Targeting EGFR in Advanced Colorectal Cancer sept 18

Targeting EGFR in Advanced Colorectal Cancer

Eric Chen, MD, PhD-

Outline

• Review of clinical data• Kras and beyond• Management of common side effects• Alternative dosing regimens

Treatment of Colorectal CancerTreatment of Colorectal Cancer

5-FULeucovorin

1962-1995

5-FULeucovorin

CapecitabineIrinotecan

1996-2002

5-FULeucovorin

CapecitabineIrinotecanOxaliplatin

BevacizumabCetuximab

Panitumumab

2004 and beyond2002 - 2004

5-FULeucovorin

CapecitabineIrinotecanOxaliplatin

Key Milestones: • Bevacizumab

– 1971, Folkman review in NEJM, Tumor-angiogenesis factor postulated

– 1989, VEGF gene – 1997, humanized mAb

described by Ferrara et al– 1997, phase I study, 25

patients/3 months– 2000, phase III initiated,813

patients/21 months– 2004, FDA approval

• Cetuximab / panitumumab– 1962, Cohen, EGF identified– 1980, Cohen, EGFR purified– 1981, Mendelsohn and Sato,

therapeutic implication– 1983, mAb 225 described– 1991, Phase I study mAb 225,

JNCI– 1994, chimeric version, C225– 2001, Phase I study of C225,

JCO– 2001, initial application rejected

by FDA– 2004, approval by FDA– 2006, panitumumab approval

Proliferation MetastasisAngiogenesisApoptosis Resistance

Shc

PI3-K

RafMEKK-1

MEKMKK-7

JNKERK

Ras

mTOR

Grb2

AKT

Sos-1

The Epidermal Growth Factor Receptor Pathway

Monoclonal Antibodies Targeting the EGFRAntibody Type Affinity Kd Half-life,

hrsDosing Development

Phase

CetuximabIgG1

Chimeric MoAb

0.39 nM 75-95 q1wk (q2w) Approved

Panitumumab IgG2 Human MoAb 50 pM 305-458

q1w q2wq3w

Approved

MatuzumabIgG1

Humanized MoAb

0.01 nM 94-180q1w q2wq3w

II

NimotuzumabIgG1

Humanized MoAb

1 nM 240 q1wI/II

approved in India, Cuba

3rd Line Trials of Anti-EGFR Therapy

• NCIC.CO17– Randomized phase III of cetuximab vs BSC

• Van Cutsem 2007– Randomized phase III of panitumumab vs BSC

Cetuximab + BSC vs. BSC: Phase III Trial

EGFR testing by IHC†

Disease Progression

or

Unacceptable Toxicity

Primary endpoint: Overall Survival (OS)Secondary endpoints: Progression-free survival (PFS)

Objective response rate (ORR)RECIST criteria

Safety and quality of life (QoL)

REGISTER

RANDOMI ZE1:11:1

Cetuximab** + BSC

BSC alone

Failed or intolerant to all recommended therapiesECOG PS* 0-2, no prior EGFR-directed therapy

*ECOG PS: Eastern Cooperative Oncology Group Performance Status

**Cetuximab 400 mg/m2 IV week 1, then 250 mg/m2 IV weekly †IHC: Immunohistochemistry

NCIC CTG CO.17 TRIAL

Jonker DJ et al, NEJM 2007, 357;20:2040-8

CETUXIMAB + BSCCENSORED

BSCCENSORED

SUBJECTS AT RISKCET+BSC 287 217 136 78 37 14 4 0 0 0

BSC 285 197 85 44 26 12 8 2 1 0

Pro

porti

on A

live

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months0 3 6 9 12 15 18 21 24 27

Overall Survival

HR 0.77 (95% CI: 0.64, 0.92)

Stratified log rank p = 0.0046

Study arm MS (months) 95% CI

Cetuximab + BSC 6.1 5.4 – 6.7BSC alone 4.6 4.2 – 4.9

MS = Median Survival

HR = Hazard Ratio



Progression-Free Survival

CETUXIMAB + BSCCENSORED

BSCCENSORED

Prop

ortio

n Pr

ogre

ssio

n-Fr

ee

0.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0

Months00 33 66 99 1212 1515

HR 0.68 (95% CI: 0.57, 0.80)

Stratified log rank p < 0.0001

Study arm Med PFS (months)

95% CI




Panitumumab PD Follow-up6.0 mg/kg Q2W+ BSC

BSC PD Follow-up

RANDOMIZE

Optional Panitumumab

Crossover Study

Randomization stratification• ECOG score: 0-1 vs. 2• Geographic region: Western EU vs.

