identification of potentially responsive subsets when cetuximab is added to...

Identification of potentially responsive subsets when cetuximab is added to

oxaliplatin-fluoropyrimidine chemotherapy (CT) in first line

advanced colorectal cancer (aCRC): mature results of the MRC COIN trial Maughan TS, Adams RA, Smith C, Seymour M, Wilson R, Meade A,

Fisher D, Madi A, Cheadle J, Kaplan R on behalf of the MRC COIN Trial Investigators

NCRI Colorectal Clinical Studies Group

http://www.ncrn.org.uk/

COIN Trial design

OxMdG: 2 weekly IV l-folinic acid 175 mg, oxaliplatin 85mg/m2 over 2 h, IV bolus 5-FU 400mg/m2, 5-FU 2400mg/m2 inf. 46 h via ambulatory pump (mFOLFOX)XELOX: 3 weekly IV oxaliplatin 130mg/m2 over 2 h, capecitabine 1000mg/m2 p.o. bd for 2 weeks (reduced to 850 mg/m2 in Arm B from July 07 for toxicity)Pts/clinicians chose OxMdG or XELOX before randomisation.

5FU or capecitabineoxaliplatin

Arm A

CONTINUOUS CT until progression, toxicity or patient choice

5FU or capecitabineoxaliplatincetuximab

Arm B

CONTINUOUS CT until progression, toxicity or patient choice

FU or capoxaliplatin



Arm C

INTERMITTENT CT Treat for 12 weeks then stop and monitor. Restart on progression for a further 12 weeks

Second Line

Chemo-therapy

IrinotecanBased

815

815

815

InclusionAdvanced colorectal

cancer, First line therapy,

No prior chemo for metastatic disease,

No prior EGFR IHC

PS0-2,Good organ

functionCOIN question 2Is intermittent CT non-inferior?Adams poster discussion Tuesday abstract #3525

COIN question 1

• Does the addition of cetuximab to oxaliplatin based chemotherapy improve overall survival?

• Primary endpoint: Overall Survival• In patients with no mutation detected in codons 12,13

and 61 of KRAS• Secondary endpoints

• Overall survival in KRAS mutant, ‘all’ wildtype (KRAS, NRAS, BRAF), ‘any’ mutant, ITT

• Progression Free Survival • Response• Quality of Life (including Dermatology Life Quality Index)• Health economic evaluation

Baseline Characteristics

All pts KRASwt

Total randomised 2,445 1,123

Choice of chemo at baseline

Xelox 66% 66%

OxMdG 34% 34%

Sex Male 65% 68%

Female 35% 32%

Age median 63 64

≥75 yrs 9% 8%

WHO PS

0 46% 47%

1 46% 47%

2 8% 6%

Prior adjuvant chemotherapy

None 75% 73%

1-6mo 4% 4%

>6mo 16% 18%

Yes, unspecified 5% 5%

Presented for entire trial population, no significant differences were identified between arms

All pts KRASwt

Total randomised 2,445 1,123

Site of primary Rectum 31% 31%

Status of primary tumour

Resected 53% 54%

Unresected 42% 39%

Local recurrence 5% 7%

Metastases

Metachronous 30% 32%

Synchronous 69% 67%

Liver only 22% 24%

Liver + others 53% 51%

Non-liver 24% 24%

No. of metastatic sites

1 36% 37%

2 40% 40%

> 2 24% 22%

Mutations in Kras, Nras and Braf: distribution and prognostic significance

BRAF mutation All patientsAny mutationKRAS mutation

KRAS wild-typeAll wild-type

Mutation status:

06

12M

edia

n PF

S (m

onth

s) Arm A Arm B

06

1218

Med

ian

OS (m

onth

s)

57340

268815

367289

45366

297815

362292

010

2030

402-

year

OS

(%)

N:

Prognostic effect of mutational status

“All-wt”n=581 (44%)

KRAS-mutn=565 (43%)

NRAS-mutn=50 (4%)

BRAF-mutn=102 (8%)

Totaln=1316 (81%)

554

11

39

102

Population N Arm A Arm B

ITT 1630 815 815Assessed for mutations

1316 648 668

of which:- KRAS mutation- NRAS mutation- BRAF mutation

565 (43%)50 (4%)102 (8%)

2681857

2973245

KRAS wt 729 (55%)

367 362

KRAS/NRAS/BRAF-wt“All wild-type”

581 (44%) 289 292

Grade 3-5 Toxicities and deaths

Neutrophils WBC

HbPlatelets Arm A

Arm B

* = p<0.05** = p<0.01

*** = p<0.001

N patients experiencing at least one CTC Grade 3+ toxicity whilst receiving COIN protocol therapy

0 50 100 150 200

***

Hand-foot Skin rash

Nail changes ******

***

Neuropathy **

Diarrhoea Vomiting

Nausea

*** Stomatitis ***

Anorexialow Mg ***

**

Others Lethargy ***

**

All pts KRASwt

Arm A Arm B Arm A Arm B

Randomised 815 815 367 362Deaths < 60 days of randomisat’n

4.4% 5.3% 4.1% 4.4%

Safety population(started allocated treatment)

791

97%

802

98%

358

98%

357

99%All deaths ≤30 days of start of last trt. cycle

6.1% 7.7% 5.6% 7.0%

Treatm’t-rel. deaths ≤30 days of start of last trt. cycle

1.3% 1.1% 1.4% 0.8%

Arm A Arm B Diff.

