Hypertension associated with antiangiogenic therapy of cancer presented by

Igor Puzanov, MD, MSCI, FACP Associate Professor of Medicine Associate Director Phase I Drug Development Program Clinical Director Renal Cancer and Melanoma Program Vanderbilt-Ingram Cancer Center

Separate Specialties with Similar Objectives

Cardiovascular Patients

Cancer Patients and Survivors

Cancer and Cardiac Complications • These are by far the two most common disease conditions in the world • Cardiac disease may pre-exist cancer therapy or may be caused/exacerbated by it • Cancer therapy is more effective than ever before at treating cancer, but has a price.. • Therapeutic choices for both cardiology and oncology have significant overlap

Rapid drug development provides more choice than ever before Prognostic factors: Described

Cytokines: Immunotherapy: IL-2 and IFN-α first to report activity1

VHL tumor suppressor gene isolated: First gene identified to cause a proportion of hereditary RCC and other tumors2

1980s 82

83

84

85

86

Bevacizumab + IFN-α: FDA approval

1990s 87

88

89

90

91

92

93

94

95

Axitinib: FDA approval

Temsirolimus: FDA approval

2000s 96

97

98

99

00

01

02

03

04

05

06

07

08

09

10

11

12

Bevacizumab: Data established VEGFR TKI FDA approval: Tivozanib: High-dose IL-2 activity of anti- Sorafenib and Sunitinib review FDA approval: angiogenic agents Phase 2 data Everolimus: in RCC3 FDA approval Pazopanib: FDA approval IFN-α=interferon-α; IL-2=interleukin-2; TKI=tyrosine kinase inhibitor; VEGFR=VEGF receptor. 1Snow

M et al. Urology 1982;20:177; 2Latif F et al. Science 1993;260:1317–1320; 3Yang J et al. N Engl J Med 2003;349:427–434.

Recent Advances in First-Line Treatment of mRCC: Continuous Improvement in PFS With Novel Agents Median progression-free survival Best supportive care INF-α alone

2005-Present

INF-α+ IL-2+5-FU

Kane 2006

Multiple studies

3-5

Gore ASCO 2008

5.3

Torisel PI

Temsirolimus Sorafenib

2–3

5.5

Szczylik ASCO, 2007

5.7

Bevacizumab + INF-α

CALGB 90206

Bevacizumab + INF-α

AVOREN

Pazopanib

2

10.2

Sternberg ASCO 2009

11.1

Motzer 2009

11.0

Sunitinib 0 1

8.4

3

4

5

6 7

8

9 10 11 12 13 14 15 16

Time (months) Kane et al. Clin Cancer Res. 2006;12:7271, Gore et al. ASCO 2008; Torisel PI; Szczylik et al. ASCO, 2007. Abstract 5025.; Escudier et al. ASCO 2009. Abstract 5020; Rini et al. ASCO 2009. Abstract LBA 5019; Sternberg et al. ASCO 2009. Abstract 5021; Motzer et al. J Clin Oncol. 2009 Jun 1. [Epub ahead of print].

Recent advances in clinical outcomes: improvement in OS

17.8 21. 8

IFN

Sunitinib

2005-Present

Temsirolimus (poor risk)

15.2

Placebo Sorafenib

TARGETs (post-cytokine)

Sunitinib

7.3 IFN Temsirolimus

10.9 18. 18. 7 5

IFN Combination

IFN-α+ IL-2+5-FU Everolimus (post-TKI)

BSC Everolimus + BSC

Pazopanib

Placebo Pazopanib

AVOREN Bev + IFN IFN Bev + IFN

CALGB 90206 0 2

4

6

26.4

8.8 NR

18. 7 21. 1 21. IFN 3 23.3 17. 4 18.3

8 10 12 14 16 18 20 22 24 26 28 30 32 Time (months)

5-FU= 5-Fluorourocil Escudier et al. J Clin Oncol. 2009; 27:3312–3318; Motzer et al. J Clin Oncol. 2009 27(22):3584–90; Hudes et al. New Engl J Med 2007;356:2271; Gore et al. J Clin Oncol 26:2008 (suppl 5039), Motzer et al. ASCO 2008. Abstract LBA 5026; Sternberg et al. ASCO 2009. Abstract. 5021; Escudier et al ASCO 2009. Abstract 5020; Rini et al. ASCO 2009. Abstract LBA 5019.

