Fighting a Smarter War On Colon Cancer:
Angiogenesis inhibition through all lines of therapy
John L. Marshall, MD
Tel: (202) 444-0275
Fax: (202) 444-1229
http://lombardi.georgetown.edu/GI
Stakeholder Motivation
Stakeholders
• FDA
• CMS/Payers
• NCI/CTEP
• PhRMA
• Community Onc
• Academic Onc
• Patients
Priority/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.
Pathway vs. Network signaling
Pathway
Network
“Newtonian”
“Chaotic”
A. Friedman and N. Perrimon, Cell 128, January 26, 2007
4
The Nature of the Disease
Multiple signaling pathways
activated in CRC
Figure adapted from Siena S et al 20092
• 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 2006
2. Siena S et al. J Natl Cancer Inst 2009
3. Kopetz S et al. J Clin Oncol 2010
CORRECT study design
mCRC after
standard therapy
R
A
N
D
O
M
I
Z
A
T
I
O
N
Regorafenib + BSC
160 mg orally once daily
3 weeks on, 1 week off
2:1
Placebo + BSC
3 weeks on, 1 week off
Primary
Endpoint: OS
90% power to
detect 33.3%
increase
(HR=0.75), with
1-sided overall
a=0.025
• 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
CORRECT Primary Endpoint:
Overall Survival
Survival Distribution Function
1.00
Median
95% CI
0.75
Regorafenib
6.4 months
Placebo
5.0 months
5.9-7.3
4.4-5.8
Hazard ratio: 0.77 (95% CI, 0.64-0.94)
1-sided P = 0.0052
0.50
0.25
Placebo (n = 255)
Regorafenib (n = 505)
0
0
50
100
150
200
250
300
Days From Randomization
350
400
450
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.
CORRECT Secondary Endpoint:
Progression-Free Survival
Survival Distribution Function
1.00
Regorafenib
Median
95% CI
0.75
1.9 months
1.9-2.1
Placebo
1.7 months
1.7-1.7
Hazard ratio: 0.49 (95% CI, 0.42-0.58)
1-sided P<0.000001
0.50
Placebo (n = 255)
Regorafenib (n = 505)
0.25
0
0
50
100
150
200
250
Days From Randomization
Grothey A et al. Lancet. 2013;381:303-312. Reprinted with permission from Elsevier.
300
350
CORRECT: Common Adverse Events
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
1.
Grothey A, et al. Lancet. 2012. [epub].
Summary of Survival From Pivotal Phase III
Bevacizumab Studies
First Line
Second Line
Continued Beyond
First Progression
AVF21071,2
(n=411 vs 402)
E32003
(n=285 vs 287)
ML181474
(n=410 vs 409)
IFL vs IFL + Bev
FOLFOX4 vs FOLFOX4 +
Bev
CT* vs CT* + Bev
OS, mos
P value
HR
15.6 vs 20.3
<0.001
0.66
10.0 vs 12.9
0.001
0.75
9.8 vs 11.2
0.0057
Unstratified HR: 0.81
PFS, mos
P value
HR
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
Trial
Treatment
*CT= Fluoropyrimidine + oxaliplatin-containing chemotherapy or Fluoropyrimidine + irinotecan-containing
chemotherapy.
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.
ML18147: Randomized, Open-Label, Phase III Study of
Bevacizumab + Chemotherapy Beyond Progression in
Bevacizumab-Treated mCRC
mCRC treated with
Bev + standard
first-line
chemotherapy
(n=820)
PD
Randomization –
switch chemotherapy:
Oxaliplatinirinotecan
Irinotecanoxaliplatin
Chemotherapy options:
Fluoropyrimidine + oxaliplatin-containing chemotherapy
Fluoropyrimidine + Irinotecan-containing chemotherapy
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
• 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.
ML18147: Demographic and
Baseline Characteristics – Well
Balanced
Characteristic
Sex, male, %
Age, median years
ECOG status, %
0
1
2
First-line PFS, %
≤9 months
>9 months
Fluoropyrimidinebased chemotherapy
alone
(n=411)
63
63
Bev +
Fluoropyrimidinebased chemotherapy
(n=409)
65
63
43
52
5
44
51
5
56
44
54
46
Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1.
ML18147: Demographic and
Baseline Characteristics – Well
Balanced (Cont.)