Median OS : mo 17.9 17.0 -0.92

2-year survival rates 36.1% 34.4% -1.66%

Arm A

Arm B Diff.

Median PFS: mo 8.6 8.6 +0.072-year survival

rates 8.83% 9.55% +0.72%

OS (primary analysis) and PFS among KRAS wild-type patients

0.00

0.25

0.50

0.75

1.00

Sur

viva

l

362 306 238 149 80 42 17 3 B 367 316 250 154 83 44 19 1A

N patients at risk:

0 6 12 18 24 30 36 42Time (months)

Arm A (OxFp)

Arm B (OxFp + cetux)

HR point estimate = 1.03895% CI = (0.90, 1.20)Χ2 = 0.18; p = 0.68

Overall Survival Progression-free Survival

361 249 103 42 22 9 6 0

367 245 92 41 18 11 6 1

0 6 12 18 24 30 36 42Time (months)


Arm A (OxFp)


Overall Survival:by mutation status: KRAS, NRAS, BRAF

Arm A Arm B Diff.

Median survival:(mo) 20.1 19.9 -0.20

2-year survival rates

40.0% 38.8%

-1.24%

292 258 211 136 70 37 15 3B 289 256 208 133 76 41 19 1A

N patients at risk:

366 290 187 108 65 27 13 0

340 285 198 108 46 19 7 1

Arm A Arm B Diff.

Median survival: (mo) 14.4 12.7 -1.64

2-year survival rates 21.2% 25.5%

+4.29%

All wild type Any mutation

0.00

0.25

0.50

0.75

1.00

Sur

viva

l

0 6 12 18 24 30 36 42Time (months)

Arm A (OxFp)



0 6 12 18 24 30 36 42Time (months)

Arm A (OxFp)



Progression Free Survival:by mutation status: KRAS, NRAS, BRAF

366 200 59 21 8 4 2 0

340 204 61 24 7 2 1 0

Time (months)

Arm A

Arm B Diff.

Median PFS: mo 8.8 9.2

+0.43

2-year PFS rates10.2

%10.8%

+0.55%

Arm A

Arm B Diff.

Median PFS: mo 6.6 6.3 -0.33

2-year PFS rates3.45%

3.19% -0.26%

All wild-type Any mutation

0.00

0.25

0.50

0.75

1.00

Sur

viva

l

292 220 94 37 19 8 5 0Arm B

289 200 75 35 18 11 6 1Arm A No at risk

0 6 12 18 24 30 36 42

Time (months)

Arm A (OxFp)


HR = 0.92295% CI = (0.80, 1.07)97% CI = (0.78, 1.09)

p = 0.36

0 6 12 18 24 30 36 42

Arm A (OxFp)


HR = 1.07995% CI = (0.95, 1.23)97% CI = (0.93, 1.25)

p = 0.33

Response

Improved response rate in KRAS wt overall and at 12 weeks

All responses are investigator assessed, with no confirmatory scans

All pts KRASwt KRASmut

Arm A Arm B Arm A Arm B Arm A Arm BN randomised 815 815 367 362 268 297Overall Response Rate at 12 weeks

45% 49% 50% 59% 41% 40%

Odds ratio (B vs A) OR=1.17P=0.124

OR=1.44P=0.015

OR=0.97P=0.877

Best Overall Response(CR/PR at any time) 51% 53% 57% 64% 46% 43%Odds ratio (B vs A) OR=1.08

P=0.428OR=1.35P=0.049

OR=0.88P=0.449

Significant reduction in 2nd-line treatment in the Cetuximab arm

62%

50%56%

44%

010

2030

4050

6070

% o

f elig

ible

pat

ient

s

Any Irinotecan

65%

53%54%

42%

Any IrinotecanP=0.015 P=0.032

Arm AArm B

P=0.006 P=0.008

All patients KRASwt patients

Second line therapy received

0.88 (0.72, 1.08)

1.05 (0.75, 1.46)

428

153

<10,000/l

≥10,000/l

All pts

Sex

Age

Met sites

Fp therapy

Subgroup

MaleFemale

<=65y>65y

0/12+

Xelox

OxMdG

581

408173

338243

230351

391

190

N

0.92 (0.78, 1.10)

0.87 (0.71, 1.07)1.02 (0.74, 1.41)

1.00 (0.80, 1.26)0.81 (0.62, 1.06)

0.73 (0.55, 0.97)1.07 (0.86, 1.33)

1.02 (0.82, 1.26)

0.72 (0.53, 0.98)

HR (95% CI)

Favours cetuximab Favours no cetuximab 10.25 0.5 2 4

Interactionp-value

P=0.381

P=0.222

P=0.036

P=0.103

Predefined Subgroup analysesTo maximise responsiveness, sample used was “all wild-type” and outcome was PFS.

