Colorectal Cancer

Axel GrotheyProfessor of OncologyMayo Clinic Rochester

Disclosures• Consulting activities

(honoraria went to the Mayo Foundation)• Amgen• Bayer• Pfizer• Roche/Genentech• BMS• Imclone/Eli-Lilly

I WILL include discussion of investigational or off-label use of a product in my presentation.

CRC as worldwide health problem• CRC Global Statistics:

• 3rd highest incidence rate (~ 1,200,000/yr)• 4th highest mortality rate (~ 608,000/yr)

CA: A Cancer Journal for Clinicians 2011;61:69-90

Worldwide Developed Developing

SporadicLynch Syndrome

Familial

Hereditary

FAP; AFAPMixed Polyposis SyndromeAshkenazi I1307KCHEK2 (HBCC)MYHTGFBR1

PJSFJPCDBRRS

= as yet undiscovered hereditary cancer variants

HamartomatousPolyposis

Syndromes

AC-1 without MMR(Familial CRC of syndrome “X”)

US Preventative Services Task Force Screening Recommendations (October 2008)

The USPSTF recommends CRC screening for men and women aged 50–75* using high-sensitivity fecal occult blood testing (FOBT), sigmoidoscopy, or colonoscopy. The decision to be screened after age 75 should be made on an individual basis.

• High-Sensitivity FOBT – once a year• Flexible Sigmoidoscopy – every 5 years • Colonoscopy – every 10 yearsOther screening tests in use or being studied (not recommended

by the USPSTF )• Double-Contrast Barium Enema• Virtual Colonoscopy• Stool DNA Test

http://www.cdc.gov/cancer/colorectal/basic_info/screening/tests.htm

*no upper age limit in all other guidelines

12.3% of patients presented with recurrent CRC.*2002 data.

24.5% stage II*

18.6% stage IV*12% stage I*

32.6% stage III*

American Cancer Society, 2005; Datamonitor, 2003.

CRC:Demographics and Presentation

• Estimated 2009 U.S. incidence (new cases): 147,000• Estimated 2008 U.S. mortality: 49,900

National Comprehensive Cancer Network (NCCN), 2008; Greene et al., 2002.AJCC = American Joint Committee on Cancer.

AJCCv6 TNM Staging DefinitionsPrimary tumor (T)    Tis Carcinoma in situ T1 Tumor invades submucosa    T2 Tumor invades muscularis propria    T3 Tumor invades through muscularis propria or subserosa T4 Tumor directly invades other organs or structures

Regional lymph nodes (N)        N0 No regional lymph node metastases    N1 Metastases in 1–3 regional lymph nodes    N2 Metastases in 4 or more regional lymph nodes

Distant metastases (M)    M0 No distant metastases    M1 Distant metastases

T4a: perf. visceral peritoneumT4b: invasion of organs

N1a: 1 N+N1b: 2-3 N+

N2a: 4-6 N+N2b: >7 N+

TNM / AJCC v7 Effective Jan 2010

AJCC v7

Gunderson et al, JCO 2009

Stage II Stage III

History of adjuvant therapy of colon cancer

• 5-FU/lev superior to surgery alone

• 5-FU/LV superior to surgery alone

• 5-FU/LV superior to 5-FU/lev

• 6- and 12-month treatment cycles equivalent

• Lev unnecessary• High-dose and low-

dose LV equivalent• Monthly and weekly

treatment equivalent

• LV5FU2 and monthly bolus equivalent

1990 1994 1998 2002Moertel et al. Ann Intern Med. 1995;122:321.Francini et al. Gastroenterol. 1994;106:899.Wolmark et al. Proc Am Soc Clin Oncol. 1996;15:205. AbstractO’Connell et al. J Clin Oncol. 1998;16:295.Haller et al. Proc Am Soc Clin Oncol. 1998;17:256a. Abstract 982.Andre et al. Proc Am Soc Clin Oncol. 2002. Abstract 529.

