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Dr. Axel GrotheyProfessor of Oncology

Mayo Clinic

Colorectal CancerUpdates ASCO 2012

Axel Grothey

Professor of Oncology

Mayo 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.

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

First-line Bevacizumab in Metastatic Colorectal Cancer: OS

OS

(M

os)

NO16966[2]AVF2107g[1]

†

*

TREE-2[4]BICC-C[3]

*P < .001; †P = .0769

1. Hurwitz H, et al. N Engl J Med. 2004;350:2335. 2. Saltz LB, et al. J Clin Oncol. 2008;26:2013-2019. 3. Fuchs C, et al. ASCO 2007. Abstract 4027. 4. Hochster, et al. ASCO 2006. Abstract 3510.

15.6

20.3 19.921.3

23.1

28.0

17.619.2

20.7

26.0 27.0

0

5

10

15

20

25

30

IFLIFL + Bevacizum

ab

FOLFOX/CapeOx + Bev

FOLFOX/CapeOx

FOLFIRI

FOLFIRI + Bevacizumab

mIFL

mIFL + Bevacizum

ab

bFOL + Bevacizumab

mFOLFOX + Bevacizum

ab

CapeOx + Bevacizumab

AIO 0504 / Roche ML18147Multinational European Trial

Any-OX+ BEV

Any-IRI+ BEV

Any-IRI+ BEV

Any-IRI Any-OXAny-OX+ BEV

R R

N = 820Primary EP: OS

Accrual completed May 31, 2010

Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients

with metastatic colorectal cancer (mCRC) previously treated with BEV + CT: Results of a randomised phase III intergroup study – TML

(ML18147)

D Arnold1, T Andre2, J Bennouna3, J Sastre4, P Österlund5, R Greil6 E Van Cutsem7, R von Moos8, I Reyes-Rivera9, B Bendahmane10, S Kubicka11

on behalf of the AIO, GERCOR, FFCD, UNICANCER GI, TTD, GEMCAD and AGMT groups

1Hamburg, Germany; 2Paris, France; 3Nantes, France; 4Madrid, Spain5Helsinki, Finland; 6Salzburg, Austria; 7Leuven, Belgium; 8Chur, Switzerland

9South San Francisco, USA; 10Basel, Switzerland; 11Reutlingen, Germany

BEV + standard first-line CT (either

oxaliplatin oririnotecan-based)

(n=820)

Randomize 1:1

Standard second-line CT (oxaliplatin or irinotecan-

based) until PD

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

based) until PD

PD

ML18147 study design (phase III)

CT switch:

Oxaliplatin → Irinotecan

Irinotecan → Oxaliplatin

Study conducted in 220 centres in Europe and Saudi Arabia

Primary endpoint • Overall survival (OS) from randomization

Secondary endpoints included

•Progression-free survival (PFS)•Best overall response rate•Safety

Stratification factors • 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)

Main eligibility criteria

Inclusion

• Patients ≥18 years with histologically confirmed diagnosis of mCRC

• Eastern Cooperative Oncology Group (ECOG) PS 0–2

• PD (≥1 measurable lesion according to RECIST v1 assessed by investigator, documented by CT or MRI), ≤4 weeks prior to start of study treatment

• Previously treated with BEV plus standard first-line CT, not candidates for primary metastasectomy

Exclusion

• Diagnosis of PD >3 months after last BEV administration

• First-line patients with PFS in first-line of <3 months

• Patients receiving <3 consecutive months of BEV in first-line

CharacteristicCT

(n=411)BEV + CT(n=409)

Male, % 63 65

Age, median years 63 63

ECOG performance status, %012

43525

44515

First-line PFS, %≤9 months>9 months

5644

5446

First-line CT, %Irinotecan-basedOxaliplatin-based

5842

5941

Demographic and baseline characteristics: Randomized patients

Patients were accrued between February 2006 and June 2010

Demographic and baseline characteristics: Randomized patients (cont’d)

aPatient population refers to sequential enrolment of patients in original AIO study and subsequent enrolment in ML18147 when study was transferred to Roche

Characteristic CT

(n=411) BEV + CT

(n=409)

Duration from last BEV dose to randomisation, %

≤42 days >42 days

7723

7723

Patient populationa, %AIOML18147

3268

3268

Liver metastasis only, %NoYes

7129

7327

No. of organs with metastasis, %1>1

3961

3664

Second-line chemotherapy during study: Randomized patients

Second-line CT regimen, % CT

(n=407) BEV + CT

(n=407)

