colon cancer synopsis 2015

COLON CANCER:WHAT SHOULD WE KNOW IN

MOHAMED ABDULLA M.D.

PROF. OF CLINICAL ONCOLOGY

KASR AL-AINI SCHOOL OF MEDICINE

CAIRO UNIVERSITY

Pfizer Headquarter Office. Wednesday; 18/02/2015

CRC: Figures & Facts:

2nd & 3rd most common cancers in females and males.

9% of cancer related deaths.

90% occurring around the age of 40 – 50 years.

OAS for entire patients = 65%.

Metastatic disease: 5-year OAS = 10%.

Organ limited metastatic disease: 5-year OAS > 40%

Median survival of metastatic disease > 30 months.

Improved OAS with exposure to all available drugs.

Unified global ideal treatment algorhytm is still controversial.

Colon Cancer Mortality:

Why Improving Outcome?

1. Better life style.

2. Risk groups and Screening utility.

High Risk Factors:

FamilialAdenomatous Polyposis

Hereditary Non Poliposis Colon Cancer

Family history of Colo Rectal Carcinoma

Previous Colorectal CA, Ovarian, Endometrial,

Breast CA

Age >50 (3/1000 at the age of 80)

Inflammatory Bowel Disease. Diet (increased fat, red meat, decreased fibre)

Smoking

Diabetes mellitus. HIV.

Radiation therapy for prostate cancer.

Risk Assessment:Ask The Following:

1. Have you had colorectal cancer or polyp?

2. Have you had inflammatory bowel disease or abdominal irradiation during childhood?

3. Have any family members had colorectal cancer or polyp?

All Answers

are NO

Average Risk

Any Answer is

Increased

Screening of CRC: Cost –

Benefit:

US Data: Screening for CRC (1987 – 2010):

The incidence of late stage from 118 –

74/100000.

The incidence of early stage disease from 77 –

67/100000.

Reduction of 550000 CRC cases over 3 decades.

Cancer 2014;120:2893-2901.

3. Identification of prognostic groups of patients More

precise adoption of adjuvant therapy Better DFS &

Recurrence Rate Over Time:

2.071.7

1.32 1.230.86

0 1 2 3 4 5 6

% RECURRENCE

> 80% of Recurrences

Within the 1st 3 Years.

Sargent DJ, et al. J Clin Oncol. 2009;27(15S): Abstract 4011.

Who Needs Adjuvant

Therapy?

60 m30 m0 monthStage

% Survival% Survival% Survival

93.296.1100I

84.791.0100IIa

72.280.2100IIb

83.491.4100IIIa

64.177.3100IIIb

52.367.1100IIIc

43.057.3100IIId

26.843.1100IIIe

8.117.3100IV

O’ConnellJB, Maggard MA, Ko CY: Colon Cancer Survival Rates with The New American Joint

Committee on Cancer, Sixth Edition Staging. J Natl Cancer Inst 2004;96:1423.

LNs = > 12

Who Should Receive Adjuvant

Therapy?

2. Mesentric Nodules: Contour Role:

T-Stage N-Stage

1. V1 (micro).

2. V2 (macro)

Isolated Tumor Cells

Micrometastases

0 – 0.2 mm (N0)

0.2 – 2 mm (N1mi)

Stage III Not IV

Cancer 2008;112:50–4.

Who Should Receive Adjuvant Therapy?

3. Peri-neural Invasion: An Under-Estimated Variable:

15 – 25%

JCO.2009.22.4949

Who Should Receive Adjuvant Therapy?

3. Peritoneal Minimal Residual Disease:

• 1/5 : Peritoneal Minimal

Residual Disease.

• 1/7 : Peritoneal Carcinomatois.

Surgical Techniques.

Intraperitoneal & Intraportal

Chemotherapy.

Prevention of The Inflammatory

Response.

thelancet.com/oncology Vol 10 January 2009

Conflicting data.

The most accepted timing is 4 – 6 weeks.

