Oncology Compass - Home - Dava Oncology DEMO.pdfOncology Compass: Renal Cell Carcinoma. ... recommendation EMEA approval oferon; oche Investigational; ongoing phase III Investigational;

Oncology Compass: Renal Cell Carcinoma

tivozanib

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Navigation Hints:• Explore the current standard of care by selecting Line of Therapy - Key clinical trials are organized on a timeline to reflect changes in regulatory and clinical standards over time

• Review key competitive agents by selecting Mechanism of Action - Each competitor profile includes key preclinical and clinical data - Detailed summaries of ongoing trials include milestone estimates and impact analyses

• Emerging data on optimal sequence of targeted therapy can be viewed by selecting Sequencing MOAs• Review impact of risk stratification and histology on the RCC treatment paradigm by selecting Patient Subsets• (Click on the word Glossary here to view a list of defined terms)

Mec

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Sequencing MOAs

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P

atient Sub

sets

Oncology Compass: Renal Cell Carcinoma

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MOA:

Immune Modulation

CytotoxicT cellCytotoxic

T cell

PD1

Antigenpresenting

cell

RCC Cell

Apoptosis

Necrosis

tumor antigen

• Cytokines activate the host immune response to tumor cells by enhancing the proliferation and function of T cells

• Interferon and IL-2 have been part of standard treatment since the 1990’s; other approaches to maximize T-cell responses are evaluated in randomized clinical trials

Anti-angiogenesis• Abnormal expression of VHL is typical in clear cell RCC, resulting in high levels of HIF and subsequent expression of VEGF and PDGF

• Consequently, RCC tumors are sensitive to VEGF or VEGF receptor targeted agents as well as rapalogues which may lower levels of HIF

Ub Ub

Ub

Ub

Normal Cell

Endothelial Cell

RCC Cell

Vascular pericyteAngiogenesis

PP P P

Angiogenesis

HIFɑHIFɑ

HIFɑHIFɑ

HIFɑ

HIFɑ

HIFɑ

HIFɑ

pVHL pVHL

HIF

bHIFb

HIFb

HIF

b

HIFb

pVHL

PDGFVEGF

VEGF

VEGF

VEG

F VEGF

VEGF

VEGF

PDGFPDGF

PDGFPDG

F

PDGF

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1998 2002IFN vs. MPA in advanced RCC

(MRC. Lancet. 1999)

IL-2 vs. IFN vs. IL-2/IFN vs. MPA in advanced RCC (Negrier. ASCO. 2005)

IFN vs. IL-2 vs. both in advanced RCC

(Negrier. NEJM. 1998)

Meta-analysis: six trials evaluating IFN in advanced RCC (Motzer. JCO. 2002)

1999 2005

MOA: Immune Modulation

Interleukin-2 Interferon-ɑ IMA901 BMS-936558 Naptumomab

MOA Cytokine; enhances the proliferation and function of T lymphocytes

T-cell response induced by vaccination with tumor-associated peptides

PD-1 Mab; targets T-cell inhibitory receptor to reactivate antitumor immunity

Fusion protein; targets tumor-associated antigen 5T4, induces T-cell response with super-antigen

Clinical status EMEA/FDA approval: aldesleukin (Proleukin; Novartis)

No FDA approval; NCCN recommendation. EMEA approval (Roferon; Roche)

Investigational; ongoing phase III

Investigational; ongoing phase IIb

Investigational; ongoing phase III

Dosing

0.6 MIU/kg IV every 8 hrs x 14 → 9 days off → 0.6 MIU/kg IV every 8 hrs x 14

9 MIU IFN, 3 x week; subq

Cyclophosphamide (300 mg/m2; 1 dose) → 10 x IMA901/ GM-CSF in 4 mo

0.3, 2, or 10 mg/kg IV; q3w

IFN + 10-15 mcg/kg naptumomab; bolus IV d1-4 q8w x 4 cycles

AEs Hypotension, fever, diarrhea

Flu-like symptoms Injection site reactions FatigueFever, hypotension, vascular leak syndrome

Biology

Ongoing trials

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MOA: Immune Modulation - biology

• Initiation of antitumor immune response requires T-cell activation by antigen-presenting cells

• Induction of T-cell response stimulated by presence of cytokines (i.e., interferon, IL-2)

• Immune response is inhibited by PD1

• Cytotoxic T-cells interact with tumor cells through T-cell receptor specific to tumor antigens expressed on the tumor cell surface

CytotoxicT cellCytotoxic

T cell

PD1

• Vaccination with tumor-associated antigens hypothesized to enhance anti-tumor response

Antigenpresenting

cell

RCC Cell

Apoptosis

Necrosis

tumor antigen

Therapy

Biology

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(MRC. Lancet. 1999)





1999 2005

Ongoing trials


Cytokines in Metastatic RCC: IFN, IL-2 or Both?

