SAMO Master Class

Colorectal Cancer

Roger von MoosRoger von Moos

Kantonsspital Graubünden

12.9.2014

Potential conflict of interest and otherPotential conflict of interest and otherstatementsstatements

Thanks to Bernhard Pestalozzi to share some slidesThanks to Bernhard Pestalozzi to share some slides

Advisory board: Amgen, Merck, Roche, Sanofi, PfizerAdvisory board: Amgen, Merck, Roche, Sanofi, Pfizer Advisory board: Amgen, Merck, Roche, Sanofi, PfizerAdvisory board: Amgen, Merck, Roche, Sanofi, Pfizer

Unrestricted research grant: Amgen, Merck, RocheUnrestricted research grant: Amgen, Merck, Roche

Speaker: Amgen, Roche, BayerSpeaker: Amgen, Roche, Bayer

IncidenceIncidence

2012 4472012 447‘‘000 new cases000 new cases

Second most frequent cancerSecond most frequent cancer

Responsible for 215Responsible for 215‘‘000 deaths000 deaths Responsible for 215Responsible for 215‘‘000 deaths000 deaths

25% of patients presents with metastases25% of patients presents with metastases

50% will develop metastasis50% will develop metastasis

5 year survival rate 60%5 year survival rate 60%

Van Cutsem, Annals of Oncol, 2014

Epidemiologie - Männer

Journal of Clinical Oncology 2007

Epidemiologie - Frauen

Journal of Clinical Oncology 2007

Risk of Colorectal Cancer (CRC)Risk of Colorectal Cancer (CRC)

General populationGeneral population

Personal history ofPersonal history ofcolorectal neoplasiacolorectal neoplasia

5%5%

15%15%––20%20%

0 20 40 60 80 100

colorectal neoplasiacolorectal neoplasia

InflammatoryInflammatorybowel diseasebowel disease

HNPCC mutationHNPCC mutation

FAPFAP

15%15%––40%40%

70%70%––80%80%

>95%>95%

Lifetime risk (%)Lifetime risk (%)

Familial Risk for Colorectal CancerFamilial Risk for Colorectal Cancer

ApproximateApproximatelifetimelifetime

60

80

100

70%70%

lifetimelifetimeCRC riskCRC risk

(%)(%)

Affected family membersAffected family members

0

20

40

NoneNone One 1One 1°° One 1One 1°°and twoand two

22°°

One 1One 1°°age <45age <45

Two 1Two 1°° HNPCCHNPCCmutationmutation

2%2%6%6% 8%8% 10%10%

17%17%

Aarnio M et al.Aarnio M et al. Int J CancerInt J Cancer 64:430, 199564:430, 1995Houlston RS et al.Houlston RS et al. Br Med JBr Med J 301:366, 1990301:366, 1990St John DJ et al.St John DJ et al. Ann Intern MedAnn Intern Med 118:785, 1993118:785, 1993

Adjuvant TherapyAdjuvant Therapyof Colon Cancerof Colon Cancer

19901990 55--FU/lev better than surgery aloneFU/lev better than surgery alone

19941994 55--FU/LV better than surgery aloneFU/LV better than surgery alone

19981998 55--FU/LV better than 5FU/LV better than 5--FU/levFU/lev

19981998 6 months = 12 months6 months = 12 months

19981998 Levamisole unnecessaryLevamisole unnecessary

19981998 HDLV = LDLVHDLV = LDLV

19981998 Weekly = monthlyWeekly = monthly

20022002 LV5FU2 = monthly bolusLV5FU2 = monthly bolus

MOSAIC: Treatment arms

R

LV5FU2

FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m²

LV5FU2

Primary:

– 3-yr Disease Free Survival (DFS)

Secondary:

– Safety (including long-term)

– Overall Survival (OS)

Endpoints

DFS by treatment arm (ITT)DFS by treatment arm (ITT)

0,8

0,9

1ProbabilityProbability

FOLFOX4 (n=1123)FOLFOX4 (n=1123) 77.8%77.8%LV5FU2 (n=1123) 72.9%LV5FU2 (n=1123) 72.9%FOLFOX4 (n=1123)FOLFOX4 (n=1123) 77.8%77.8%LV5FU2 (n=1123) 72.9%LV5FU2 (n=1123) 72.9%

