Renal Cell Carcinoma: Renal Cell Carcinoma: A New Standard of CareA New Standard of Care

Roberto Pili M.D.

Associate Professor of Oncology and Urology The Sydney Kimmel Comprehensive Cancer Center at

Johns Hopkins Baltimore MD

6th Advancing Cancer Care in the Elderly Conference Taking Aim with Targeted Therapies: Are We Hitting the Right Marks?

DisclosureDisclosure

• Research funding: Pfizer, Cephalon, Celgene

• Consultant: Active Biotech, Locus, Novartis, Genentech

ObjectivesObjectives

• To review the biological and clinical features of renal cell carcinoma

• To summarize the clinical activity & toxicity profiles of antiangiogenesis agents in renal cell carcinoma

• To describe the future development of anti angiogenesis therapies for renal cell carcinoma

Renal Cell CarcinomaRenal Cell Carcinoma• In the United States in 2008:

– 54,390 estimated new cases of RCC– 13,010 estimated deaths

• Risk factors:– Male sex (3:2), Cigarette smoking (2:1), Hypertension,

Obesity– Hereditary syndromes (15-40% lifetime risk)

• Incidence:– Increasing (median age 65 y.o.)

• For mRCC:– Median survival: 10.9-26.4 months– 20%-30% of patients present with mRCC– 20%-40% of patients will develop mRCC after

nephrectomy

Staging of RCCStaging of RCC

Cohen , NEJM 2005

BHD=Birt-Hogg-Dubé; FH=fumarate hydratase; VHL=von Hippel-Lindau.Modified from Linehan WM et al. J Urol. 2003;170:2163-2172.

Histological ClassificationHistological Classificationof Human Renal Epithelial Neoplasmsof Human Renal Epithelial Neoplasms

RCC

Clear cell

75%

Type

Incidence (%)

Associated mutations VHL

Papillary type 1

5%

c-Met

Papillary type 2

10%

FH

Chromophobe

5%

BHD

Oncocytoma

5%

BHD

Kinase expression: Genetic SignaturesKinase expression: Genetic Signatures

Teh BT, 2006

Clear cell

Papillary

Chromophobe

OncocytomaKinomeExpression in Renal Tumors

C-KIT

C-MET

- -

Factors Predicting Prognosis in RCCFactors Predicting Prognosis in RCC

Anatomic

• Tumor size• Metastasis • Venous

involvement • Lymph node

involvement

Histologic • Fuhrman grade• Morphology• Microvascular

invasion• Tumor necrosis

Clinical• PS • Cachexia-related

symptoms • Thrombocytosis

Shuch BM, et al. Semin Oncol. 2006;33:563-575.

PS = performance status.

Motzer RJ et al. J Clin Oncol. 2002;20:289-296.

MSKCC Risk Factor Model in mRCC-MSKCC Risk Factor Model in mRCC-IFN daysIFN days

0 risk factors (n=80 patients)

1 or 2 risk factors (n=269 patients)

3, 4, or 5 risk factors (n=88 patients)

Risk factors associated with worse prognosis

• KPS <80

• Low serum hemoglobin (13 g/dL/11.5 g/dL: M/F)

• High corrected calcium (10 mg/dL)

• High LDH (300 U/L)

• Time from Dx to IFN-α <1 yr

Time From Start of IFN-α (years)

Pro

po

rtio

n S

urv

ivin

g

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 1614131195436 151210876

MS:20 mo10 mo4 mo

Targets in RCCTargets in RCC

Adapted from Brugarolas J NEJM 2007

Bevacizumab

VEGF-Trap

Vorinostat

LBH589Everolimus

AxitinibPazopanib

Everolimus

Temsirolimus

Cell division AngiogenesisCell proliferation

Angiogenesis

Rational Targets in RCCRational Targets in RCC

• IL-2

- immune response FDA approved for RCC 1992

• Sorafenib FDA approved for RCC 12/05

– VEGFR, PDGFR, RAF

• Sunitinib FDA approved for RCC 1/06

– VEGFR, PDGFR

• Temsirolimus - mTor FDA approved for RCC 5/07

• Everolimus - mTor

• Bevacizumab -VEGF

• VEGF-Trap -VEGF

• Erlotinib - EGFR

EGFR=epidermal growth factor receptor.