Recurrence rate over time

83% of recurrencesoccur within the

first 3 years

Sargent et al., ASCO 2009

Beyond 5-FU in the adjuvant settingCompleted studies:• Capecitabine (X-ACT)• Oxaliplatin (MOSAIC, NSABP C-07, XELOXA)• Irinotecan (CALGB 89803, ACCORD-2, PETACC-3)• Bevacizumab (NSABP C-08, AVANT)• Cetuximab in KRAS wt CC (N1047, PETACC-8)

Ongoing studies:• QUASAR2 (Cape +/- BEV)

X-ACT: Cape vs Mayo - 5-year DFS

(median follow-up 6.8 years)5-year n DFS (%)Capecitabine 1, 004 60.85-FU/LV 983 56.7

1.0

0.8

0.6

0.4

0.2

0

0 6 42 48 78 96Months

HR=0.88 (95% CI: 0.77–1.01)NI margin 1.20

12 18 24 30 36 54 60 66 72 84 90

ITT population

Estim

ated

pro

babi

lity

ITT (intent-to-treat) population; NI = non-inferiorityTwelves C, et al. Eur J Cancer Suppl

2007;5:1 (Abstract 1LB)

102

Test of non-inferiority p<0.0001Test of superiority p=0.0682

MOSAIC: Study Design

Primary end-point: disease-free survivalSecondary end-points: safety, overall survival

n=2246

Enrollment:Oct 1998–Jan 2001 (146 centres; 20 countries)• Completely resected colon

cancer• Stage II, 40%; Stage III, 60%• Age 18–75 years• KPS ≥60• No prior chemotherapy

RLV5FU2

FOLFOX4(LV5FU2 + oxaliplatin 85 mg/m²)

(n=1123)

(n=1123)

LV5FU2, Leucovorin 200 mg/m2 iv over 2 hours followed by 5-fluorouracil 400 mg/m2 bolus and 5-fluorouracil 600 mg/m2 iv over 22 hours on Days 1 and 2, every 14 days; FOLFOX4, LV5FU2 + oxaliplatin 85 mg/m2 iv over 2 hours on Day 1

Andre NEJM 2004

MOSAIC: Disease-free Survival - Final Update

5-year DFS %

HR [95% CI] p-value FOLFOX4 LV5FU2

ITT 73.3 67.4 0.80[0.68–0.93]

0.003

Stage III 66.4 58.9 0.78[0.65–0.93]

0.005

Stage II 83.7 79.9 0.84[0.62–1.14]

0.258

High-risk stage II n=576

82.1 74.9 0.74[0.52–1.06]

—

Low-risk stage II n=323

86.3 89.1 1.22[0.66–2.26]

—

Data cut-off: June 2006

Δ7.5

Δ7.2

Andre JCO 2009

MOSAIC: OS: Stage II and Stage III

0.1%

4.4%

Andre JCO 2009

Long-term Safety

Data cut-off: January 2007

Peripheral Sensory Neuropathy

Evaluable patients n=811

Grade 0 84.3%

Grade 1 12.0%

Grade 2 2.8%

Grade 3 0.7%

Andre JCO 2009

Should patients with stage II colon cancer receive adjuvant therapy?

% o

f Pat

ient

sQUASAR: OS in patients with “no clear indication for chemo” (mostly stage II)

5-FU/LV vs surgery alone

P = .025-year OS, Observation = 77.4% vs Chemotherapy = 80.3%Relative risk = 0.83 (95% CI, 0.71-0.97)

YearsQUASAR group, Lancet 2007

0 1 2 3 4 5 6 7 8 9 100

20

40

60

80

100Observation (n=1622)Chemotherapy (n=1617)

5-yr OS difference: 2.9%

“High-risk” Stage II Colon Cancer

• Clinical-pathological parameters• T4 tumors• Less than 10 (12) LNs examined• Obstruction/perforation• Lymphatic or vascular invasion• Undifferentiated histology

• Molecular parameters• Single marker vs signature - TBD

Defective MMR (dMMR) - Colon cancer

• Characterized by presence of MSI & loss of MLH1, MSH2, MSH6 or PMS2 expression

• ~15% of Sporadic CC, >90% loss of MLH1 • Clinical Correlations: Right sided, female,

early stage, excellent prognosis!• Tumors: Poorly differentiated, Signet-ring-

cell, Lymphocytic infiltration, near diploid• dMMR cells resistant to 5-FU1,2

1Carethers, 1999; 2Arnold 2003

Decision Algorithm in Adjuvant Therapy

Resected Colon Ca

Stage II Stage III

FOLFOXXELOX

High-Risk

dMMR

No therapy! 5-FU/LV orCapecitabine

*

*

*pts not considered candidates for oxaliplatin

T4 and/or<12 LNs

Low-Risk

Intermed. Risk

yes

yes

no

no

?Marker signature?

Grothey, Oncology 2010

What is the Standard Adjuvant Therapy in Colon Cancer ?

