Fighting a Smarter War On Colon Cancer:

John L. Marshall, MD

Angiogenesis inhibition through all lines of therapy

Tel: (202) 444-0275Fax: (202) 444-1229

http://lombardi.georgetown.edu/GI

Stakeholder Motivation

StakeholdersStakeholders•FDA•CMS/Payers•NCI/CTEP•PhRMA•Community Onc•Academic Onc•Patients

Priority/AgendaPriority/Agenda•Safety and Efficacy•Cost Control/Value•Cure Cancer•Markets, ROI•Efficient/Quality Care•Clinical Trial Accrual•Cure/Benefit/Altruism

2012 ESMO Guidelines: Sequence of Treatment by Line

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

4A. Friedman and N. Perrimon, Cell 128, January 26, 2007

Pathway vs. Network signalingPathway vs. Network signaling

Network

“Chaotic”

Pathway

“Newtonian”

The Nature of the Disease

Multiple signaling pathways activated in CRC

• Multiple pathways implicated in CRC,including:1–3

– EGF / EGFR

– VEGF / VEGFR

– PDGF / PDGFR

– FGF / FGFR

– Downstream pathways:

• RAS–RAF–MEK–ERK

• PI3K–PTEN–AKT–mTOR

• Kopetz et al showed that several compensatory pathways are activated during therapy with bevacizumab + FOLFIRI3

• Provides rationale for using a multitargeted agent following progression

1. Macarulla T et al. Clin Colorectal Cancer 20062. Siena S et al. J Natl Cancer Inst 20093. Kopetz S et al. J Clin Oncol 2010

Figure adapted from Siena S et al 20092

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: OS

90% power to detect 33.3%

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

=0.025

Primary Endpoint: OS

90% power to detect 33.3%

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

=0.025

CORRECT Primary Endpoint:Overall Survival

1.00

0.50

0.25

0

0.75

200100500 150 300250 400350 450Days From Randomization

Su

rviv

al D

istr

ibu

tio

n F

un

ctio

n

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

Median 6.4 months 5.0 months95% CI 5.9-7.3 4.4-5.8

Hazard ratio: 0.77 (95% CI, 0.64-0.94)

1-sided P = 0.0052

Placebo

Primary endpoint met prespecified stopping criteria at interim analysis. (1-sided P<0.009279 at approximately 74% of events required for final analysis).Grothey A et al. Lancet. 2013;381:303-312. Reprinted with permission from Elsevier.

Regorafenib

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 = 255)Regorafenib (n = 505)

Regorafenib Placebo

Median 1.9 months 1.7 months95% CI 1.9-2.1 1.7-1.7

Hazard ratio: 0.49 (95% CI, 0.42-0.58)

1-sided P<0.000001

Grothey A et al. Lancet. 2013;381:303-312. Reprinted with permission from Elsevier.

CORRECT Secondary Endpoint: Progression-Free Survival

CORRECT: Common Adverse Events

1. Grothey A, et al. Lancet. 2012. [epub].

Treatment-related adverse events occurring in >10% of patients in either group from start of treatment to 30 days after end of treatment

Regorafanib (n=500) Placebo (n=253)

Any Gr Gr 3 Gr 4 Any Gr Gr 3 Gr 4

Fatigue, n (%) 237 (47) 46 (9) 2 (<1) 71 (28) 12 (5) 1 (<1)

Hand-foot skin reaction, n (%) 233 (47) 83 (17) 0 19 (8) 1 (<1) 0

Diarrhea, n (%) 169 (34) 35 (7) 1 (<1) 21 (8) 2 (1) 0

Anorexia, n (%) 152 (30) 16 (3) 0 39 (15) 7 (3) 0

Voice changes, n (%) 147 (29) 1 (<1) 0 14 (6) 0 0

Hypertension, n (%) 139 (28) 36 (7) 0 15 (6) 2 (1) 0

Oral mucositis, n (%) 136 (27) 15 (3) 0 9 (4) 0 0

Rash or desquamation, n (%) 130 (26) 29 (6) 0 10 (4) 0 0

Nausea, n (%) 72 (14) 2 (<1) 0 28 (11) 0 0

Weight loss, n (%) 69 (14) 0 0 6 (2) 0 0

Thrombocytopenia, n (%) 63 (13) 13 (3) 1 (<1) 5 (2) 1 (<1) 0

First Line Second LineContinued Beyond First Progression

TrialAVF21071,2

(n=411 vs 402)E32003

(n=285 vs 287)ML181474

(n=410 vs 409)

Treatment IFL vs IFL + BevFOLFOX4 vs FOLFOX4 +

BevCT* vs CT* + Bev

OS, mosP valueHR

15.6 vs 20.3<0.001

0.66

10.0 vs 12.90.0010.75

9.8 vs 11.20.0057

Unstratified HR: 0.81

PFS, mos P valueHR

6.2 vs 10.6<0.001

0.54

4.7 vs 7.3<0.0001

0.61

4.4 vs 5.7<0.0001

Unstratified HR: 0.68

Summary of Survival From Pivotal Phase III Bevacizumab Studies

Data represent a summary of reported data and are not intended for cross-trial comparisons. 1. Hurwitz, et al. N Engl J Med. 2004;350:2335-2342. 2. Hurwitz, et al. Oncologist. 2009;14:22-28. 3. Giantonio, et al. J Clin Oncol. 2007;25:1539-1544. 4. Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1.