WBCP=0.411

Forest plot (PFS): kras status; choice of Fp; no of metastatic sites

KRAS-wt

KRAS-wt

KRAS-wt

KRAS-wt

KRAS-wt

KRAS-mut

KRAS-mut

KRAS-mut

KRAS-mut

KRAS-mut

Mutational status

OxMdG

Xelox

OxMdG

Xelox

OxMdG

Xelox

OxMdG

Xelox

OxFp therapy

0/1

0/1

2+

2+

0/1

0/1

2+

2+

N metastatic sites at baseline

729

96

184

148

301

565

63

135

116

251

N

0.96 (0.82, 1.12)

0.55 (0.35, 0.87)

1.02 (0.75, 1.40)

1.03 (0.73, 1.44)

1.05 (0.83, 1.33)

1.07 (0.90, 1.26)

0.96 (0.57, 1.61)

0.86 (0.60, 1.23)

1.06 (0.73, 1.54)

1.25 (0.96, 1.61)

HR (95% CI)

0.55 (0.35, 0.87)

10.33 0.5 2

All All

All All

Favours cetuximab Favours no cetuximab

Increased GI toxicity led toCapecitabine dose reduction

Capecitabine dose was reduced in arm B from 1000 to 850 mg/m2 b.d. because of increased Gastrointestinal toxicity

Xelox:

OxMdG

% of all randomised pts reporting diarrhoea G3+at any time whilst on trial

P-values

vs OxMdG,Arm B

B vs A

P=0.00520%11%

P=0.030P<0.00126%15%All

P=0.002P<0.00130%17%Before dose reduction

P=0.41P=0.2516%12%After dose reduction

279

536 534

Arm A Arm Bn n

281

153

381

Differentiating infusional 5FU/FA (OxMdG) and capecitabine (XELOX)

OxMdG XELOXIn Control Arm (A) Higher toxicity

Neutropenia, stomatitis

Higher dose intensity

In combination arm (B)

Maintained oxaliplatin dose

intensity

Higher GI toxicityProtocol reduction of

capecitabine doseReduced DI

Duration of therapy No differences with addition of cetuximab

Second line therapy Significantly lower usage of second

line therapy

Trend to reduction in second line

therapy

Summary

• Largest trial of EGFR targeted treatment in first-line ACRC setting• Prospective overall survival analysis by KRAS status

• >80% patients genotyped for KRAS, NRAS and BRAF• 43% KRAS mutation; 4% NRAS mutation; 8% BRAF mutation

• The addition of cetuximab to oxaliplatin based chemotherapy is associated with:• For all patients

• Increased non-haematological toxicity• No change in OS or PFS

• For KRASwt patients• Increased non-haematological toxicity• No change in OS (primary endpoint) or PFS• Increased response rate

Conclusions

• In this negative study, subgroup analyses suggest that there may be a benefit for cetuximab in combination with oxaliplatin chemotherapy in patients with• KRAS wildtype tumours, • Limited metastatic disease (0/1 metastatic sites), • Used in combination with infusional 5FU and oxaliplatin

• The differential benefit for choice of fluoropyrimidine and distribution of disease requires validation from other datasets

• Strong prognostic effect of KRAS, BRAF and NRAS mutation status independent of the use of cetuximab

Thank you

2445 Patients and families for agreeing to enter the trial• PIs/clinicians• Research nurses• Research networks

• NCRN• WCTN• SCRN• NICRN• ICORG

• Cancer Research-UK• MRC• Merck-Serono• NHS R&D• Cancer Research Wales• Cardiff University• NCRI

MRC CTUTrial Managers Sarah Kenny, Ed KayStatisticians David Fisher, Lindsay ThompsonData Managers Jenna Mitchell, Laura Nichols, Cheryl

Courtney, Louise Clement, Ben SydesSenior staff Angela Meade, Rick Kaplan, Max Parmar

Lynda Harper

Trial Management GroupCo-applicants Matt Seymour, Richard Wilson, Jim CassidyTrial Fellows Richard Adams, Ayman MadiPharmacy, Nurse Elizabeth Hodgkinson, Penny RogersQL, HE Richard Stephens, Mark SculpherPatient Malcolm PopeMedical Genetics Cardiff Jeremy Cheadle, Chris Smith, Bharat

Jasani, Michelle James, Shelley Idziaszczyk, Wales Cancer Bank Alison Parry-JonesLeuven Dieter Lambrechts

http://www.ncrn.org.uk/

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