FOLFIRI PLUS CETUXIMAB VERSUS FOLFIRI

PLUS BEVACIZUMAB AS

FIRST-LINE TREATMENT FOR PATIENTS WITH

METASTATIC COLORECTAL

CANCER (FIRE-3): A RANDOMIZED, OPEN-

LABEL, PHASE 3 TRIAL

Ahmed Allam A. MohamedAssistant Lecturer of Clinical Oncology

Assiut University Hospitals

→ The FIRE-3 trial of the Arbeitsgemeinschaft InternistischeOnkologie (AIO),is a two-group, open-label, multicentric,randomized, phase III trial, patients were recruited from Germanyand Austria.

→ sponsored by : Klinikum Großhadern, University of Munich.

→ Funded by : Merck KGaA

→ Recruitment in the trail:• January 23rd 2007: No K-RAS mutation status was required.• October 7th 2008: inclusion was restricted to only patients with

K-RAS exon 2 wild-type tumors.

Development of Mabagainst EGFR

80-90’s-----2004----------06-----------07----------Jan 08-------June08----------2009

• Retrospectivedate aboutkras in 30 ptnstreated withcetuximab*

• Amdao presented krasdata with panitumumab

• Conditional marketing authorization and approval of panitumumab in Europe to kras wild **

• Kras aspredictivePACCE***

Subgroupanalysis of kraspresentation ofCRYSTAL & OPUSin ASCO

NCI bulletin: ptnswith mCRC withmKras shouldn’treceive Cetuximab

• FDA changedthe labels forPanitumumab- Cetuximabto involvekras exon 2status.

• FDA approval ofCetuximab inadvanced CRC

• aged 18–75 years

• with stage IV, adenocarcinoma of the colon or rectum.

• K-RAS status. !!!!

• an ECOG P.S of 0–2.

• an estimated life expectancy of greater than 3 months.

• adequate organ function (WBC ≥3·0 × 10⁹ /L, neutrophils ≥1·5 × 10⁹ /L, platelets ≥100 × 10⁹ / L and HGB ≥ 9 g/dL, serum bilirubin ≤1·5 × ULN; AST & ALT ≤2·5 × ULN or ≤5 × ULN in the presence of liver metastases, and s.creatinine ≤1·5 × ULN).

• no surgery within the 4 weeks before the start of study treatment.

• The presence of at least one measurable reference lesion according to (RECIST) version 1.09 was also required.

INCLUSION

CRITERIA

• known or suspected brain metastases.• previous treatment with an EGFR-targeting agent or bevacizumab.• previous chemotherapy for colorectal cancer, excluding adjuvant

therapy completed at least 6 months before trial enrolment.• receipt of any experimental drug treatment within 30 days before

enrolment.• clinically relevant coronary heart disease, myocardial infarction within

the past 12 months or a risk of uncontrolled arrhythmia.• acute or subacute intestinal obstruction or a history of chronic infl

ammatory disease or chronic diarrhoea.• symptomatic peritoneal carcinomatosis.• serious, non-healing wounds, ulcers or bone fractures.• uncontrolled hypertension.• pronounced proteinuria (nephrotic syndrome).• arterial thromboembolisms or severe haemorrhages within 6 months

before study enrolment (except a bleeding tumor before tumor resection surgery).

• haemorrhagic diathesis or thrombotic tendency; a pre-existing dihydropyrimidine dehydrogenase defi ciency.

• a pre-existing glucuronidation defect (Gilbert-Meulengrachtsyndrome).

• a history of secondary malignancy within the past 5 years, except for basalioma or carcinoma in situ of the cervix if treated with curative intent.

• or been receiving therapeutic anticoagulation therapy.

EXCLUSION

CRITERIA

Patients with previously untreated

KRAS WT mCRC (ITT: n=592)

Bevacizumab+ FOLFIRI (n=295)

R

PD

PD

•Primary endpoint: ORR

•Secondary endpoints: progression-free survival, overall survival.

