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![Page 1: Novel Biologics in the Treatment of Colorectal Cancer Howard S. Hochster, MD Professor of Medicine, NYU School of Medicine Director, GI Program NYU Cancer.](https://reader035.fdocuments.in/reader035/viewer/2022062518/56649dc45503460f94ab644f/html5/thumbnails/1.jpg)
Novel Biologics in the Treatment of Colorectal
Cancer
Howard S. Hochster, MD
Professor of Medicine, NYU School of Medicine
Director, GI Program NYU Cancer Institute
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Current Therapies Fluoropyrimidines Oxaliplatin Irinotecan Bevacizumab; anti-angiogenic MoAB Cetuximab; anti-growth factor MoAB
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5-Fluorouracil: History
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Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5768 Patients
OS (mos) = 13.2 + ([%3drugs] x 0.1), R^2 = 0.85 Grothey & 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
22
21
20
19
18
17
16
15
14
13
12
Med
ian O
S (
mo
)
Patients with 3 drugs (%)
P =.0001
First-Line Therapy
Multivariate analysis:Effect on OS P
First-line doublet 0.69All 3 drugs 0.005
Source: Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line. J Clin Oncol 2005;23(36):9441-2. Adapted with permission from the American Society of Clinical Oncology.
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Functions of Cell Surface Receptors
Proliferation Invasion Migration Survival Angiogenesis
EGFR √ √ √ √ √ √
IGFR √ √ √ √ √ √
c-MET √ √ √ √ √
VEGFR1 √ √ √
uPAR √ √ √ √
Integrins √ √ √ √ √
The best targeted therapies may be those that mediate cell survival
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AN INTERESTING
DILEMMA:
Bevacizumab studied with bIFL; how will it be used with oxaliplatin-based Rx?
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THE TREE TRIAL (2 cohorts)comparing oxaliplatin schedules
Given that:– 5-FU may be administered as an infusion,
a bolus, or as an oral prodrug formulation– 3 oxaliplatin-fluoropyrimidine regimens
would have: Similar efficacy, if there were equivalent
dose intensities Variant AE profiles, related to the mode of
fluoropyrimidine administration
TREE-1 Rationale
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TREE-1 and TREE-2: Treatment Schema
RRAANNDDOOMMIIZZAATTIIOONN
mFOLFOX6 (q14 days)Oxaliplatin-85 mg/m2
LV-350 mg (fixed dose)5-FU-400 mg/m2 IV bolus followed by 2400
mg/m2 IV infusion over 46 hrs on D1
CapeOx (q21days)Oxaliplatin-130 mg/m2 over 2 hours on D1
Capecitabine-1000 mg/m2 twice daily on Days 1-15
bFOL (every 28 days)
Oxaliplatin - 85 mg/m2 IV x 2 hrs days 1,15LV - 20 mg/m2 IV bolus on Days 1,8,15
5-FU - 500 mg/m2 IV bolus on Days 1,8,15
TREE-1 (N=150)(Nov 2002-Oct 30, 2003)
mFOLFOX6 +
Bevacizumab (5 mg/kg q14 days)
CapeOxCapecitabine 850 mg/m2 bid day 1-5
+ Bevacizumab(7.5 mg/kg q21days)
bFOL+
Bevacizumab (5 mg/kg q 2 weeks)
TREE-2 (N=223)(Nov 2003 – April 2004)
RRAANNDDOOMMIIZZAATTIIOONN
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TREE-1 TREE-2
mFOLFOX
n=50*
bFOL
n=50*
CapeOx
n=50*
mFOLFOX-B
N=75*
bFOL-B
N=74*
CapeOx-B
N=74*
Median age
(range)
61
(35-79)
62
(31-84)
62.5
(32-84)
64
(31-83)
57.5
(30-85)
62
(32-82)
Gender(%):
Male/Female58/42 62/38 62/38 61/39 49/51 60/40
ECOG PS:
0/1 %62/38 58/42 50/50 59/41 55/45 66/34
Prior adjuvant
therapy (%)44 16 26 23 32 31
* ITT population
TREE-1 vs. TREE-2: Demographics
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TREE-1: 5-FU/Capecitabine Dose Reductions
FOLFOXFOLFOX
(149 cycles)(149 cycles)
bFOLbFOL
(82 cycles)(82 cycles)