• FOLFOX (or XELOX) is standard adjuvant therapy in • stage III and • can be considered in high-risk stage II colon cancer• very consistent results for oxaliplatin across trials

• Capecitabine (or 5FU/LV) for • patients who are not considered candidates for

oxaliplatin (elderly?)• unselected stage II, pMMR

• Irinotecan, bevacizumab, and cetuximab have failed!

Advances in the Treatment of Stage IV CRC

1980 1985 1990 1995 2000 2005

5-FUIrinotecan

CapecitabineOxaliplatin

CetuximabBevacizumab

Best supportive care (BSC)

median overall survival

Panitumumab

Treatment paradigms for mCRC• Some patients with stage IV disease can be

cured by an interdisciplinary approach• In the palliative setting: FOLFOX = XELOX =

FOLFIRI (XELIRI has problems with toxicity)• Most patients tolerate a chemotherapy

doublet, but not all need it• The addition of biologics to chemotherapy

has improved outcomes, but not as much as we hoped

• We are on the verge of individualized therapy based on molecular predictive factors

Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5768 Patients

OS (mos) = 13.2 + (%3drugs x 0.1), R^2 = 0.85Grothey & Sargent, JCO 2005

0 10 20 30 40 50 60 70 80

Infusional 5-FU/LV + irinotecanInfusional 5-FU/LV + oxaliplatinBolus 5-FU/LV + irinotecanIrinotecan + oxaliplatinBolus 5-FU/LV

LV5FU2

FOLFOXIRI

CAIRO

2221201918171615141312

Med

ian

OS

(mo)

Patients with 3 drugs (%)

P =.0001

First-Line Therapy

2007

Murine Ab“momab”

ChimericMouse-Human Ab

“ximab”

Humanized Ab“zumab”

Fc

Fab

Human Ab“mumab”

Biologic Agents in Colorectal Cancer = Monoclonal Antibodies

(17-1A) Cetuximab Bevacizumab

PanitumumabEGFR

VEGF

Nomenclature of Monoclonal Antibodies-mab monoclonal antibody

-mo-mab mouse mab-xi-mab chimeric mab-zu-mab humanized mab

-mu-mab human mab-tu-xx-mab tumor-directed xx mab-li-xx-mab immune-directed xx mab-ci-xx-mab cardiovascular-directed xx mab-vi-xx-mab virus-directed xx mab

Inf-li-xi-mab Beva-ci-zu-mab Ri-tu-xi-mab Pani-tu-mu-mab

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

IFL+ Placebo (n=411)

IFL+ Bevacizumab(n=402) P Value

Median survival (mo) 15.6 20.3 0.00004

PFS (mo) 6.2 10.6 <0.00001

ORR (%) CR PR

352.2 32.5

453.7

41.2

0.0036

Duration of resp. (mo) 7.1 10.4 0.0014

Hurwitz et al. N Engl J Med 2004

Phase III Trial of IFL +/-Bevacizumab in MCRC: PFS

HR=0.54, P<0.00001Median PFS: 6.2 vs 10.6 mo

0.2

0 10 20 300

0.8

1.0

0.4

0.6

Progression-free survival (mo)

Prop

ortio

n pr

ogre

ssio

n-fr

ee

Treatment GroupIFL + placeboIFL + bevacizumab

Hurwitz et al. N Engl J Med 2004

XELOX + placebo N=350

FOLFOX4 + placebo N=351

XELOX + bevacizumab

N=350

FOLFOX4 + bevacizumab

N=350

XELOX N=317

FOLFOX4 N=317

Initial 2-arm open-label study

(N=634)

Protocol amended to 2x2 placebo-controled design after bevacizumab

phase III data1 became available (N=1401)

RecruitmentJune 2003 – May 2004

RecruitmentFeb 2004 – Feb 2005

XELOX vs FOLFOX +/- Bevacizumab Roche NO16966 study design

1Hurwitz H, et al. Proc ASCO 2003;22 (Abstract 3646) Cassidy & Saltz, JCO 2008

PFS chemotherapy + bevacizumab superiority: primary endpoint

0 5 10 15 20 25Months

PFS

estim

ate

HR = 0.83 [97.5% CI 0.72–0.95] (ITT)p = 0.0023

9.48.0

1.0

0.8

0.6

0.4

0.2

0

FOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events

Saltz et al., JCO 2008

CONcePT study: IO arm2400

x 8

Cumulative oxaliplatin

680 mg/m2

Months

42400

x 8 8680 mg/m2

2400

200855

2005

200855 x 8

1360 mg/m2 12etc.

