A trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) and the Australasian Gastro-Intestinal Trials Group (AGITG) A Randomized

A trial of the National Cancer Institute of Canada Clinical Trials Group

(NCIC CTG)

and theAustralasian Gastro-Intestinal Trials Group

(AGITG)

A Randomized Phase III Trial of Cetuximab + A Randomized Phase III Trial of Cetuximab + Best Supportive Care (BSC) versus BSC Alone in Best Supportive Care (BSC) versus BSC Alone in

Patients with Pre-treated Metastatic EGFR-Patients with Pre-treated Metastatic EGFR-Positive Colorectal Cancer Positive Colorectal Cancer (NCIC CTG CO.17)(NCIC CTG CO.17)

The Influence of The Influence of K-rasK-ras Exon 2 Exon 2 Mutations on Outcomes Mutations on Outcomes

InIn

NCIC CTG CO.17: Randomized Phase III Trial in mCRC

EGFR EGFR testing testing

by IHCby IHC

* Cetuximab 400 mg/m* Cetuximab 400 mg/m2 2 IV week 1 then 250 mg/m IV week 1 then 250 mg/m22 IV weekly IV weekly

Disease Disease Progression Progression

oror

Unacceptable Unacceptable ToxicityToxicity

RREEGGIISSTTEERR

RRAANNDDOOMMI I ZZEE

1:11:1

Cetuximab* + BSC

BSC alone

Failed or intolerant to all recommended therapies, Failed or intolerant to all recommended therapies, ECOG 0-2, No Prior EGFR directed therapyECOG 0-2, No Prior EGFR directed therapy

Primary Endpoint: Primary Endpoint: Overall Survival Overall Survival Secondary Endpoints: Secondary Endpoints: Progression Free SurvivalProgression Free Survival

Objective Response Rate (RECIST Objective Response Rate (RECIST criteria)criteria)

Safety and Quality of Life Safety and Quality of Life

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

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

MONTHS

0 3 6 9 12 15 18 21 24 27

NCIC CTG CO.17: Overall Survival

HR 0.77HR 0.77 (95% CI =0.64 – 0.92) (95% CI =0.64 – 0.92)

Stratified log rankStratified log rank p-value = 0.0046 p-value = 0.0046

Study armStudy arm MS MS (months)(months)

95% CI95% CI

Cetuximab + Cetuximab + BSCBSC

6.16.1 5.4 – 6.75.4 – 6.7

BSC aloneBSC alone 4.64.6 4.2 – 4.94.2 – 4.9

Jonker et al , NEJM 2007

NCIC CTG CO.17: Progression Free Survival

CETUXIMAB + BSCCETUXIMAB + BSCCENSOREDCENSORED

BSCBSCCENSOREDCENSORED

Prop

ortio

n Pr

ogre

ssio

n-Fr

eePr

opor

tion

Prog

ress

ion-

Free

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

MONTHSMONTHS00 33 66 99 1212 1515

HR 0.68HR 0.68 (95% CI =0.57 – 0.80) (95% CI =0.57 – 0.80)

Stratified log rankStratified log rank p-value < 0.0001 p-value < 0.0001

Study armStudy arm Med PFS Med PFS (months)(months)

95% CI95% CI

Cetuximab + BSCCetuximab + BSC 1.91.9 1.8 – 1.8 – 2.12.1

BSC aloneBSC alone 1.81.8 1.8 – 1.8 – 1.91.9

Jonker et al , NEJM 2007

Which patients benefit?

A reliable biomarker is needed: A reliable biomarker is needed: • to provide an accurate prediction of who will to provide an accurate prediction of who will

respond and benefit from cetuximab respond and benefit from cetuximab • to improve the therapeutic index to improve the therapeutic index • to improve cost effectiveness of EGFR to improve cost effectiveness of EGFR

monoclonal antibody based therapy of pre-monoclonal antibody based therapy of pre-treated colorectal cancer treated colorectal cancer

The predictive value of the biomarker would need The predictive value of the biomarker would need to be differentiated from its prognostic to be differentiated from its prognostic implicationsimplications

The The K-rasK-ras mutation status of the bowel cancer may mutation status of the bowel cancer may be such a marker of response and a predictor of be such a marker of response and a predictor of benefitbenefit

EGFR Signaling Cascade and EGFR Signaling Cascade and K-rasK-ras

Akt

SOS

FOS Myc

P13K

FKHRmTOR

PTEN

MEK 1/2

MAPK

BADGSK-3

Shc

Grb-2

Ras

Raf

Junp27

Cyclin D-1

LigandLigand

SignalSignalAdaptersAdaptersand Enzymesand Enzymes

SignalSignalCascadeCascade

EGFREGFR dimerdimer

TranscriptionTranscriptionFactorsFactors

STAT

K-ras is a small G protein K-ras is a small G protein

Self inactivating – from GDP to GTP stateSelf inactivating – from GDP to GTP stateSwitched off by intrinsic GTPase activitySwitched off by intrinsic GTPase activityK-ras mutation leads to constitutive K-ras mutation leads to constitutive activation activation mediated through reduced GTPase activitymediated through reduced GTPase activity Inhibitors upstream may be ineffectiveInhibitors upstream may be ineffective