CapeOXCapeOX
(88 cycles)(88 cycles)
5-FU or 5-FU or
capecitabine capecitabine
dose reductions: dose reductions:
cycles (%)cycles (%)
1717 1212 5050
DSMB recommended that the capecitabine dose be reduced
(to 850 mg/m2 b.i.d. x 14 days) in the CapeOX arm (30/10/03)
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TREE-1 vs. TREE-2Comparative Grade 3/4 toxicities –First 12 weeks of treatment
EventsTREE 1 TREE 2
mFOLFOX
n=49*
bFOL
n=50*
CapeOx
n=48*
mFOLFOX-B
n=71*
bFOL-B
n=70*
CapeOx-B
n=72*
Vomiting 8 6 19 1 11 7Dehydration 4 10 21 6 11 8Diarrhea 22 22 27 10 26 17Neutropenia 35 14 13 35 13 4Febrile neutropenia 0 0 2 3 1 0Hand-foot syndrome 6 2 13 0 0 7Neurotoxicity 4 4 19 3 4 7Hypertension 0 0 0 9 4 10Bleeding 0 4 2 0 4 1Thrombosis (arterial) 0 0 2 0 0 1Proteinuria 0 0 0 0 0 1Any Grade 3 or 4 76 44 73 65 60 58
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TREE-2: Grade 3/4Toxicities during the First 12 Weeks of Rx
0
10
20
30
40
Neutropenia FebrileNeutropenia
Vomiting Dehydration Diarrhea Gr. 3Neurotoxicity
Bleeding Thromboembolic
Event
mFOLFOX6 +Bev
bFOL+Bev
CapeOx+Bev
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mFOLFOX+Bev
n=71 (%)
bFOL+Bev
n =70(%)
CapeOx+Bev
n=72(%)
GI Perforation 3 (4.2) 2 (2.9) 2(2.8)
Impaired Wound Healing 4 (5.6) 1 (1.4) 4 (5.6)
Treatment-related Deaths 0
3 (4.3)
(2 sepsis,
1 peritonitis)
3 (4.2)
(1 arrhythmia,
1 CVA,
1 SBO)
TREE-2: Absolute Number of Patients with Specific Treatment-related Toxicities
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TREE-1 vs. TREE-2Comparative Response Rate
0
10
20
30
40
50
60
70
FOLFOX FOLFOX+B bFOL bFOL+B CapeOx CapeOx+B
Confirmed ORR Best ORR
(p<0.004, from the pooled logistic regression analysis, likelihood ratio test)
FOLFOX bFOL CapeOX
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TREE-1 vs. TREE-2Comparative Analysis
FOLFOX CapeOx bFOL
- BEV
N=49
+ BEV
N=71
- BEV
N=48
+ BEV
N=72
- BEV
N=49
+ BEV
N=71
Conf. RR (%) 41 52 27 46 20 35
TTF (mo) 5.7 5.8 4.2 5.5 4.8 5.5
TTP (mo) 8.4 9.9 5.9 10.3 6.9 8.3
Hochster et al., ASCO 2005 and GI ASCO 2006
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TREE-2 Conclusions Two sequential cohorts within same protocol, same
investigators CapeOX not tolerated at 1000 mg/m2 bid x 14 days;
good tolerance at 850 mg/m2 bid Addition of Bevacizumab to oxaliplatin plus
fluoropyrimidines is safe with expected toxicities and overall gr 3-4 rates
Addition of Bevacizumab increases RR by approximately 10%– Also improves TTP – TTF is increased less by bevacizumab
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• Chemical differences
• PK differences
• Differences in spectrum of activity– VEGFR and other receptors
Differences in toxicity
All TKIs Are Not the Same
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Small Molecule Inhibitors• 1st Generation
PTK787 /ZK 22854 SU5416SU6668SU11248
Newer InhibitorsAAL993CEP-7055CP-547,632GW654652AMG 706AZ 2171
• Combined InhibitorsZD6474AEE788BAY 43-9006
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PTK787/ ZK 225846 (Vatalanib)
Aminophthalazine Well tolerated oral
inhibitor of VEGFR-1,2,3 Also inhibits c-kit and
PDGFR Promising phase I, II
data Inhibits blood flow on
DCE-MRI CONFIRM 1-2 trials
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Phase III Trial of Vatalanib in First-Line MCRC (CONFIRM-1)
Primary end point: PFS, OS
Secondary end points: TTP, TTF, ORR
FOLFOX4 + placebo
n=585PD
n=583PD
•Previously untreated MCRC
•WHO PS 0-2
FOLFOX4 + Vatalanib 1250 mg po qd
RANDOMIZATION
Hecht et al. ASCO, 2005. Abstract 3. Updated from oral presentation.
