VEGF-Targeted Therapies: Resistance and Revisiting Our

Assumptions

Lee M. Ellis, MDDepts. of Surgical Oncology and Cancer Biology

U.T. M.D. Anderson Cancer CenterHouston, Texas, USA

A reality check now that we have clinical data.

Disclosures• Ad hoc consulting

– Genentech/Roche, sanofi-aventis, Bayer• Most of the data involves bevacizumab as this drug is

approved in more disease types than others in the class

• Thank you for sharing slides– Lillian Siu– Axel Grothey/Eric Van Cutsem– Josep Tabernero/Carmen Allegra

• Data collected from searches on Pubmed, Clinicaltrials.gov, ASCO, and AACR websites

Anti-angiogenic Assumptions: Then and Now

Assumptions 20-40 yrs ago Assumptions 2002-2010 What we know from clinical trial results (in 2012

Angio inhibition would induce dormancy in all tumor types

Angio inhibition would provide benefit across tumor types

Benefit is tumor dependent and context dependent (+/- chemo)

Little discussion of multiplicity of angiogenic factors

Other angiogenic factors are important and may contribute

to resistance

Dual targeting of bypass pathways have not led to major

advancesResistance would not occur Resistance is inevitable Continuation of therapy may be

of some benefit

Did not consider consequences of induction of

hypoxia

VEGF inhibitors may increase tumor aggressiveness

In GBM, VEGF inhibitors may increase invasion and

metastasis, but patients still benefit from therapy

Did not consider consequences of withdraw

Preclinical and anecdotes- Withdraw may lead to “flare”

No hard data to support that withdraw lead to “flare”

Did not think about biomarkers Biomarkers are elusive Maybe? Need validation

Resistance to Anti-VEGF Therapy

• Introduction/Background• Resistance in preclinical studies

– And were these studies confirmed in the clinic• Resistance/Sensitivity Beyond Progression

Almost All Malignancies Are Inherently Resistant To VEGF

Targeted Therapies(Exception-rcc)

To Understand Resistance We Need to Better Understand Mechanisms of

Action

MOA: Do We (I) Have Any Clue?

Ellis, Hicklin. Nat Rev Ca 2008

Proposed MOA 1995 2000 2005 2010 2012 2015?

Anti-angiogenic (EC proliferation)

+++ +++ +++ ++ ?

Anti-angiogenic(Bone Marrow Derived Progenitor Cells)

+ +++ ?

“Normalization” with improved delivery of chemo

+++ ?

Direct effect on tumor + + + ?Vascular “constriction” ++ +++ +++ ?

Offset effects of stress ++ ++ ++ ?

Disrupt the cancer stem cell niche

+ + ?

Immune function + ++ ++ ?

The benefits of a long career is that you can change you mind many, many times

Anti-VEGF Therapy: My Theory on Different Mechanisms of Action in Different Tumor Systems

Renal Cell Carcinoma/NETs Colon Carcinoma

With diverse MOAs, understanding resistance is likely to be tumor dependent, and/or site dependent.

Resistance to Anti-VEGF Therapy

• Introduction/Background• Resistance in preclinical studies

– And were these studies confirmed in the clinic• Resistance/Sensitivity Beyond Progression

Most Resistance Manuscripts and Reviews Focus on Redundant Angiogenic Pathways

Ellis, Hicklin, CCR 2008

c-Met

FGF

FGFs

Hypothesis Generating Clinical Study in CRC

Blood drawn at each cycle and at progression

Cytokines Increased Prior to Progression On FOLFIRI + Bev

Kopetz JCO 2009

Results of a Recently Reported Clinical Trial Targeting FGF-R in CRC

Clinicaltrial.gov search May, 2012The only randomized Phase III trial with FGF

inhibitor

Brivanib

And others at higher IC50s…. Diaz-Padilla, SiuExp Opin Invest Drugs 2011

CO.20 Trial: Cetuximab +/- BrivanibK-Ras WT Chemo-refractory CRC

Cetuximab + Placebo

Cetuximab + Brivanib

P Value

PFS 3.4 5.0 <0.0001 (HR=0.72)

RR 7.2 13.6 0.044 Siu et al

Commentary/Discussion

• This is but a single study-some hints of activity– Biomarker Driven Study:

» Phase II Study of Second-line Irinotecan Plus Brivanib, a Dual Tyrosine Inhibitor of VEGFR and FGFR, in Metastatic Colorectal Cancer Patients Enriched for Elevated Levels of Plasma FGF Following Progression on Bevacizumab-based Treatment: Mike Overman, MDACC

• There are numerous bypass pathways• Kopetz/Heymach JCO: B-FGF, HGF, PlGF, Eotaxin, MMP-9, and more

• Not all tumors are p-NETs

VEGFR-1(Flt-1)

NRP-1/NRP-2 NRP-2

VEGF-D

VEGF-C

VEGF-B VEGF-A

PlGF

VEGFR-2(Flk-1/KDR)

VEGFR-3(Flt-4)

VasculogenesisAngiogenesis

Lymphangiogenesis

PlGF

Induction of PlGF by Anti-VEGF Therapy

The PlGF Debate!

VEGFR-1(Flt-1)

NRP-1/NRP-2 NRP-2

VEGF-D

VEGF-CVEGF-B VEGF-A

PlGF

VEGFR-2(Flk-1/KDR)

VEGFR-3(Flt-4)

VasculogenesisAngiogenesis

Lymphangiogenesis

BEVACIZUMAB*

VEGF-TRAP

18F1 1121B

TG-403

Tyrosine Kinase InhibitorsSunitinib*Sorafenib*Pazopanib*

Axitinib*MotesanibCedirinibBrivanib

Many, many others

VEGF Targeted Agents in the Clinic or In Clinical Trials

Ellis, Hicklin Nat Rev Ca. 2008* FDA approved agents

Do we see improved outcomes in patients

treated with agents that target PlGF/VEGFR-1?

VELOUR Study Design

Metastatic Colorectal Cancer

RANDOMIZE

Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks

Placebo IV, day 1+ FOLFIRIq2 weeks

1:1 Disease Progression Death

600

600Stratification factors:- ECOG PS (0 vs 1 vs 2)- Prior bevacizumab (Y/N)

Primary endpoint: Overall survivalSample size: HR 0.8, 90% power and a 2-sided type I error 0.05 Final analysis of OS: Analyzed at 863th death event using a 2-sided nominal significance level of 0.0466 (α spending function)

Overall Survival, ITT Population

Cut-off date = February 7, 2011; Median follow-up = 22.28 months

Presented at ESMO/WCGC meeting 2011, Barcelona: Abstract O-0024

1.4 mo increase in median OS

FDA Approvals Of VEGF-Targeted AgentsThat Have Been in Clinical Development for “Awhile”

Bevacizumab Aflibercept TKIsCRC Pending

- Neg front line Ph II trial

Pending (Regorafenib)

NSCLC Neg Neg

Breast withdrawn Neg

GBM Neg

RCC

P-NETs

HCC

If PlGF/VEGFR-1 is important in VEGF/VEGFR-2 resistance, Aflibercept and TKIs should be more effective

PlGF/VEGFR-1 Targeting

Commentary/Discussion

• Agents that target VEGF + PlGF are no more efficacious than those that target VEGF

– In the only head-head Phase III study in CRC, Chemo + Bev vs Chemo + TKI (Cediranab), the primary endpoint for Cediranib was not met

C-Met/HGFDrug Class of DrugARQ197 TKI

GSK1363089 (XL880) TKI

AMG 102 MoAB HGF

AMG 208 TKI

AV-299 MoAB HGF

PF-02341066 TKI

PF-04217903 TKI

MP470 TKI

MGCD265 TKI

MetMab MoAB Met

Modified Yap et al. Cancer Drug Targets 2011

Hypothesis: Combination Therapy with a VEGF-R TKI and c-Met TKI Is Better Than Either Therapy Alone

“In conclusion, our study indicates a role for HGF/c-Met pathway in development of resistance to antiangiogenic therapy and suggests a potential strategy to circumvent resistance to vascular endothelial the clinic.”