Negrier et al., N Engl J Med. 1998; 338: p1272

ToxicityEfficacyDesignImpact

• Cytokines involved in activation of the host immune response are moderately active in metastatic RCC; interferon and IL-2 have been part of standard treatment since the 1990’s• Groupe Français d’Immunothérapie hypothesized that the combination of both cytokines could improve outcome in this randomized phase III trial• Lack of improvement of OS with the combination as well as poor toxicity profile associated with both combination and single agent IL-2; consequently, IFN considered SOC and comparator for future phase III trials

http://www.ncbi.nlm.nih.gov/pubmed/9562581

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(MRC. Lancet. 1999)





1999 2005

Ongoing trials




Eligibility Criteria• Progressive metastatic RCC• No prior systemic therapy• ECOG PS 0 - 1Primary Endpoint• ORRAccrual Window• March 1992 – June 1995

Patient Characteristics

R IFN

IL-2

IL-2 + IFN

N= 42

5

IL-2 18 x 106 IU D1-5 (CIVI)IFN 6 or 18 x 106 IU 3qw (SQ)

Dosing & Schedule

ToxicityEfficacyImpact Design


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(MRC. Lancet. 1999)





1999 2005

Ongoing trials




Eligibility Criteria• Progressive metastatic RCC• No prior systemic therapy• ECOG PS 0 - 1


Prior TherapyYes No

15%

85%

Metastatic Sites

31%24%

45%

1 2 ≥3


ECOG PS0 1 1 Unknown

77%

20% 2%1%


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(MRC. Lancet. 1999)





1999 2005

Ongoing trials




EFS Rate at 1-year

p-value

IL-2 15%0.01IFN 12%

IL-2 + IFN 20%

0

60

80

40

20

100

Months

0 186 12 3024 36

EFS

OS

ORR

ToxicityDesign EfficacyImpact

Event-free survival rates were significantly higher in the group receiving combined cytokine treatment (P=0.01).

p=0.01

12%

20%15%


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(MRC. Lancet. 1999)





1999 2005

Ongoing trials




EFSMedian OS p-value

IL-2 12 mo0.55IFN 13 mo

IL-2 + IFN 17 mo

0

60

80

40

20

100

Months

0 186 12 3024 36

OS

ORR


No significant difference in median overall survival among the three groups (p=0.55).

p=0.55

12 mo13 mo

17 mo


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(MRC. Lancet. 1999)





1999 2005

Ongoing trials




OS

ORR

0

30

40

20

10

50

IL-2 IFN IL-2 + IFN

8%5%

18%

1% 1%

EFS


ORR, the primary endpoint, was significantly improved in the combination arm (p<0.01); higher response rates were associated with improved EFS, but not OS.

p<0.01

PRCR


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(MRC. Lancet. 1999)





1999 2005

Ongoing trials




IFN IL-2 IL-2 + IFN All Gr. 3/4 All Gr. 3/4 All Gr. 3/4

Hypertension: – 0.7% – 68.1% – 67.1%Fever: – 5.4% – 42.8% – 56.4%

Pulmonary symptoms: – 3.4% – 15.9% – 15%Nausea or vomiting: – 4.8% – 34.1% – 30.7%

Diarrhea: – 0.7% – 27.5% – 25%

Efficacy ToxicityDesignImpact

Significantly less vs. control

Significantly increased vs. control (data not available)


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Ongoing trials

MOA: Immune Modulation – ongoing trials

Trial/sponsor RE Pts-3 Design Endpoint N Status Data

IMPRINT Treatment-naïve, advanced RCC

Sunitinib ± IMA901 OS 330 Initiated 1Q2011 2014

BMS Advanced RCC, prior VEGF(R)-targeted agent

Different BMS-936558 dosing levels

PFS 150 Initiated 2Q2011 2013

Active Bio. Advanced RCC, prior VEGF(R)-targeted agent

IFN ± naptumomab OS 526 Initiated 1Q2007 2012

2012 2013 2014 2015 2016 2017 2018

IMA901 (Immatics) ASCO

BMS-936558(BMS) ASCO

Naptumomab(Active Biotech) ASCO

Launch

Launch

Launchgo/no go

Top-line data 1st full report regulatory filing/review


(MRC. Lancet. 1999)





1999 2005

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R

Impact PotentialSunitinib add-on strategy in HLA-A*02 positive RCC (~50% of pts); Pfizer collaboration suggests potential for commercial partnering

Ph II

I tria

l

RC

C a

djuv

ant

Dat

a av

aila

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Localized RCC:• Sponsor: BMS• PI: Rini, Eisen• N =330• Status: Accruing• Inclusion Criteria: - HLA-A*02 positive clear cell RCC - locally advanced or metastatic - treatment-naïve

Primary Endpoint• OS

IMPRINT (Immatics)

NCT01265901










Timing Design Key highlightsESMO 2010 Ph II: IMA901 vaccinations with or

without cyclophosphamide priming(Brugger et al., ESMO. 2010)Efficacy: Median OS of 19.8 months in pts with prior cytokines; median OS not reached (>26 months) in treatment-naïve patientsToxicity: Mostly injection site related