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Dr. Dimitris Voliotis • #24
Phase III Renal Cell Cancer Interim analysis
positive
Filed for market approval in RCC July 2005
Phase III Hepatocellular Carcinoma Started March 2005
Phase II/III Malignant Melanoma Started May 2005
Sorafenib (BAY 43-9006)
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Dr. Dimitris Voliotis • #25
* Placebo patients whoprogressed could cross over to sorafenib
• Randomized Discontinuation Design represents an innovative approach for studying novel anticancer drugs
• Bayer and Onyx were the first to apply this design in a major oncology setting
Randomized Discontinuation Study – Treatment Plan
Sorafenib 12-week run-in
Tumor shrinkage ≥25%
Tumor growth/ shrinkage <25%
Tumor growth ≥25%
Off study
Placebo* 12 weeks
Sorafenib 12 weeks
Sorafenib open label
% Progression free at 24 weeks
Ratain MJ, et al. Presented at: ASCO; May 13-17, 2005; Orlando, Fla.
N=202 N= 166 N=32
N=33
N= 79
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Dr. Dimitris Voliotis • #26
Data shown for 166 patients (12-week bidimensional measurements were not available for 36 patients).
Tumor Size Changes After 12 Weeks of Treatment as Measured by Radiographic Measurements
≥25% growth
<25% change
≥25% shrinkage
-100
-75
-50
-25
0
25
50
75
100
125
% c
han
ge
fro
m b
asel
ine
in b
idim
ensi
on
al
tum
or
mea
sure
me
nt
Patients with increasein tumor size
Patients with decrease
in tumor size
Source: With permission. Ratain MJ et al. Presentation. ASCO 2005. Abstract 4544
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Dr. Dimitris Voliotis • #27
0.00
0.25
0.50
0.75
1.00
Pro
po
rtio
n o
f p
atie
nts
p
rog
ress
ion
-fre
e
0 100 200 300 400 500
Days from randomization
Sorafenib (n=32)
Placebo (n=33)
Censored
12-week run-in period
-84
Median progression-free survival from randomization:Placebo=6 weeksSorafenib=24 weeksp=0.0087
Median Progression-Free Survival for Patients with Renal Cell Cancer Randomized to Placebo or Sorafenib
Source: With permission. Ratain MJ et al. Presentation. ASCO 2005. Abstract 4544
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AZD2171 Clinical Data
Extensive and innovative phase I program in a number of tumours:
– 253 patients treated in monotherapy and combination studies
Program has led to a clear view of:
– Pharmacokinetics
– Evidence of inhibition of VEGF signalling in man
– Initial evidence of anti-tumour activity
– Tolerability profile
– Dosing strategy
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VEGF Trap (AVE0005)
A novel potent VEGF inhibitor
in Oncology
VEGF Trap (AVE0005)
A novel potent VEGF inhibitor
in Oncology
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VEGF TrapPhase I experience
Phase I SQ administration– 25 ug/kg 800 q week 800 ug sq biw– 8/10 stable at 800 ug/kg q wk or biw; one PR in
refractory BAL NSCLC– Toxicity: HTN, proteinuria– T ½ = 25 + 3 days
Phase I IV administration– 0.3 5 ug/kg iv q 2 wks– Usual toxicities– PR: ovarian (ascites), thymoma; 2 MRs
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IV VEGF Trap Program:Summary of Ongoing Phase I and Phase II Studies
IV VEGF Trap Program:Summary of Ongoing Phase I and Phase II Studies
Phase I Single-Agent IV Study
Phase Ib Combination-Agent Studies Phase Ib combination with oxaliplatin/5-FU/LV