Systemic Effects of Anti-VEGF Therapy Tumor Tissues

Normal Tissues

(VEGF upregulated)

(VEGF constitutively expressed)

Hypertensive remodeling Microvascular rarefaction Cardiomyopathy (sunitinib and sorafenib)

Lung cancer (bevacizumab) Inhibition of tumor growth, tumor cavitation

Hepatocellular carcinoma (sorafenib) Tumor necrosis

1

2

3

Microcirculation: 1. normal arteriole, 2. functional rarefaction (endothelial dysfunction,vasoconstriction), 3. anatomic rarefaction Renal cell carcinoma (sunitinib) Tumor shrinkage, tumor cell necrosis

Thrombotic microangiopathy Glomerulopathy / glomerulonephritis Proteinuria Hypertensive nephropathy Colorectal cancer (bevacizumab) Deceleration of tumor growth efficient chemotherapy delivery

Vaklavos, et al Oncologist 2010, p 130.

Tyrosine Kinases

Growth Factors

src, , fgr, yes lyn, syn, slk, fps, abl, rel,

(PDGF-),PDGF-B, GDVEGF FGFs, (acidic, basic hst,int-2, FGF5 FGF6, KGF) TGF (1-8), activin, BMPs, MIS, IGF-I, IGF-II EGF,TGFa, JE KC

GTP

Ca

Effectors PLA2, PLC,crk

Protein Kinases raf/mil, l(1)polehole, mos

Nuclear Proteins c,L,N,B myc fos, fosB, fra-1,-2 jun (AP1), junB, junD myb erbA ski

PKC

Coupling Proteins

H, K, N, R ras rho, ral, rev, ypt, rap, bcl2

Intracellular Messengers

GDP

Receptors

EGF-R (erb), neu, erbB-2, PDGF-Rs (A, B), kit, fms IGF-R, ros, met FGFR, flg, trk

Cardiac Signaling Pathways

Ca MK

TF determination genes (myoD,myogenin, myf-5, MRF4; ld) homeotic genes (Xhox,3) “zinc finger” transcription factors (EGR1) B-ZIP trasnscription factors (CREB) anti-oncogenes (rb, p53, s-myc)

Cardiovascular Complications of Anti-Cancer Therapy • Left Ventricular Dysfunction Systolic/Diastolic • Hypertension • Myocardial Infarction • Pericardial Diseases • Arterial/Venous Thrombosis • Rhythm Disturbances • Volume-Overload/Edema

HTN prevalence with anti-VEGF therapies Drug (IC50 for HTN, All Grades, VEGF-R2) % Patients, n Axitinib (0.25 nM) 61 36

Cancer Type Solid tumors

Reference Rugo et al. (40)

33 44

25 32

RCC Melanoma

Rini et al. (37) Fruehauf et al. (14)

AMG706 (3 nM)

39 42

307 71

Solid tumors Solid tumors

Rini et al. (38) Rosen et al. (39)

AV-951 (0.16 nM)

56

41

Solid tumors

Eskens et al. (9)

AZD2171 (0.5 nM) 35

83

Solid tumors

Drevs et al. (6)

31 72 28

26 60 37

HRPC Reproductive Solid tumors

Ryan et al. (41) Hirte et al. (20) Suttle et al. (49)

32 16

111 43

STS Solid tumors

Sleijfer et al. (46) Thomas et al. (50)

Sorafenib (90 nM) 43

202

RCC

Ratain et al. (34)

8 28 27

384 29 58

RCC RCC RCC

18

28

Solid tumors

Escudier et al. (8) Shepard et al. (43) Riechelmann et al. (36) Faivre et al. (11)

5 41 42 30 23 11

63 17 43 10 22 63

RCC Thyroid Thyroid Glioma SCCHN NSCLC

Motzer et al. (30) Ravaud et al. (35) Cohen et al. (4) Chaskis et al. (1) Choong et al. (3) Socinski et al. (47)

18

77

Solid tumors

Holden et al. (21)

GW786034 (30 nM) PTK/ZK (37 nM)

Sunitinib (10 nM)

ZD6474 (40 nM)

Sunitinib, a novel oral chemotherapeutic agent with anti-VEGF properties, is associated with hypertension and heart failure

Khakoo, et al, 2008; 112:2500-8

An Improved Mechanistic Understanding of Hypertension with VEGF Inhibition is Needed Decrease in capillary density & perfusion

Many Current Hypotheses Exist with Probable Multifactorial Etiology

Vascular stiffness & smooth muscle effects

Thyroid dysfunction

VEGF Inhibition Alterations in neurohormones (renin)

Decrease in NO production

Cardiac-renal interaction

Maitland, et al. J Natl Cancer Inst. 2010. Wu, et al. Lancet Oncol. 2008. Izzedine, et al. Eur J Cancer. 2010. Kappers, et al. J Hypertens. 2009.