RCC: Current NCCN Treatment ParadigmRCC: Current NCCN Treatment Paradigm

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: kidney cancer. V.1.2008. http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf. Accessed 01/14/2008.

*Category 1†Selected patients‡ Category 1 following cytokine therapy and category 2A following TKI§ Category 2A following cytokine therapy and category 2B following TKI¶Category 2B.

CRN = cytoreductive nephrectomy; IL-2 = interleukin-2; NCCN = National Comprehensive Cancer Network; TKI = tyrosine kinase inhibitor.

First LineClinical trial

Sunitinib*Temsirolimus

(poor prognosis patients)*

Bevacizumab + IFN High-

dose IL-2†

Sorafenib†

Best supportive care

Nephrectomy + metastasectomy or

CRN (if unresectable,

proceed to first-line systemic therapy)

Observation or consider adjuvant therapy in a clinical trial

Relapse

Stage I/II/IIISurgical excision

Second LineClinical trialSorafenib‡

Sunitinib‡

Temsirolimus§

IFN¶

High-dose IL-2¶

Low-dose IL-2 ± IFN¶

Bevacizumab¶

Best supportive care

Stage IV (metastatic)

Sorafenib for mRCC:Sorafenib for mRCC:Phase III Study Design (TARGET)Phase III Study Design (TARGET)

Sorafenib, 400 mg bid (n=451)

• 1° end point: OS• 2° end points: ORR, PFS, safety, HR-QoL• Demographics

– MSKCC good or intermediate risk patients(57/41)

– Clear-cell carcinoma

Unresectable and/or mRCC,

1 prior systemic Tx in last 8 months, ECOG PS 0/1

(N=903*) Placebo (n=452)

Escudier, NEJM 2007

Sorafenib for mRCC:Sorafenib for mRCC:Response Rate* (TARGET)Response Rate* (TARGET)

38 (8)18 (4)Missing

167 (37) 56 (12)Progressive disease

239 (53)333 (74)Stable disease

8 (2) 43 (10)Partial response

— 1 (<1)Complete response

Placebo (n=452)

n (%)

Sorafenib (n=451)n (%)Best Response by RECIST

Escudier, NEJM 2007

5.5

2.8

Sorafenib

Placebo0.51Hazard ratio

Median (months)PFS

Time From Randomization (months)

Pro

po

rtio

n o

f P

atie

nts

Pro

gre

ssio

n F

ree

0

0.25

0.50

0.75

1.00

0 4 10 202 6 8 12 14 16 18

Sorafenib for mRCC: Sorafenib for mRCC: Progression-Free Survival* (TARGETProgression-Free Survival* (TARGET)

Placebo (n=452)

Sorafenib (n=451)

Escudier, NEJM 2007

Sorafenib: Phase III TARGETs—Sorafenib: Phase III TARGETs—Summary of OS AnalysisSummary of OS Analysis

n/a

0.01

0.74

14.3 months

19.3 months

OS 6 Months Post-Crossover

With Placebo Censored2

13.5%30%39%Increase in OS

17.8 months19.3 monthsNot reachedSorafenib med. OS

≤0.0370.00940.0005O’Brien-Fleming stopping boundary

0.1460.020.02P value

0.880.770.72Hazard ratio

15.2 months15.9 months14.7 monthsPlacebo median OS

Final OS 16 Months

Post-Crossover3

OS 6 Months Post-

Crossover1*

OS at Crossover1

*At the time of analysis, 216/452 (48%) of patients in the placebo group had crossed over to receive Sorafenib.1. Escudier B et al. New Engl J Med. 2007;356:125-134.2. Eisen T et al. Presented at: ASCO 20063. Adapted from: Escudier B et al. 2007

• In the final OS analysis, 62% of total patient-years of exposure to study drug in the placebo arm corresponded to Sorafenib

Sorafenib vs IFN-Sorafenib vs IFN-αα : Randomized Phase II : Randomized Phase II

PFS by Independent ReviewPFS by Independent Review

97 75 30 16 492 57 34 24 7

SorafenibInterferon

Patients at risk Time From Randomization (months)