(FOLFOX4) Phase Ib combination with LV5FU2-CPT11
Phase Ib combination with docetaxel/cisplatin/
fluorouracil Phase Ib combination with docetaxel, then
docetaxel/cisplatin Phase Ib combination with gemcitabine, then GEMOX
Phase II Single-Agent Studies 3rd Line Non-Small-Cell Lung Adenocarcinoma 3rd-Line Advanced Ovarian Cancer Advanced Ovarian Cancer with Symptomatic Malignant
Ascites
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PropertiesCetuximab/IMC-C225
IgG1 (chimerized antibody)
Exclusive for EGFR and its heterodimers
Prevents ligand binding to EGFR
Binds to EGFR with high affinity (Kd = 2.0 x 10–10 M) = ONE log higher than the natural ligand
Stimulates receptor internalization
Blocks receptor dimerization, tyrosine kinase phosphorylation, and signal transduction
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Cetuximab ± Irinotecan in CRC
Patients with CRC progressed
on or within 3 months of
irinotecan-based chemotherapy
RANDOMIZATION
Irinotecan dose and schedule used during progression
Cetuximab 400 mg/m2 1st infusion, then 250 mg/m2/week
Cetuximab 400 mg/m2 1st infusion,
then 250 mg/m2/week
Irinotecan dose and schedule used during
progression Cetuximab 400 mg/m2
1st infusion, then 250 mg/m2/week
PD
Schema
n=111
n=218
Cunningham D, et al. Proc Am Soc Clin Oncol. 2003;22:252. Abstract 1012 and oral presentation (slide 6).
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Combination Antibody Therapy MCRCNCI 5844 (“BOND-2”)
Patients with MCRC who progressed with irinotecan
(N=150)
Bevacizumab + cetuximab + irinotecan
Bevacizumab + cetuximab
At: http://ctep.cancer.gov/forms.
Primary end point:
Response rate
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Efficacy Comparison (Historical Controls)
Cetux-Irino
(historical)
Cetux-Irino + Bev
Resp Rate 23% 38%
TTP 4 m 8.5 m
Cetux alone
(historical)
Cetux + Bev
Resp Rate 11% 23%
TTP 1.5 m 6.9 m
“BOND” “BOND-2”
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CALGB/SWOG Intergroup Trial 80405
Bevacizumab
Cetuximab
Bevacizumab +Cetuximab
FOLFOXor FOLFIRI
“Dealer’s Choice”
R
N=2289 Primary endpoint: OSHR 1.25 (22 vs 27.5 months)
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PACCE Trial*
Bevacizumab
Bevacizumab +Panitumumab
FOLFOXor FOLFIRI
“Dealer’s Choice”
N=1000 Primary endpoint: PFS
R
PACCE: Panitumumab Advanced Colorectal Cancer Evaluation; opened April 2005
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Strategies for future developments
“Pile-on” Approach– Combo-chemo+bev– Combo-chemo + bev + cetuximab– Combo-chemo + bev + TKI + cetuximab– Combo-chemo + bev + cetuximab + novel
biologic 1 + novel biologic 2 Semi-STOP and GO
– Biologic interludes Avoid cytotoxics altogether
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CONCLUSIONS
Combination Chemotherapy – Effective; “all 3-drugs” OS plateau– Platform for biologics
Angiogenesis Pathway– Validated target for combination with chemotherapy– Multiple approaches– Combinations of VEGF inhibitors?
Growth Factor Pathway– EGFR inhibitors validated– Can we use EGFR-TKIs in colorectal cancer
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CONCLUSIONS
Studies underway combining dual-blockade with two antibodies plus chemotherapy
Future goals– Improved survival, decreased toxicity– Identifying the correct target– Confirming adequate inhibition of target