*CT= Fluoropyrimidine + oxaliplatin-containing chemotherapy or Fluoropyrimidine + irinotecan-containing chemotherapy.

ML18147: Randomized, Open-Label, Phase III Study of Bevacizumab + Chemotherapy Beyond Progression in Bevacizumab-Treated mCRC

• Stratification:

– First-line chemotherapy (oxaliplatin-based, irinotecan-based), first-line PFS (≤ or >9 months), time from last dose of bevacizumab (≤ or > 42 days), and ECOG PS (0, ≥1)

• Primary endpoint: OS post progression

• Secondary endpoints: PFS post progression, ORR post progression

Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1.

PD

Fluoropyrimidine-based chemotherapy until PD

Bevacizumab 5 mg/kg every

2 weeks or 7.5 mg/kg every 3 weeks +

Fluoropyrimidine-based chemotherapy until PD

mCRC treated with Bev + standard

first-line chemotherapy

(n=820)

Randomization – switch chemotherapy:OxaliplatinirinotecanIrinotecanoxaliplatin

Chemotherapy options:Fluoropyrimidine + oxaliplatin-containing chemotherapyFluoropyrimidine + Irinotecan-containing chemotherapy

ML18147: Demographic and Baseline Characteristics – Well Balanced

Characteristic Fluoropyrimidine-based chemotherapy

alone(n=411)

Bev + Fluoropyrimidine-

based chemotherapy(n=409)

Sex, male, % 63 65Age, median years 63 63ECOG status, %

0 43 441 52 512 5 5

First-line PFS, %≤9 months 56 54>9 months 44 46

Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1.

Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1.

Fluoropyrimidine-based chemotherapy

alone(n=411)

Bev +Fluoropyrimidine-

based chemotherapy

(n=409)

First-line chemo, %

Irinotecan based 58 59

Oxaliplatin based 42 41

Duration from last bevacizumab dose to randomization, %

≤42 days 77 77

>42 days 23 23

Liver metastasis only, %

No 71 73

Yes 29 27

Number of organs with metastasis, %

1 39 36

>1 61 64

ML18147: Demographic and Baseline Characteristics – Well Balanced (Cont.)

ML18147: Second-line Chemotherapy During Study – Physician’s Choice

Second-line Chemotherapy Regimen, %

Fluoropyrimidine-based chemotherapy alone

(n=407)

Bevacizumab +Fluoropyrimidine-based

chemotherapy(n=407)

sFOLFIRI 14 16

XELIRI 12 12

LV5FU2 + CPT11 7 7

FOLFOX4 9 9

sFOLFOX4 9 9

FOLFOX6 13 16

FUFOX 9 6

XELOX 11 14

Other regimens 16 12sFOLFIRI=simplified fluorouracil 400 mg/m2 intravenous bolus and 2400 mg/m2 over 46 h, folinate 400 mg/m2 intravenously, and irinotecan 180 mg/m2 intravenously on day 1 every 2 weeks. LV5FU2 CPT11=fluorouracil 400 mg/m2 intravenous bolus and 600 mg/m2 (central venous line) over 22 h on days 1, 2, 15, and 16, folinate 200 mg/m2 intravenously on days 1, 2, 15, and 16, and irinotecan 180 mg/m2 intravenously on days 1 and 15 every 4 weeks. FOLFOX4=fluorouracil 400 mg/m2 intravenous bolus and 600 mg/m2 intravenously over 22 h on days 1 and 2, folinate 200 mg/m2 intravenously on days 1 and 2, and oxaliplatin 85 mg/m2 intravenously on day 1 every 2 weeks. sFOLFOX4=simplified folinate 400 mg/m2, fluorouracil 400 mg/m2 intravenous bolus, fluorouracil 2400 mg/m2 continuous infusion (over 46 h), and oxaliplatin 85 mg/m2 on day 1 every 2 weeks. FOLFOX6=fluorouracil 400 mg/m2 intravenous bolus and 2400 mg/m2 intravenously over 46 h on days 1 and 15, folinate 400 mg/m2 intravenously on days 1 and 15, and oxaliplatin 100 mg/m2 intravenously on days 1 and 15 every 4 weeks. FUFOX=fluorouracil 2000 mg/m2 over 22 h (central venous line) on days 1, 8, 15, and 22, folinate 500 mg/m 2 intravenously on days 1, 8, 15, and 22, and oxaliplatin 50 mg/ m2 intravenously on days 1, 8, 15, and 22 every 5 weeks. XELIRI=capecitabine 800 mg/m2 orally twice daily on days 1–14 and 22–35, and irinotecan 200 mg/m2 intravenously on days 1 and 22 every 6 weeks. XELOX=capecitabine 1000 mg/m2 orally twice daily on days 1–14 and 22–35, and oxaliplatin 130 mg/m2 intravenously on days 1 and 22 every 6 weeks. *Six of 409 patients in the bevacizumab and chemotherapy group and four of 411 in the chemotherapy group were not given any treatment; however, four patients in the Bevacizumab and chemotherapy group were misreported as having been given chemotherapy.Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1.