Fluoropyrimidinebased chemotherapy
alone
(n=411)
Bev +
Fluoropyrimidinebased
chemotherapy
(n=409)
58
42
59
41
First-line chemo, %
Irinotecan based
Oxaliplatin based
Duration from last bevacizumab dose to randomization, %
≤42 days
77
77
>42 days
23
23
No
71
73
Yes
29
27
1
39
36
>1
61
64
Liver metastasis only, %
Number of organs with metastasis, %
Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1.
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
12
sFOLFIRI=simplified fluorouracil 400 mg/m 2 intravenous bolus and 2400 mg/m 2 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/m 2 (central venous line) over 22 h on days 1, 2, 15, and 16, folinate 200 mg/m 2 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/m 2 intravenous bolus and 600 mg/m 2 intravenously over 22 h on days 1 and 2,
folinate 200 mg/m2 intravenously on days 1 and 2, and oxaliplatin 85 mg/m 2 intravenously on day 1 every 2 weeks. sFOLFOX4=simplified folinate 400 mg/m 2, 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/m 2 intravenously on days 1 and 15, and oxaliplatin 100 mg/m 2 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/ m 2 intravenously
on days 1, 8, 15, and 22 every 5 weeks. XELIRI=capecitabine 800 mg/m 2 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/m 2 orally twice daily on days 1–14 and 22–35, and oxaliplatin 130 mg/m 2 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.
ML18147: Overall Survival (OS)a – ITT
Population
1.0
Fluoropyrimidine-based chemotherapy alone (n=410)
Bev + Fluoropyrimidine-based chemotherapy (n=409)
OS Estimate
0.8
Unstratifiedb HR: 0.81 (95% CI: 0.69-0.94)
P=0.0057 (log-rank test)
0.6
0.4
0.2
9.8
0
11.2
0
6
12
18
24
30
Time, Months
410
293
162
51
24
409
328
189
64
29
38
42
48
7
3
2
0
13
4
1
0
Number at risk
Fluoropyrimidine-based
Chemotherapy alone
Bev+Fluoropyrimidine-based
Chemotherapy
aFrom
randomization.
analysis method.
Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1.
bPrimary
ML18147: Secondary Endpoints
PFSa – ITT Population
1.0
Fluoropyrimidine-based chemotherapy alone (n=410)
Bev + Fluoropyrimidine-based chemotherapy (n=409)
PFS Estimate
0.8
Unstratifiedb HR: 0.68 (95% CI: 0.59-0.78)
P<0.0001 (log-rank test)
0.6
0.4
0.2
4.1
0
5.7
0
6
12
410
119
20
6
409
169
45
12
Number at risk
Fluoropyrimidine-based
Chemotherapy alone
Bev+Fluoropyrimidine-based
Chemotherapy
•
aFrom
18
24
Time, Months
38
42
4
0
0
0
5
2
2
0
There was no significant difference in response rate.
randomization.
analysis method.
Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1.
bPrimary
30
What about VEGF + EGFR?
 Bond-2 vs CAIRO 2 and PACCE
18
18
“Bond-2”
C225
Alone
C225 +
Bev
PR
11%
23%
TTP
1.5 mo
OS
6.9 mo
P
C225 +
CPT-11
C225 +
CPT-11 +
Bev
P Value
0.05
23%
38%
0.03
5.6 mo
>0.01
4.1 mo
7.9 mo
>0.01
NR
-
8.6 mo
NR
-
Value
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
Colon Cancer is more than one disease
40-50%
50-60%
kRAS mutant
kRAS Wild Type
+ EGFR Agents
15-20%
MSI-High
80-85%
- EGFR Agents
MSS
? No 5FU
And of course it is very many more than the
4 sub-groups above
22
Clinical Research 2.0
Value Metric
Agent
HR
$ Cost/Month
(÷100)
Toxicity
(G1+2) * (G3+4)
# Patients
Imatinib vs IFN
CML
0.17
55.90
0.67
Nilotinib vs Imat
CML
0.8
76.40
0.17
Imatinib
GIST
0.4
55.90
1.22
Erlotinib vs
Chemo
Mut NSCL
0.75
52.80
0.71
Erlotinib
Pancreas
0.82
52.80
11.9
Bevacizumab 2nd
line CRC
0.74
22.90
0.8
Aflibercept
2nd line CRC
0.79
????-
3.0
QOL/Utility Score
Pass/Fail
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 Care
Yesterday
Tomorrow
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
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
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