small and large-molecule angiogenesis inhibitors: excitement and disappointments
DESCRIPTION
Small and Large-Molecule Angiogenesis Inhibitors: Excitement and Disappointments . CT-322 VEGFR2 Adnectin. Cediranib VEGFR Kinase Inhibitor. Scott Kopetz, MD, PhD Gastrointestinal Medical Oncology University of Texas, M D Anderson Cancer Center. Outline. - PowerPoint PPT PresentationTRANSCRIPT
Small and Large-Molecule
Angiogenesis Inhibitors:
Excitement and Disappointments
Scott Kopetz, MD, PhDGastrointestinal Medical Oncology
University of Texas, M D Anderson Cancer Center
CT-322VEGFR2Adnectin
CediranibVEGFR
Kinase Inhibitor
Outline
· Anti-Angiogenesis: Where are we now?- Overview of Agents Targeting VEGF
· Disappointments:- VEGF Tyrosine Kinase Inhibitors
· Excitement: - Large Molecule VEGF inhibitors- Beyond VEGF: Alternate angiogenesis
inhibitors
Current Benefits of Anti-Angiogenic Therapy: Bevacizumab in Phase III
AVF2107g NO16966 E32000
3
6
9
12
6.2
8
4.7
10.6
9.4
7.3
Prog
ress
ion-
free
surv
ival
(m
onth
s)
Hurwitz et al NEJM 2004; Saltz et al JCO 2008; Giantonio et al JCO 2007
IFL
IFL
+ B
ev
FOLF
OX
/XE
LOX
FOLF
OX
/XE
LOX
+ B
ev
FOLF
OX
FOLF
OX
+ B
ev
Why the interest in alternate angiogenesis inhibitors?· There is clearly room to improve on anti-
angiogenic therapy in CRC· VEGF and angiogenesis are known to be
relevant in CRC- Anti-VEGF development is viewed as a
lower risk than a completely novel target· Agents with oral bioavailability and lower
production costs may have market advantage
Cell membrane
VEGF-A
VEGF-R1(Flt-1)
MigrationInvasionSurvival
VEGF-R3(Flt-4)
Lymphangio-genesis
VEGF-R2(KDR/Flk-1)Proliferation
SurvivalPermeability
PlGF VEGF-B
VEGF-C, VEGF-D
Func
tions
VEGF Biology
VEGF-A
VEGF-R1(Flt-1)
MigrationInvasionSurvival
VEGF-R3(Flt-4)
Lymphangio-genesis
VEGF-R2(KDR/Flk-1)Proliferation
SurvivalPermeability
PlGF VEGF-C, VEGF-D
Func
tions
Large molecule VEGF inhibitors
Y
Bevacizumab
YVGX-100
YRamucirumab(IMC-1121B) II
CT-322
Y
IMC-18F1
Aflibercept (VEGF Trap)
Y
TB403
Cell membrane
VEGF-A
VEGF-R1(Flt-1)
MigrationInvasionSurvival
VEGF-R3(Flt-4)
Lymphangio-genesis
VEGF-R2(KDR/Flk-1)Proliferation
SurvivalPermeability
PlGF VEGF-B
VEGF-C, VEGF-D
Func
tions
Small molecule VEGFR inhibitors
X X XVEGFRTyrosine KinaseInhibitors (TKIs)
Small Molecule VEGFR Inhibitors in CRCAgent a.k.a mCRC Trials CRC Patients
Cediranib AZD2171 2 Phase III 3,194Semaxinib SU5416 2 Phase III 2,084Vatalanib PTK787 2 Phase III 2,050Sunitinib SU11248 Phase III 1,623Brivanib BMS-582664 Phase III 926
Regorafenib BAY 73-4506 Phase III 730Sorafenib BAY 43-9006 Phase IIB 814
Vandetanib ZD6474 Phase IIB 356Axitinib AG-013736 Phase IIB 299Linifanib ABT-869 Phase IIB 147Vargateg BIBF 1120 Phase II 166Tivozanib AV-951 Phase II 80Motesanib AMG-706 Phase IB 148Pazopanib GW786034 Phase IB 94
Clinicaltrials.gov >10,000
“VEGF” TKIs Vary By Kinase Selectivity and PK
Agent VEGFR2 IC50 T1/2 Other primary kinasesSorafenib 90nM 27h Raf, RETSunitinib 10nM 44hPazopanib 30nM 35hVandetanib 40nM 120h RET (100nM), EGFR (500nM)Cediranib 0.5nM ~24h c-Kit (2M), PDGFR (5nM), FGFR (26nM)Vatalanib 17nM ~5hAxitinib 0.2nM ~3hSemaxanib 100nM 1.3hRegorafenib 40nM ? Tie2, PDGFR, FGFR, Kit, RET, Raf (69nM)Motesanib 3nM ~6h c-Kit (8nM), PDGFR (84nM), RET (59nM)Brivanib 25nM 3h FGFR (148nM)Vargatef 21nM 12h FGFR (70nM), PDGFR (60nM), Src (150nM)