Pro

po

rtio

n o

f P

atie

nts

Pro

gre

ssio

n-F

ree

0 151 2 3 4 5 6 7 8 9 10 11 12 13 14

1.00

0.25

0

0.50

Median PFS

Sorafenib=5.7 months

Interferon=5.6 months

Hazard ratio=0.88 (95% Cl: 0.61-1.27)

P value (log-rank test)=0.504

0.75

Sorafenib

IFN-αα

Adapted from Escudier B et al. Presented at: 5th Intl Symposium on TAT; March 8-10, 2007; Amsterdam, The Netherlands.

Sunitinib vs IFN-Sunitinib vs IFN-αα for mRCC: for mRCC:Phase III Study DesignPhase III Study Design

Sunitinib, 50 mg qd (n=375)

• 1° end point: PFS• 2° end points: RR, OS, safety, patient reported outcomes• Demographics

– MSKCC good or intermediate risk patients(34/47)– Clear-cell carcinoma

Unresectable and/or mRCC,

No prior systemic Tx, ECOG PS 0/1

(N=750)

IFN-α (n=375)

4 weeks on, 2 weeks off (4/2)

3 MU tiw, 6 MU tiw, 9 MU tiw

Motzer et al , NEJM 2007

Treatment-Related Adverse EventsTreatment-Related Adverse Events

11/<1*51751Fatigue

0135*53Diarrhea

0291 6Chills

<1 2125Stomatitis

<116<1 5Myalgia

1 3210Ejection fraction decline

<1 18*24Hypertension

0 15*20Hand-foot syndrome

<1 80 1Flu-like symptoms

0341 7Pyrexia

Grade 3/4Grade 3/4

IFN-α (%)

133

All grade

344

All grade

Sunitinib (%)

Nausea

Event

* Greater frequency, P <0.05Motzer, NEJM 2007

First-Line Sunitinib vs IFN-First-Line Sunitinib vs IFN-αα: PFS : PFS and Response Rateand Response Rate

PFS = progression-free survival.

Motzer RJ, et al. N Engl J Med. 2007;356:115-124. Motzer RJ, et al. 2007 ASCO Annual Meeting; Abstract 5024.

0

5

10

15

20

25

30

35

Sunitinib IFN-α

Ob

ject

ive

Res

po

nse

Rat

e (%

)

Treatment

31%

6%

0 2 4 6 8 10 14

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months

PF

S

Hazard Ratio = 0.42; 95% CI (0.32–0.54); P<0.001

Sunitinib

IFN-α

1 3 5 7 9 1211 13

Sunitinib (n = 375) Median: 11.0 months(95% CI: 10.0-12.0) IFN-α (n = 375) Median: 5.0 months(95% CI: 4.0-6.0)

Sunitinib (n = 375)

IFN-α (n = 375)

P<0.001

Patients at Risk (n)

Sunitinib 375 235 90 32 2 IFN-α 375 152 42 18 0

Sunitinib vs IFN-Sunitinib vs IFN-αα : Final Overall Survival: Final Overall Survival

Sunitinib (n = 375) Median: 26.4 months (95% CI: 23.0 - 32.9)IFN-α (n = 375) Median: 21.8 months (95% CI: 17.9 - 26.9)

Total DeathSunitinib 190IFN-α 200

0 3 6 9 12 15 18 21 24

27 30 33 36Time (months)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Ov

era

ll S

urv

iva

l Pro

ba

bili

ty

Hazard Ratio = 0.821(95% CI: 0.673 - 1.001)P = 0.051 (Log-rank)

Figlin RA, et al. 2008 ASCO Annual Meeting; Abstract 5024.

Figlin RA, et al. 2008 ASCO Annual Meeting; Abstract 5024.