LVOXBEV

5-FU

Grothey et al, ASCO 2008

AIO 0504 / Roche ML18147Multinational European Trial

Any-OX+ BEV

Any-IRI+ BEV

Any-IRI+ BEVAny-IRI Any-OX

Any-OX+ BEV

R R

N = 820Primary EP: OS

Accrual completed May 31, 2010

AIO 0504 / Roche ML18147Multinational European Trial

Any-OX+ BEV

Any-IRI+ BEV

Any-IRI+ BEVAny-IRI Any-OX

Any-OX+ BEV

R R

N = 820Primary EP: OS

Accrual completed May 31, 2010

January 26, 2012: Press release.Trial met primary endpoint of improvedoverall survival! ASCO 2012!

Pertinent Side-Effects of Anti-VEGF Therapy

• Hypertension• Arterial thrombotic/ thromboembolic

events (ATEs)• Gastrointestinal perforation (GIP)• Bleeding• Delayed wound healing• (Proteinuria)

Safety and Effectiveness Outcomes, by Age Subgroup in BRiTE (US Patient Registry)

All(N = 1953)

<65 y(n = 1057)

65–74 y(n = 533)

≥75 y(n = 363)

≥80 y(n = 161)

Safety, %

GI perforation 2.0 2.6 1.5 1.1 0.6

Post-op bleeding or WHCs 5.1 5.5 4.5 4.5 3.8

ATE 1.9 1.6 1.3 3.9 3.7

Grade 3/4 bleeding 2.6 2.2 3.4 2.5 1.2

New/worsening HTN 20.7 20.5 20.6 21.2 21.1

Survival

Median PFS, months 9.9 10.2 9.7 9.8 9.2

1-yr survival rate, % 74.4 77.1 72.5 69.4 65.8

Median OS, months 23.5 27.3 21.3 19.5 16.2

Kozloff et al. Oncology 2010

mAbs Target Tumor Cell-Bound EGFR

Extracellular

Intracellular

Ligand

EGF-R

PI3K

AktRaf

MEK

MAPK

Cell Motility

MetastasisAngiogenesisProliferation

Cell survivalDNA

PTEN

Ras

mAbs Target Tumor Cell-Bound EGFR

Extracellular

Intracellular

Ligand

EGF-R

PI3K

AktRaf

MEK

MAPK

Cell Motility

MetastasisAngiogenesisProliferation

Cell survivalDNA

Ras

PTEN

NCIC CTG CO.17: Randomized Phase III Trial in mCRCCetuximab vs BSC (no cross-over)

KRAS mut KRAS wild-type All patients

BSCn=83

Cetuxn=81

BSCn=113

Cetuxn=117

BSCn=285

Cetuxn=287

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

PFS (mos) 1.8 1.8 1.9 3.8 1.8 1.9

OS (mos) 4.6 4.5 4.8 9.5 4.6 6.1

Karapetis et al. NEJM 2008

<0.0001

<0.0001 <0.0001

0.0046

CRYSTAL Study (1st Line)

FOLFIRI + Cetuximab

FOLFIRI

EGFR-expressingmetastatic CRC PFS

Stratified by:• Regions • ECOG PS

• Primary Endpoint: PFS (independent review)• Secondary Endpoints: RR, DCR, OS, Safety, QoL• Sample Size: 1217 patients randomized, ITT: 1198 pts

N = 599

N = 599

Van Cutsem et al. NEJM 2009

R

5-FU/LV/IRI (FOLFIRI) ± Cetuximab: PFSNon-KRAS adjusted

PFS (mos)