Linifanib 4nM 17h PDGFR (2nM), CSF-1R (7nM)Dovitinib 10nM 17h FLT3 (1nM), c-KIT (2nM), FGFR (8nM)
Outline
· Anti-Angiogenesis: Where are we now?- Overview of Agents Targeting VEGF
· Disappointments:- VEGF Tyrosine Kinase Inhibitors
· Excitement: - Large Molecule VEGF inhibitors- Beyond VEGF: Alternate angiogenesis
inhibitors
FOLFOX4 + PTK787FOLFOX4
CONFIRM-1 Hecht, ASCO 2005; Pharmacia Press Release Feb 2002
5+ Years ago… “First Generation” VEGFR TKIs
Vatalanib (PTK787)Negative Study
0
25
50
75
100
0 2 4 6 8 10 12
Pro
gres
sion
-free
sur
viva
l, %
Months
5-FU + SU5416
5-FU
0 30 60 9010 20 5040 70 800
25
50
75
100
Weeks
Ove
rall
Sur
viva
l
Semaxinib (SU5416)Negative Study
Lessons Learned with “First Generation” VEGFR TKIs
Vatalanib Semaxinib
· Continuous VEGF inhibition appears to be necessary· Pharmacokinetics matter
· Phase III trials are too late to determine the optimal pharmacokinetics and biomarkers of activity
· Don’t skip Phase II studies!
Strategies Being Employed in “Second Generation” VEGFR TKI studies
· Frontline chemo + Bevacizumab vs. VEGFR TKI- Testing superiority of VEGFR TKI
· Frontline chemo +/- VEGFR TKI- Demonstrate benefit in “easier” setting- Approval outside of US
· Bevacizumab-refractory: Second-line chemo +/- VEGFR TKI- Testing benefit of continued VEGF inhibition- Evaluating relevance of alternate VEGF signaling after
bevacizumab· Dual Inhibition: Bevacizumab + VEGF TKI *
- More “complete” inhibition of VEGF pathway
* Grothey et al ASCO 2010 GI (Colorectal) Poster Session #3549
“Second Generation” VEGFR TKIs: Disappointing Recent Results
· Sunitinib- Phase III: First line FOLFIRI +/- Sunitinib
· Cediranib- Phase II: Second Line FOLFOX Bev vs. Cediranib- Phase III: First Line FOLFOX Bev vs Cediranib- Phase III: First Line FOLFOX +/- Cediranib
· Vandetanib- Phase IIB: Second Line FOLFOX +/- Vandetanib
Phase III: Frontline Sunitinib
1st Line Met CRC
N=720 patients
Primary endpoint: PFS
R
FOLFIRI + Placebo
FOLFIRI + Sunitinib
Europe/S.America/Asia study
Failed to meet interim analysis and was closed for futility
Phase IIB: First line FOLFOX Bev vs SunitinibHecht et al, ASCO 2010 #127 (Tues Poster Disc)
Phase IIB: FOLFOX Bevacizumab vs. FOLFOX Cediranib · Toxicities: Thrombocytopenia, fatigue· More frequent dose reductions in oxaliplatin in cediranib arms
2nd Line mCRCwith PD on FOLFIRI
N=215 patients
No prior anti-VEGF
R
FOLFOX + Bevacizumab
FOLFOX + Cediranib 20mg/d
FOLFOX + Cediranib 30mg/d
0.0 0.5 1.0 1.5 2.0
Favors Experimental Favors ControlHazard Ratio
Cunningham, ASCO 2008 Abs 4028
Phase III: Cediranib (HORIZON III)
1st Line Met CRC
N=1600 patients
Primary endpoint: PFS
R
FOLFOX + Bevacizumab
FOLFOX + Cediranib 20mg/d
Europe/US study
Failed to meet primary endpoint
Press release 3/10/10
Phase III: Cediranib (HORIZON II)
1st Line Met CRC
N=1050 patients
Co-primary endpoint: PFS, OS
R
FOLFOX + Placebo
FOLFOX + Cediranib 20mg/d
Europe/Asia study
“Met PFS endpoint”, but …
Press release May 2010
failed to meet OS endpoint.Development in CRC halted.
