Adjuvant mFOLFOX6 +/- cetuximab in patients with K-ras mutant resected stage III colon cancer

1

Adjuvant mFOLFOX6 +/- cetuximab Adjuvant mFOLFOX6 +/- cetuximab in patients in patients with K-ras mutantwith K-ras mutant

resected stage III colon cancerresected stage III colon cancer

Adjuvant mFOLFOX6 +/- cetuximab Adjuvant mFOLFOX6 +/- cetuximab in patients in patients with K-ras mutantwith K-ras mutant

resected stage III colon cancerresected stage III colon cancer

Richard Goldberg, Daniel Sargent, Stephen Thibodeau, Richard Goldberg, Daniel Sargent, Stephen Thibodeau, Michelle Mahoney, Anthony Shields, Emily Chan, Sharlene Michelle Mahoney, Anthony Shields, Emily Chan, Sharlene Gill, Morton Kahlenberg, Suresh Nair, Steven AlbertsGill, Morton Kahlenberg, Suresh Nair, Steven Alberts

Richard Goldberg, Daniel Sargent, Stephen Thibodeau, Richard Goldberg, Daniel Sargent, Stephen Thibodeau, Michelle Mahoney, Anthony Shields, Emily Chan, Sharlene Michelle Mahoney, Anthony Shields, Emily Chan, Sharlene Gill, Morton Kahlenberg, Suresh Nair, Steven AlbertsGill, Morton Kahlenberg, Suresh Nair, Steven Alberts

* Coordinating group

Cooperative Group Trial N0147NCCTG*, CALGB, ECOG, NCIC,

NSABP, SWOG

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DisclosuresDisclosuresDisclosuresDisclosures

• Dr Goldberg has received Dr Goldberg has received honoraria, consulting fees or honoraria, consulting fees or research support from research support from • Bristol Meyers SquibbBristol Meyers Squibb• ImCloneImClone• sanofi-aventissanofi-aventis

• Dr Goldberg has received Dr Goldberg has received honoraria, consulting fees or honoraria, consulting fees or research support from research support from • Bristol Meyers SquibbBristol Meyers Squibb• ImCloneImClone• sanofi-aventissanofi-aventis

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Survival (anti-apoptosis)

Gene transcriptionGene transcriptionCell-cycle progressionCell-cycle progression

Angiogenesis

Invasion andmetastasis

Chemotherapy /radiotherapy resistance

Proliferation

pY

Ligand

Antibodies to EGFRcetuximab, panitumumab

EGFR-TKpY

EGF Receptor:EGF Receptor: Its Role in CRC Therapy Its Role in CRC Therapy

EGF Receptor:EGF Receptor: Its Role in CRC Therapy Its Role in CRC Therapy

Venook, Oncologist 2005Venook, Oncologist 2005Venook, Oncologist 2005Venook, Oncologist 2005

RAS RAF

MEK

MAPK

PI3K

AKTSTAT

PTEN

pY

pY

4



Angiogenesis



Proliferation

pY

Ligand

EGFR-TKpY

EGF Receptor:EGF Receptor:EGF Receptor:EGF Receptor:


RAS RAF

MEK

MAPK

PI3K

AKTSTAT

PTEN

pY

pY

5



Angiogenesis



Proliferation

pY

Ligand

EGFR-TKpY

EGF Receptor:EGF Receptor:EGF Receptor:EGF Receptor:


RAS RAF

MEK

MAPK

PI3K

AKTSTAT

PTEN

pY

pY

6

Epidermal Growth Factor Receptor Pathway Map

7

““Bypass” Pathways and EGFR Bypass” Pathways and EGFR ResistanceResistance

““Bypass” Pathways and EGFR Bypass” Pathways and EGFR ResistanceResistance

Clin Ca Res, Jan 2005

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Initial 2-arm Design for N0147Initial 2-arm Design for N0147Initial 2-arm Design for N0147Initial 2-arm Design for N0147

Stage 3 Stage 3 Colon Colon CancerCancer(N = 2300)(N = 2300)

RRAANNDDOOMMIIZZEE

mFOLFOX6 (12 cycles)mFOLFOX6 (12 cycles)• Oxaliplatin 85 mg/mOxaliplatin 85 mg/m22

• LV 400 mg/mLV 400 mg/m22 & & • 5-FU 2,400 mg/m5-FU 2,400 mg/m22 over over

46 hrs every 2 weeks46 hrs every 2 weeks

mFOLFOX6 + CetuximabmFOLFOX6 + Cetuximab (12 cycles)(12 cycles)