33--yearyear

0,5

0,6

0,7

0 10 20 30 40 50DFS (months)DFS (months)

Hazard ratio: 0.77 [0.65Hazard ratio: 0.77 [0.65 –– 0.92]0.92] p < 0.01p < 0.01

23% risk reduction in the FOLFOX4 arm23% risk reduction in the FOLFOX4 arm

DiseaseDisease--Free SurvivalFree SurvivalStage III patientsStage III patients

0,7

0,8

0,9

1ProbabilityProbability

FOLFOX4 (n=672) 71.8%LV5FU2 (n=675) 65.5%FOLFOX4 (n=672) 71.8%LV5FU2 (n=675) 65.5%

33--yearyear

0,5

0,6

0,7

0 10 20 30 40 50DFS (months)DFS (months)

24% risk reduction for stage III patients24% risk reduction for stage III patients

in the FOLFOX4 armin the FOLFOX4 arm

Hazard ratio: 0.76 [0.62Hazard ratio: 0.76 [0.62--0.92]0.92]

ConclusionConclusion

Initial data showed DFS improvment (77.8 vsInitial data showed DFS improvment (77.8 vs72.9%)72.9%)

Follow up after 6 years no OS benefit for allFollow up after 6 years no OS benefit for all Follow up after 6 years no OS benefit for allFollow up after 6 years no OS benefit for allpatientspatients

Stage III subset 72.9 vs 68.7% stat significantStage III subset 72.9 vs 68.7% stat significant(HR 0.80; 0.65(HR 0.80; 0.65--0.97)0.97)

More neutropenia and more neurotoxicityMore neutropenia and more neurotoxicity

XX--ACT trial in adjuvant treatment of DukesACT trial in adjuvant treatment of Dukes’’ CCcolon cancercolon cancer

1° endpoint: disease-free

Capecitabine1250mg/m2 twice daily,

d1–14, q21dn = 1004

Recruitment1998–2001

1° endpoint: disease-freesurvival (DFS)

2° endpoints

relapse-free survival (RFS)

overall survival

tolerability (NCIC CTG)

pharmacoeconomics

QoL

Chemo-naïveDukes’ C,

resection 8 weeks

Bolus 5-FU/LV5-FU 425mg/m2 plus

LV 20mg/m2, d1–5, q28dn = 983

24 weeks

XX--ACT powered to establish at least equivalenceACT powered to establish at least equivalenceof capecitabine to bolus 5of capecitabine to bolus 5--FU/LVFU/LV

Primary endpoint DFSPrimary endpoint DFS

80% power for at least equivalence80% power for at least equivalence

if upper limit of 95% CI for HR <1.25, then primary endpointif upper limit of 95% CI for HR <1.25, then primary endpointmetmetmetmet

DFS = RFS + all deaths from other causesDFS = RFS + all deaths from other causes

RFS:RFS: relapses/new colon cancer + all deaths due to colon cancerrelapses/new colon cancer + all deaths due to colon canceror treatmentor treatment

All analyses shown were prospectively plannedAll analyses shown were prospectively planned

Primary endpoint metPrimary endpoint metand trend to superior DFS (ITT)and trend to superior DFS (ITT)

1.0

0.8

Esti

mate

dp

rob

ab

ilit

y

HR = 0.87 (95% CI: 0.75–1.00)p=0.0528

3-yearCapecitabine (n=1004) 64.2%5-FU/LV (n=983) 60.6%

• Confirmed by per protocol analysis, HR 0.89 (95% CI 0.76-1.04)