Temsirolimus (TEMSR, CCI-779) for mRCC: Temsirolimus (TEMSR, CCI-779) for mRCC: Phase III Study DesignPhase III Study Design

Hudes G et al. Presented at: ASCO; June 2-6, 2006; Atlanta, GA. Hudes G et al. NEJM 2007

IFN-α escalating to 18 MU SC tiw

TEMSR25 mg IV qw

TEMSR15 mg IV qw + IFN-α 6 MU tiw

Advanced RCCNo prior therapy

KPS ≥60(N=626)

• 1° end point: OS• 2° end points: PFS, TTF, OR, and clinical benefit• Demographics

– MSKCC poor (~70%) or intermediate risk patients

– Predominately clear-cell carcinoma

Temsirolimus vs IFN-Temsirolimus vs IFN-αα : :

Selected Adverse EventsSelected Adverse Events

Hudes G et al. N Engl J Med. 2007;356:2271-2281.

Stomatitis

Anemia

Dyspnea

Rash

Diarrhea

Nausea

Asthenia

TemsirolimusIFN-α

Any Grade 3/4

Hyperlipidemia

Hyperglycemia

Neutropenia

67NA78NA

12004

20452242

327114

1126211

314110Creatinine Increase

37712

27

28

47

37

51

All Grades

20

24

6

41

64

All Grades Grade 3/4Grade 3/4

96

40

12

24

1126

Adverse Event

Patients (%)

P = 0.02

TEMSR for mRCC:TEMSR for mRCC:Response RatesResponse Rates

86 (41)96 (46)60 (29)

Clinical benefit (CR + PR [SD ≥16 wks])

24 (11)19 (9)15 (7)Objective response (CR + PR)

TEMSR + IFN-α (n=210)

n (%)

TEMSR(n=209)n (%)

IFN-α(n=207)n (%)Best response

Hudes G et al. Presented at: ASCO; June 2-6, 2006; Atlanta, GA. Hudes G et al. NEJM 2007

Temsirolimus vs IFN-Temsirolimus vs IFN-αα : : OS by Treatment ArmOS by Treatment Arm

Hudes G, et al. N Engl J Med. 2007;356:2271-2281. Copyright © 2007 Massachusetts Medical Society. All rights reserved.

Arm 3: Temsirolimus + IFN-α (n = 210)

Arm 2: Temsirolimus (n = 209)

Arm 1: IFN-α (n = 207)

Time From Randomization (months)

Pro

bab

ilit

y o

f S

urv

ival

1.00

0.75

0.50

0.25

0.000 5 10 15 20 25 30 35

P = 0.008; IFN-α vs temsirolimus

P = 0.70; IFN-α vs IFN-α + temsirolimus

Patients at Risk (n)IFN-α 207 126 80 42 15 3 0Temsirolimus 209 159 110 56 19 3 0

Temsirolimus vs IFN-Temsirolimus vs IFN-αα, Poor-Risk , Poor-Risk mRCC: mRCC: Correlation With SurvivalCorrelation With Survival

HistologyClear cellOther

287129

115301

Age<65 Years≥65 Years

Prognostic RiskIntermediatePoor

Subgroup N HR (95% CI)

33973

Dutcher JP, et al. 2007 ASCO Annual Meeting; Abstract 5033.

0.0 0.5 1.0 1.5 2.0

Temsirolimus Better IFN-α Better

AVOREN AVOREN for mRCC: for mRCC: Phase III Study DesignPhase III Study Design

• Bevacizumab/placebo 10mg/kg i.v. q2w until progression

• IFN-α2a 9MIU s.c. three times/week (maximum of 52 weeks) (dose reduction allowed)

• Multinational ex-US study: 101 study sites in 18 countries

• Stratification factors: country and Motzer score

Escudier, ASCO 2007Escudier, Lancet 2007

PD = progression of disease; i.v. = intravenous; s.c. = subcutaneous

1:1

IFN-α2a + placebo (n=322)

Advanced RCCNo prior therapy

KPS ≥60(N=649)

Bevacizumab + IFN-α2a (n=327)

AVOREN: Selected grade 3/4 AVOREN: Selected grade 3/4 adverse events*adverse events*

Number of patients (%)