2 meta-analyses:

One showed no effect.

Other showed significant impact on mortality and

disease relapse.

Timing of Chemotherapy:

Des Guetz G, Nicolas P, Perret GY, Morere JF, Uzzan B. Eur J Cancer. 2010;46(6):1049.

Biagi JJ, Raphael MJ, Mackillop WJ, Kong W, King WD, Booth CM JAMA.

2011;305(22):2335.

Which Program & What

Schedule?

Modulated/

Non-Modulated

Oxaliplatin

Irinotecan

Capecitabine

Anti-EGFR

Angiogeni

Accepted Standards of Care:

Stage III Colon Cancer

Stage III Colon Cancer Patients

5-Fu/Leucovorin

Mayo Clinic Roswell Park De Gramont

Lower Toxicity Profile

& Better Compliance

IMPACT

NCIC-CTG30%

Adjuvant FOLFOX4 in Stage II-III

Colon Cancer: MOSAIC Study

Schema

de Gramont A, et al. ASCO 2007. Abstract 4007.

FOLFOX4

Leucovorin 200 mg/m2 IV +

5-FU 400 mg/m2 bolus +

5-FU 600 mg/m2 IV over 22 hrs +

Oxaliplatin 85 mg/m2 IV

(n = 1123)

LV5FU2

Leucovorin 200 mg/m2 IV +

5-FU 400 mg/m2 bolus +

5-FU 600 mg/m2 IV over 22 hrs

(n = 1123)

Patients with previously

untreated, completely resected

stage II-III

colon cancer

(N = 2246)

MOSAIC Study: 6-Y OAS; by Treatment

J Clin Oncol. 2009,27:3109-3116

MOSAIC Study: 6-Y OAS; by Treatment

Arm & Stage:

J Clin Oncol. 2009,27:3109-3116

Final MOSAIC Results (cont’d)

Rate of peripheral sensory neuropathy decreased over

At 4 yrs

Grade 1: 12.0%

Grade 2: 2.8%

Grade 3: 0.7%

Neutropenia ≥ grade 3 in 41.0% of patients receiving

FOLFOX4 vs 4.7% of patients receiving LV5FU2

Febrile neutropenia in 1.8% of patients receiving FOLFOX4

de Gramont A, et al. ASCO 2007. Abstract 4007.

MOSAIC Patients > 70 Years:

NSABP C – 07:

2407 Colon Cancer

Stage 2 & 3

Weekly

Bolus 5-Fu and LV

+ Oxaliplatin on wks 1, 3

• 5-y DFS: 69% vs 64% (HR 0.82)

• OAS: 80% vs 78% (HR 0.88)

• High toxicity profile

X-ACT: Xeloda (capecitabine) Adjuvant

Chemotherapy Trial of stage III colon

cancer

Primary endpoint: non-inferiority in DFS

Secondary endpoint: OS

Bolus 5-FU/LV

5-FU 425mg/m2 +

LV 20mg/m2

days 1–5 q4w

Capecitabine

1,250mg/m2 b.i.d.

days 1–14 q3w

Chemonaïve stage III

resection 8 weeks

n=1,004

RANDO MISATION

Data cut-off: January 2007

b.i.d. = twice dailyTwelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)

X-ACT: 5-year OS

(median follow-up 6.8 years)

• Non inferior: p = 0.000116

• Trend of Superiority: p = 0.06

• Lower toxicity profile except for hand &

foot syndrome.

Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)

Role of Irinotecan in Adjuvant Treatment

of Stage III Colon Cancer PETACC-3

Study:

J Clin Oncol.2009,27:3117-3125

Study:

J Clin Oncol.2009,27:3117-3125

Study:

J Clin Oncol.2009,27:3117-3125

After Exclusion of Cases Developed Second Primary in Both Arms

XELOXA: Adjuvant CAPOX

Chemo/radiotherapy

naive stage III

colon cancer

CAPOX Capecitabine 1000 mg/m2 BID

days 1-15 Oxaliplatin 130 mg/m2 day 1

Bolus 5FU/LV Mayo Clinic or Roswell

Duration of therapy: 24 weeks

Primary endpoint: Disease-free survival Haller DG, et al. J Clin Oncol. 2011;29(11):

1465-1471.