• mFOLFOX6 mFOLFOX6 • Cetuximab days 1,8Cetuximab days 1,8 - 400 mg/m- 400 mg/m22 loading dose loading dose - 250 mg/m- 250 mg/m22 weekly weekly

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Treatment Assignment,Treatment Assignment,by K-ras Statusby K-ras Status

Treatment Assignment,Treatment Assignment,by K-ras Statusby K-ras Status

FOLFOX FOLFOX+Cmab

Total

K-ras WT 909 955 1864

K-ras Mut

374 343 717

Total 1283 1298 2581

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0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36

Time (Months)

%Al

ive

and

Dis

ease

Fre

e

FOLFOX

FOLFOX + Cmab

DFS: FOLFOX +/- Cmab by DFS: FOLFOX +/- Cmab by K-ras status K-ras status

DFS: FOLFOX +/- Cmab by DFS: FOLFOX +/- Cmab by K-ras status K-ras status

K-Ras WTK-Ras WTK-Ras WTK-Ras WT K-Ras MutK-Ras MutK-Ras MutK-Ras Mut

ArmArm 3 Year Rates 3 Year Rates

(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-P-valuevalue

FOLFOXFOLFOX

N=374N=374

67.2%67.2%

(61.4-73.5%)(61.4-73.5%)

1.21.2

(0.9-1.6)(0.9-1.6)

0.130.13

FOLFOX FOLFOX + Cmab+ Cmab

N=343N=343

64.2%64.2%

(58.7-70.2%)(58.7-70.2%)

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36

Time (Months)

% A

live

and

Dis

ease

Fre

e

FOLFOXFOLFOX + Cmab


(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-P-valuevalue

FOLFOXFOLFOX

N=902N=902

75.8%75.8%

(72.1-79.6%)(72.1-79.6%)

1.21.2

(0.96-(0.96-1.5)1.5)

0.220.22


N=945N=945

72.3%72.3%

(68.5-76.4%)(68.5-76.4%)

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0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36

Time (Months)

%A

live

FOLFOX

FOLFOX + Cmab

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36

Time (Months)

% A

live

FOLFOXFOLFOX + Cmab

K-Ras WTK-Ras WTK-Ras WTK-Ras WT K-Ras MutK-Ras MutK-Ras MutK-Ras Mut


(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-P-valuevalue

FOLFOXFOLFOX

N=374N=374

88.0%88.0%

(83.8%-92.5%)(83.8%-92.5%)

1.51.5

(0.9-2.3)(0.9-2.3)

0.120.12


N=343N=343

80.4%80.4%

(74.8%-86.4%)(74.8%-86.4%)


(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-P-valuevalue

FOLFOXFOLFOX

N=902N=902

87.8%87.8%

(84.7%-90.9%)(84.7%-90.9%)

1.31.3

(0.96-(0.96-1.8)1.8)

0.130.13


N=945N=945

83.9%83.9%

(80.3%-87.6%)(80.3%-87.6%)

OS: FOLFOX +/- Cmab by OS: FOLFOX +/- Cmab by K-ras status K-ras status

OS: FOLFOX +/- Cmab by OS: FOLFOX +/- Cmab by K-ras status K-ras status

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Duration of TherapyDuration of TherapyDuration of TherapyDuration of Therapy

K-Ras WT

CycleCycle FOLFOXFOLFOX

(N=871)(N=871)

FOLFOX+FOLFOX+

CmabCmab

(N=925)(N=925)

P-valueP-value

66 89%89% 79%79% <0.0001<0.0001

88 85%85% 75%75% <0.0001<0.0001

1010 82%82% 72%72% <0.0001<0.0001

1212 78%78% 67%67% <0.0001<0.0001

K-Ras Mut

CycleCycle FOLFOXFOLFOX

(N=374)(N=374)

FOLFOX+FOLFOX+

CmabCmab

(N=343)(N=343)

P-valueP-value

66 87%87% 87%87% 0.740.74

88 84%84% 81%81% 0.310.31

1010 81%81% 76%76% 0.090.09

1212 75%75% 70%70% 0.100.10

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Was adverse impact of Cetuximab Was adverse impact of Cetuximab due to dosing issues?due to dosing issues?