13 (3.9) 2 (0.7) Hypertension

4 (1.2) 1 (0.3) Arterial ischemia

5 (1.5) 0 (0) Gastrointestinal perforation

6 (1.8) 2 (0.7) Venous thromboembolism

11 (3.3) 1 (0.3) Hemorrhage

22 (6.5) 0 (0) Proteinuria

76 (23) 46 (15) Fatigue/asthenia/malaise

203 (60) 137 (45)Any grade 3/4 adverse event

Bevacizumab + IFN

(n=337)

IFN +placebo(n=304)Adverse event

*Based on safety population

AVOREN: Tumor response AVOREN: Tumor response

31

1

30

13

2

11

Overall response rate (%)*

Complete response

Partial response

p<0.0001

13

10

11

7

Median duration of response (months)

Median duration of stable disease (months)

Bevacizumab + IFN(n=306)

IFN + placebo(n=289)

Response

*Patients with measurable disease only

Median PFS

Bevacizumab + IFN-α 2a = 10.2 mo

IFN-α 2a + placebo = 5.4 mo

HR = 0.63, P<0.0001

Pro

bab

ility

of

Bei

ng

P

rog

ress

ion

Fre

eAVOREN: Investigator-Assessed AVOREN: Investigator-Assessed

PFSPFS

Time (months)0 6 12 18 24

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

05.4 10.2

Escudier B, et al. Lancet. 2007;370:2103-2111.

AVOREN: PFS Is Maintained With AVOREN: PFS Is Maintained With Bevacizumab + Lower-Dose IFNBevacizumab + Lower-Dose IFN

Melichar B, et al. Ann Oncol. 2008 April. [Epub ahead of print.]

0 3 6 9 12 15 18 21 24

Time (months)

Bevacizumab + lower-dose IFN = 13.6 monthsAll bevacizumab + IFN patients = 13.5 months

Pro

bab

ility

of

Bei

ng

P

rog

ress

ion

Fre

e

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Median PFS

Renal Cell Cancer-Targeted RxRenal Cell Cancer-Targeted Rx

III

II

III

II

III

III

II

Phase

31/70

10/

9/54

10/82

37/84

41/67

PR/ORR

10.2 vs.5.4

4.8

vs. IFN1

2

649

116

Bevacizumab

3.7 vs. 1.9vs. IFNI626Temsirolimus

(poor risk)

5.7

5.5 vs. 2.8vs. placebo1

2

189

903

Sorafenib

11 vs. 5

8.2

vs.IFNI

2

750

169

Sunitinib

PFS

(months)

RegimenI/II line

NDrug

Efficacy of Sequencing Antiangiogenic Efficacy of Sequencing Antiangiogenic Agents in Resistant RCCAgents in Resistant RCC

Sorafenib (Phase III;

IFN-Resistant) 1

(n=451)

Sunitinib (Ph II: Bevacizumab -

Resistant) (n=61)2

Axitinib (Phase II: IFN-

Resistant) (n=52)3

Axitinib (Phase II; Soraf-/Sunit-Resistant)

(n=62)4

Pazopanib (Phase II; First -Line/Interferon -

Resistant) (n=225)5

Median PFS, months

5.5 23.6* NR 7.4/6.1

(n=62/14**) NR

ORR, % 10 16 46 21 26/30

(n=154/71)

Stable Disease, %

53 61 40 34 45/48 (n=154/71)

*TTP **Patients received both sorafenib and sunitinib 1. Escudier B, et al. N Engl J Med 2007; 356:125 -34 2. Rini BI, et al. ASCO 2006; # 4522 3. Rini BI, et al. ASCO 2005; #4509 4. Rini BI, et al. ASCO 2007; # 5032 5. Hutson TE, et al. ASCO 2007; abstract 5031

Everolimus After Progression on Everolimus After Progression on VEGFR-TKI: Study DesignVEGFR-TKI: Study Design

• 410 patients randomized between September 2006 and October 2007• Second interim analysis cutoff: October 15, 2007, based on 191 PFS events• Independent Data Monitoring Committee recommended termination of study

RRAANNDDOOMMIIZZAATTIIOONN

2:12:1

Upon Disease

Progression

Interim Analysis

Interim Analysis

N = 410

Stratification

Prior VEGFR-TKI: 1 or 2

MSKCC risk group: favorable, intermediate, or poor

=Final

Analysis

Everolimus + best supportive care

(n = 272)(n = 272)

