Treatment Beyond Progression-is there a new standard of care

for wt kras?

Heinz-Josef Lenz

Associate Director, Clinical Research

Kathryn Balakrishnan Chair for Cancer Research

Co-Director, USC Center for Molecular Pathways and Drug Discovery

Co-Leader GI Oncology Program

USC/Norris Comprehensive Cancer Center

Options for wt kras…wt ..

• Continue Anti VEGF therapy (bevacizumab, aflibercept)

• Switch to anti EGFR AB

Acquired Functional

Capabilities of Cancer Cells

Self-sufficiency in growth signals

Insensitivity to antigrowth

signals

Tissue invasion and metastasis

Limitless potential to

replicate

Sustained angiogenesis

Evading apoptosis

Hallmarks of Cancer – Therapeutic Targeting

EGFR inhibitors

Cyclin-dependent kinase inhibitors

Inhibitors of HGF/c-Met

Telomerase inhibitors

Inhibitors of VEGF signaling

Proapoptotic BH3 mimetics

VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor; HGF, hepatocyte growth factor.Hanahan D, et al. Cell. 2011;144:646-674. 15

Genetic Changes in CRC

Cancer Genome Atlas Network. Nature. 2012;487:330-337.

Genomics: Cancer Genome Atlas

Cancer Genome Atlas Network. Nature. 2012;487:330-337.

VEGF expression throughout tumour life cycle1

Pre-clinical data suggest continuous VEGF suppression is key to achieving and maintaining tumour control2

VEGF = vascular endothelial growth factor

bFGF = basic fibroblast growth factor

TGFb-1 = transforming growth factor b-1

PD-ECGF = platelet-derived endothelial cell growth factor

Tumour evolution

VEGFbFGF

TGFb-1

VEGF

bFGFTGFb-1

PIGF

VEGF

bFGFTGFb-1

PIGFPD-ECGF

VEGFPIGFPD-ECGFPleiotrophin

bFGFTGFb-1

VEGF

1. Folkman. Cancer: Principles and Practice of Oncology, 7th ed. 20052. Bagri et al. Clin Cancer Res 2010

VEGF-A, VEGF-B, and PlGF are involved in multiple pathways of angiogenic response

ENDOTHELIAL CELLSurvival, Migration, Proliferation

VEGF-A

VEGF

R-1

STROMAL CELLPERICYTE, SMC

MigrationProliferation

sVEGFR-1

MACROPHAGERecruitment and activation

Release of angiogenic factors

BM PROGENITORS LEUKEMIC CELLProliferation, Migration, Survival

VEGF-A

DENDRITIC CELLSuppression ofantigen recognition

VEGF-A

TUMOR CELLProliferationand migrationChemoprotection

PlGF

VEGF-B

VEGF

R-2

Adapted from Fischer. Nat Cancer Rev. 2008;8:942–956.

5Courtesy of Heinz-Josef Lenz, MD.

Pharmacologic Approaches to Blocking Angiogenesis

• Neutralizing VEGF activity(e.g., bevacizumab, aflibercept)1,2

• Inhibition of receptorkinase activity (e.g., sunitinib,sorafenib, pazopanib, etc.)3-5

• Reducing expression of VEGFby inhibiting tumor growth pathways(e.g., anti-EGFR therapies)6-9

THREE GENERAL MECHANISMS OF ANGIOGENESISINHIBITORS THAT BLOCK THE VEGF PATHWAY

1. Avastin PI. 2010. Genentech Inc. 2. Holash. PNAS. 2002;99:11393–11398. 3. Sutent PI. 2010. 4. Nexavar PI. 2010. 5. Votrient PI. 2010. 6. Petit. Am J Pathol. 1997;151:1523–1530. 7. Tarceva PI. 2010. 8. Erbitux PI 2010. 9. Vectibix PI. 2010

Block VEGF receptor•Anti-VEGFR-2 TKIs

(sunitinib, etc)

VEGF

Neutralize VEGF•Aflibercept

•Bevacizumab

Extracellular

VEGFR-2Tumorcell

Block VEGFexpression•Erlotinib

•Cetuximab•Panitumumab

Intracellular

ANGIOGENESIS INHIBITORS

VEGFR-1

(Flt-1)

NRP-1/NRP-2 NRP-

2

VEGF-D

VEGF-CVEGF-B VEGF-A

PlGF

VEGFR-2(Flk-

1/KDR)

VEGFR-3

(Flt-4)

VasculogenesisAngiogenesis

Lymphangiogenesis

BEVACIZUMAB*

VEGF-TRAP

18F1 1121B

TG-403

Tyrosine Kinase InhibitorsSunitinib*Sorafenib*Pazopanib*

Axitinib*MotesanibCedirinibBrivanib

Many, many others

VEGF Targeted Agents in the Clinic or In Clinical Trials

Ellis, Hicklin Nat Rev Ca. 2008

* FDA approved agents

Do we see improved outcomes in patients treated with agents that target

PlGF/VEGFR-1?