• In post-hoc analysis, attempted to In post-hoc analysis, attempted to identify ‘ideal’ patientsidentify ‘ideal’ patients• First 6 cycles with First 6 cycles with >> 80% dose 80% dose

intensity for all drugsintensity for all drugs• Consider only patients aged < 70Consider only patients aged < 70

• If no benefit in these pts (young, If no benefit in these pts (young, >> 80% 80% dose rec’d), then adverse impact not dose rec’d), then adverse impact not likely due to reduced dosinglikely due to reduced dosing

• In post-hoc analysis, attempted to In post-hoc analysis, attempted to identify ‘ideal’ patientsidentify ‘ideal’ patients• First 6 cycles with First 6 cycles with >> 80% dose 80% dose

intensity for all drugsintensity for all drugs• Consider only patients aged < 70Consider only patients aged < 70

• If no benefit in these pts (young, If no benefit in these pts (young, >> 80% 80% dose rec’d), then adverse impact not dose rec’d), then adverse impact not likely due to reduced dosinglikely due to reduced dosing

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• Comparison based on dosing not Comparison based on dosing not protected by randomization, thus protected by randomization, thus possibly confounded with other reasons possibly confounded with other reasons for stopping treatmentfor stopping treatment

• AlternativeAlternative• Use Time to Recurrence endpointUse Time to Recurrence endpoint• Most sensitiveMost sensitive• Least confoundedLeast confounded

• Comparison based on dosing not Comparison based on dosing not protected by randomization, thus protected by randomization, thus possibly confounded with other reasons possibly confounded with other reasons for stopping treatmentfor stopping treatment

• AlternativeAlternative• Use Time to Recurrence endpointUse Time to Recurrence endpoint• Most sensitiveMost sensitive• Least confoundedLeast confounded

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Dose Intensity (% with Dose Intensity (% with >> 80%) 80%) K-ras WTK-ras WT

Dose Intensity (% with Dose Intensity (% with >> 80%) 80%) K-ras WTK-ras WT

ArmArm OxaliplatinOxaliplatin 5-FU5-FU CetuximabCetuximab

FOLFOX FOLFOX

(N=672)(N=672)

69%69% 85%85% N/AN/A

FOLFOX + CmabFOLFOX + Cmab

(N=645)(N=645)

61%61% 74%74% 63%63%

P-valueP-value 0.00030.0003 <0.0001<0.0001


FOLFOXFOLFOX

(N=613)(N=613)

50%50% 81%81% N/AN/A


(N=582)(N=582)

44%44% 65%65% 55%55%

P-valueP-value 0.030.03 <0.0001<0.0001

Cycle 6

Cycle 10

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Dose Intensity (% with Dose Intensity (% with >> 80%) 80%) K-ras MutK-ras Mut

Dose Intensity (% with Dose Intensity (% with >> 80%) 80%) K-ras MutK-ras Mut


FOLFOX FOLFOX

(N=300)(N=300)

66%66% 84%84% N/AN/A


(N=278)(N=278)

60%60% 73%73% 59%59%

P-valueP-value 0.140.14 0.0010.001


FOLFOXFOLFOX

(N=276)(N=276)

44%44% 78%78% N/AN/A


(N=238)(N=238)

41%41% 63%63% 53%53%

P-valueP-value 0.480.48 0.00020.0002

Cycle 6

Cycle 10

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0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36

Time (Months)

%Di

seas

e Fr

ee

FOLFOX

FOLFOX + Cmab

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36

Time (Months)

%Di

seas

e Fr

ee

FOLFOX

FOLFOX + Cmab

““Idealized” Patient Comparison: Idealized” Patient Comparison: Time to Recurrence – K-Ras WTTime to Recurrence – K-Ras WT““Idealized” Patient Comparison: Idealized” Patient Comparison: Time to Recurrence – K-Ras WTTime to Recurrence – K-Ras WT

All PatientsAll PatientsAll PatientsAll Patients ““Ideal” PatientsIdeal” Patients““Ideal” PatientsIdeal” Patients


(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-P-valuevalue

FOLFOXFOLFOX

N=902N=902

77.1%77.1%

(73.4-80.8%)(73.4-80.8%)

1.21.2

(0.9-1.5)(0.9-1.5)

0.350.35


N=945N=945

73.7%73.7%

(69.7-77.9%)(69.7-77.9%)


(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-P-valuevalue

FOLFOXFOLFOX

N=485N=485

75.9%75.9%

(71.0-81.0%)(71.0-81.0%)

1.21.2

(0.6-2.2)(0.6-2.2)

0.980.98


N=191N=191

77.7%77.7%

(70.7-85.3%)(70.7-85.3%)

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36

Time (Months)

% D

isea

se F

ree

FOLFOXFOLFOX + Cmab

18

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36

Time (Months)

% D

isea

se F

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FOLFOX

FOLFOX + Cmab

0

10

20

30

40

50

60

70

80

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100

0 6 12 18 24 30 36

Time (Months)

%D

isea

se F

ree

FOLFOXFOLFOX + Cmab

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36

Time (Months)