Central & Eastern EU vs.Rest of World

1:1

EGFR+

VanCutsem E et al, JCO 2007, 25;13:1658-1664

Primary endpoint: Progression-free survival (PFS)Secondary endpoints: Objective response

Overall survivalSafety

Panitumumab vs BSC TRIAL

Study Design

PD = Progressive disease

Even

t-fre

e Pr

obab

ility

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Weeks from Randomization0 8 16 24 32 40 48 56

HR 0.54 (95% CI: 0.44, 0.66)

Stratified log-rank test p < 0.001

Progression-Free SurvivalPanitumumab

BSC

Patients at risk:PanitumumabBSC

231 118 49 31 13 5 1232 75 17 7 3 1 1

All Randomly assigned analysis set



% S

urvi

ving

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months from randomization

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Panitumumab (N=231)BSC (N=232)

HR 0.93 (95% CI: 0.73, 1.19)

Stratified log-rank p = 0.6065

Patients at risk:PanitumumabBSC

231 219 204 170 136 103 81 60 47 31 21 16 11 6 5 3 0 0 0232 221 199 175 139 98 76 60 41 29 20 18 12 8 7 5 3 1 0

00

Overall Survival



Objective Tumor ResponseObjective Tumor ResponseCO-17 Panitumumab

(N = 287) (N = 231)

PR, n (%) 19 (6.6) 22 (10)

SD, n (%) 84 (29.3) 62 (27)

PD, n (%) 133 (46.3) 147 (63)

PR + SD, n (%) 103 (35.9) 84 (37)

Van Cutsem, E. et al. J Clin Oncol; 25:1658-1664 2007

Jonker, D. et al AACR 2007

Not all patients benefit from anti-EGFR antibodies

EGFR Pathway and KRAS Gene• EGFR signaling pathway is activated

in response to ligand binding to cell-surface receptors: these ligands include TGFα and EGF

• In the early part of the signaling cascade, the protein RAS (RAt Sarcoma) regulates downstream proteins involved in these effects

• Kras gene is the gene that encodes the Kras protein. It could be normal (wild-type) or mutated.

• Kras protein cycles between “on” and “off” states. It is activated (on) for a short period of time once EGFR is activated.

Source: www.kras-info.com

TGF α = Transforming Growth Factor alphaEGF = Epidermal Growth FactorVEGF = Vascular Endothelial Growth Factor

• Wild-type KRAS protein is active for a short period when the EGFR is stimulated– The effects of the protein are closely controlled

• When KRAS is mutated the protein is permanently turned on (constitutively activated), even without being triggered by EGFR-mediated signaling– The effects of KRAS that lead to tumor growth and spread

continue unregulated

– 40% patients with advanced colorectal cancer have K-ras mutation

EGFR Pathway and KRAS

Adapted from www.kras-info.com

RAS-GDP

Khambata et al JCO 2008

KRAS Analysis

• Genomic DNA extracted from FFPET slides or sections• Assessed by bidirectional sequencing for codon 12/13 mutations• No difference between KRAS-mutated and wild-type patients re:

demographics, previous treatment or other variables

N=572 randomized: ITT subset

N=394: K-Ras assessed subset (69%)

N=164 (42%)N=164 (42%)mutantmutant

N=230 (58%)N=230 (58%)wildwild--typetype

Karapetis C et al, NEJM 2008, 359;17:1757-65


ITT = Intent to treatFFPET = Formalin-fixed paraffin-embedded tissue

PFS in Wild-Type KRAS Patients

HR 0.40 (95% CI: 0.30,0.54) Stratified Log rank p<0.0001




0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12

Time from Randomisation (Months)

Pro

porti

on P

rogr

essi

on F

ree

CetuximabBSC

CetuximabBSC

117 74 50 26 8 5113 43 14 2 1 1


PFS in KRAS Mutant Patients

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12

Time from Randomisation (Months)