Sunitinib + 10 x IMA901 vaccinations

50 mg/d (4 wks/2 wks off) sunitinib

http://clinicaltrials.gov/ct2/show/NCT01265901

http://annonc.oxfordjournals.org/content/21/suppl_8/viii271.full.pdf+html

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R










Impact PotentialBMS building on success of CTLA4 Mab ipilimumab which targets the same immuno-suppressive pathway; highly likely to proceed to pivotal trial in RCC by 2012

Ph II

I tria

l

RC

C a

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Dat

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Localized RCC:• Sponsor: BMS• PI: Unknown• N =150• Status: Accruing• Inclusion Criteria: - clear cell RCC - locally advanced or metastatic - prior VEGF(R)-targeted therapy

Primary Endpoint• PFS

CA209-010 (BMS)

NCT01354431

Timing Design Key highlightsASCO 2010 Dose escalation of biweekly BMS-

936558 in pts with solid tumors(Sznol et al., ASCO. 2010; #2506)Efficacy: 28% ORR in relapsed/refractory RCC; responses > 6 mo Toxicity: Fatigue most common Gr. 3/4 AE (5%)

BMS-936558 0.3 mg/kg; q3w

BMS-936558 2.0 mg/kg; q3w

BMS-936558 10 mg/kg; q3w


http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=49563

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R










Impact PotentialEven if positive, naptumomab would have to compete with established VEGFR TKIs in 1L/2L; no global partner for commercialization and launch

Ph II

I tria

l

RC

C a

djuv

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Localized RCC:• Sponsor: Active Biotech• PI: Unknown• N = 526• Status: Awaiting data• Inclusion Criteria: - clear cell or papillary RCC - locally advanced or metastatic - treatment-naïve

Primary Endpoint• OS

06762004 (ABR)

NCT00420888

Timing Design Key highlights2007 Ph II single agent, single arm study in

advanced RCC(Shaw et al., Br. J Ca. 2007)Efficacy: median OS of 19.7 mo in pts with prior cytokine treatmentToxicity: pyrexia, lethargy/fatigue, hypotension

IFN + 10-15 mcg/kg naptumomab; bolus IV d1-4 every 8 weeks for 4 cycles

9 MIU IFN, 3 x week; subq


http://www.ncbi.nlm.nih.gov/pubmed?term=17285137

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MOA: Anti-angiogenesis

Ub Ub

Ub

Ub

• Innormoxicenvironment,VHLprotein promotesdegradationofhypoxia- induciblefactorɑ(HIFɑ)• InRCC,abnormalVHLallowsincreased levelsofHIFresultinginexpressionof VEGFandPDGF• BindingofVEGFandPDGFtotheir respectivereceptorsactivatesangiogenesis

• Inhibitstheserine/threoninekinase activityofmTORC1;TORC1regulates translationofHIF-1ɑ

• BindstoVEGFtopreventbindingof ligandtoVEGFreceptor

• Targetstyrosinekinasedomainof VEGFreceptortopreventactivationof downstreamsignaling

NormalCell

EndothelialCell

RCCCell

Rapalogue (mTOR)

VEGF Mab

VEGFR TKI

VascularpericyteAngiogenesis

PP P P

Angiogenesis

HIFɑHIFɑ

HIFɑHIFɑ

HIFɑ

HIFɑ

HIFɑ

HIFɑ

pVHL pVHL

HIF

bHIFb

HIFb

HIF

b

HIFb

pVHL

PDGFVEGF

VEGF

VEGF

VEGF VEG

F

VEGF

VEGF

PDGFPDGF

PDGFPDG

F

PDGF

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VEGFR TKIs: TolerabilityVEGFR TKIs: Efficacy

MOA: Anti-angiogenesis – VEGFR TKI

Sorafenib

ORR PFS

5% 5.7 mo

11% 6.5 mo

3.4 mo

Sunitinib

ORR PFS

31% 11 mo

34% 8.3 mo

Pazopanib

ORR PFS

32% 11 mo

29% 7.4 mo

Axitinib

ORR PFS

12 mo

4.8 mo

Dovitinib

ORR PFS

3.4% 5.6 mo

Tivozanib

ORR PFS

24% 11.7 mo

Pivotal trial data Phase II data

Treatment-naïve:

Prior cytokines:

Prior VEGFR TKI:

References

IC50 (nM/L)