0.6

0.40 1 2 3 4 5 6

Years

Esti

mate

dp

rob

ab

ilit

y

p=0.0528

Trend to improved overall survival (ITT)Trend to improved overall survival (ITT)E

sti

mate

dp

rob

ab

ilit

y

1.0

0.8

3-yearCapecitabine (n=1004) 81.3%5-FU/LV (n=983) 77.6%

Esti

mate

dp

rob

ab

ilit

y

0 1 2 3 4 5 6

Years

HR = 0.84 (95% CI: 0.69–1.01)p=0.0706

0.6

0.4

XX--ACT study conclusionsACT study conclusions

DFS at 3 years equivalent to 5FU/LVDFS at 3 years equivalent to 5FU/LV

HFS and hyperbilirubinemia more often,HFS and hyperbilirubinemia more often,diarhoea, nausea and vomiting, stomatitis anddiarhoea, nausea and vomiting, stomatitis anddiarhoea, nausea and vomiting, stomatitis anddiarhoea, nausea and vomiting, stomatitis andneutropenia significantly lessneutropenia significantly less

In 57% of patients required dose modificationIn 57% of patients required dose modification

Capecitabine is the standard todayCapecitabine is the standard today

Metastatic colorectal cancerMetastatic colorectal cancer

Management of MCRC:Management of MCRC:Placement comes first: Interdisciplinary tumorboardPlacement comes first: Interdisciplinary tumorboard

Diagnosis of MCRC

Resectable (20%) Unresectable

Borderline/

+/- Adjuvant Therapy

Surgery

Neoadjuvant/Preoperative

Therapy

First-Line

Second-Line

Palliation

Borderline/Potentially

Resectable (20%)

NCCN, 2010.

Liver metastases from colorectal cancerLiver metastases from colorectal cancer

• Liver is the most common site of metastases from CRC

• - 50 to 75% of patients with advanced CRCwill develop liver metastases (1)

• - 15 to 25% of patients have liver metastasesat presentation (1, 2)

•1 - N. Kemeny, F. Fata, J. Hepatobiliary Pancreas Surg., 1999; 6: 39-492 - JK. Seifert, J. R. Coll. Surg. Edinb., 1998; 43: 141-543 - MM. Borner, Ann. Oncol., 1999; 10, 6: 623-26

at presentation (1, 2)

• - 20 to 35% of patients will have metastatic diseaseconfined to the liver (3)

• Improving the outlook of advanced colorectal cancer necessitates better

management of liver metastases

Original EPOC Trial:Original EPOC Trial:Phase III EORTC 40983Phase III EORTC 40983

SurgeryFOLFOX4 FOLFOX4

6 cycles

(3 months)

6 cycles

(3 months)

Surgery

N=364 patients

Primary endpoint: PFS

Nordlinger et al: Lancet 2008; Lanc Onc 2013

EORTC 40983: Peri-Op FOLFOX for Liver Mets

Overall SurvivalHR=0.88 (p=0.34)mOS, 61m vs 54mAbsolute difference: 3.4%

No survival advantage to

Nordlinger, Lancet Oncology 2013;14:1208-15

Progression-Free SurvivalHR=0.81 (p=0.068)(p=0.035 for eligible pts)mPFS, 20m vs 12.5mAbsolute difference: 8.2%

No survival advantage toperi-operative chemo!

Chemotherapy Liver Toxicity:Selected Reports

Karoui, Ann Surg 2006 More isnotbetter!

Influence of Number of Cycles of Pre-Op Chemo on Morbidity

But someis OK!

History of different agentsHistory of different agents

2000 2005 2008 2009 2010

Capecitabine

Irinotecan

5-FU

2012

CapecitabineOxaliplatin

Cetuximab

Panitumumab

Bevacizumab

KRAS

5-FU, fluorouracil.

National Cancer Institute. Colon cancer treatment (PDQ). 2012.National Cancer Institute. Cancer drug information. 2011.

Aflibercept

Regorafenib

Full RAS

2

Slide 24

2 Würde Zeitachse um 2012 ergänzen und Targeted therapies wegennehmen, erstens englisch zweitens müsste sonst die Klammer Afliberceptund Regorafenib auch umfassenRoger von Moos; 13.10.2013

RAS Wild type, what is the standard treatment ?RAS Wild type, what is the standard treatment ?