Pro

porti

on P

rogr

essi

on F

ree

CetuximabBSC

CetuximabBSC

81 21 8 383 27 9 4

HR 0.99 (95% CI: 0.73,1.35) Stratified Log rank p= 0.96





Overall Survival in KRAS Wild-Type Patients

HR 0.55 (95% CI: 0.41,0.74) Stratified Log rank p <0.0001




0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12 14 16 18Time from Randomisation (Months)

Prop

ortio

n Al

ive

CetuximabBSC

CetuximabBSC

117 108 95 81 52 34 20 9 6 2113 92 69 36 24 17 12 5 3 3


Overall Survival in KRAS Mutant Patients

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12 14 16 18Time from Randomisation (Months)

Pro

porti

on A

live

CetuximabBSC

CetuximabBSC

81 69 46 27 16 11 7 483 69 42 28 20 13 11 7

HR 0.98 (95% CI: 0.70 - 1.37) Stratified Log rank p <0.0001





Maximum Percent Decrease in Target Lesions Maximum Percent Decrease in Target Lesions Final Analysis, Final Analysis, KRASKRAS Evaluable GroupEvaluable Group

160140120100

80604020%

Cha

nge

-20-40-60-80

0

PR (0%) SD (12%) PD (70%)

Mutant

Patient

Pmab+ BSC

160140120100

80604020%

Cha

nge

-20-40-60-80

0

PR (17%) SD (34%) PD (36%)

Wild-Type

Patient160140120100

80604020

% C

hang

e

-20-40-60-80

0

PR (0%) SD (8%) PD (60%)

Patient

BSCAlone

16014012010080604020%

Cha

nge

-20-40-60-80

0

PR (0%) SD (12%) PD (75%)

Patient

Mutant Mutant KRASKRAS Subgroup:Subgroup:PFS by TreatmentPFS by Treatment

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Prop

ortio

n w

ith P

FS

Pmab + BSCBSC Alone

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34Weeks

36 38 40 42 44 46 48 50 52

Patients at Risk78 76 72 26 10 8 6 5 5 5 5 4 4 4 4 2 2 2 2 2 2 2 1 1 191 77 61 37 22 19 10 9 8 6 5 5 4 4 4 4 4 4 3 3 3 2 2 2 2

84100

76/84 (90) 7.4 9.995/100 (95) 7.3 10.2

Pmab + BSCBSC Alone

Events/N (%)Median

In WeeksMean

In Weeks

HR = 0.99 (95% CI: 0.73–1.36)

WildWild--type type KRASKRAS Subgroup: PFS by TreatmentSubgroup: PFS by Treatment

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34Weeks

36 38 40 42 44 46 48 50 52

7 7 6 5 510 9 9 6 6 6 5 4 3 3 2 2 2 2 1

124

115/124 (93) 12.3 19.0114/119 (96) 7.3 9.3

Pmab + BSCBSC Alone

Events/N (%)Median

In WeeksMean

In Weeks

HR = 0.45 (95% CI: 0.34–0.59)Stratified log-rank test, p < 0.0001

Pmab + BSCBSC Alone

Patients at Risk119 112 106 80 69 63 58 50 45 44 44 33 25 21 20 17 13 13 13 10

119 109 91 81 38 20 15 15 14 11 6

Prop

ortio

n w

ith P

FSp < 0.0001 for quantitative-interaction test comparing PFS log-HR

(pmab/BSC) between KRAS groups

Study Treatment Total number of patients with

KRAStested/total number of

patients on trial

Mutated KRAS

patients treated with anti-EGFR antibody

Mutated KRASpatients NOTtreated with anti-EGFR antibody

Wild-type KRAS

patients treated with anti-EGFR antibody

Wild-type KRAS

patients NOTtreated with anti-EGFR antibody

Per Protocol PFSHazard Ratio (HR)

Per Protocol PFSHazard Ratio (HR)

Jonker 2007

C0.17:BSC +/-

cetuximab (3rd line)

394/572(69%)

1.8 mos 1.8 mosHR 0.99

3.8 mos 1.9 mosHR 0.40

Amado 2008

Panitumumab vs BSC (3rd line)

427 / 463 (62%)

7.4 wks 7.3 wks HR 0.99

12.3 wks 7.3 wksHR 0.45

Van Cutsem

2008

CRYSTAL: FOLFIRI +/-

cetuximab (1st line)