• Patients treated with FOLFOXIRI-bevacizumab* were screened for VEGF, PlGF levels

Biomarker profiles may indicate resistance against VEGF inhibition

Loupakis F et al, BJC, 2011, 104: 1262-9* Masi G et al, Lancet Oncol, 2010: 11, 845-52

Cytokine increase on BEV therapy

Kopetz et al., JCO 2010

EFC10262: VELOURPhase III Trial 2nd Line FOLFIRI +/-

VEGF-TRAP (Aflibercept)

Stratification factors:Prior bevacizumab (Y/N)ECOG PS (0 vs 1 vs 2)

1:1

mCRC afterfailure of an oxaliplatin

based regimenR

600 ptsAflibercept 4 mg/kg

IV+ FOLFIRI q 2 weeks

600 pts Placebo + FOLFIRIq 2 weeks

13

30% of patients had prior BEVPIs: Allegra, Van Cutsem

2L aflibercept plus FOLFIRI significantly improved OS and PFS compared with FOLFIRIImprovement in OS and PFS with aflibercept appears to be independent

of prior treatment with bevacizumab

VELOUR: phase III trial of second-line aflibercept plus FOLFIRI – efficacy (ITT)

Van Cutsem, et al. JCO 2012*Stratified, cut-off date = February 7, 2011†Stratified, cut-off date = May 6, 2011

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Aflibercept + FOLFIRI (n=612)

Placebo + FOLFIRI (n=614)

0 3 6 9 12 15 18 21 24 27 30

PF

S e

stim

ate1

12.1 13.5 4.7 6.9

OS* PFS†

Aflibercept + FOLFIRI (n=612)

Placebo + FOLFIRI (n=614)

OS

est

imat

e1

1.0

0.8

0.6

0.4

0

0.2

1.0

0.8

0.6

0.4

0

0.2

Time (months)Time (months)

HR*=0.82 p=0.0032

HR*=0.76 p=0.00007

Strata (as per UVRS) N HR (95.34% CI) HRInteraction

P

All patients 1,226 0.817 (0.713-0.937)

Prior bevacizumab No Yes

853

3730.788 (0.669-0.927)0.862 (0.673-1.104)

.5668

0 1 2 3

Favors placeboFavors aflibercept

Strata (as per UVRS) N HR (95% CI) HRInteraction

P

All patients 1,226 0.758 (0.661-0.869)

Prior bevacizumab No Yes

853

3730.797 (0.679-0.936)0.661 (0.512-0.852)

.1958

0 1 2 3

Favors placeboFavors aflibercept

Overall Survival

Progression-Free Survival

Aflibercept: VELOUR Phase III: OS and PFS Stratified by Prior Bevacizumab

Adapted from Van Cutsem E, et al. J Clin Oncol. 2012 Sep 4. [Epub ahead of print].

Primary Endpoint

Allegra Abstract

#3505

Response Rates

Van Cutsem et al., JCO 2012

Safety – Most frequent AEs, with ≥ 5% difference in incidence between treatment arms, excluding anti-VEGF class events

Safety Population, % of patients

Placebo, N = 605 Aflibercept N = 611

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

AEs leading to treatment discontinuation:AFL: 26.6%PL: 12.1%

Van Cutsem et al., JCO 2012

Meyerhardt JA, Mayer RJ. N Engl J Med. 2005;352:476-487; Venook A. Oncologist. 2005;10:250-261.

Survival (anti-

apoptosis)

Gene transcriptionCell-cycle progression

MYC

MYC Cyclin D1

FOSJUN

PP

Cyclin D1

AngiogenesisInvasion andmetastasis

Chemotherapy/radiotherapy resistance

Proliferation/maturation

MAPK

MEK

RAS RAFSOS

GRB2

PTEN AKTSTAT

P13KpY

pY

Ligand: AREG, EREG

EGFR-TKTarget for EGFT-TK inhibitor

pY

EGF Receptor: A Rational Target for CRC Therapy

CRYSTAL PRIME OPUS COIN NORDIC CAIRO2 181 PICCOLO

-20

-15

-10

-5

0

5

10

15

20

25

30

17

7

24

7

-1

11

25

22

-5

0

-16

-3

9

-13

-1

-5

KRAS wtKRAS mut

Ch

ang

es i

n r

esp

on

se r

ates

(%

)