PFS

estim

ate

1.0

0.8

0.9

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 2 4 6 8 10 12 14 16 18 20

FOLFIRIFOLFIRI + Cetuximab

HR = 0.851P = 0.0479

8.0 vs 8.9 mos

Subgroupeffect

No benefit

Van Cutsem et al, 2009

Relating KRAS status to efficacyPrimary endpoint: PFS – KRAS wild-type

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16 18

Months

Prog

ress

ion-

free

sur

viva

l est

imat

e

Cetuximab + FOLFIRI FOLFIRI

KRAS wild-type (n=348) HR=0.68; p=0.017

mPFS Cetuximab + FOLFIRI: 9.9 months mPFS FOLFIRI: 8.7 months

1-yr PFS rate25% vs 43%

Van Cutsem et al. NEJM 2009

CRYSTAL: Efficacy UpdateAfter Additional KRAS Testing

Van Cutsem et al. JCO 2011

KRAS wild-type FOLFIRI FOLFIRI + cetuximab

P value

n 350 316

RR (%) 39.7 57.3 < 0.0001

mPFS (mos) 8.4 9.9 0.0012

mOS (mos) 20 23.5 0.0093

KRAS mutated FOLFIRI FOLFIRI + cetuximab

P value

n 183 214

RR (%) 36.1 31.3 0.34

mPFS (mos) 7.7 7.4 0.26

mOS (mos) 16.7 16.2 0.75

HR 0.7HR 0.8

CRYSTAL

PRIME OPUS COIN NORDIC CAIRO2 181 PIC-COLO

-20

-15

-10

-5

0

5

10

15

20

25

30

17

7

24

7

-1

11

25

22

-5

0

-16

-3

9

-13

-1

-5

KRAS wtKRAS mut

Cha

nges

in re

spon

se ra

tes

(%)

2nd Line 1st Line

IRI OX OX OX OX OX IRI IRI

Grothey & Lenz, JCO 2012

CAIRO2: Study design

Primary endpoint• Progression-free survival

Secondary endpoints• RR• OS time• Toxicity• Translational research

CapOx + BEV

(COB, n=368)

CapOx + BEV + Cetuximab

(COB-C, n=368)

EGFR-detectablemCRC R

Tol et al. NEJM 2009

Oxaliplatin d/c’d after 6 cyclesi.e. after 18 weeks = 4.5 mos

KRAS wild-typen = 314 (61%)

KRAS mutatedn = 196 (39%) p value

Median PFS (months)COB 10.6 12.5 0.80

COB-C 10.5 8.1 0.04

p value 0.30 0.003

Median OS (months)COB 22.4 24.9 0.82

COB-C 21.8 17.2 0.06

p value 0.64 0.03

CAIRO2 - KRAS genotyping (n=501)

Tol et al. NEJM 2009

Bevacizumab vs EGFR Antibodies in Advanced CRC - Simplified

Agent Strength Weakness

Bevacizumab • Delay in tumor progression

• Gain in time• Toxicity profile

• Limited single agent activity

• Weak effect on RR(per RECIST)

EGFR antibodies

• Single agent activity• Consistent increase

in RR• Activity independent

of line of therapy• Negative predictive

marker available

• Gain in time to progression moderate

• Toxicity profile

VEGF-A

VEGF-R1(Flt-1)

MigrationInvasionSurvival

VEGF-R3(Flt-4)

Lymphangio-genesis

VEGF-R2(KDR/Flk-1)Proliferation

SurvivalPermeability

PlGFVEGF-B

VEGF-C, VEGF-D

Func

tions

Large molecule VEGF inhibitors

Y

Bevacizumab

YRamucirumab

Aflibercept (VEGF Trap)

EFC10262: VELOURPhase III Trial 2nd Line FOLFIRI +/-

VEGF-TRAP (Aflibercept)

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

1:1

mCRC afterfailure of an oxaliplatin

based regimenR

600 ptsAflibercept 4 mg/kg

IV+ FOLFIRI q 2 weeks

600 pts Placebo + FOLFIRIq 2 weeks

51

30% of patients had prior BEVPIs: Allegra, Van Cutsem

Safety – Most frequent AEs, with ≥ 5% difference in incidence between treatment arms, excluding anti-VEGF class events

Safety Population, % of patientsPlacebo, N = 605 Aflibercept N = 611All

Grades Grade 3-4 All Grades Grade 3-4

Diarrhea 56.5 7.8 69.2 19.3Neutropenia** Complicated neutropenia

56.3 29.52.8

67.8 36.75.7

Asthenic conditions (HLT) 50.2 10.6 60.4 16.9Stomatitis & ulceration (HLT) 34.9 5.0 54.8 13.7Thrombocytopenia** 33.8 1.7 47.4 3.3Infections (SOC) 32.7 6.9 46.2 12.3Decrease appetite 23.8 1.8 31.9 3.4Weight decreased 14.4 0.8 31.9 2.6Palmar plantar erythrodysaesthesia 4.3 0.5 11.0 2.8

Skin hyperpigmentation 2.8 0 8.2 0Dehydration 3.0 1.3 9.0 4.3

Van Cutsem, et al. WCGC 2011

AEs leading to treatment discontinuation:AFL: 26.6%PL: 12.1%

Overall Survival - ITT Population

Cut-off date = February 7, 2011; Median follow-up = 22.28 monthsVan Cutsem, et al. WCGC 2011