540 / 1198 (45%)

7.6 mos 8.1 mos HR 1.07

9.9 mos 8.7 mosHR 0.68

Bokemeyer 2008

OPUS: FOLFOX +/-


233 / 337 (69%)

5.5 mos 8.6 mos HR 1.83

7.7 mos 7.2 mosHR 0.57

Punt 2008

CAIRO2: CapOx/BV +/-


501 / 755 (66%)

8.6 mos 12.5 mosHR not reported

10.5 mos 10.7 mosHR not reported

KRAS Summary

Objective Tumor Response Objective Tumor Response (Central Radiology)(Central Radiology)

KRAS

All Evaluablen (%)

Mutantn (%)

Wild-typen (%)

ResponsePmab

(N = 208)

BSC

(N = 219)

Pmab

(N = 84)

BSC

(N = 100)

Pmab

(N = 124)

BSC

(N = 119)

CR 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

PR 21 (10) 0 (0) 0 (0) 0 (0) 21 (17) 0 (0)

SD 52 (25) 22 (10) 10 (12) 8 (8) 42 (34) 14 (12)

PD 104 (50) 149 (68) 59 (70) 60 (60) 45 (36) 89 (75)

CR, PR, SD 73 (35) 22 (10) 10 (12) 8 (8) 63 (51) 14 (12)

Pmab, panitumumab; BSC, best supportive care; CR, complete response; PR partial response; SD, stable disease; PD, disease progression

7 Common Mutations

Mutation Base Change

Gly12Ala GGT>GCT

Gly12Asp GGT>GAT

Gly12Arg GGT>CGT

Gly12Cys GGT>TGT

Gly12Ser GGT>AGT

Gly12Val GGT>GTT

Gly13Asp GGC>GAC

These mutations cover 98.5% of KRAS mutations in CRC

Possible Reasons for resistance to anti-EGFR antibodies• detection technique

– direct sequencing with PCR vs mutation-enriched sequencing

– Mutations on other codons or in other memebers of ras family

• mutations in other members of the EGFR pathway– BRAF, PTEN

• over-production of EGFR ligands– epiregulin, amphiregulin

Rajagopalan et al Nature 2002

Copyright © American Society of Clinical Oncology

Di Nicolantonio, F. et al. J Clin Oncol; 26:5705-5712 2008

Fig 1. KRAS and BRAF mutations correlate with lack of response to treatment with monoclonal antibodies targeting epidermal growth factor receptor

Tol et al NEJM 2009

Loupakis et al JCO 2009

Loupakis et al JCO 2009

Amphiregulin and epiruglin mRNA expression in primary tumors predicts outcomes in metastatic colon cancer treated with cetuximabJacobs et al JCO 2009

• 220 patients participated in 4 trials and treated with single agent cetuximab

• gene expression and kras mutation on archival formalin-fixed paraffin-embeded primary tumor samples

Jacobs et al JCO 2009

Kaplan-Meier plots of (A) PFS and (B) OS by K-ras status and dichotomized epiregulin expression levels

Jacobs et al JCO 2009

Khambata-Ford et al JCO 2008

Cetuximab PanitumumabAntibody IgG1, chimeric IgG2, human

Approved Schedule Q weekly Q 2 weeks

Loading Dose Yes No

Mechanism other than EGFR ligand inhibition

Antibody dependent cell cytotoxicity

Not described

Approved Indication EGFR+, irinotecan-pretreated mCRC in

combination with irinotecan or as

monotherapy

EGFR+, wild-type KRAS mCRC, after

failure of 5FU, oxaliplatin and irinotecan as monotherapy

Cetuximab or Panitumumab ?