%D

isea

se F

ree

FOLFOXFOLFOX + Cmab

““Idealized” Patient Comparison: Idealized” Patient Comparison: Time to Recurrence – K-Ras MutTime to Recurrence – K-Ras Mut““Idealized” Patient Comparison: Idealized” Patient Comparison: Time to Recurrence – K-Ras MutTime to Recurrence – K-Ras Mut

All PatientsAll PatientsAll PatientsAll Patients ““Ideal” PatientsIdeal” Patients““Ideal” PatientsIdeal” Patients


(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-P-valuevalue

FOLFOXFOLFOX

N=198N=198

65.9%65.9%

(57.6-75.3%)(57.6-75.3%)

1.11.1

(0.5-2.6)(0.5-2.6)

0.160.16


N=70N=70

56.9%56.9%

(43.0-75.3%)(43.0-75.3%)


(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-P-valuevalue

FOLFOXFOLFOX

N=374N=374

66.8%66.8%

(60.7-73.4%)(60.7-73.4%)

1.11.1

(0.8-1.5)(0.8-1.5)

0.260.26


N=343N=343

65.3%65.3%

(59.6-71.5%)(59.6-71.5%)

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0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36

Time (Months)

% D

isea

se F

ree

FOLFOXFOLFOX + Cmab

0

10

20

30

40

50

60

70

80

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100

0 6 12 18 24 30 36

Time (Months)

% D

iseas

e Fre

e

FOLFOXFOLFOX + Cmab

Age < 70Age < 70Age < 70Age < 70 Age Age >> 70 70Age Age >> 70 70


(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-P-valuevalue

FOLFOXFOLFOX

N=112N=112

84.4%84.4%

(76.7-92.8%)(76.7-92.8%)

1.81.8

(0.9-3.4)(0.9-3.4)

0.070.07


N=146N=146

70.8%70.8%

(61.3-81.7%)(61.3-81.7%)


(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-P-valuevalue

FOLFOXFOLFOX

N=790N=790

75.7%75.7%

(71.7-80.0%)(71.7-80.0%)

1.11.1

(0.9-1.4)(0.9-1.4)

0.800.80


N=799N=799

74.1%74.1%

(69.8-78.8%)(69.8-78.8%)

Time to Recurrence: FOLFOX Time to Recurrence: FOLFOX +/- Cmab in K-Ras WT +/- Cmab in K-Ras WT

Time to Recurrence: FOLFOX Time to Recurrence: FOLFOX +/- Cmab in K-Ras WT +/- Cmab in K-Ras WT

20

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36

Time (Months)

% D

isea

se F

ree

FOLFOX

FOLFOX + Cmab

0

10

20

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40

50

60

70

80

90

100

0 6 12 18 24 30 36

Time (Months)

% D

iseas

e Fre

e

FOLFOXFOLFOX + Cmab

Age < 70Age < 70Age < 70Age < 70 Age Age >> 70 70Age Age >> 70 70


(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-P-valuevalue

FOLFOXFOLFOX

N=320N=320

67.1%67.1%

(60.6-74.2%)(60.6-74.2%)

1.11.1

(0.8-1.5)(0.8-1.5)

0.290.29


N=296N=296

65.5%65.5%

(59.5-72.2%)(59.5-72.2%)


(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-P-valuevalue

FOLFOXFOLFOX

N=54N=54

65.0%65.0%

(49.8-84.7%)(49.8-84.7%)

1.31.3

(0.6-2.7)(0.6-2.7)

0.600.60


N=47N=47

62.5%62.5%

(47.2-82.9%)(47.2-82.9%)

Time to Recurrence: FOLFOX Time to Recurrence: FOLFOX +/- Cmab in K-Ras Mut +/- Cmab in K-Ras Mut

Time to Recurrence: FOLFOX Time to Recurrence: FOLFOX +/- Cmab in K-Ras Mut +/- Cmab in K-Ras Mut

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% Grade 3+ Adverse Events% Grade 3+ Adverse Events% Grade 3+ Adverse Events% Grade 3+ Adverse EventsK-Ras WTK-Ras WTK-Ras WTK-Ras WT K-Ras MutK-Ras MutK-Ras MutK-Ras Mut

Adverse EventAdverse Event FOLFOXFOLFOX

(N=883)(N=883)

FOLFOX + CFOLFOX + C

(N=919)(N=919)

ParesthesiasParesthesias 99 77

N-penia (Gr 4+)N-penia (Gr 4+) 1010 1111

DiarrheaDiarrhea 88 1515

NauseaNausea 33 44

ThrombosisThrombosis 33 33

HypokalemiaHypokalemia 33 88

FatigueFatigue 33 66

HypersensitivityHypersensitivity 22 66

VomitingVomiting 33 33

RashRash 0.10.1 88

MucositisMucositis 22 77

Adverse EventAdverse Event FOLFOXFOLFOX

(N=364)(N=364)

