Small and Large-Molecule Angiogenesis Inhibitors: Excitement and Disappointments

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

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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)


VEGF-R3(Flt-4)

Lymphangio-genesis



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)


VEGF-R3(Flt-4)

Lymphangio-genesis



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




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


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


R

FOLFOX + Bevacizumab


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


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




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


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


Phase IIB

R

mFOLFOX6

mFOLFOX6 + IMC-18F1(Anti-VEGFR1)

Results Summer 2012

mFOLFOX6 + IMC-1121B(Anti-VEGFR2)

Outline




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



Angiopoietins and Tie2 in Angiogenesis

2nd line CRC (after treatment with oxaliplatin-based therapy)

N=138 patients


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


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



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


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

Documents

Small and Large-Molecule Angiogenesis Inhibitors: Excitement and Disappointments