Irinotecan-based CT 43 42

FOLFIRI 14 16

LV5FU2 + CPT11 (Douillard regimen1) 7 7

XELIRI 12 12

Other regimens 10 7

Oxaliplatin-based CT 57 58

FOLFOX4 / mFOLFOX4 18 19

FOLFOX6 13 16

FUFOX 9 6

XELOX 11 14

Other regimens 6 4

1. Douillard et al. Lancet 2000;355:1041–7

OS: ITT population

No. at riskCT 410 293 162 51 24 7 3 2BEV + CT409 328 188 64 29 13 4 1

OS

est

imat

e

Time (months)

1.0

0.8

0.6

0.4

0.2

0

0 6 12 18 24 30 36 42

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

9.8 mo 11.2 mo

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

p=0.0062 (log-rank test)

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

p=0.0211 (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)

Subgroup analysis of OS: ITT population

aPatient population refers to sequential enrolment of patients in original AIO and subsequent enrolment in ML18147 when study was transferred to Roche. All patients listed under AIO were included in primary analysis

Category Subgroup n HR (95% CI)

All All 819 0.81 (0.69–0.94)

Patient populationa AIO 260 0.86 (0.67–1.11)

ML18147 559 0.78 (0.64–0.94)

Gender Female 294 0.99 (0.77–1.28)

Male 525 0.73 (0.60–0.88)

Age <65 years 458 0.79 (0.65–0.98)

≥65 years 361 0.83 (0.66–1.04)

ECOG performance status 0 357 0.74 (0.59–0.94)

≥1 458 0.87 (0.71–1.06)

First-line PFS ≤9 months 449 0.89 (0.73–1.09)

>9 months 369 0.73 (0.58–0.92)

First-line CT Oxaliplatin-based 343 0.79 (0.62–1.00)

Irinotecan-based 476 0.82 (0.67–1.00)

Time from last BEV ≤42 days 630 0.82 (0.69–0.97)

>42 days 189 0.76 (0.55–1.06)

Liver metastasis only No 592 0.81 (0.67–0.97)

Yes 226 0.79 (0.59–1.05)

No. of organswith metastasis

1 307 0.83 (0.64–1.08)

>1 511 0.77 (0.64–0.94)

HR 0 1 2

PFS: ITT populationP

FS

est

imat

e

Time (months)

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 36

No. at riskCT 410 119 20 6 4 0BEV + CT 409 189 45 12 5 2

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

4.1 mo 5.7 mo

Unstratifieda HR: 0.68 (95% CI: (0.59–0.78) p<0.0001 (log-rank test)

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

p<0.0001 (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)

Best overall response: Measurable disease population

aPatients with a best overall response of confirmed complete or partial responsebThis analysis was not prespecifiedcIncludes ‘not-evaluable’ or ‘no tumour assessment’ following baseline visit

Outcome CT

(n=406) BEV + CT

(n=404)

Respondersa, n (%) 16 (3.9) 22 (5.4)

p-value 0.3113

Complete response, n (%) 2 (<1) 1 (<1)

Partial response, n (%) 14 (3) 21 (5)

Stable disease, n (%) 204 (50) 253 (63)

Disease control rate, n (%) 220 (54) 275 (68)

p-valueb <0.0001

PD, n (%) 142 (35) 87 (22)

Missingc, n (%) 44 (11) 42 (10)

Grade 3–5 adverse events (incidence ≥2%) in any arm: Safety population

Adverse event, %CT

(n=409)BEV + CT(n=401)

Neutropenia 13 16Leukopenia 3 4Diarrhoea 8 10Vomiting 3 4Nausea 3 3Abdominal pain 3 4Subileus <1 2Asthenia 4 6Fatigue 2 4Mucosal inflammation 1 3Dyspnoea 3 2Pulmonary embolism 2 3Polyneuropathy 2 3Neuropathy peripheral 2 1Hypokalaemia 2 2Decreased appetite 2 1

Adverse events of special interest to BEV: Safety population

Patients, %

CT(n=409)

BEV + CT(n=401)

All grades Grade 3–5 All grades Grade 3–5

AEs of special interest to BEV 21 6 41 12

Hypertension 7 1 12 2

Proteinuria 1 – 5 <1

Bleeding/haemorrhage 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

<1 <1 1 <1

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

Conclusions

• First randomized clinical trial that prospectively investigated the impact of continued VEGF inhibition with BEV beyond first progression

• Study confirms that continuing BEV beyond first progression while modifying CT is beneficial for patients with mCRC and leads to a significant improvement in OS and PFS

• This provides a new second-line treatment option for patients who have been treated with BEV + standard CT in first line while maintaining an acceptable safety profile

• Findings indicate a potential new model for treatment approaches through multiple lines and this is currently being investigated in other tumour types

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

Fu

nct

ion

s

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

28

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

VELOUR Study

• Overall results• Adding aflibercept to FOLFIRI in mCRC patients previously treated

with an oxaliplatin-based regimen resulted in significant OS and PFS benefits

Van Cutsem E et al. ESMO/WCGC 2011, Barcelona, Abstract O-0024.