Agent T1/2 VEGFR-1 VEGFR-2 VEGFR-3 PDGFR-ß FGFR-1 OtherSorafenib 24 hrs NR Raf

Sunitinib 40-60 hrs Flt-3

Pazopanib 30 hrs

Axitinib 2-5 hrs

Dovitinib 17 hrs Flt-3

Tivozanib 100 hrs

IC50 >500 nM

IC50 >100 nM

IC50 10-100 nM

IC50 1-10 nM

IC50 < 1 nM

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Sorafenib

All Gr. 3/4

17% 4%

43% 2%

30% 6%

37% 6%

40% 1%

Sunitinib

All Gr. 3/4

34% 13%

66% 10%

29% 8%

62% 15%

29% 8%

71% 16%

Pazopanib

All Gr. 3/4

40% 4%

52% 4%

6%

19% 2%

8%

34% 2%

Axitinib

All Gr. 3/4

40% 16%

55% 11%

27% 5%

39% 11%

13% <1%

6% 1%

Dovitinib

All Gr. 3/4

25% 10%

66% 10%

36% 14%

22%

77% 16%

Tivozanib

All Gr. 3/4

45% 12%

12% 2%

4% <1%

8% 2%

Product Insert Phase IIPhase III

Hypertension:

Diarrhea:

Hand-foot syndr:

Fatigue:

Rash:

Neutropenia:

References

IC50 (nM/L)



Pazopanib 30 hrs

Axitinib 2-5 hrs


Tivozanib 100 hrs

IC50 >500 nM

IC50 >100 nM

IC50 10-100 nM

IC50 1-10 nM

IC50 < 1 nM

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References 1. Wilhelm SM et al., Cancer Res. 2004; 64: p70992. Mendel DB et al., Clin Cancer Res. 2003; 9: p3273. Chow L et al., J Clin Oncol. 2007; 25: p884 4. Podar K et al., Proc Natl Acad Sci USA. 2006; 103: p194785. Hu-Lowe et al., Clin Cancer Res. 2008; 14: p72726. Lee et al., Clin Cancer Res. 2005; 11: p36337. Nakamura et al., Cancer Res. 2006; 66: p9134

IC50 (nM/L)



Pazopanib 30 hrs

Axitinib 2-5 hrs


Tivozanib 100 hrs

IC50 >500 nM

IC50 >100 nM

IC50 10-100 nM

IC50 1-10 nM

IC50 < 1 nM








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Ongoing trials

MOA: Anti-angiogenesis – VEGFR TKI – sorafenib

FDA & EMEA approval

2005 20102011

Ph IIb: sorafenib vs. IFN in 1L

(Escudier. JCO. 2009)

Ph II: sorafenib in sunitinib or bevacizumab-refractory mRCC

(Garcia. Cancer. 2010)

Ph II: sorafenib in sunitinib-refractory mRCC

(Di Lorenzo. JCO. 2009

Sorafenib Expanded Access Program (EU-ARCCS)

(Beck. Ann Oncol. 2011)

Sorafenib Expanded Access Program (NA-ARCCS)

(Stadler. Cancer. 2010)

Pivotal ph III: sorafenib in cytokine-refractory RCC (Escudier. JCO. 2009)

2009

Sorafenib (Nexavar; Bayer/Onyx)

IndicationFDA patients with advanced RCC

EMEA patients with advanced RCC who have failed prior IFNɑ or IL-2 based therapy or are considered unsuitable for such therapy

Dosing 400 mg (2 x 200-mg tablets) twice daily without foodPK T1/2 = 24 hrs

MOA

AE profile Hypertension, hand-foot syndrome, diarrhea

VEGFR-2 (*nM/L) PDGFR FGFR Other

IC50: 90 ✓ Raf, cKIT

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Ongoing trials

FDA & EMEA approval

2005 20102011













Sorafenib in Advanced RCC: Pivotal Trial

Escudier et al., J Clin Oncol. 2009; 27: p3312

2009

ToxicityEfficacyDesignImpact

• RCC tumors are highly vascularized as angiogenesis is driven by HIF-1ɑ, a protein over-expressed in clear cell RCC due to aberrant expression of VHL; HIF-1ɑ upregulates expression of VEGF• Sorafenib, a VEGFR-targeted tyrosine kinase inhibitor, was compared to placebo in this randomized phase III trial which enrolled pts with prior cytokines• FDA approved sorafenib for “advanced RCC” in 2006; EMEA indication limited to pts with prior cytokines


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Ongoing trials

FDA & EMEA approval

2005 20102011















2009

Eligibility Criteria• Metastatic RCC• Progressive disease following systemic treatment within the last 8 months• ECOG PS 0 - 1Primary Endpoint• OSAccrual Window• November 2003 – March 2005


R Sorafenib

PlaceboN= 90

3

Sorafenib 400 mg BID (PO)Dosing & Schedule



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Ongoing trials

FDA & EMEA approval

2005 20102011















2009

Eligibility Criteria• Metastatic RCC• Progressive disease following systemic treatment within the last 8 months• ECOG PS 0 - 1


MSKCC Prognostic Score

Low Intermediate

48%

52%

Metastatic Sites

29%14%

57%

1 2 >2


ECOG Performance Score

0 1 2

48%

51%1%82% of pts received prior cytokine

treatment.