Selection for EGFR wild typSelection for EGFR wild typ PRIME data (phase III disadvantage for panitumumab in KRASPRIME data (phase III disadvantage for panitumumab in KRAS

mutant)mutant)

Data to use EGFR antibodies or Bevacizumab inData to use EGFR antibodies or Bevacizumab in Data to use EGFR antibodies or Bevacizumab inData to use EGFR antibodies or Bevacizumab infirst line in wild type patients ?first line in wild type patients ?

FIREFIRE--33

PEAK (not shown)PEAK (not shown)

CALGB 80405CALGB 80405

Prevalence KRAS, NRAS,BRAF in the Prime trial

EXON 1 EXON 2 EXON 4EXON 3

EXON 1 EXON 2 EXON 4EXON 3

RAS Analysis Subset

KRAS90%*

40% 5.8%3.8%

12 13 59 61 117 146

EXON 1 EXON 2 EXON 4EXON 3

EXON 1…. EXON 15 EXON 16…

NRAS

BRAF

RAS/RAF Analysis Subset

90%*3.5% 0%4.1%

8.6%

12 13 59 61 117 146

600

*Tumor sample ascertainment Rate

CRC: Clonal evolutionCRC: Clonal evolutionDiscordance in primary vs metastatic CRCDiscordance in primary vs metastatic CRCKopetz S et al #3509; N = 115 samples from MDACCKopetz S et al #3509; N = 115 samples from MDACC

Pestalozzi PostASCO June 12, 2014

#3509ASCO 2014

Pestalozzi PostASCO June 12, 2014 Courtesy E. van Cutsem

Phase III study design

FOLFIRI + CetuximabCetuximab: 400 mg/m2 i.v. 120min initial dose

250 mg/m2 i.v. 60min q 1w

FOLFIRI + BevacizumabBevacizumab: 5 mg/kg i.v. 30-90min q 2w

mCRC1st-line therapyKRAS wild-type

N= 592

Randomize 1:1

FOLFIRI: 5-FU: 400 mg/m2 (i.v. bolus); folinic acid: 400mg/m2

• Key inclusion criteria

– Patients ≥18 years with histologically confirmed diagnosis of mCRC

– ECOG PS 0-2

– prior adjuvant chemotherapy allowed if completed >6 month before inclusion

• Amendment in October 2008 to include only KRAS wildtype patients

• 150 active centers in Germany and Austria

FOLFIRI: 5-FU: 400 mg/m2 (i.v. bolus); folinic acid: 400mg/m2

irinotecan: 180 mg/m2

5-FU: 2,400 mg/m2 (i.v. 46h)

Primary endpoint

• ORR (mRECIST 1.0, investigators‘ read)

Secondary endpoints

• Progression-free survival (PFS)

• Overall survival (OS)

Endpoints

• Overall survival (OS)

• Time to failure of strategy (time to failure of 1st-line therapy) (TFS)

• Deepness of response (percent of tumor shrinkage compared to baseline)

• Secondary resections of liver metastases with potentially curative intention

• Safety and tolerability according to NCI-CTCAE criteria

analyses were performed in the ITT and assessable for response population

Progression-free survival

0.75

1.0

0.50

Pro

bab

ilit

yof

surv

ival

Events

n/N (%)

Median

(months)

95% CI

― FOLFIRI + Cetuximab 250/297

(84.2%)

10.0 8.8 – 10.8

― FOLFIRI + Bevacizumab 242/295

(82.0%)

10.3 9.8 – 11.3

HR 1.06 (95% CI 0.88 – 1.26)

Log-rank p= 0.5470.50

0.25

12 24 36 48 60 72

months since start of treatment

297295

numbersat risk

10099

1915

106

54

3

0.0

Pro

bab

ilit

yof

surv

ival

Log-rank p= 0.547

Overall survival

Events

n/N (%)

Median

(months)

95% CI

― FOLFIRI + Cetuximab 158/297

(53.2%)

28.7 24.0 – 36.6

― FOLFIRI + Bevacizumab 185/295

(62.7%)

25.0 22.7 – 27.6

HR 0.77 (95% CI: 0.62 – 0.96)