Placebo + best supportive care

(n = 138)(n = 138)

Motzer RJ, et al. 2008 ASCO; Motzer RJ, Lancet 2008

Everolimus After Progression on Everolimus After Progression on VEGFR-TKI: Prior TherapiesVEGFR-TKI: Prior Therapies

10 9 Bevacizumab

4446 Sunitinib

1613 Chemotherapy

5050 Interferon

2422 Interleukin 2

VEGFR-TKI therapy

Placebo (n = 138)

%

2626 Sunitinib and sorafenib

Other systemic therapy

30

28

95

31Radiotherapy

96Nephrectomy

28 Sorafenib

Everolimus (n = 272)

%Prior Treatment

Motzer RJ, et al. 2008 ASCO ; Motzer RJ, Lancet 2008

Treatment-Related Adverse Events*

124 337Asthenia / fatigue

03 010Edema peripheral 04 012Cough

02 310Infections†

0 0

0 0 0 0 0 0

0Grade 3

4< 125Rash

2 18Dyspnea

2 114Mucosal inflammation4 012Vomiting

0 38Pneumonitis†

863

8All Grades

Placebo%, (n = 135)

117Diarrhea< 116Anorexia 015Nausea

3Grade 3

40Stomatitis†

All Grades

Everolimus%, (n = 269)

*≥ 10% of everolimus patients and additional selected AEs.†Significant difference between sum of grade 3/4 events for everolimus and placebo groups (P < .05) .

Motzer R et al. ASCO 2008

−100%

−75%

−50%

−25%

0%

25%

50%

75%

100%

Best Response n (%)

PR 3 (1) Stable 171 (63) PD 53 (20) NE 45 (16)

Best Response n (%)

PR 0 Stable 44 (32) PD 63 (46) NE 31 (22)

Maximum % Change in Target Lesions Maximum % Change in Target Lesions and Objective Response Rate*and Objective Response Rate*

EverolimusEverolimus PlaceboPlacebo

NE = not evaluable

* Central Radiology Review

Everolimus vs Placebo: PFS by Central Radiology

Review

Motzer RJ, et al. 2008 ASCO Annual Meeting; Abstract LBA5026.

100

80

60

40

20

0

0 2 4 6 8 10 12

PF

S P

rob

abili

ty (

%)

Everolimus (n = 272) Placebo (n = 138)

Hazard ratio = 0.30 95% CI (0.22, 0.40) Log-rank P<0.001 Median PFS Everolimus: 4.0 mo Placebo: 1.9 mo

Months

Prospective Trials of Sequential Targeted Agents

4.0 months

3.8 months

7.4 months

7.1 months

PFS

1/50410Phase 3: RAD001 vs placebo in TKI-refractory

RAD0014

480Phase 3: Temsirolimus vs sorafenib in patients previously treated with sunitinib

Temsirolimus

540Phase 3: Axitinib vs sorafenib in previously treated patients

Axitinib

3/3826 eachPhase 2: Bevacizumab-or sunitinib-refractory

Sorafenib3

23/5562Phase 2: Sorafenib-refractoryAxitinib2

23/7562Phase 2: Bevacizumab-refractorySunitinib1

OR/TS(%)

NPopulationAgent

1. Rini, et al. J Clin Oncol (in press); 2. Rini, et al. 2007 ASCO Annual Meeting; 3. Sheppard, et al. 2008 ASCO Annual Meeting; 4. Motzer, et al. 2008 ASCO Annual Meeting.

OR = overall response; TS = tumor shrinkage.

RCC Therapies 2008RCC Therapies 2008

Clinical trialPrior mTOR

inhibitor

IL-2 (selected pts)

Bevacizumab +/- IFN-α

Clinical trial (Everolimus)

Prior VEGFr-TKI

Sorafenib/SunitinibPrior cytokine

Previously treated

TemsirolimusPoor risk*

Clinical trial

SunitinibGood or intermediate risk*Treatment-

naive

Treatment Setting

*MSKCC risk status.