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Ongoing trials

FDA & EMEA approval

2005 20102011















2009

Median PFS HR

Sorafenib 5.5 mo 0.51(p < 0.001)Placebo 2.8 mo

0

60

80

40

20

100

Months

0 124 8 16 18

PFS

OS

ORR


p<0.001

2.8 mo 5.5 mo


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Ongoing trials

FDA & EMEA approval

2005 20102011















2009

PFS

OS

ORR


0

60

80

40

20

100

Months

0 186 12 30 36240

60

80

40

20

100

Months

0 186 12 30 3624

ITT Median OS HR

Sorafenib 17.8 mo 0.88

(p = 0.146)Placebo 15.2 mo

No cross-over Median OS HR

Sorafenib 17.8 mo 0.78

(p = 0.0287)Placebo 14.3 mo

17.8 mo 17.8 mo15.2 mo 14.3 mo


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Ongoing trials

FDA & EMEA approval

2005 20102011















2009

0

30

40

20

10

50

Sorafenib Placebo

2%

10%

<1%

PFS

OS

ORR


p<0.001

PRCR


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Ongoing trials

FDA & EMEA approval

2005 20102011















2009

Placebo Sorafenib All Gr. 3/4 All Gr. 3/4

Hypertension: 2% <1% 17% 4%Fatigue: 28% 4% 37% 5%

Diarrhea: 13% 1% 43% 2%Rash: 16% 1% 40% 1%

Hand-foot syndrome: 7% 0% 30% 6%

Efficacy ToxicityDesignImpact

The most commonly reported toxic effects were dermatological symptoms and diarrhea.

Significantly less vs. control

Significantly increased vs. control (data not available)


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Line of Therapy

Adjuvant

Prior Cytokines

Prior VEGFR TKI (2L) Prior VEGFR and mTOR (3L)

Treatment-naïve (1L)

Cytokines

VEGFR TKI

mTOR

Cytokines

VEGFR TKI

VEGF Mab

Ongoing Trials

Ongoing TrialsOngoing Trials Ongoing Trials

]

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Trials INTORACTUS (ECOG): Interferon vs. Observation Messing. JCO. 2003; 21: p1214UK (Cytokine Working Group): Interleukin-2 vs. Observation Clark. JCO. 2003; 21: p3133

Key

Ongoing Trials

Line of Therapy – adjuvantIL-2 in localized RCC (Clark. JCO. 2003)

IFN in localized RCC (Messing. JCO. 2003)

2003

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2003

Adjuvant Therapy in Localized RCC: No Role for Interferon

Messing et al., J Clin Oncol. 2003; 21: p1214

• CytokinesinvolvedinactivationofthehostimmuneresponsearemoderatelyactiveinmetastaticRCC; interferonandIL-2havebeenpartofstandardtreatmentsincethe1990’s• UScooperativegrouptrialevaluatedroleofadjuvant interferon afterinptswithlocallyextensiveRCC (N+/M0);mostN+/M0RCCptsareexpectedtohaverecurrentdiseasewithdistantmetastasesevenafter complete resection• Adjuvant interferondidnotimpactsurvivalordiseaserecurrencewhencomparedtoobservation; consequently,observationremainstheSOC

DesignImpact Efficacy Toxicity


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2003



Eligibility Criteria• Locallyadvanced(StageT3-4a)andor node positive RCC• NodisseminatedmetastasisPrimary Endpoint• RFSAccrual Window• May1987–April1992

PatientCharacteristics

RN=283

IFN 3to20x106 U/m2 Qd(5d) q3w (IM)Dosing & Schedule

Observation

IFN

EfficacyImpact Design Toxicity


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2003




Eligibility Criteria• Locallyadvanced(StageT3-4a)andor node positive RCC• Nodisseminatedmetastasis

ECOG PS0 1

66%

34%

Histologic SubtypeClear CellMixed

PapillaryOther

12%

13%

69%6%

2 cm5-10 cm

2-5 cm>10 cm

Primary Tumor Size

10%

36%

53%

1%



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2003



RFS

OSMedian RFS P-value

IFN 2.2 yrs0.33

Observation 4.8yrs

0

0.6

0.8

0.4

0.2

1.0

Years0 6 12102 4 8 14

Trend to improved outcome in favor of thecontrolarm.

Impact ToxicityDesign Efficacy

4.8yrs 2.2 yrs

p=0.33


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2003



Median OS P-value

Interferon-α 5.1 yrs0.09

Observation 7.4yrs

Trend to improved outcome in favor of thecontrolarm.

0

0.6

0.8

0.4

0.2

1.0

Years0 6 12102 4 8 14

RFS

OS


5.1 yrs7.4yrs

p=0.09


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2003



Observation IFN All Gr. 3/4 All Gr. 3/4

Neutropenia: – – – 17%Flu-like symptoms: – – – 23%

Myalgia: – – – 21%Fatigue: – – – 21%

Themostcommongrade3/4sideeffectsexperiencedbypatientstreatedwithinterferonwereflu-likesymptomssuchasfeverandchills,fatigueandmyalgia.