Cetuximab in Adjuvant Sitting:

N0147 Trial:

Cetuximab in Adjuvant Sitting:

N0 147 Trial:

NSABP Protocol C-08: mFOLFOX

± Bevacizumab in Stage II/III CRC

Wolmark N, et al. ASCO 2009. Abstract LBA4.

Arm A: mFOLFOX6 Q2W x 26 (n = 1356)

Arm B: mFOLFOX6 + Bevacizumab 5 mg/kg Q2W x 26

(n = 1354)

Pts with stage II or III colon adenocarcinoma with ECOG PS of 0/11

(N = 2710)

Pts stratified by number of positive lymph nodes and randomized between Days 29 and 50 postoperatively

mFOLFOX6 regimen: LV 400 mg/m2 IV, 5-FU 400 mg/m2 IV, 5-FU 2400 mg/m2 over 46 hours; oxaliplatin 85 mg/m2 IV

Primary endpoint: DFS

NSABP Protocol C-08:

3-Yr DFS Results:

Wolmark N, et al. ASCO 2009. Abstract LBA4.

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

HR: 0.89 (P = .15)mFF6 + BmFF6

Events291312

3-Yr DFS77.475.5

Where Do We Go in Adjuvant

Therapy of Colon Cancer?

Shorten Duration: “Less is More”

6 months versus 3 months.

Non inferiority trial design.

Don’t lose any curability in adjuvant sitting.

More is Better:

FOLFIRINOX in high risk Stage III.

Toxicity and compliance are of upfront concern.

Quasar Collaborative G, Gray R, Barnwell J, et al. Adjuvant chemotherapy versus observation in patients with colorectal

cancer: a randomized study. Lancet 2007; 370:2020-9.

Stage II

Colon Cancer

80% Cured by Surgery only

16% will Recur Regardless Treatment

4% will Benefit of Treatment

Who Needs Adjuvant Therapy?

Treatment Related Mortality

Who Needs Adjuvant

Therapy? Stage II:

Uptodate.com 01/06/2014

Molecular Markers:1. ++MSI Poor response to fluoroupyremidine

therapy No Role of Adjuvant Chemotherapy.

2. Chromosomal Instability: Worse outcome.

3. LOH 18q: Worse outcome.

Genetic Expression Profiling:1. Oncotype DX:

7 Recurrence Genes.

5 Reference Genes +

5 Treatment Benefit Genes.

2. Coloprint.

Who Needs Adjuvant

Therapy? Stage II:

Stage II Colon Cancer:

Trials of Better Identification:

NSABP C 01, 02, 04, 06

(1851 Pts)

5 Reference

7Recurrence

6Treatment Benefit

QUASAR Study(1436/3239 Pts)

Surgery Surgery + 5-

Kerr D, et al. ASCO 2009. Abstract 4000.

Translational Study on PETACC 3:

Results:

Strong effect in stage II, decreases in stage III disease

Parameter, % HR 95% CI P Value

Both stage II and III (N = 1233)

RFS 0.569 0.400-0.811 .0018

OS 0.548 0.357-0.842 .006

Stage II (n = 391)

RFS 0.265 0.107-0.661 .0044

OS 0.159 0.039-0.659 .011

Stage III (n = 842)

RFS 0.693 0.473-1.02 .06

OS 0.699 0.446-1.09 .12

Roth AD, et al. ASCO 2009. Abstract 4002.

3. Identification of prognostic groups of patients More

precise adoption of adjuvant therapy Better DFS &

4. Identification of molecular key players of growth &

aggressiveness Better RR, PFS and OAS.