NCI-CTC v4.0 for HTN Grade 1 Prehypertension (SBP 120-139 or DBP 80-89mmHg)

2

3

Stage 1 HTN (SBP 140-159 or DBP 90-99); medical intervention indicated; recurrent, persistent (≥24 hrs), or symptomatic increase in DBP by >20 mmHg or to >140/90 if prior WNL

Stage 2 HTN (SBP≥160mmHg or DBP ≥ 100); medical intervention indicated; > 1 drug or more intensive therapy than prior

Monotherapy may be indicated

4 Life-threatening consequences (e.g. malignant htn, transient or permanent neuro deficit, htn crisis)

5 Death

Urgent intervention indicated NCI CTC v4.03. 2010.

ESH Guidelines Emphasize Importance of Total Risk Stratification • Total cardiovascular risk evaluation is necessary to optimize treatment initiation, intensity, and goals of long-term mortality risk reduction

Mancia, et al. J Hypertens. 2009. Mancia, et al. J Hypertens. 2007.

Progression-free Survival vs Exposure: Retrospective Analysis of Phase II RCC Data Pts with AUC12 ≥ 150 ng·hr/mL before titration

1.0

Fraction of Patients

Pts with AUC12 < 150 ng·hr/mL before titration

900 800 700

AUC12 (ng·hr/mL)

Pooled RCC Patients AUC12 after Dose Titration AUC12 < 150 ng·hr/mL

0.8

AUC12 ≥ 150 ng·hr/mL 0.6 0.4 0.2

600 0.0 500

0

20

40

60

80

100

120

140

PFS (weeks)

400 300

mPFS, wks (95% CI)

200 100 0

ALL patients No Before After titration titration titration before titration 5 mg BID 7 mg BID

Before

After

titration

titration

10 mg BID

AUC12 = area under the plasma concentration-time curve from 0 to 12 hr

AUC12 < 150 ng·hr/mL

AUC12 ≥ 150 ng·hr/mL

HR (95% CI)

32 (24, 48) n=36, 26

52 (43, 69) n=139, 83

0.56 (0.359, 0.874)

n=number of patients meeting AUC criterion, number of PFS events assessed by investigator 2 0

Abstract No. 4503

Axitinib for first-line metastatic RCC: Overall efficacy and pharmacokinetic analyses from a randomized phase II study BI Rini1, V Grünwald2, MN Fishman3, B Melichar4, T Ueda5, PA Karlov6, AH Bair7, Y Chen7, S Kim7, E Jonasch8 1Cleveland

Clinic Taussig Cancer Institute, Cleveland, OH, USA; 2Hannover Medical School, Hannover, Germany; 3H. Lee Moffitt Cancer Center, Tampa, FL, USA; 4University Hospital, Olomouc, Czech Republic; 5Chiba Cancer Center, Urology, Chiba, Japan; 6City Clinical Oncology Dispensary, Saint-Petersburg, Russia; 7Pfizer Oncology, San Diego, CA, USA; 8The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

Study Design Arm A Randomization criteriaa Lead-in period (Cycle 1) Axitinib 5 mg BID (4 wks)

During Cycle 1 (subset of patients)

BP ≤150/90 mmHg and ≤2 concurrent anti-HTN medications and No grade 3 or 4 axitinib-related toxicities and No dose reduction

Yes

No

R A N D O M I Z E 1:1

Axitinib 5 mg BID + Axitinib dose titrationb (blinded therapy)

Arm B Axitinib 5 mg BID + Placebo dose titrationb (blinded therapy)

ABPMc 6-h PK samplingd

Arm C a

For at least 2 consecutive weeks

Axitinib ≤ 5 mg BID (no dose titration)

b

Titrated stepwise to 7 mg BID and then to a maximum of 10 mg BID if criteria for randomization to dose titration were met C

Ambulatory blood pressure monitoring performed at baseline and on Cycle 1 Days 4 and 15

d

6-hr PK sampling performed on Cycle 1 Day 15

22

Axitinib Pharmacokinetic Parameters on Cycle 1 Day 15 Arm C Not eligible for dose titration

Arms A + B Eligible for dose titration

P valuea

AUC12, ng•h/mLb,c

234

99