Impact Design Efficacy Toxicity

Significantlyless vs. control

Significantlyincreased vs. control (data not available)


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2003

Adjuvant Therapy in Localized RCC: No Role for IL-2

Clark et al., J Clin Oncol. 2003; 21: p3133

• CytokinesinvolvedinactivationofthehostimmuneresponsearemoderatelyactiveinmetastaticRCC; interferon and IL-2havebeenpartofstandardtreatmentsincethe1990’s• Small,randomizedtrialevaluatesroleforIL-2,onlyFDA-approvedsystemictherapyformetastaticRCCat thattime,inptswithlocallyextensiveRCC• Likeadjuvantinterferon,IL-2didnotimpactsurvivalordiseaserecurrencewhencomparedtoobservation; observationafterresectionremainstheSOC

DesignImpact Efficacy Toxicity




2003



Eligibility Criteria• ResectedAdvancedhighriskRCC (Stage T3-T4, N+, M+)• Nopriorsystemictherapy• ECOGPS0-1Primary Endpoint• DFS• OSAccrual Window• September1997–June2002


RN=69

IL-2 6x105 U/kgD1-5;D15-19;28

cycles(IV)

Dosing & Schedule

Observation

IL-2



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2003



Eligibility Criteria• ResectedAdvancedhighriskRCC (Stage T3-T4, N+, M+)• Nopriorsystemictherapy• ECOGPS0-1


ECOG PS0 1

86%

14%


T3/N0 or T1-3/N1N2 or N3/T1-4

T3 or T4/N0-1

Disease Stage

36%

28%

22%

14%

M1

Histologic SubtypeRenal NOSPapillary

Clear Cell

14%

33%

46%7%

Other


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2003



Median DFS P-value

IL-2 19.5mo0.4308

Observation 36 mo

0

60

80

40

20

100

Months0 502010 4030 60

ThistrialwasclosedearlyduetotheinabilityoftheIL-2armtoreach30%improvementin2year DFS.

DFS

OS


19.5mo 36 mo

p=0.4308


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2003



3-yr OS (%) P-value

IL-2 800.9065

Observation 86

0

60

80

40

20

100

Months0 502010 4030 60

OS was similar between treatment arms at a median followupof22months.

DFS

OS


86%

80%

p=0.9065


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2003



Observation IL-2 All Gr. 3/4 All Gr. 3/4

Hypertension: – – – 52%

GI: – – – 27%

Electrolyte Abnormalities: – – – 27%

Anorexia, Fatigue, Fever: – – – 18%

Eightypercentofpatientstreatedwithinterleukinexperiencedatleastonegrade3/4AE;Themostcommonwashypotensionoccurringin52%ofpatients.

Impact Design Efficacy Toxicity

Significantlyless vs. control

Significantlyincreased vs. control (data not available)


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Line of Therapy – adjuvant – ongoing trials

ASSURE SORCE S-Trac PROTECT EVERESTSponsor ECOG(E2805) MRC - UK Pfizer–Global GSK - Global SWOG(S0931)Initiated 1Q 2006 3Q2007 3Q2007 4Q 2010 2Q 2011Target N 1932 1650 500 1500 1218Design •Arm1:1yrsunitinib

•Arm2:1yrsorafenib•Arm3:1yrplacebo

•Arm1:3yrsplacebo•Arm2:1yr.sorafenib + 2 yrs placebo•Arm3:3yrssorafenib

•Arm1:1yrsunitinib•Arm2:1yrplacebo

•Arm1:1yrpazopanib•Arm2:1yrplacebo

•Arm1:1yreverolimus•Arm2:1yrplacebo

Pts Intermediateorhighrisk Onlyclearcell,highrisk Intermediateorhighrisk Intermediateorhighrisk

Status Accrual complete (3Q 10) Accrual at 54% Accruing Accruing AccruingNCI ID NCT00326898 NCT00492258 NCT00375674 NCT01235962 NCT01120249

2012 2013 2014 2015 2016 2017 2018

ASSURE (ECOG) sorafenib vs. sunitinib ASCO

SORCE (MRC) sorafenib ASCO

S-Trac (Pfizer) sunitinib ASCO

PROTECT (GSK) pazopanib ASCO

EVEREST (SWOG) everolimus ASCO

Launch

Top-line data 1st full report regulatoryfiling/review

Launch






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Sequencing MOAs:

Re-challenge Switch to TKI Switch to mTOR

Third Line

VEGFR TKI

VEGFR TKI

VEGF Mab

VEGFR TKI

VEGFR TKI

VEGF(R) Tx

Rapalogue

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Ongoing trials

Sequencing MOAs: VEGFR TKI re-challenge

2010Pivotal ph III: Axitinib vs. sorafenib in 2L mRCC (Rini. ASCO. 2011)

Ph II: Sorafenib in sunitinib or bevacizumab-refractory mRCC


2009 2011

Ph II: Axitinib in sorafenib-refractory mRCC(Rini. JCO. 2009)

Ph II: Sorafenib in sunitinib-refractory mRCC

(Di Lorenzo. JCO. 2009)