752 ptns randomly assigned

KRAS mutant :100

KRAS unknown: 43

No treatment 17

BASELINE CHARACTERISTICS OF THE INTENTION-TO-TREAT AND RAS-ASSESSABLE

POPULATIONS

Evaluation of ORR

FOLFIRI + Cetuximab FOLFIRI + Bevacizumab

Odds ratio pORR % 95%-CI % 95%-CI

KRAS exon 2 WTITT population*

(N= 592)

62.0 56.2 – 67.5 58.0 52.1 – 63.7 1.180.85–1.64

0.183

RAS WT

(N= 342)

65.5 57.9 – 72.6 59.6 51.9 – 67.1 1.280.83–1.99

0.32

RAS MT

(N= 65)

38.2 22.2 – 56.4 58.1 39.1 – 75.5 0.450.17–1.21

0.14

KRAS exon 2 MT and RAS MT

(N=178)

38.0 28.1–48.8 51.2 40.0–62.1 0.590.32–1.06

0.097

Evaluation of PFS

FOLFIRI + CetuximabFOLFIRI +

BevacizumabHazard

ratio pPFS Months 95%-CI Months 95%-CI

KRAS exon 2 WTITT population

(N=592)

10.0 8.8–10.8 10.3 9.8–11.3 1.06(0.88–1.26)

0.547

RAS WT

(N=342)

10.4 9.5–12.2 10.2 9.3–11.5 0.93(0.74–1.17)

0.54

RAS MT

(N=65)

6.1 5.3–8.5 12.2 9.7–13.9 2.22(1.28–3.86)

0.004

KRAS exon 2 MT and RAS MT

(N=178)

7.5 6.1–9.0 10.1 8.9–12.2 1.31(0.98–1.78)

0.085

0.75

1.0

0.50

0.25

12 24 36 48 60 72

171

171

No. at risk64

57

14

8

8

34

1

2

0.0

PFS

est

imat

ePROGRESSION-FREE SURVIVAL RAS* WT

Eventsn/N (%)

Median(months) 95% CI

FOLFIRI + Cetuximab 144/171 (84.2%) 10.4 9.5–12.2

FOLFIRI + Bevacizumab 143/171 (83.6%) 10.2 9.3–11.5

HR=0.93 (95% CI 0.74–1.17)

p (log-rank)=0.54

*RAS wild-type: KRAS 61/146; NRAS Exon2, NRAS Exon3

0

Time (months)

FOLFIRI + CetuximabFOLFIRI +

Bevacizumab Hazardratio

p

PFS Months 95%-CI Months 95%-CI

KRAS exon 2 WTITT population

(N=592)

28.7 24.0 – 36.6 25.0 22.7 – 27.60.77

(0.62 – 0.96)0.017

RAS WT

(N=342)33.1 24.5 – 39.4 25.6 22.7 – 28.6

0.70(0.53 – 0.92)

0.011

RAS MT

(N=65)16.4 15.9 – 27.6 20.6 17.0 – 28.4

1.20(0.64 – 2.28)

0.57

KRAS exon 2 MT and RAS MT

(N=178)

20.3 16.4– 23.4 20.6 17.0 – 26.71.09

(0.78 – 1.52)0.60

EVALUATION OF OS

Internal Use Only

Patients at risk297 218 111 60 29 9295 214 111 47 18 2

OS

est

imat

e

1.0

0.75

0.50

0.25

0

Time (months)

0 12 24 36 48 60 72

Cetuximab + FOLFIRI

Beavcizumab + FOLFIRI

Median, months

28.7 25.0

HR (95% CI)p-value

0.77 (0.62–0.96)p=0.017

28.725.0

Median duration of treatment~5 months (all 3 agents)

Median PFS~10.0 months

Δ = 7.5 months

OVERALL SURVIVAL RAS* WT

0.75

1.0

0.50

0.25

12 24 36 48 60 72

171

171

No. at risk128

127

71

68

39

2620

9

6

1

0.0

OS

est

imat

e

Eventsn/N (%)

Median(months) 95% CI

FOLFIRI + Cetuximab 91/171 (53.2%) 33.1 24.5–39.4

FOLFIRI + Bevacizumab 110/171 (64.3%) 25.6 22.7–28.6

HR=0.70 (95% CI 0.53–0.92)

p (log-rank)=0.011

*RAS : KRAS 61/146; NRAS Exon2, NRAS Exon3

0

Time (months)