FOLFOX + CFOLFOX + C

(N=339)(N=339)

ParesthesiasParesthesias 1313 99

N-penia (Gr 4+)N-penia (Gr 4+) 1212 1313

DiarrheaDiarrhea 88 1515

NauseaNausea 22 66

ThrombosisThrombosis 33 55

HypokalemiaHypokalemia 33 55

FatigueFatigue 33 44

HypersensitivityHypersensitivity 33 66

VomitingVomiting 33 55

RashRash 00 99

MucositisMucositis 33 77

AEs did not differ by KRAS status

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0

10

20

30

40

50

60

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100

0 6 12 18 24 30 36

Time (Months)

% A

live

an

d D

ise

ase

Fre

e

MutWT

Is K-ras prognostic in FOLFOX Is K-ras prognostic in FOLFOX treated patients?treated patients?

Is K-ras prognostic in FOLFOX Is K-ras prognostic in FOLFOX treated patients?treated patients?

K-ras K-ras StatusStatus

3 Year Rates 3 Year Rates

(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-P-valuevalue

WTWT

N=902N=902

75.8%75.8%

(72.1-79.6%)(72.1-79.6%)

0.70.7

(0.5-0.9)(0.5-0.9)

0.040.04

MutMut

N=374N=374

67.2%67.2%

(61.4-73.5%)(61.4-73.5%)

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0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36

Time (Months)

% A

live

and

Dis

ease

Fre

e

MutWT

Is K-ras prognostic in Is K-ras prognostic in FOLFOX+Cmab treated patients?FOLFOX+Cmab treated patients?

Is K-ras prognostic in Is K-ras prognostic in FOLFOX+Cmab treated patients?FOLFOX+Cmab treated patients?

K-ras K-ras StatusStatus

3 Year Rates 3 Year Rates

(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-P-valuevalue

WTWT

N=945N=945

72.3%72.3%

(68.5-76.4%)(68.5-76.4%)

0.70.7

(0.5-0.9)(0.5-0.9)

0.0040.004

MutMut

N=343N=343

64.2%64.2%

(58.7-70.2%)(58.7-70.2%)

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Why did patients with K-ras Mut Why did patients with K-ras Mut treated with Cetuximab do worse?treated with Cetuximab do worse?Why did patients with K-ras Mut Why did patients with K-ras Mut

treated with Cetuximab do worse?treated with Cetuximab do worse?

• While they had lower drug exposure, While they had lower drug exposure, we don’t believe that is the key reason we don’t believe that is the key reason based on the idealized patient analysisbased on the idealized patient analysis

• We believe that the explanation is We believe that the explanation is related to tumor biologyrelated to tumor biology

• Hypothesis: Cetuximab treatment of K-Hypothesis: Cetuximab treatment of K-ras mutated tumors drives ras mutated tumors drives chemotherapy resistance chemotherapy resistance

• While they had lower drug exposure, While they had lower drug exposure, we don’t believe that is the key reason we don’t believe that is the key reason based on the idealized patient analysisbased on the idealized patient analysis

• We believe that the explanation is We believe that the explanation is related to tumor biologyrelated to tumor biology

• Hypothesis: Cetuximab treatment of K-Hypothesis: Cetuximab treatment of K-ras mutated tumors drives ras mutated tumors drives chemotherapy resistance chemotherapy resistance

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Epidermal Growth Factor Receptor Pathway Map

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ConclusionConclusionConclusionConclusion

• The outcomes are surprisingThe outcomes are surprising

• Understanding the interactions of Understanding the interactions of tumor genotype and patient biology tumor genotype and patient biology challenge us.challenge us.

• The key to individualizing care lies The key to individualizing care lies in that understanding.in that understanding.

• We hope to find the answers in the We hope to find the answers in the tumor blockstumor blocks

• The outcomes are surprisingThe outcomes are surprising

• Understanding the interactions of Understanding the interactions of tumor genotype and patient biology tumor genotype and patient biology challenge us.challenge us.

• The key to individualizing care lies The key to individualizing care lies in that understanding.in that understanding.

• We hope to find the answers in the We hope to find the answers in the tumor blockstumor blocks

Adjuvant mFOLFOX6 +/- cetuximab in patients with K-ras mutant resected stage III colon cancer

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Transcript of Adjuvant mFOLFOX6 +/- cetuximab in patients with K-ras mutant resected stage III colon cancer