VEGFR TKI

VEGFR TKI

Metastatic, Clear Cell RCC

7.8 mo 4.2 mo

7.5 mo 3.9 mo

8.4 mo 7.9 mo

5.7 mo 2.9 mo

4.8 mo 13.4 mo

5.1 mo 3.1 mo

6.0 mo 5.8 mo

Sunitinib Sorafenib VEGFR

13.7 mo 7.2 mo

Retrospective: VEGFR TKI rechallenge

(Al Marrawi. ASCO. 2011)

Retrospective: sequential sunitinib and sorafenib

(Porta. BJUI. 2011)

Retrospective: sequential sorafenib and sunitinib (Sablin. J Urol. 2009)

Retrospective: sequential sorafenib and sunitinib (Dudek. Cancer. 2009)

Retrospective: sunitinib rechallenge

(Zama. Cancer. 2010)

Retrospective: VEGFR TKI rechallenge

(Al Marrawi. ASCO. 2011)

http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=81103





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Patient Subsets:

Histology:

Clear CellPapillaryChromophobeSarcomatoid

10%5%

75%

15%

Age:

<6565-7475-84>84

6%

25%

50%

19%

Risk Score:

PoorIntermediateGood

50%

25% 25%

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Papillary Chromophobe SarcomatoidType 1 Type 2

Pathology Small basophilic cells; finger-like growth pattern

Large, irregularly shaped eosinophilic cells; finger-like growth pattern

Sheets of cells with granular cytoplasm

High grade dedifferentiation of any RCC subtype

Patient Subsets: Non-Clear Cell Histology

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Papillary Chromophobe SarcomatoidType 1 Type 2

Pathology Small basophilic cells; finger-like growth pattern

Large, irregularly shaped eosinophilic cells; finger-like growth pattern

Sheets of cells with granular cytoplasm

High grade dedifferentiation of any RCC subtype

Incidence 15% 5% 5-10%

Tumor Biology

• MET activation at 7q31 (familial)• MET amplification (sporadic)

• MYC amplification (sporadic) -- P53 over-expression

Tumor characteristics• Low Fuhrman grade• Limited microvascular invasion

• High Fuhrman grade• Microvascular invasion• Nodal involvement

Typically low-stage, low-grade tumors

Advanced stage, high grade tumors

Outcome

Outcome similar between clear cell and papillary RCC; however, papillary type 1 associated with better outcome compared to type 2 (Lee. Urology. 2010)

Improved compared to clear cell or papillary RCC (Przybycin. Am J Surg Pathol. 2011)

RCC with sarcomatoid elements associated with poor outcome

Patient Subsets: Non-Clear Cell Histology - PapillaryO

ngoing trials

Retrospective: VEGFR TKIs in papillary mRCC

(Choueiri. JCO. 2008)

Retrospective: temsirolimus in papillary mRCC

(Dutcher. Med Oncol. 2010)

2008 20102009

Ph II: Sunitinib in papillary mRCC

(Plimack. ASCO. 2010)

Ph II: Erlotinib in papillary locally advanced or mRCC

(Gordon. JCO. 2009)



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Risk FactorsIFN era TKI era

MSKCC IKCWG

Karnofsky PS <80% ✓ ✓

Time from diagnosis to treatment < 1 yr ✓ ✓

LDH > 1.5 ULN ✓ ✓

Calcium > ULN ✓ ✓

Hemoglobin < LLN ✓ ✓

Neutrophils > ULN ✓

Risk Factors UISS Leibovich

T-stage ✓ ✓

N-stage ✓

Tumor size ✓

Fuhrman Grade ✓ ✓

Tumor necrosis ✓

ECOG PS ✓

Patient Subsets: Risk Score

Non-resectable or metastatic setting

Resectable diseaseTrials in poor risk pts

Trials in poor risk pts

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MSKCC IKCWG



LDH > 1.5 ULN ✓ ✓




No. of risk factors Risk Group Median PFS 6 mo PFS 12 mo PFS

0 Good (18%) 8.3 mo 60% 39%

1 or 2 Intermediate (62%) 5.1 mo 45% 24%

3 or more Poor (20%) 2.5 mo 19% 10%

No. of risk factors Risk Group Median OS 1-yr OS 3-yr OS

0 Good (18%) 29.6 mo 83% 45%

1 or 2 Intermediate (62%) 13.8 mo 58% 17%

3 or more Poor (20%) 4.9 mo 20% 2%

Patient Subsets: Risk Score - MSKCC


Motzer et al., J Clin Oncol. 1999; 17: p25300

0.6

0.8

0.4

0.2

1.0

Years

0 124 8 16

0 risk factors

1 or 2 risk factors

3, 4, or 5 risk factors

Pro

porti

on S

urvi

ving


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MSKCC IKCWG



LDH > 1.5 ULN ✓ ✓




No. of risk factors Risk Group Median OS 1-yr OS

0 Good (18%) 26.9 mo 80%

1 or 2 Intermediate (62%) 11.5 mo 50%

3 or more Poor (20%) 4.2 mo 18%

No. of risk factors Risk Group Median OS 1-yr OS

0 Good (25%) 44.6 mo 90%

1 or 2 Intermediate (50%) 22.6 mo 75%

3 or more Poor (25%) 6.7 mo 36%

Patient Subsets: Risk Score - IKCWG


Manola et al., Clin Ca Res. 2011; 17: p54430

0.6

0.8

0.4

0.2

1.0

Years

0 4 8 12

Good risk

Intermediate risk

Poor risk

Model data set

Validation data set

Model set (IFN era)