The Adenoma-Carcinoma

Process:

Kinzler KW, et al. New York, The genetic basis of human cancer. NY: McGraw-Hill, 1998:565-87. Vogelstein B, et al.

N Engl J Med. 1988;319:525-532. Fearon ER, et al. Cell. 1990;61:759-767.

Normal colonic epithelium

Dysplastic aberrant crypt foci

Initial adenoma develops

Intermediate adenoma

Late adenoma

Carcinoma

Metastasis

Mutation in APC

Mutation in K-ras

Mutation in DCC

Mutation in p53

Other alteration?

EGFR & VEGF

SOS RAS

MEKMPA

Gene Transcription & Cell Cycle

Progression

1. Angiogenesis

2. Survival

3. Proliferation

4. Progression

Molecular Key Players: EGFR

Carter P. Nat Rev. Cancer 2001.

Heinemann V et al. Cancer Treat Rev. 2009.

Formation of New Blood

Vessels

Physiological

Wound Healing

Placental Implantation

Growth

Pathological

Pre-Eclampsia

Diabetic Retinopathy

Tumors

Molecular Key Players:

Angiogenesis:

Disease Overview:Angiogenesis:

Hallmark of Malignancy:

Proliferation Invasion Metastases

Treatment FailureApoptosis

Resistance

VEGF +

Angiogenesis Process:

Release of GFsReceptor

Activation

Degradation &

Proteolytic Enz.

Disruption of

ECM & Wall

Invasion &

Migration

Proliferation

Angiogenic Factors:

Tyrosine Kinase

Receptors

VEGFR -

1VEGFR -

VEGFR -

3NRP - 1 NRP - 2

VEGF -

AVEGF -

VEGF -

Angiogenesis in Malignancy:

Hypoxia

VEGF VEGFR on Nearby

Vessels

VEGFR on Tumor

Vessels

Resistance to Angiogenesis

Inhibitors “Types”:

Keep in Mind:

• Number of LNs > 12.

• Timing: 4-8 wks.

• Age.

• Molecular Markers.

• 5-Fu/LV is the Backbone.

• Stage II Disease: Better Assessment.

• Stage III Disease: MOSAIC & X-ACT.

• NO Role for Adjuvant Targeted Therapy.

Metastatic Colon Cancer

Advances in the Treatment of Stage IV CRC:

1980 1985 1990 1995 2000 2005

Best supportive care (BSC)

Irinotecan

CapecitabineOxaliplatin

Cetuximab

Bevacizumab

Panitumumab

Advances in the Treatment of Stage IV CRC:

1980 1985 1990 1995 2000 2005

Best supportive care (BSC)

Irinotecan

CapecitabineOxaliplatin

Cetuximab

Bevacizumab

Panitumumab

Median Overall Survival

Management of Met. CRC:

Playing a Strategic Game:

The King Should

SURVIVESURVIVA

What You Have to Play? Pharmaceuticals

How to Play? 1st, 2nd , 3rd …seniL .

Try to be Creative Research

mCRC patient segmentation:potentially resectable and long-term disease control

Resection

Optimising PFS and OS –represents majority of patients

Treatment goal

Required

outcome

Long-termDFS

10% 20% 70%

Curative surgery

Presentation Unresectable diseaseUpfront resectable

Un-resectablePotentially resectable

Most patients remain

unresectable

Van Cutsem, WCGIC 2012

Treatment for mCRCComparing Combination Chemotherapy Regimen

The Tournigand Study: Scheme

FOLFIRI

Tournigand at al. J Clin Oncol 2004; 22: 229-237

FOLFOX6

FOLFIRI

Till Progression Till Progression

226 ptStage IVmCRC

CPT-11 180 mg /m2 IV + Simplified LV5FU

Oxaliplatin 100 mg/m2 IV+Siplified LV5FU

The Tournigand Study: Time to Progression

There is no statistical difference in TTP regardless of sequence or arm.There is a slight improvement in TTP in 2nd line favoring FOLFOX, but not significant