Exploratory subgroup analysis for OS

(ITT)

Cetuximab + FOLFIRI Bevacizumab + FLOFIRI

Alive after 1st line 87.5% 84.7%

Alive after 2nd line 78.5% n(204) 76.4% n(191)

Second line drugs

Oxaliplatin 63.7% 62.8%

Irinotican 15.7 % 15.7%

Bevacizumab 46.6% 17.3%

Anti-EGFR mAb 15.2% 41.4%

2nd Line treatment and crossover

3rd Line Therapy

Cetuximab + FLOFIRI Bevacizumab + FOLFIRI

Received 3rd line 36% ( n=107) 40% (n= 118)

HAEMATOLOGICAL TOXICITY

Adverse event, %Cetuximab + FOLFIRI

(n=297)Bevacizumab + FOLFIRI

(n=295)p-value

(grade ≥3)

Any grade Grade ≥3 Any grade Grade ≥3

Leucopenia 66.7 12.8 66.8 11.2 0.613

Anaemia 87.9 2.4 90.9 1.4 0.545

Thrombocytopenia 25.6 0.3 23.4 0.3 >0.999

Neutropenia 61.3 24.2 60.3 22.8 0.699

Febrile neutropenia 1.7 1.7 3.0 1.0 0.725

NON-HAEMATOLOGICAL TOXICITY

Adverse event, % Cetuximab + FOLFIRI (n=297)Bevacizumab + FOLFIRI

(n=295)p-value (grade

≥3)

Any-grade Grade ≥3 Any-grade Grade ≥3

Any adverse event 100.0 71.0 100.0 63.7 0.066

Nausea 48.2 3.4 62.4 4.8 0.414

Vomiting 24.6 2.4 32.9 3.4 0.473

Diarrhoea 57.2 11.5 62.7 13.6 0.458

Mucositis/stomatitis 42.1 3.7 44.8 4.1 0.835

Fatigue 50.2 0.7 54.9 1.4 0.449

Pain 50.2 5.4 58.0 7.1 0.401

Hand-foot syndrome 26.6§ 3.4 14.2 0.7 0.037

Fatal adverse events N/A 0.0 N/A 1.7 0.030

Grade ≥3 adverse events of special interest.

Adverse event, % Cetuximab + FOLFIRI (n=297)Bevacizumab + FOLFIRI

(n=295)p-value (grade

≥3)

Any-grade Grade ≥3 Any-grade Grade ≥3

Acneiform exanthema 77.4 16.8 7.8 0.0 <0.0001

Desquamation 35.4 6.7 11.5 0.7 0.0001

Paronychia 37.4 5.7 9.2 0.0 <0.0001

Infusion-related allergic reaction

7.7 4.0 0.0 0.0 0.0004

Hypocalcaemia 27.6 4.0 15.3 2.4 0.351

Hypomagnesaemia 63.3 4.4 39.7 0.7 0.007

Adverse event, % Cetuximab + FOLFIRI (n=297)Bevacizumab + FOLFIRI

(n=295)p-value (grade

≥3)

Any-grade Grade ≥3 Any-grade Grade ≥3

Hypertension 21.2 6.4 38.3 6.8 0.870

Proteinuria 2.7 0 2.0 0.3 0.498

Bleeding 21.2ǂ 0.7 28.5 0.3 >0.999

Abscesses/fistulae 1.4 0.3 5.4§ 1.0 0.372

GI perforation 0.3 0.3 0.7 0.7 0.623

Thrombosis (any) 9.4 6.1 11.5 6.1 >0.999

Thromboembolic event 7.4 5.1 7.1 5.8 0.720

Wound healing complications

2.0 0.3 2.7 1.4 0.216

Five deaths, all during treatment with FOLFIRI plus bevacizumab, werereported to be related to adverse events:• arrhythmia (1)• Sepsis (1)• thromboembolic event (1)• infection with neutropenia (2).

Two of these deaths (arrhythmia, and infection with neutropenia) were deemed to be related to study treatment.

Death Report During TTT

“The roots of education are bitter, but the fruit is sweet”Aristotle