were confined to Ras WT patients

Mut WT

Amado, R. G. et al. J Clin Oncol; 26:1626-1634 2008

Mechanism-based toxicity: Skin Rash with EGFR Blockade

This is a pharmacodynamic biomarker- is it predictive?

M Peeters et al, Cancer, 2009

More severe skin toxicity and associated symptoms led to prolonged survival in this subset analysis

Grade 2+ skin toxicity

Greater skin toxicity symptoms

Skin Rash: Maybe necessary but not sufficient for antitumor activity

Summary and Lessons Learned with EGFR Inhibitors in CRC

• EGFR-targeted antibodies have very modest single-agent activity in refractory CRC but appear to improve responses to chemotherapy

• Biomarker studies have demonstrated that benefit is restricted to KRAS WT patients

• Surprisingly, no benefit was observed in the adjuvant studies• Ongoing questions remain regarding the extent to which

immune mechanisms contribute to antitumor effects and how to integrate skin rash data in dosing decisions

• The EGFR TKIs (oral drugs) have not exhibited activity in CRC

What About the Combination of Biologics- is More Better????

PACCE Trial:

Randomized phase III trial of 1000 patients comparing chemo/Bev with or without panitumumab

Previously untreated metastatic colorectal cancerN=1000

5-FU/Oxali/BevN=800

5-FU/Irino/BevN=200

Hecht, World GI 2007

+ panitumumab

+ panitumumab

(alone)

(alone)

PACCE TrialProgression-Free Survival

Hecht, World GI 2007

Months

413 267 92 21 3

410 298 96 21 1

0 5 10 15 20

Pmab+bev/Ox-CT N

bev/Ox-CT N

Patients at risk:

# PFS events (%)

Median (95%CI), mos

206 (50) 9.0 (8.5-10.4)

172 (42) 10.5 (9.7-11.6)

Pmab+bev/Ox-CT

Bev/Ox-CT

HR= 1.29 (95% CI: 1.05-1.58)

Pro

po

rtio

n P

rog

ress

ion

-Fre

e 100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

ITT set

Control group did better!

TCGA Data: Many Pathways to Target

Conclusions• Novel biological agents targeting the EGFR and VEGF pathways

have extended survival and provided new options for CRC patients with advanced disease

• Unfortunately, these results have not translated to adjuvant therapy and the reasons for this are not well understood

• Biomarkers have been instrumental in further defining a potentially responsive patient population

• These results, along with the issues of combining “double biologics” in unselected patients, are driving the field forward towards personalized therapy and more rational combinations

• Despite the advances in therapy, more effective agents are needed and luckily drug development is robust, but very dependent on clinical trials

Thank You- Questions?

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