Phase IIB: FOLFOX +/- Vandetanib· Once daily oral VEGFR + EGFR TKI· Added toxicities of thrombocytopenia (+15%), diarrhea (+20%)
2nd Line mCRCwith PD on FOLFIRI
N=106 patientsNo prior
bevacizumab
R
FOLFOX + Placebo
FOLFOX + Vandetanib 100mg
FOLFOX + Vandetanib 300mg
0.5 1.0 1.5 2.0
Favors Experimental Favors ControlHazard Ratio
Yang, ASCO 2009 Abs 4084
Agent FOLFOX Irinotecan FOLFIRI
EGFRi + Irinotecan Other
Bevacizumab Phase III Phase III Phase IIB
Sunitinib Phase IIB Phase III Phase I/II
Vandetanib Phase IIB Phase IIB Phase I
Cediranib Phase II/III Phase IIB Phase I
Vatalanib Phase IIIs
Axitinib Phase IIB Bevacizumab
Semaxinib Phase III 5-FU, phase III
Motesanib Phase I Phase I Phase I
Sorafenib Phase IIB Phase IIB Phase I/II Bevacizumab
Pazopanib Phase I Phase I
Brivanib Phase I/II Cetux, Phase III
Vargatef Phase I/II
Regorafenib Phase I Phase I Alone, Phase III
Linifanib Phase IIB
Negative
Positive
Ongoing
Negative studies across multiple regimens
Summary of VEGF TKI Activity· Is there activity of VEGF TKI therapies?
- In contrast to HCC, RCC, minimal activity seen in CRC· Are they equivalent to bevacizumab?
- No evidence· Are they superior to bevacizumab?
- Increasingly unlikely· Does the same hold for large-molecule VEGF inhibitors?
- Too early
Why are VEGF TKIs failing?· Compliance? Possible Toxicities? Unlikely· Failing to understand the difference between targeting
VEGF receptor and ligands· The benefit of VEGF inhibition by any method may be
less than we think with current chemotherapy regimens
Lessons from “Second Generation” of VEGF TKI Studies
· Don’t ignore phase II study results· Biomarker development is still lagging
clinical development - Phase II is also too late
· Added toxicities are non-trivial· TKIs inhibiting multiple kinases beyond
VEGF have not yet shown greater activity
Outline
· Anti-Angiogenesis: Where are we now?- Overview of Agents Targeting VEGF
· Disappointments:- VEGF Tyrosine Kinase Inhibitors
· Excitement: - Large Molecule VEGF inhibitors- Beyond VEGF: Alternate angiogenesis
inhibitors
Phase III VEGF Trap (Aflibercept) after Bevacizumab
2nd line CRC (after treatment with
oxaliplatin-based therapy)
N=1200 patients
Primary endpoint: OS
R
FOLFIRI + Placebo
FOLFIRI + Aflibercept 4mg/kg
Results expected Dec 2010
“VELOUR” Study
Phase IIB ECOG 7208 : Anti-VEGFR2 Monoclonal Antibody after Bevacizumab
2nd line CRC (after oxaliplatin and
bevacizumab)
KRAS Wild type
N=147 patients
Primary endpoint: PFS
90% power to detect difference between 4.5 months
for control vs. 7.65 months for experimental arm (α = 0.10, β =
0.10)
R
Cetuximab + Irinotecan
Cetuximab + Irinotecan + Ramucirumab (IMC-1121B)
Courtesy of H. Hochster, PI
Comparing Anti-VEGFR2 or Anti-VEGFR1 Monoclonal Antibodies after Bevacizumab
2nd line CRC (after irinotecan +/-
bevacizumab)
N=150 patients
Primary endpoint: PFS
Phase IIB
R
mFOLFOX6
mFOLFOX6 + IMC-18F1(Anti-VEGFR1)
Results Summer 2012
mFOLFOX6 + IMC-1121B(Anti-VEGFR2)
Outline
· Anti-Angiogenesis: Where are we now?- Overview of Agents Targeting VEGF