NCIC CTG CO.17 K-Ras Analysis

• Genomic DNA extracted from FFPET slides or sections• Assessed by bidirectional sequencing for codon 12/13 mutations• No difference between K-ras mutated and WT 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%)wild-typewild-type

Comparison of ITT and Comparison of ITT and K-ras K-ras assessed assessed subsetssubsets

BaselineBaselineCharacteristicCharacteristic

ITTITT(N = 572)(N = 572)

Mutated Mutated K-ras K-ras

(N = 164)(N = 164)

Wild-type Wild-type K-rasK-ras

(N = 230)(N = 230)

p-p-valuevalue

**Age – medianAge – median 63.263.2 62.062.0 63.563.5 0.5690.569Gender FGender F 204 ( 35.7)204 ( 35.7) 63 ( 38.4)63 ( 38.4) 74 ( 32.2)74 ( 32.2) 0.2000.200 MM 368 ( 64.3)368 ( 64.3) 101 ( 61.6)101 ( 61.6) 156 ( 67.8)156 ( 67.8)ECOG PS 0 ECOG PS 0 136 ( 23.8)136 ( 23.8) 34 ( 20.7)34 ( 20.7) 56 ( 24.3)56 ( 24.3) 0.6950.695 11 302 ( 52.8)302 ( 52.8) 94 ( 57.3)94 ( 57.3) 127 ( 55.2)127 ( 55.2) 22 134 ( 23.4)134 ( 23.4) 36 ( 22.0)36 ( 22.0) 47 ( 20.4)47 ( 20.4)Prior XRTPrior XRT 202 (35.3)202 (35.3) 50 ( 30.5)50 ( 30.5) 77 ( 33.5)77 ( 33.5) 0.5310.531Prior chemoRxPrior chemoRx adjuvantadjuvant 211 (36.9)211 (36.9) 57 ( 34.8)57 ( 34.8) 83 ( 36.1)83 ( 36.1) 0.7860.786 antiTS antiTS 572 (100.0)572 (100.0) 164 (100.0)164 (100.0) 230 (100.0)230 (100.0) irinotecanirinotecan 550 (96.2)550 (96.2) 161 ( 98.2)161 ( 98.2) 219 ( 95.2)219 ( 95.2) 0.1190.119 oxaliplatinoxaliplatin 559 (97.7)559 (97.7) 163 ( 99.4)163 ( 99.4) 222 ( 96.5)222 ( 96.5) 0.0600.060Arm CETArm CET 287 (50.2)287 (50.2) 81 ( 49.4)81 ( 49.4) 117 ( 50.9)117 ( 50.9) 0.7720.772

BSC BSC

285 (49.8)285 (49.8)83 ( 50.6)83 ( 50.6) 113 ( 49.1)113 ( 49.1)*between mutated and wild-type K-RAS groups from chi-square test for categorical *between mutated and wild-type K-RAS groups from chi-square test for categorical

variables and t-test for continuous variables. variables and t-test for continuous variables.

NCIC CTG C0.17: NCIC CTG C0.17: Primary endpoint overall survival

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12 14 16 18

Time from Randomisation (Months)

Pro

porti

on A

live

CetuximabBSC

CetuximabBSC

287 245 189 136 87 60 37 20 13 4285 235 157 85 58 37 26 15 11 8

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12 14 16 18


Pro

porti

on A

live

CetuximabBSC

CetuximabBSC

198 177 141 108 68 45 27 13 8 3196 161 111 64 44 30 23 12 8 5

Total study Total study population (ITT population (ITT

analysis)analysis)K-rasK-ras assessed assessed

subsetsubset

NCIC CTG C0.17: PFS in the NCIC CTG C0.17: PFS in the Mutant Mutant K-ras K-ras SubgroupSubgroup

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12


Pro

porti

on P

rogr

essi

on F

ree

CetuximabBSC

CetuximabBSC

81 21 8 383 27 9 4

HR HR 0.99 0.99 95% CI (0.73,1.35) 95% CI (0.73,1.35)

Log rank p-value: Log rank p-value: 0.960.96


95% CI95% CI


1.81.8 1.7 – 1.81.7 – 1.8


NCIC CTG C0.17: PFS in the NCIC CTG C0.17: PFS in the K-K-rasras Wild-Type Patients Wild-Type Patients