Log-rank p= 0.017

0.75

1.0

0.50

Pro

bab

ilit

yof

surv

ival

Log-rank p= 0.017

0.012 24 36 48 60 72

months since start of treatment

297295

numbersat risk

218214

111111

6047

2918

92

0.50

0.25

0.0

Pro

bab

ilit

yof

surv

ival

CALGB/SWOG 80405: ConclusionCALGB/SWOG 80405: ConclusionVenook A et al LBA3, Plenary SessionVenook A et al LBA3, Plenary Session

LBA #3LBA #3

Pestalozzi PostASCOJune 12, 2014

36

CALGB/SWOG 80405: ConclusionCALGB/SWOG 80405: ConclusionVenook A et al LBA3, Plenary SessionVenook A et al LBA3, Plenary Session

LBA #3

37

CALGB/SWOG 80405: ConclusionCALGB/SWOG 80405: ConclusionVenook A et al LBA3, Plenary SessionVenook A et al LBA3, Plenary Session

LBA #3

38

CALGB/SWOG 80405: ConclusionCALGB/SWOG 80405: ConclusionVenook A et al LBA3, Plenary SessionVenook A et al LBA3, Plenary Session

LBA #3

39

CALGB/SWOG 80405: ConclusionCALGB/SWOG 80405: ConclusionVenook A et al LBA3, Plenary SessionVenook A et al LBA3, Plenary Session

LBA #3

40

Second Line DataSecond Line Data

BEV + standard first-lineCT (Oxaliplatin oderIrinotecan-basiert)

(n=820)Randomisierung 1:1

Standard second-line CT (oxaliplatinoder irinotecan-based) bis PD (n=411)

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

oder irinotecan-based) bis PD (n=409)

PD

ML18147 study design (Phase III)ML18147 study design (Phase III)

CT switch:

Oxaliplatin → Irinotecan

CT switch:

Oxaliplatin → IrinotecanOxaliplatin → Irinotecan

Irinotecan → Oxaliplatin

Oxaliplatin → Irinotecan

Irinotecan → Oxaliplatin

Primärer Endpunkt • Gesamtüberleben (OS) ab Randomisierung

Sekundäre Endpunkte • Progressionsfreie Überleben (PFS)• Ansprechrate (ORR)• Verträglichkeit

Explorative Endpunkte • Tumor, Plasma und DNA Biomarker

OS

OS

esti

ma

te

1.0

0.8

0.6

PFS

PF

Ses

tim

ate

1.0

0.8

0.6

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

Gesamtüberleben und Progressionsfreies Überleben in derGesamtüberleben und Progressionsfreies Überleben in derITTITT--PopulationPopulation

0 6 12 18 24 30 36 42 48

OS

esti

ma

te

Time (months)

0.6

0.4

0.2

0

No. at riskCT 410 293 162 51 24 7 3 2 0BEV + CT 409 328 188 64 29 13 4 1 0

9.8 11.2

HR: 0.81 (95% CI: 0.69–0.94)

p=0.0062 (log-rank test)

PF

Ses

tim

ate

Time (months)

0.6

0.4

0.2

0

410 119 20 6 4 0 0 0409 189 45 12 5 2 2 0

4.1 5.7

HR: 0.68 (95% CI: 0.59–0.78)

p<0.0001 (log-rank test)

0 6 12 18 24 30 36 42

VELOUR: Aflibercept Phase III Studie bei vortherapiertenVELOUR: Aflibercept Phase III Studie bei vortherapiertenmCRC PatientenmCRC Patienten

1:1 PROGRESSION TODPatienten mit mCRC nachVersagen von Oxaliplatin-

basierten RegimeR

600 pts

Aflibercept 4 mg/kg IV+ FOLFIRI q 2 Wochen

600 pts

Primärer Endpunkt: OS

Sekundäre Endpunkte:ORR, PFS, safety, PK

FIRST PATIENT IN: November 2007

ENROLLMENT BEENDET:1226 randomisiert, 1216 behandelt

Finale Analyse be 863 OS events

STRATIFIKATIONSFAKTOREN:Vorghergehende

Bevacizumab Therapie(J/N)ECOG PS (0 vs 1 vs 2)