ERBITUX Product Monograph, September 2008

VECTIBIX Product Monograph, July 2008

Managing Common Adverse Effects of anti-EGFR

Antibodies

Hypersensitivity Reactions

• Infusion reaction: – 20% cetuximab, 4% panitumumab– usually after 1st dose

• Severe (grade 3/4) relatively rare– 0.5% for CO-17

• Grade 3/4 reaction:– symptomatic bronchospasm, associated with

edema/hypotension– anaphylaxis

O’Neil et al JCO 2007

Chung et al NEJM 2008

Potential antigenic sites on cetuximab

Management of infusion reactions

• Mild/moderate– discontinue infusion– H1 and H2 antihistamines, corticosteroids

• Severe– epinephrine, s.c. 0.2 – 0.5 mg in cases of respiratory

distress/hypotension– H1 and H2 antihistamines, corticosteroids, inhaled

bronchodilators• Subsequent treatments

– Antihistamine/corticosteroids pre-med– slower infusion rate for patients with mild/moderate

reactions– discontinue for patients with severe reactions

Langerak et al CCC, 2009

hypomangnesiumia

• Magnesum homeostasis– absorption: intestine– excretion: renal– re-absorption: loop of Henle

• EGFR strongly expressed in kidney– EGF: paracrine hormone in Mg reabsorption– EGFR inhibition: reduced Mg reabsorption and

wasting

Vincenzi et al CCR 2008

Vincenzi et al CCR 2008

Magnesium Supplement

• IV– MgSO4, 2-5 g over 2 hours

• Oral– various magnesium salts– magnesium oxide:

• highest content of Mg2+

• 1-2 tablets BID

1 2 3 4 5 6 7 8 9

EGFR Inhibitor–Induced Skin Reactions

Descriptionof severe

cases

Post inflammatory effectsAcne-like rash

Paronychia

Dry skin

Topical antiacnecreams (drying effect)

± tetracyclines± antihistamines

Pruritus

Pulse dye laser

Emollients Hydrocolloid dressing or propylene glycol ±acetylsalicyl

Antiseptic soaks, silver nitrate (pyogenic granuloma)

Fissura

Segaert S, et al. Ann Oncol. 2005;16:1425-1433.

Therapy Suggestions

Impact of Pre-emptive skin toxicity treatment on panitumumab-related skin

toxicities and quality of life in patients with metastatic colorectal cancer (STEPP)

LaCouture et al, ASCO GI 2009

Prophylactic skin treatment• Skin moisturizer

– apply to face, hands, feet, neck, chest and back daily in the morning upon rising

• Sunscreen (PABA free, SPF≥ 15, UVA/UVB protection)– apply to exposed areas before going outdoors

• Topical steroids (1% hydrocortisone cream)– apply to face, hands, feet, neck, back and chest at

bedtime• Doxycycline 100 mg BID

LaCouture et al ASCO GI 2009

Endpoints

• Primary– rates of ≥ grade 2 skin toxicity in 2 groups

• Secondary– efficacy of skin toxicity events– efficacy of panitumumab with

chemotherapy– patient-reported outcomes– safety

Primary endpointProphylactic

skin treatment (n=48)

Reactive skin treatment

(n=47)Patients with grade 2 or higher skin toxicity, n (%)

14 (29) 29 (62)

Odd ratio (95% CI) 0.3 (0.1 – 0.6)

Total panitumumab dose administered, n 155 141

Total panitumumab dose delayed, n (%) 1 (1) 9 (8)

Best Overall ResponseProphylactic

skin treatment (n=48)

Reactive skin treatment

(n=47)

Best Overall Response, n (%) 7 (15) 5 (11)

complete response 0 (0) 0 (0)

partial response 7 (15) 5 (11)

Stable disease 24 (50) 25 (53)

Disease progression 9 (19) 10 (21)

Not evaluable/available 8 (17) 7 (15)


Scope, A. et al. J Clin Oncol; 25:5390-5396 2007

Fig 1. Study schema, patient disposition, and attrition data by study week



Fig 2. Scatter plot of log lesion counts for minocycline and placebo groups for each of the four study time points



Fig 5. Scatter plot of differences in lesion counts for tazarotene and observation sides of the face for each of the four study time points

Martin-Martorell et al BJC 2008

Martin-Martorell et al BJC 2008

Stephenson et al CCC 2009

Comparison of panitumumab Cmax after 30 min and 60 min infusions

Stephenson et al CCC 2009

Summary• Anti-EGFR mAbs prolong survival in mCRC

patients with WT K-ras• Biomarkers could predict responses to

cetuximab/panitumumab• Skin toxicity could be reduced/delayed by

prophylactic use of topical and systemic treatments

• Cetuximab could be administered Q2W without compromising its efficacy or increasing toxicty

Documents

Targeting EGFR in Advanced Colorectal Cancer sept 18