The Tournigand Study: Overall Survival

0 10 20 30 40 50

FOLFIRI/FOLFOX6

FOLFOX6/FOLFIRI

Overall Survival

P = .99FOLFIRI/FOLFOX6 21.6

FOLFOX6/FOLFIR 20.6

The Tournigand Study: Summary of Efficacy results

Endpoint FOLFIRI FOLFOX P value

RR 1st line 54 % 56% 0.26

RR 2nd line 4% 15% 0.05

TTP 1st line 8.5 mo 8.0 0.26

TTP 2nd line 2.5 mo 4.2 mo 0.64

OS 1st line 21.5 mo 20 mo 0.99

• How can biologics in combination with conventionalchemotherapy be used to their full potential?

• Duration of therapy

• Predictive markers

• Can a patient population be identified that wouldbenefit most from one specific treatment strategy?

Challenges in The Palliative Treatment of Stage

IV CRC:

Anti-VEGF Agents

Phase III Trial IFL +/-Bevacizumab in MCRC: Efficacy

Placebo

(n = 411)

Hurwitz H, et al. N Engl J Med. 2004;350(23):2335-2342.

Bevacizumab

(n = 402) P Value

Median survival, months 15.6 20.3 .00004

Progression-free survival (PFS),

months6.2 10.6 <.00001

Overall response rate (ORR), %

Complete response (CR)

Partial response (PR)

Duration of response, months 7.1 10.4 .0014

XELOX N = 317

FOLFOX4 N = 317

Initial 2-armopen-label study (N = 634)

Protocol amended to 2x2 placebo-controlled design after bevacizumabphase III data1 became available(N = 1401)

RecruitmentJune 2003 – May 2004

RecruitmentFeb 2004 – Feb 2005

XELOX vs FOLFOX +/- BevacizumabNO16966

Study Design

1. Hurwitz H, et al. Proc Am Soc Clin Oncol. 2003;22: Abstract 3646.

Saltz LB, et al. J Clin Oncol. 2008;26(12):2013-2019.

XELOX + placebo

N = 350

XELOX +

bevacizumab

N = 350

FOLFOX4 + placebo

N = 351

FOLFOX4 +

bevacizumab

N = 350

NO16966 PFS Subgroup Analyses: On-Treatment Population

HR = 0.61 [97.5% CI 0.48–0.78]P≤.0001

HR = 0.65 [97.5% CI 0.50–0.84]P = .0002

XELOX + placeboFOLFOX4 +

placeboXELOX + Bev

FOLFOX-4 +BevVS VS

XELOX Group FOLFOX Group

00 100 200 300 400 500

Study Day

00 100 200 300 400 500

Study Day

10.6 m

Saltz L, et al. Presented at: 2007 Gastrointestinal Cancer Symposium; January 19-21, 2007: Orlando, Florida. Abstract.

8.4 m9.5 m7.0 m

CAIRO-3: Validation of BEV-ContainingMaintenance Therapy (MT)

XELOX-Bx6 CTX-BEV

R PD1 PD2

MT CFI

8.5 4.1

11.8 10.5

PFS1,months

0.44<.00001

months

TT2PD 19.8 15.00.67

<.00001

OS 21.7 18.20.87.16

MT:LD-Cape (625 mg/m2 BID daily)

+ BEV (7.5 mg/kg every 3 weeks)

N = 558

PFS2: time from R until PD upon re-introduction of XELOX-B

TT2PD: time from R until PD upon any treatment after PFS1

CFI, observation; OS, overall survival; PFS1, first progression; PFS2, second progression; TT2PD, time to second progression

Koopman M, et al. J Clin Oncol. 2013;31(suppl): Abstract 3502.

BEV + standard

first-line CT (either

oxaliplatin or

irinotecan-based)

(n = 820)

BEV (2.5 mg/kg/wk) +standard second-line CT

(oxali or irino-based) until PD

PDRandomize

CT switch:

Bennouna J, et al. Lancet Oncol. 2012;14(1):29-37.