2nd Line 1st Line

IRI OX OX OX OX OX IRI IRI

PFS/DFS for EGFR inhibitors improves across lines of therapy in KRAS WT mCRC

CR

YS

TAL

5

CO

IN3

PR

IME

4

NO

RD

IC V

II2

CO

.17

9

Am

ad

o8

N0

14

71

1- H

R

1L 2L Salvage (single agent)

Adjuvant

0.7

0.5

0.3

0.2

–0.1

–0.2

–0.31

817

PIC

CO

LO

6

0.6

0.4

0.1

0

Cetuximab

Panitumumab

1. Alberts, et al. JAMA 2012; 2. Tveit, et al. JCO 2012; 3. Maughan, et al. Lancet 2011 4. Douillard, et al. JCO 2010; 5. Van Cutsem, et al. JCO 2011; 6. Seymour, et al. ASCO 2011

7. Peeters, et al. JCO 2010; 8. Amado, et al. JCO 2008; 9. Karapetis, et al. NEJM 2008

181 vs EPIC181

(n = 1083; 597 WT)WT only

EPIC(n = 1298) WT + Mut

Pmab-FOLFIRI

FOLFIRI Cetux-Iri Iri

OS median(mo)

14.5 12.5 10.7 10.0

OS HR (p) .92 (.37) .98 (.7)

PFS median(mo)

6.7 4.9 4.0 2.6

PFS HR* (p) .82 (.023) .69 (<.001)

RR (%) 36.0 9.8(p<.001)

16.4 4.2(p<.0001)

Subsequent EGFR Ab (%)

12 34 ~0 46.9

A Sobrero et al. GI Symposium 2012A Sobrero et al. J Clin Oncol 2008. 26:2311-2319.

181: FOLFIRI +/- PanitumumabPFS and OS

Median (95% CI), months

6.7 (5.8, 7.4)

4.9 (3.8, 5.5)FOLFIRI alone

Panitumumab + FOLFIRI

PFS

Median (95% CI), months

14.5 (13.0, 16.1)

12.5 (11.2, 14.2)FOLFIRI alone

Panitumumab + FOLFIRI

MonthsMonths

OS

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

Panitumumab + FOLFIRI (n=303)

FOLFIRI alone (n=294)

Panitumumab + FOLFIRI (n=238)

FOLFIRI alone (n=248)

Adapted from: A Sobrero et al. GI Symposium 2012

* PFS “on treatment” HR = .73; p= .001

Hazard ratio (95% CI): 0.82 (0.69, 0.97)

P-value: 0.023

Hazard ratio (95% CI): 0.92 (0.78, 1.10)

P-value: 0.37

SWOG 0600/iBET: A Phase III of Irinotecan and Cetuximab With or Without Bevacizumab in Patients With mCRC That Progressed During First-Line Therapy

Gold, Grothey et al..

• Primary endpoint: OS

• Secondary endpoints: PFS, objective tumor response, tolerability, and safety

• June 2007 – October 2010

Second line

PD

RANDOMIZE

CT + dual biologic arm removed

mCRCKRAS

wild-typepreviously

treated with Bevacizumab

and oxaliplatin- based CT(n=1260)

Bevacizumab 5 mg/kg +(FOLFIRI or Irinotecan +

Capecitabine)

Cetuximab +(FOLFIRI or Irinotecan +

Capecitabine)N = 68

PEAK study: FOLFOX + Pmab vs. FOLFOX + Beva

Pmab+FOLFOX 6

Bev+FOLFOX6

HR(95% CI)

P-value

RAS wtNPAT 80 80

Median OS

Mo (95% CI)

n.r.(28,8 – nr)

29,0(24,3 – nr)

0.55(0.3 – 1,01)

0.06

Median PFSMo

(95%CI)

13.1(10.7 – 15.1)

9.5(7.9 – 12.7)

0.63(0.43 – 0.94)

0.02

Schwartzberg L et al ASCO 2013

CO.20 Trial: Cetuximab +/- BrivanibK-Ras WT Chemo-refractory CRC

Cetuximab + Placebo

Cetuximab + Brivanib

P Value

PFS 3.4 5.0 <0.0001 (HR=0.72)

RR 7.2 13.6 0.044Siu et al

Conclusions• Anti Angiogenesis Therapy effective through all

lines of therapy (1.4 months!) • Not only kras exon 12/13 but all other codons

and nras may be used to select patients for second line anti EGFR Therapies (prior to resistant!?)

• Emergent Mechanisms of Resistance in EGFR and VEGF pathways may be a key for combination therapies

Are All KRAS Mutations Created Equal? – G13D

Tejpar et al., ASCO 2011Pooled analysis of OPUS and CRYSTAL