ML18147: Overall Survival (OS)a – ITT Population

OS

Est

imat

e

Time, Months

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 38 42 48

Fluoropyrimidine-based chemotherapy alone (n=410)Bev + Fluoropyrimidine-based chemotherapy (n=409)

9.8 11.2

Unstratifiedb HR: 0.81 (95% CI: 0.69-0.94)

P=0.0057 (log-rank test)

aFrom randomization.bPrimary analysis method.Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1.

410

409

293

328

162

189

51

64

24

29

7

13

3

4

2

1

0

0

Number at riskFluoropyrimidine-based Chemotherapy aloneBev+Fluoropyrimidine-based Chemotherapy

ML18147: Secondary EndpointsP

FS

Est

imat

e

Time, Months

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 38 42

4.1 5.7

aFrom randomization.bPrimary analysis method.Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1.

Unstratifiedb HR: 0.68 (95% CI: 0.59-0.78) P<0.0001 (log-rank test)

410

409

119

169

20

45

6

12

4

5

0

2

0

2

0

0

PFSa – ITT Population

• There was no significant difference in response rate.

Fluoropyrimidine-based chemotherapy alone (n=410)Bev + Fluoropyrimidine-based chemotherapy (n=409)

Number at riskFluoropyrimidine-based Chemotherapy aloneBev+Fluoropyrimidine-based Chemotherapy

18

What about VEGF + EGFR?

Bond-2 vs CAIRO 2 and PACCE

18

““Bond-2”Bond-2”

C225 C225 AloneAlone

C225 + C225 + BevBev

PP

ValueValue

C225 + C225 + CPT-11CPT-11

C225 + C225 + CPT-11 + CPT-11 +

BevBev

P ValueP Value

PRPR 11%11% 23%23% 0.05 23%23% 38%38% 0.03

TTPTTP 1.5 mo1.5 mo 5.6 mo5.6 mo >0.01 4.1 mo4.1 mo 7.9 mo7.9 mo >0.01

OSOS 6.9 mo6.9 mo NRNR - 8.6 mo8.6 mo NRNR -

Kaplan-Meier estimates of time to tumor progression: arm A (cetuximab, bevacizumab, irinotecan) versus arm B (cetuximab, bevacizumab).

Saltz L B et al. JCO 2007;25:4557-4561

©2007 by American Society of Clinical Oncology

Kaplan-Meier estimates of survival: arm A (cetuximab, bevacizumab, irinotecan) versus arm B (cetuximab, bevacizumab).

Saltz L B et al. JCO 2007;25:4557-4561

©2007 by American Society of Clinical Oncology

22

Colon Cancer is more than one disease

kRAS Wild Type kRAS mutant

MSI-High MSS

+ EGFR Agents - EGFR Agents

? No 5FU

50-60% 40-50%

15-20% 80-85%

And of course it is very many more than the 4 sub-groups above

Clinical Research 2.0

Agent HR $ Cost/Month(÷100)

Toxicity(G1+2) * (G3+4) # Patients

QOL/Utility ScorePass/Fail

Imatinib vs IFNCML

0.17 55.90 0.67

Nilotinib vs ImatCML

0.8 76.40 0.17

ImatinibGIST

0.4 55.90 1.22

Erlotinib vs ChemoMut NSCL

0.75 52.80 0.71

ErlotinibPancreas

0.82 52.80 11.9

Bevacizumab 2nd line CRC

0.74 22.90 0.8

Aflibercept2nd line CRC

0.79 ????- 3.0

Value Metric

Finding Value

• Come together• Listen to each other• Respect what we hear• Find the common threads• Weave a new fabric

- provide global healthcare with value

Engaging the 97%• Better education/information• Incentives for patients and providers

– No added incentives for delivering SOC– Honor our “soldiers” in the war on cancer

• Recognized the shared investment in research– Docs, hospitals, NCI, Industry, Payers, Patients

• Target “substantial therapeutic benefit”– “Breakthrough Designation”

• Reduce concept to approval time line• Embrace the emerging markets

Fundamental Shifts In Cancer CareYesterdayYesterday•Consumption•Individual Practices•Rich Countries•Microscope•Safety and Efficacy•Large trials•1.4 months•QOL•Patient as a “Subject”•Chaotic Data Collection•Institutional IRBs•National Approvals

TomorrowTomorrow•Outcomes•Healthcare Systems•All Countries•Gene Profile•Value•Small trials•“Substantial Improvement”•Patient Reported Outcomes•Patient as a “Partner”•Standard Data Collection•Central/National IRBs•Global Approvals