Standard second-line CT (oxaliplatin or irinotecan-

based) until PD

ML18147 (TML) Study Design (Phase III)

Oxaliplatin → Irinotecan

Irinotecan → Oxaliplatin

Primary endpoint

Secondary endpoints

included

• OS from randomization

• PFS

• Best ORR

• Safety

• First-line CT (oxaliplatin-based, irinotecan-based)

• First-line PFS (≤9 months, >9 months)

• Time from last BEV dose (≤42 days, >42 days)

• ECOG PS at baseline (0/1, 2)

Stratification factors

OS: ITT Population

11.2 mo

12 18 24 30 36 42

9.8 mo

P = .0211 (log-rank test)

aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)

Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0)

CT (n = 410)BEV + CT (n = 409)

Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)

P = .0062 (log-rank test)

Stratifiedb HR: 0.83 (95% CI: 0.71–0.97)

0 6 12 18 24 36

CT (n=410)BEV + CT (n=409)

4.1 mo 5.7 mo

Unstratifieda HR: 0.68 (95% CI: (0.59–0.78)

P<.0001 (log-rank test)

Stratifiedb HR: 0.67 (95% CI: 0.58–0.78)

P<.0001 (log-rank test)

PFS:\ITT Population

No. at risk Time , Months Time, Months

No. at risk

CT 410 293 162 51 24 7 3 2 CT 410 119 20 6 4 0

BEV + CT409 328 188 64 29 13 4 1 BEV + CT409 189 45 12 5 2

Adverse Events (AEs) of Special Interestto BEV: Safety Population

Patients, %

Chemotherapy n = 409

All Grades Grade 3–5

BEV + Chemon = 401

All Grades Grade 3–5

41 12AEs of special interest to BEV

ATE, arterial thromboembolic events; GI, gastrointestinal; RPLS, reverse posterior leukoencephalopathy syndrome; VTE, venous thromboembolic events

Hypertension 7 1 12 2

Proteinuria 1 – 5 <1

Bleeding/hemorrhage 9 <1 26 2

Abscesses and fistulae – – 1 <1

GI perforation <1 <1 3 2

Congestive heart failure <1 <1 <1 –

VTE 4 3 6 5

ATE 1 <1 <1 <1

Wound-healing complications

EFC10262: VELOURPhase III Trial Second-Line FOLFIRI +/-

VEGF-TRAP (Aflibercept)

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

mCRC after failure of an oxaliplatin

based regimen

600 ptsAflibercept 4 mg/kg

IV+ FOLFIRI q 2 weeks

600 ptsPlacebo + FOLFIRI

q 2 weeks

Principle investigators: Allegra, Van Cutsem

30% of patients had prior BEV

VELOUR Study

HR 0.82

HR 0.76

Van Cutsem E, et al. J Clin Oncol. 2012;30(28):3499-3506.

Time, Months Time, Months

Overall Survival

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

All patients

Prior BEVNo Yes

1226 0.82 (0.713-0.937)

853373

0.79 (0.669-0.927)

0.86 (0.673-1.104)

Favors aflibercept

Favors placebo

Progression-Free SurvivalStrata (as per UVRS) N HR (95% CI) HR

InteractionP

All patients

Prior BEVNo Yes

1226 0.76 (0.661-0.869)

853373

0.80 (0.679-0.936)

0.66 (0.512-0.852)

Favors aflibercept

Favors placebo

Aflibercept: VELOUR Phase III: OS and

PFS Stratified by Prior Bevacizumab

Conclusion Anti-VEGF Therapy

• Duration of VEGF-inhibition matters– Treatment to progression

– Maintenance strategies

– Treatment beyond progression

• Clinical synergism between FP +

bevacizumab

• Positive distinguishing factors for aflibercept

vs BEV in second-line Tx not clear

– Head-to-head comparison warranted(Efficacy? Toxicity?)