Combination VEGF/Met Targeted Trials

Other Resistance Pathways Not Discussed

Mostly refuted

Untested in the clinic

Untested in the clinic

Under investigation:Are we targeting ECs or Cancer Stem Cells

or Both?(Notch inhibitors slow in

development)

Resistance to Anti-VEGF Therapy

• Introduction/Background• Resistance in preclinical studies

– And were these studies confirmed in the clinic• Resistance/Sensitivity Beyond Progression

PFS in Patients Receiving TKIs After Prior VEGFR TKIs

2008

Continuation of VEGF-Targeted Therapy After First Line Progression in mCRC

Trial STUDY DESIGN OUTCOME COMMENTS ASCO 2012 Abstract

VELOUR FOLFIRI +/- Aflibercept after

progression

OS HR = 0.817*PFS HR = 0.76

OS HR Prior Bev 0.86

~30% Received Prior

Bev

Abstract #3505

CORRECT Regorafenib vs Placebo in

refractory patients

OS HR= 0.77*PFS HR = 0.49

All Received Prior Bev

Abstract #3502

TML18147 Bev + alternate chemo after

progression on Bev + first line chemo

Primary endpoint of improved OS

met*

All Received Prior Bev

Abstract #CRA3503

* Met primary endpoint

Primary Endpoint

Allegra Abstract

#3505

TML18147-OS*: ITT population(“Bev Beyond Progression”)

*From randomisation

OS

estim

ate

Time (months)

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 38 42 48

Number at riskChemo 410 293 162 51 24 7 3 2 0Bev + chemo 409 328 189 64 29 13 4 1 0

Chemo Bev + chemo

9.8 11.2

Arnold, Abstract #CRA3503

Chemo(n=411)

Bev + chemo(n=409)

Median time to event (mos)

9.8 11.2

HR (95% CI) 0.81 (0.69–0.94)

p-value 0.0062

1.00

0.50

0.25

0

0.75

200100500 150 300250 350

Days from randomizationS

urvi

val d

istri

butio

n fu

nctio

n

Placebo N=255 Regorafenib N=505

Regorafenib Placebo

Median 1.9 mos 1.7 mos(95% CI) (1.9–2.1) (1.7–1.7))

Hazard ratio: 0.49 (95% CI: 0.42–0.58)

1-sided p-value: <0.000001

CORRECT: OS and PFSRegorafenib vs BSC

Grothey et al. ASCO GI 2012 (LBA 385).

1.00

0.50

0.25

0

0.75

200100500 150 300250 400350 450

Days from randomization

Sur

viva

l dis

tribu

tion

func

tion

Placebo N=255

Regorafenib N=505

Median 6.4 mos 5.0 mos95% CI (5.9–7.3) (4.4–5.8)

Hazard ratio: 0.77 (95% CI: 0.64–0.94) 1-sided p-value: 0.0052

• Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p<0.009279 at approximately 74% of events required for final analysis)

Regorafenib Placebo

Overall Survival Progression-Free Survival

Conclusions• The more we learn about the tumor vasculature, the less

sure we about the MOA of VEGF-targeted agents• There are numerous redundant pathways that mediate

resistance to VEGF-targeted agents– Will we need to inhibit multiple pathways (>2) to obtain meaningful

clinical benefit? Is this feasible????? (tox) • VEGF inhibition beyond progression provides some degree

of patient benefit…i.e. complete resistance may not occur• Biomarkers of sensitivity and resistance will improve patient

outcomes---in my opinion, the only way to make a major advance at this stage– Michael Maitland to discuss

Thank You for Your Attention

Bev + standard 1L chemo (either oxaliplatin or

irinotecan-based)(n=820)

Standard 2Lchemo (oxaliplatin

or irinotecan-based)*until PD

Bev (2.5mg/kg/wk) + standard 2L chemo

(oxaliplatin or irinotecan-based)*until PD

PD

Key eligibility criteria • Histologically confirmed diagnosis of metastatic colorectal cancer• ≥3 months of standard 1L bev plus chemo• PD <3 months after last bev administration

Primary endpoint OS from randomisationSecondary endpoints PFS, overall response rate (ORR), OS from start of 1L therapy

TML18147 Study Design (Phase III)

* Cross-over:Oxaliplatin → IrinotecanIrinotecan → Oxaliplatin

PD = disease progression

Randomize 1:1

Arnold, Abstract #CRA3503

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

Primary Endpoint: OS

90% power to detect 33.3% increase

(HR=0.75), with 1-sided overall

a=0.025

Regorafenib + BSC 160 mg orally once daily 3 weeks on, 1 week off

Placebo + BSC 3 weeks on, 1 week off

R 2:1

mCRC after standard therapy

Grothey et al. ASCO GI 2012 (LBA 385).