Adapted from Atkins M ASCO 2006

Issues in Sequencing Anti-Angiogenesis Issues in Sequencing Anti-Angiogenesis Agents in RCCAgents in RCC

Why do we still observe responses after sequencing anti VEGF agents?

- Do some drugs have better PK profile? Interpatient PK variability?

- Is it due to OFF VEGF target mechanisms?

- Is the target VEGF always inhibited?Does the sequence affect toxicity? What are the mechanisms of resistance to anti VEGF therapies?

BMDCs

CAFsSDF1α

Bone marrow derived cells (i.e myeliod suppressive cells) Cancer associated fibroblasts

Adapted from Casanovas O Cancer Cell 2005

Osteopontin

Potential Mechanism of Resistance Potential Mechanism of Resistance to VEGF Inhibitorsto VEGF Inhibitors

SDF1α

MMP9

1Oromi A et al Cell 2005 3Du R Cancer Cell 20082Ebos JM et al PNAS 2007

PDGF

RCC Microenvironment is ResponsibleRCC Microenvironment is Responsible

for Tumor Response/Resistance to RTKIs for Tumor Response/Resistance to RTKIs

0.00

200.00

400.00

600.00

800.00

1000.00

0 20 40 60 80 100

Days post implantation of tumor piece

Ave

Tum

or V

olu

me

(mm

3)

Sunitinib 40mg/kg

Sorafenib 30mg/kg

Vehicle CTL

Hammers H et al AACR 2008

Tu

mo

r vo

lum

e

0 62.5 125 250 5000

25

50

75

100

Sunitinib (nM)In v

itro

pro

life

rati

on

(%

of

con

tro

l)

Sunitinib resistant disease

Tum

or S

ize

Combination Strategies: Sequential ApproachCombination Strategies: Sequential Approach

7

6

5

4

3

2

1

0

0 2 4 6 8 10 12MonthRTKI

Anti-VEGF w/wo HIF-1α Inhibitor RTK = receptor tyrosine kinase

VEGFdependence

Sequential Approach: Phase II Study of Sequential Approach: Phase II Study of VEGF Trap in Metastatic RCC (ECOG 4805)VEGF Trap in Metastatic RCC (ECOG 4805)

Eligibility Criteria• Confirmed clear cell RCC• Measurable metastatic

disease• Prior TKI treatment

VEGF Trap 4 mgIV d1-15

(N=120*)

Primary end points: PFSSecondary end points: ORR,SD, duration of response, , safety

RANDOMIZATION

VEGF Trap 1 mgIV d1-15

Crossover allowed

Stratification• Low vs intermediate vs high

risk (Motzer criteria)• Prior cytokine : yes vs no• Prior nephrectomy: yes vs no

Tum

or S

ize

7

6

5

4

3

2

1

0

0 2 4 6 8 10 12MonthRTKI

RTKI + HIF-1α Inhibitor

Delay TTP

Combination Strategies: Concomitant ApproachCombination Strategies: Concomitant Approach VEGF

dependenceHIF-1α

dependence

Phase II Study of Bevacizumab, Sorafenib, and Temsirolimus in mRCC

(ECOG 2804 “BeST” Trial): Study Design

Eligibility Criteria• Confirmed clear cell RCC• Measurable metastatic disease• <25% of any other histology

(papillary, chromophobe, or oncocytic)

• Primary or metastatic lesion • Not curable by standard

radiotherapy or surgery • Prior nephrectomy

Bevacizumab IV over 30-90 min d1-15

+TemsirolimusIV over 30 min

d1, d8, d15, d22

Bevacizumab IV over 30-90

min d1-15

Primary end point: PFS*Expected enrollment.At: http://www.clinicaltrials.gov.

(N=360*)

+Sorafenib

bid PO, d1-28

Bevacizumab IV over 30-90

min d1-15

+ SorafenibPO bid, d1-28

TemsirolimusIV over 30 min

d1, d8, d15, d22

RANDOMIZATION

Toxicities in RCC Patients Receiving Toxicities in RCC Patients Receiving

RTKIsRTKIs • Most common:

– Fatigue– Hypertension– Hand-foot syndrome– Diarrhea

• Rarer but potentially mores serious:– Cardiac events– Hypothyroidism– Thromboembolic events– Bleeding

• To date no validated predictors• No clear linear association with pharmacokinetics• Limiting factor in combination strategies

Kinase Dendrogram

KINASE INHIBITION

CLINICALEFFICACY ?