Validation set (TKI era)


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T-stage ✓ ✓

N-stage ✓

Tumor size ✓


Tumor necrosis ✓

ECOG PS ✓

Resectable disease


Low (27%) INTM (41%)

High (32%)

90% 82% 56%

84% 72% 44%

95% 88% 64%

91% 80% 55%

Low (14%)

INTM (78%)

High (8%)

51% 31% 0%

30% 19% 0%

56% 31% 0%

32% 19% 0%

Risk Group:

3-yr OS

5-yr OS

3-yr DSS

5-yr DSS

968472600

60

80

40

20

100

Months following nephrectomy

0 2412 4836

LR

IR

HR

Patient Subsets: Risk Score - UISS

T stage 1 2 3 4

Grade 1-2 3-4 1 >1ECOG

PS 0 ≥1 0 ≥1 0 ≥1 0 ≥1

Risk Low Intermediate High

Stage N1M0 N2M0 / M1

Grade 1 2 3 4ECOG

PS 0 ≥1 0 ≥1 0 ≥1 0 ≥1

Risk Low INTM Low INTM High

NM at diagnosis: M at diagnosis:

NM

M LR

IR

HR

% D

isea

se s

peci

fic s

urvi

val

p=0.072

Zisman et al., J Clin Oncol. 2002; 20: p4559


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T-stage ✓ ✓

N-stage ✓

Tumor size ✓


Tumor necrosis ✓

ECOG PS ✓

Resectable disease


Low INTM

High

0-2 3-5 >5

41% 36% 22%

98% 80% 58%

97% 74% 31%

Feature Score

Pathologic T stage

pT1a 0

pT1b 2pT2 3

pT3 or 4 4N stage pNx or 0 0

pN1 or 2 2

Tumor size<10 cm 0

>10 cm 1

Fuhrman grade

1-2 03 14 3

Tumor necrosis

No 0Yes 1

Total Risk Score: 0-15

Risk Group:

Score

% of pts

3-yr MFS

5-yr MFS

Patient Subsets: Risk Score - Leibovich

Leibovich et al., Cancer. 2003; 97: p1663

100

60

80

40

20

100

Years to metastases or last follow up

0 42 86

0-1

2Low

INTM

HighMet

asta

ses-

free

surv

ival

3

4

5

6

7

≥8


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ITT intent to treatIU international unitsIV intravenousJAMA Journal of the American Medical AssociationJCO Journal of Clinical OncologyMab monoclonal antibodyMIU million international unitsMo monthMOA mechanism of actionMPA medroxyprogesterone acetate MRC Medical Research CouncilmRCC metastatic renal cell carcinomaMSKCC Memorial Sloan-Kettering Cancer Center mTOR mammalian target of rapamycinMU million unitsNCC non-clear cellNED no evidence of diseaseNEJM New England Journal of MedicineNS not shown (value not listed in reference)ORR overall response rateOS overall survivalPDGF Platelet-derived growth factorPFS progression free survivalPh phasePI principal investigatorPK pharmacokineticsPO per os (by mouth)PR partial response

1L first lineAE adverse event ALT alanine aminotransferaseASCO American Society of Clinical OncologyBID bis in die (twice a day)CALGB Cancer and Leukemia Group BCDD continuous daily dosingCI confidence intervalCIVI continuous intravenous infusionCR complete responseDFS disease free survivalECOG Eastern Cooperative Oncology GroupEFS event free survivalEMEA European Medicines Evaluation Agency ESMO European Society of Medical OncologyEU European UnionFDA Food and Drug AdministrationFGFR fibroblast growth factor receptorFLT-3 Fms-like tyrosine kinase 3GI gastrointestinalGr. gradeGS Gleason score HIF-1α hypoxia-inducible factor-1 alphaHR hazard ratiohrs hoursIFN interferon IL-2 interleukin-2

Glossary

PS performance statuspt patientq3w quaque 3 weeks (every 3 weeks) qd quaque daily (every day)QOL quality of life RCC renal cell carcinomaSD stable diseaseSOC standard of careSubq subcutaneousSQ subcutaneousTKI tyrosine kinase inhibitorTTP time to progressionUK United KingdomUS United StatesVEGF vascular endothelial growth factorVEGFR vascular endothelial growth factor receptorVHL Von Hippel-LindauWHO World Health Organizationwks weeksw.o. withoutyr year

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