• BEV combinable with FOLFOXIRI (TRIBE)

EGFR Monoclonal Antibodies

NCIC CTG CO.17:Randomized Phase III Trial in mCRC Cetuximab vs BSC (No Cross-Over)

BSC Cetux

n = 83 n = 81

n = 113

n = 117

n = 285

n = 287

RR 0% 1.2% 0% 12.8% 0% 6.6%

PFS,months

1.8 1.8 1.9 3.8 1.8 1.9

OS,months

4.6 4.5 4.8 9.5 4.6 6.1

<.0001 <.0001

Karapetis CS, et al. N Engl J Med. 2008;359(17):1757-1765.

KRAS Mut KRAS Wildtype All Patients

<.0001 .0046

CRYSTAL: FOLFIRI +/- CetuximabPFS in Patients With KRAS Wildtype Tumors

Number of patients

FOLFIRI 350

FOLFIRI + cetuximab 316

FOLFIRI

(n = 350)

FOLFIRI + Cetuximab

(n = 316)

No of events 189

8.4 months

[7.4‒9.2]

9.9 months

[9.0‒11.3]

Median PFS

[95% CI]

HR [95% Cl]

P value

0.70 [0.558‒0.867]

Time, Months

120 4 8 16 20

FOLFIRI

FOLFIRI + cetuximab

PRIME (FOLFOX +/- Panitumumab) PFS by KRAS Mutation Status

“Final Analysis”

Median, months(95% CI)

Panitumumab + FOLFOX4

FOLFOX4

10.0 (9.3 – 11.4)

8.6 (7.5 – 9.5)

HR = 0.80 (95% CI: 0.67 – 0.95)

Log-rank P value = .01

Median, months (95% CI)

Panitumumab+ FOLFOX4

FOLFOX4

7.4 (6.9 – 8.1)

9.2 (8.1 – 9.9)

HR = 1.27 (95% CI: 1.04 – 1.55)

Log-rank P value = .02

WT KRAS MT KRAS

Event-

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

Months

36 38 40 42 44

Douillard J, et al. J Clin Oncol. 2011;29(Suppl): Abstract 3510.

18 20 22 24 26 28 30 32 34

Months

0 2 4 6 8 10 12 14 16 36 38 40 42 44

FOLFIRI + BevacizumabBevaciizumab: 5 mg/kg iIV.v.3300-9-900miin q 2ww

Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506.

FIRE-3 Phase III Study DesignFOLFIRI + Cetuximab

first-line therapy

KRAS wildtype

N = 592

Randomize 1:1

FOLFIRI: 5FU: 400 mg/m2 (IV bolus); folinic acid: 400 mg/m2

irinotecan: 180 mg/m2

5FU: 2400 mg/m2 (IV 46h)

• Primary objective: ORR (investigator assessed)

• Designed to detect a difference of 12% in ORR induced by FOLFIRI + cetuximab (62%) as compared to FOLFIRI +bevacizumab (50%)

• 284 evaluable patients per arm needed to achieve 80% power for an one-sided Fisher‘s exact test at an alpha level of 2.5%

Cetuximab: 400 mg/m2 IV 120 min initial dose

250 mg/m2 IV 60 min q 1 w

FIRE-3 ORRPrimary Endpoint

FOLFIRI + Cetuximab FOLFIRI + BevacizumabOdds

ratioP

Assessable

for response

(N = 526)

72.2 66.2 – 77.6 63.1 57.1 – 68.91.52

1.05-2.19.017

1.180.85-1.64

P = Fisher´s exact test (one-sided)

ORR % 95%-CI % 95%-CI

ITTpopulation

(N = 592)62.0 56.2 – 67.5 58.0

52.1 –63.7

Events

n/N (%)

Median

(months)

95% CI

8.8 – 10.8

HR 1.06 (95% CI 0.88 – 1.26)

10.3 9.8 – 11.3

Log-rank P = .547

0.012 24 36 48

Months Since Start of Treatment

—FOLFIRI + Cetuximab 250/297

(84.2%)