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12


Pro

porti

on P

rogr

essi

on F

ree

CetuximabBSC

CetuximabBSC

117 74 50 26 8 5113 43 14 2 1 1

HR HR 0.40 0.40 95% CI (0.30,0.54) 95% CI (0.30,0.54)

Log rank p-value: Log rank p-value: <0.0001<0.0001


95% CI95% CI


3.83.8 3.1 – 5.13.1 – 5.1


NCIC CTG C0.17: Overall NCIC CTG C0.17: Overall survival in survival in K-rasK-ras Mutant Mutant

patientspatients

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12 14 16 18


Pro

porti

on A

live

CetuximabBSC

CetuximabBSC

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

HR HR 0.98 0.98 95% CI (0.70,1.37) 95% CI (0.70,1.37)



95% CI95% CI


4.54.5 3.8 – 5.63.8 – 5.6


NCIC CTG C0.17: Overall NCIC CTG C0.17: Overall survival in survival in K-rasK-ras Wild-Type Wild-Type

patientspatients

HR HR 0.550.55 95% CI (0.41,0.74) 95% CI (0.41,0.74)

Log rank p-value: Log rank p-value: <0.0001<0.0001

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12 14 16 18


Prop

ortio

n Ali

ve

CetuximabBSC

CetuximabBSC

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


95% CI95% CI


9.59.5 7.7 – 7.7 – 10.310.3


NCIC CTG C0.17: NCIC CTG C0.17: Overall Survival by K-ras Status in BSC

ARM

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12 14 16 18


Pro

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live

MutatedWild Type

MutatedWild Type

83 69 42 28 20 13 11 7113 92 69 36 24 17 12 5

HR HR 1.01 1.01 95% CI (0.74,1.37) 95% CI (0.74,1.37)


KRAS statusKRAS status MS MS (months)(months)

95% CI95% CI

MutatedMutated 4.64.6 3.6 – 5.53.6 – 5.5Wild-TypeWild-Type 4.84.8 4.2 – 5.54.2 – 5.5

NCIC CTG C0.17: NCIC CTG C0.17: Overall Survival by K-ras Status in BSC

ARM

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12 14 16 18


Pro

porti

on A

live

MutatedWild Type

MutatedWild Type

83 69 42 28 20 13 11 7113 92 69 36 24 17 12 5

HR HR 1.01 1.01 95% CI (0.74,1.37) 95% CI (0.74,1.37)


KRAS statusKRAS status MS MS (months)(months)

95% CI95% CI

MutatedMutated 4.64.6 3.6 – 5.53.6 – 5.5Wild-TypeWild-Type 4.84.8 4.2 – 5.54.2 – 5.5

NO PROGNOSTIC IMPACT NO PROGNOSTIC IMPACT OF K-ras STATUSOF K-ras STATUS

NCIC CTG CO.17: Response Assessment

• In the BSC arm there was no response

• In cetuximab treated patients:

02468

101214

ORR (% )

MutantWild Type

n=13n=1312.8%12.8%

n=1n=11.2%1.2%

NCIC CTG CO.17: NCIC CTG CO.17: K-rasK-ras and Cetuximab Conclusions and Cetuximab Conclusions

In the context of pre-treated advanced colorectal In the context of pre-treated advanced colorectal cancer:cancer:

• There is no benefit in using cetuximab monotherapy There is no benefit in using cetuximab monotherapy in patients that have mutated in patients that have mutated K-rasK-ras tumours tumours

• There is 4.7 month improvement in median survival There is 4.7 month improvement in median survival with cetuximab in patients with with cetuximab in patients with K-rasK-ras wild-type wild-type tumourstumours

• The p-value for the interaction between The p-value for the interaction between K-rasK-ras status status and treatment is 0.01and treatment is 0.01

• There is an improvement in PFS with cetuximab in There is an improvement in PFS with cetuximab in K-K-rasras wild-type tumours wild-type tumours

• K-rasK-ras mutation status does not have a treatment- mutation status does not have a treatment-independent prognostic effectindependent prognostic effect

AcknowledgementsFrom NCIC CTG:Derek JonkerChris O’CallaghanMalcolm MooreDongsheng TuHeather-Jane AuShakeel VirkSonia RobitailleLois Shepherd

From AGITG:Christos KarapetisJohn ZalcbergJohn SimesNiall TebbuttTim PriceJeremy Shapiro

From BMS: Shirin Khambata-FordChristiane LangerDaniel MalonePaola TeegardenChristopher Harbison

All Other NCIC CTG and All Other NCIC CTG and AGITG Investigators AGITG Investigators and Central Office Staffand Central Office Staff

Study Nurses, Study Nurses, Coordinators, MonitorsCoordinators, Monitors

Acknowledgements

Special thanks and appreciation to Special thanks and appreciation to all the patients and their familiesall the patients and their families

Documents

A trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) and the Australasian Gastro-Intestinal Trials Group (AGITG) A Randomized