Regorafenib – A Multi-Kinase Inhibitor

Cellular Phosphorylation Assays IC50 nMVEGFR-2 Phosphorylation, 293 Cells 8

TIE2-Receptor Phosphorylation, CHO Cells 31PDGFR-β Phosphorylation, Aortic SM Cells 90

mVEGFR3 Phosphorylation, 293 Cells 150Mutant RET Phosphorylation, Thyroid TT Cells 10Mutant c-KIT Phosphorylation, GIST 882 Cells 20

FGF-10 FGFR MCF-7 Cells 150-300 MAPK ERK-P HCC, HepG2 Cells 500

Cell Proliferation Assays IC50 nMVEGF/HuVEC (2% FCS) BrdU 4 bFGF/ HuVEC (2% FCS) BrdU 120

PDGFBB/Aortic SM (0.1% BSA) BrdU 121 Thyroid TT RET C643W (10% FCS) 33

GIST 882 KIT K642E (10% FCS) 45 Breast, MDA MB 231 (10% FCS) 570

Melanoma, A375 (10% FCS) 900HCC HepG2 (10% FCS) 560

CORRECT study design

• Multicenter, randomized, double-blind, placebo-controlled, phase III• 2:1 randomization• Strat. factors: prior anti-VEGF therapy, time from diagnosis of mCRC,

geographical region• Global trial: 16 countries, 114 active centers

• 1,052 patients screened, 760 patients randomized within 10 months• Secondary endpoints: PFS, ORR, DCR• Tertiary endpoints: duration of response / stable disease, QOL, pharmacokinetics,

biomarkers

mCRC after standard therapy

RANDOM I ZAT I ON

Regorafenib + BSC 160 mg orally once daily

3 weeks on, 1 week off

Placebo + BSC 3 weeks on, 1 week off

2 : 1

Primary Endpoint:

OS90% power to detect 33.3%

increase (HR=0.75), with 1-sided overall

a=0.025

Overall survival (primary endpoint)

Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p<0.009279 at approximately 74% of events required for final analysis)

1.00

0.50

0.25

0

0.75

200100500 150 300250 400350 450

Days from randomization

Surv

ival

dis

trib

utio

n fu

nctio

n

Placebo N=255Regorafenib N=505

Median 6.4 mos 5.0 mos95% CI 5.9–7.3 4.4–5.8

Hazard ratio: 0.77 (95% CI: 0.64–0.94) 1-sided p-value: 0.0052

Regorafenib Placebo

Drug-related, treatment-emergent adverse events occurring in ≥10% of patients at any grade

Adverse event, % RegorafenibN=500

PlaceboN=253

All grades

Grade 3

Grade 4

Grade 5

All grades

Grade 3

Grade 4

Grade 5

Hand–foot skin reaction 46.6 16.6 0 0 7.5 0.4 0 0Fatigue 47.4 9.2 0.4 0 28.1 4.7 0.4 0Hypertension 27.8 7.2 0 0 5.9 0.8 0 0Diarrhea 33.8 7.0 0.2 0 8.3 0.8 0 0Rash/desquamation 26.0 5.8 0 0 4.0 0 0 0Anorexia 30.4 3.2 0 0 15.4 2.8 0 0Mucositis, oral 27.2 3.0 0 0 3.6 0 0 0Thrombocytopenia 12.6 2.6 0.2 0 2.0 0.4 0 0Fever 10.4 0.8 0 0 2.8 0 0 0Nausea 14.4 0.4 0 0 11.1 0 0 0Bleeding 11.4 0.4 0 0.4 2.8 0 0 0Voice changes 29.4 0.2 0 0 5.5 0 0 0Weight loss 13.8 0 0 0 2.4 0 0 0Adverse events leading to permanent Tx discontinuation 8.2% 1.2%

Take-Home Messages: Optimized Medical Therapy of Advanced CRC

1. Identify the goal of therapy• For most patients gain of time and

maintaining QOL is more important• Strength of BEV – duration of therapy

matters• RR only matters for

• conversion therapy of liver metastases or• if patient is symptomatic from his tumor

burden

Take-Home Messages: Optimized Medical Therapy of Advanced CRC

2. Treat to progression – and beyond Be mindful about toxicities, stop oxaliplatin before neurotoxicity develops• Some select patients can have CFI

3. Expose patients to all potentially active agents• These agents are the oncologist’s tools to

keep patients alive• Use fluoropyrimidine-based combinations as

default backbone, reserve sequential single agent therapy for select patients

4. We finally have new active agents in CRC: Aflibercept and regorafenib