— FOLFIRI + Bevacizumab 242/295

(82.0%)

Number 297 100 19 10 5 3

at risk 295 99 15 6 4

FIRE-3 PFS:

Events

n/N (%)

Median

(months)

95% CI

— FOLFIRI + Cetuximab 158/297

(53.2%)

185/295

(62.7%)

24.0 – 36.6

— FOLFIRI + Bevacizumab

HR 0.77 (95% CI: 0.62 – 0.96)

25.0 22.7 – 27.6

Log-rank P = .017

0.012 24 36 48 60 72

Number 297

at risk 295218214

111111

Split of

curves

FIRE-3 OS:

— FOLFIRI + Cetuximab

— FOLFIRI + Bevacizumab PTEN, EGFR ligands

0.012 24 36 48

Who are these patients?

Analysis of

RAS, PIK3CA, BRAF,

Number 297 218 111 60 29 9

at risk 295 214 111 47 18 2

FIRE-3 OS:

Progression-Free Survival ByArm (All RAS WildtypePatients)100 –

80 –

60 –

40 –

20 –

0 –0 12

24 36 48

Months From Study Entry

No at Risk

Chemo +

Lenz H-J, et al. Ann Oncol. 2014;25(Suppl 4): Abstract 5010.

256 112 49 23 13 6

270 126 49 18 5 2 1

(Events)

Median

(95% CI)

HR (95% CI) P

(10.3-12.6)

(9.6-12.9)

1.1(0.9-1.3)

Overall Survival By Arm (All RAS Wildtype Patients)

100 –

80 –

60 –

40 –

20 –

0 –0 12 24 36 48 60 72 84 96

Chemo +

(Events)

Median

(95% CI)

HR (95% CI) P

(26.9-34.3)

(27.6-38.5)

0.9(0.7-1.1)

No at Risk Months From Study Entry

256 199 147 77 35 16 5 2

270 205 164 88 41 24 7 1 1

Conclusions EGFR mAbs (2)

• All-RAS wildtype CRC = 40% to 45% of CRC

• Further molecular refinements in future (PTEN, EGFR ligands, PIK3CA…) could cut the patient population suitable for EGFR mAbs down to 30% to 35%

• This refined patient population could sustaina marked benefit from use of first-line EGFR mAbs!

Progression-Free Survival Overall Survival

(Events)

Median

(95% CI)

(95% CI)P

(Events)

Median

(95% CI)

(95% CI)P

+ Cetux

(9.5-13.1)1.1

(0.9-1.4).3

(24.0-32.8)0.86

(0.6-1.1).2

(9.4-13.1)

(26.1-40.4)

All RAS Wildtype FOLFOX Patients

Progression-Free Survival

Overall Survival

(Events)

Median

(95% CI)

(95% CI)P

(Events)

Median

(95% CI)

(95% CI)P

+ Cetux

(10.3-14.8)1.1

(0.7-1.5).7

(28.3-41.3)1.1

(0.7-1.6).7

(8.9-14.1)

(25.6-42.9)

All RAS Wildtype FOLFIRI Patients

Outcomes by Chemotherapy

Backbone

Bevacizumab + oxaliplatin-based regimens:

Bevacizumab + irinotecan-based regimens

First-line efficacy of EGFR inhibitors in KRAS WT populations

1. Van Cutsem et al. ASCO GI 2010; 2. Maughan, et al. ASCO 2010; 3. Tvelt, et al. ESMO 2010; 4. Doulliard, et al. JCO 2010

Irinotecan vs Oxaliplatin for Cetuximab??

Take Home Message:

• Exposure to all available agents is mandatory to optimize OAS.

• Unified global treatment algorhytm is still controversial.

• Careful interpretation of available clinical trials to establish guidelines of management.

• FIRE3 trial should not be used as a practice changing guideline although it might point to a better selection of patients for anti-EGFR therapy.

• Cost-effective studies should be kept in mind especially in developing regions of the world.

Thank You

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