Placebo + FOLFIRIq 2 Wochen

E. Van Cutsem et al, J Clin Oncol 2012;30:3499-506

3

Slide 44

3 UebersetzungRoger von Moos; 13.10.2013

VELOUR: Gesamtüberleben: ITT PopulationVELOUR: Gesamtüberleben: ITT Population

1.0

0.9

0.8

0.7

0.6

0.5

0.4

KA

PL

AN

-ME

IER

ES

TIM

AT

E

Stratifizierte HR = 0.817 [95.34% CI, 0.713–0.937]Log-rank P = 0.0032

Zensiert

Aflibercept/FOLFIRI: Median = 13.50 MonatePlacebo/FOLFIRI: Median = 12.06 Monate

614 573 485 401 286 193 131 87 51 31 14

612 566 498 416 311 216 148 104 75 49 33

0 3 6 9 12 15 18 21 24 27 30 33 36 39

0.4

0.3

0.2

0.1

0.0

KA

PL

AN

ES

TIM

AT

E

NUMBERAT RISK

ZEIT

(MO

NAT

EN)

Cut-off Datum: Februar 7, 2011Mediane Follow-up: 22.28 Monate

79.1% 50.3% 30.9% 18.7% 12.0%

81.9% 56.1% 38.5% 28.0% 22.3%

ÜBERLEBENS-WAHRSCHEINLICHKEIT

E. Van Cutsem et al, J Clin Oncol 2012;30:3499-506

4

Slide 45

4 Hier müssten Farben angepasst werden und UebersetzungRoger von Moos; 13.10.2013

CORRECT: Multicenter, Randomisiert, DoppeltCORRECT: Multicenter, Randomisiert, Doppelt--Blind, PlaceboBlind, Placebo--Kontrollierte, Phase III Studie von Regorafenib im mCRCKontrollierte, Phase III Studie von Regorafenib im mCRC

Behandlung bis zur Progression /nicht tolerierbarer Toxizität/ Arzt-

oder Patientenentscheidung

Behandlung bis zur Progression /nicht tolerierbarer Toxizität/ Arzt-

oder Patientenentscheidung2 : 1

Regorafenib + BSC(n = 505)

160 mg 1 x tgl.3 Wochen on, 1 Woche off

Regorafenib + BSC(n = 505)

160 mg 1 x tgl.3 Wochen on, 1 Woche off

RANDO

M ISIE

Patienten mit mCRC therapiertmit allen vorhandenenStandardtherapien undprogredient von 3 Monaten

Patienten mit mCRC therapiertmit allen vorhandenenStandardtherapien undprogredient von 3 Monaten

Radiologische Evaluierung alle 8 Wochen

Grothey A, Van Cutsem E , et al. Lancet. 2013;381:303-312..

Placebo + BSC(n = 255)

3 Wochen on, 1 Woche off

Placebo + BSC(n = 255)

3 Wochen on, 1 Woche off

ER

UNG

progredient von 3 Monatenprogredient von 3 Monaten

Stratification:•Vorhergehende Anti-VEGF Therapie•Zeitpunkt Diagnose metasasierten Erkrankung•Geographische Region

Regorafenibn = 505

Placebon = 255

Mediane OS, Monate(IQRa) 6.4 (3.6-11.8) 5.0 (2.8-10.4)

HR (95% CI) 0.77 (0.64-0.94)

P value .0052

100

75

50

Ge

sam

tüb

erl

eb

en

%Gesamtüberleben Regorafenib versus Placebo

• OS Raten waren konstant höher mit Regorafenib vs. Placebo nach 6Monaten und 9 Monaten

PlaceboRegorafenibPatients at Risk, N

452221

352150

18775

9332

339

73

Zeit ab Randomisierung, Monate

aIQR, interquartile range0

0 6 10 14842 12

Regorafenib + BSC (n = 505)Placebo + BSC (n = 255)

50

25

Ge

sam

tüb

erl

eb

en

%

BSC, best supportive care; IQR, interquartile range; OS, overall survival.Grothey A, Van Cutsem E , et al. Lancet. 2013;381:303-312..