· Disappointments:- VEGF Tyrosine Kinase Inhibitors
· Excitement: - Large Molecule VEGF inhibitors- Beyond VEGF: Alternate angiogenesis
inhibitors
Angiogenic Factors Beyond VEGF
Folkman, Nat Rev Drug Discovery 2007
Areas of Excitement: Alternate Angiogenesis Targets
Tumors have an inherent or acquired upregulation of one of the redundant pro-angiogenic pathways
Pathway Target Agents in development
Angiopoietins/Tie-2 Ang-1,2 AMG-386, Regorafinib
Fibroblast growth factor FGFR AZD4547, Brivinib, Dovitinib
Platelet-derived growth factor PDGFR ABT-869, Imatinib
Hepatocyte growth factor HGF/cMet ARQ-197, AMG-102
Notch/DLL/Jagged γ-secretase RO4929097
Placental Growth Factor VEGFR1 All VEGF TKIs, IMC-18F1
Angiogenic Factors Beyond VEGF
Folkman, Nat Rev Drug Discovery 2007
Angiopoietins and Tie2 in Angiogenesis
2nd line CRC (after treatment with oxaliplatin-based therapy)
N=138 patients
Primary endpoint: PFS
R
FOLFIRI + Placebo
FOLFIRI + AMG-386
Results expected late 2010, early 2011
Phase IIB AMG-386 (Ang 1/2 neutralizing peptibody)
Yu, Fut Oncol 2005
Angiogenesis
VEGF
Single Agent VEGFR + Tie2 TKI: Regorafenib (BAY 73-4506)
Phase III
Refractory CRC
N=690 patients
Primary endpoint: OS
R
Regorafenib 160 mg PO 3 weeks on, 1 week off
Placebo
“CORRECT” Study
Initiated Spring 2010See Kies et al ASCO 2010 poster 7585
Also inhibits PDGFR, FGFR, Kit, RET, Raf
Angiogenic Factors Beyond VEGF
Folkman, Nat Rev Drug Discovery 2007
Example: bFGF and Restored Angiogenesis Despite VEGF Inhibition
VEGFR2 resistance can be reversed by
targeting FGF
Casanovas et al. Cancer Cell ‘05 Kopetz, et al JCO 2010
Baseli
ne
After B
evac
izumab
After F
OLFIRI+B
Prior t
o Progres
sion
Progres
sion of D
iseas
e0
10
20
30
40 p=0.05
p<0.001
p<0.05
FGF-
2 (p
g/m
L)
FGF-2 Levels are Increased in Patients at Progression
on FOLFIRI + Bevacizumab
Example: Translating FGF Research to the Clinic
FOLFOX + Bevacizumab-
Refractory CRC
N=100 screened
Primary endpoint: non-
comparative PFS
HIGH plasma bFGF (n=30):
Irinotecan 180mg/m2Brivanib 800mg PO qd
Low/normal bFGF (n=30):
Irinotecan 180mg/m2Brivanib 800mg PO qdP
lasm
a bF
GF
Leve
lsOpening Fall 201 MDACC: Lieu, Overman PI’s
Enrichment Phase II Trial: Inhibition of FGFR + VEGFR
after Bevacizumab-failure
0.5
1
2
4
8
16
32
64
Patients
Fold
cha
nge
in b
FGF
Kopetz, et al JCO 2010
Heterogeneous Elevations in bFGF in the clinic
Ongoing Phase III: NCIC Brivanib
Refractory CRCKRAS Wild type
N=750 patients
Primary endpoint: OS
R
Cetuximab
Cetuximab + Brivanib
Phase III Studies: Opportunities for Retrospective Evaluation of Plasma Markers
NCIC study, Lillian Siu, PI
Conclusions
· No evidence yet that anti-angiogenesis agents besides bevacizumab provide meaningful benefit- despite >10,000 enrolled patients
· Recommendations for Path Forward:- Look Beyond VEGF: Understanding the mechanisms of
acquired and inherent resistance to bevacizumab - Incorporate biomarker-driven enrichment studies- Utilize correlatives from completed randomized trials
“Insanity is repeating the same mistakes and expecting different results” Albert Einstein