Adapted from Fabian et al, Nature Biotech 2006

TOXICITY ?

VATALANIB SORAFENIB SUNITINIB

Predictors of Toxicity with RTKIs

• Pharmacogenomics: Single nucleotide polymorphism (SNPs) may correlate with sunitinib treatment-related toxicity *- larger study needed

• Some SNPs may be associated with tissue restricted toxicity (i.e. creatine kinase and cardiac toxicity)

• Correlation of SNPs, toxicity and pharmacokinetcs to be assessed

• Awaiting for analysis from E2805 adjuvant study • Is age a predictor factor?

* Faber PW et al ASCO 2008 abstract #5009* Faber PW et al ASCO 2008 abstract #5009

Probability of Severe Toxicityfrom Sunitinib in Older Adults

van der Veldt AAM British Journal of Cancer (2008) 99(2), 259 – 265

1For advanced diseaseNeoadjuvant therapy

Adjuvant therapy

IL-2, IFN-αOther immunotherapy strategies

Targeted agents• VEGF inhibitors• mTOR inhibitors• Others (ie, HDAC inhibitors)

Chemotherapy?• Capecitabine• Gemcitabine• Others

2Optimizing dose and schedule

to overcome resistance?VEGF inhibitormTOR inhibitor

3Combination strategies

HDAC = histone deacetylase.

Clinical Development of Clinical Development of Antiangiogenesis in RCCAntiangiogenesis in RCC

RCC: Role for Palliative NephrectomyRCC: Role for Palliative Nephrectomy

1) EORTC:N CR PR Survival (mo)

Nx + IFN 42 12 7 17IFN 43 2 6 7 p=0.03

2) SWOG:N CR PR Survival (mo)

Nx + IFN 120 0 3 11.1IFN 121 0 3 8.1 p=0.05

Two randomized trials:IFN

Nx + IFN

1 Mickisch, Lancet 358, 2001; 2 Flanigan, NEJM 345, 2001.

n=444

n=444

n=444

Treatment repeats every 6 weeks for up to 9 courses in the absence of disease progression or unacceptable toxicity

Sunitinib 50 mg PO qd for 4 of 6 wk +

Sorafenib placebo for 6 wk

Sorafenib 400 mg PO bid for 6 wk+

Sunitinib malate placebo for 6 wk

Placebo for sunitinib malateand sorafenib for 6 wk

ASSURE Trial (ECOG 2805)ASSURE Trial (ECOG 2805)

Primary end point: Disease-free survival Secondary end points: OS, safety, analysis of molecular markers

N=1332*

Eligibility Criteria• pT1b, G3-4; pT2-4; N+

disease, no metastatic disease

• Confirmed clear cell or non–clear cell RCC

• Intermediate high–risk or very high–risk disease

• Prior radical or partial nephrectomy

RANDOMIZATION

Future Directions for Individualized Future Directions for Individualized Treatments for RCC Treatments for RCC

• Predict tumor behavior by molecular signatures

– Patient prognosis

• Stratify patients into risk categories by clinical/molecular parameters

– Predict disease recurrence and cancer-related death

• Select treatment approach and predict response

– Based on the target expression

– Minimize unnecessary exposure to treatment toxicity

Adapted from Eppert JT, et al. BJU Int. 2007;99:1208-1211.

• Individualizing treatment; attention for possible age-related effects on PK and PD in older adults

• Optimal duration of treatment and timing for changing treatments

• Selecting treatment for patients with comorbid conditions

• Integration of molecular targeted therapies with surgery

Future Directions for Individualized Future Directions for Individualized

Treatments for RCCTreatments for RCC

Conclusions

• The treatment of patients with metastatic RCC continues to evolve with several drugs already FDA approved

• Preclinical and clinical trials will determine the most effective dosing schemes, optimal sequencing, and treatment combinations

• The goal remains individualized treatments to optimize patient outcomes