5

Slide 47

5 Bitte alles auf deusch übersetzenRoger von Moos; 13.10.2013

CORRECT: Therapie assoziierte Nebenwirkungen in ≥10% derCORRECT: Therapie assoziierte Nebenwirkungen in ≥10% derPatientenPatienten

Nebenwirkungen, %Regorafenib + BSC arm

n = 500Placebo + BSC arm

n = 253

Alle Grade Grad 3/4 Alle Grade Grad 3/4

Hand-Fuß Hautreaktionen 47 17 8 <1

Fatigue 47 9 28 5

Hypertension 28 7 6 1

Diarrhö 34 7 8 1

Rash / desquamation 26 6 4 0

Anorexie 30 3 15 3

Mucositis, oral 27 3 4 0

Thrombozytopenie 13 3 2 <1

Fieber 10 1 3 0

Nausea 14 <1 11 0

Nasenbluten 7 0 2 0

Stimmveränderungen 29 <1 6 0

Gewichtsverlust 14 0 2 0

Grothey A, Van Cutsem E , et al. Lancet. 2013;381:303-312. Stivarga PI.

Therapie-assoziierte Nebenwirkungen welche in Therapieabbruch resultierten: 8.2% im Regorafenib-Arm vs.1.2% unter Placebo

Treatment algorithm by ESMOTreatment algorithm by ESMO

Oxaliplatin-Based First-line

Irinotecan-Based First-Line

Chemo-Triplet

5-FU/IRI + 5-FU/OX +

5-FU/OX +bev

FOLFOX +pan or ceta

(FOLF)IRI +

FU/IRI +ceta5-FU/OX

5-FU/OX5-FU/IRI

5-FU/IRI5-FU/OX/IRI

Pan/ceta ±IRI or

FOLFIRI +

Firstline

Second

5-FU/IRI +bev

FOLFOX +

Regorafenib

Regorafenib RegorafenibPan/ceta

± IRI5-FU +

bev5-FU +

bev

5-FU/IRI +bev

5-FU/OX +bev

(FOLF)IRI +pan/ceta 5-FU/OX5-FU/IRI IRI or

FU/bev

FOLFIRI +aflib

Secondline

Thirdline

Fourthline

Regorafenib

FOLFOX +cet/(pan)a

aKRAS wildtype only.5-FU, 5-fluorouracil; aflib, aflibercept; bev, bevacizumab; cet, cetuximab; FOLFIRI, 5-FU + leucovorin + irinotecan; FOLFOX, 5-FU + leucovorin + oxaliplatin; IRI, irinotecan; OX, oxaliplatin; pan,

panitumumab; ESMO, European Soceity for Medical Oncology.

Schmoll HJ, et al. Ann Oncol. 2012;23:2479-2516.

Pan/ceta

± IRI

Regorafenib

ESMO Guidelines 2014ESMO Guidelines 2014

ResectablePotentiallyresectable Disseminated

ConclusionConclusion Full RAS and BRAF analysis is necessary in all patients who are candidate forFull RAS and BRAF analysis is necessary in all patients who are candidate for

systemic treatmentsystemic treatment

Irinotecan and Oxaliplatin regimens are both effective in first and second lineIrinotecan and Oxaliplatin regimens are both effective in first and second line

Capecitabine as monotherapy is an alternative for patients not tolerating aCapecitabine as monotherapy is an alternative for patients not tolerating acombination chemotherapycombination chemotherapy

In RAS wild type patients, EGFR antibodies seems to be more effective thanIn RAS wild type patients, EGFR antibodies seems to be more effective thanbevacizumab (lets wait for new data at ESMO in 2 weeks)bevacizumab (lets wait for new data at ESMO in 2 weeks)

Good data for Bevacizumab are available for RAS mutant, and second lineGood data for Bevacizumab are available for RAS mutant, and second linetreatmenttreatment

The TML showed a survival benefit for patients treated with Bevacizumab inThe TML showed a survival benefit for patients treated with Bevacizumab infirst and second linefirst and second line

Aflibercept has shown acitivity in second line therapyAflibercept has shown acitivity in second line therapy

Patients in good condition are candidates for further line treatment withPatients in good condition are candidates for further line treatment withRegorafenibRegorafenib