OS PFS

Overall Survival: Stratified by Prior Bevacizumab – ITT Population

Progression-Free Survival: Stratified by Prior Bevacizumab – ITT Population

Response Rates

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

Safety Population, % of patients

Placebo, N = 605 Aflibercept N = 611

All Grades Grade 3-4 All

Grades Grade 3-4

Diarrhea 56.5 7.8 69.2 19.3

Neutropenia** Complicated neutropenia

56.3 29.52.8

67.8 36.75.7

Asthenic conditions (HLT) 50.2 10.6 60.4 16.9

Stomatitis & ulceration (HLT) 34.9 5.0 54.8 13.7

Thrombocytopenia** 33.8 1.7 47.4 3.3

Infections (SOC) 32.7 6.9 46.2 12.3

Decrease appetite 23.8 1.8 31.9 3.4

Weight decreased 14.4 0.8 31.9 2.6

Palmar plantar erythrodysaesthesia 4.3 0.5 11.0 2.8

Skin hyperpigmentation 2.8 0 8.2 0

Dehydration 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%

Cytokine increase on BEV therapy

Kopetz et al., JCO 2010

Regorafenib – A Multi-Kinase Inhibitor

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

TIE2-Receptor Phosphorylation, CHO Cells 31

PDGFR-β Phosphorylation, Aortic SM Cells 90

mVEGFR3 Phosphorylation, 293 Cells 150

Mutant RET Phosphorylation, Thyroid TT Cells 10

Mutant 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) 900

HCC 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

mCRC after standard therapy

RANDOM I ZAT I ON

RANDOM I ZAT I ON

Regorafenib + BSC 160 mg orally once daily

3 weeks on, 1 week off

Regorafenib + BSC 160 mg orally once daily

3 weeks on, 1 week off

Placebo + BSC 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

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

Su

rviv

al d

istr

ibu

tio

n f

un

ctio

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

1.00

0.50

0.25

0

0.75

200100500 150 300250 350

Days from randomization

Su

rviv

al d

istr

ibu

tio

n f

un

ctio

n

Placebo N=255Regorafenib N=505

Regorafenib Placebo

Median 1.9 mos 1.7 mos95% CI 1.9–2.1 1.7–1.7

Hazard ratio: 0.49 (95% CI: 0.42–0.58)

1-sided p-value: <0.000001

Progression-free survival (secondary endpoint)

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

Adverse event, %Regorafenib

N=500PlaceboN=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 0

Fatigue 47.4 9.2 0.4 0 28.1 4.7 0.4 0

Hypertension 27.8 7.2 0 0 5.9 0.8 0 0

Diarrhea 33.8 7.0 0.2 0 8.3 0.8 0 0

Rash/desquamation 26.0 5.8 0 0 4.0 0 0 0

Anorexia 30.4 3.2 0 0 15.4 2.8 0 0

Mucositis, oral 27.2 3.0 0 0 3.6 0 0 0

Thrombocytopenia 12.6 2.6 0.2 0 2.0 0.4 0 0

Fever 10.4 0.8 0 0 2.8 0 0 0

Nausea 14.4 0.4 0 0 11.1 0 0 0

Bleeding 11.4 0.4 0 0.4 2.8 0 0 0

Voice changes 29.4 0.2 0 0 5.5 0 0 0

Weight loss 13.8 0 0 0 2.4 0 0 0

Adverse 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

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

Example of Continuum of Care

KEY POINTS

• For elderly patients consider start of sequence with FP+/- BEV

• First-line oxaliplatin-based therapy needs to be “optimoxed”

• Sequences of FOLFOX -> FOLFIRI or FOLFIRI -> FOLFOX are interchangeable

• BEV beyond progression (BBP) supported by phase III results

• EGFR mAb retain their activity in later lines of therapy

FOLFOX-BEVx8

FP-BEVUntil PD

FOLFOX-BEV

FOLFIRI-BEV

(Irino-) EGFR mAb

Regorafenib

if TTP of FP-BEV>6 mos

if KRAS wt

median overall survival

Advances in the Treatment of Stage IV CRC

1980 1985 1990 1995 2000 2005

5-FUIrinotecan

CapecitabineOxaliplatin

CetuximabBevacizumab

BSC

Panitumumab

20152010

Aflibercept

Regorafenib

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