Contemporary Management of Advanced Renal Cell Carcinoma. Epidemiology of RCC

(1)

Contemporary Management of

Advanced Renal Cell

Carcinoma

A.

A. Karim Kader MD PhD FRCSC

Karim Kader MD PhD FRCSC

Clinical Fellow in Urologic Oncology

The University of Texas

M. D. Anderson Cancer Center

1.

1. JemalJemalAetAetal. Cancer statistics, 2006. CA Cancer J al. Cancer statistics, 2006. CA Cancer J ClinClin2006;56:1062006;56:106--30.30.

2.

2. PantuckPantuckAJ et al J. AJ et al J. UrolUrol2001;166:16112001;166:1611--23.23.

Epidemiology of RCC

•

• ~39,000 new cases of kidney cancer in the United States~39,000 new cases of kidney cancer in the United States11 •

• ~13,000 patients will die each year~13,000 patients will die each year11 •

• Since 1950 there has been a 126% Since 1950 there has been a 126% increaseincreasein incidence and a in incidence and a 36.5%

36.5% increaseincreasein annual mortalityin annual mortality22 •

• Risk FactorsRisk Factors

–

– 2:1 male to female ratio2:1 male to female ratio –

– VHLVHL –

– Chronic dialysis/cystsChronic dialysis/cysts –

(2)

Diagnosis of RCC

•

• Presenting symptoms

Presenting symptoms

–

–Classic diagnostic triad (hematuria, pain, palpable Classic diagnostic triad (hematuria, pain, palpable mass) uncommon today

mass) uncommon today

•

• RCC is a frequent incidental discovery via

RCC is a frequent incidental discovery via

ultrasonography

and CT scan

•

• 25%

25%

–

30% of patients have metastases at initial

presentation

11

1. Godley PA et al

1. Godley PA et al CurrCurrOpinOpinOncolOncol2001;13:1992001;13:199--203.203.

Incidental Detection

Jayson

JaysonM et al Urology 1998;51:203M et al Urology 1998;51:203--5.5.

(3)

Trends in Survival With RCC

Pantuck

PantuckAJ et al J. AJ et al J. UrolUrol2001;166:16112001;166:1611--23.23.

Histological Classification

of Epithelial Neoplasms of the Kidney

Clear cell

Clear cell Papillary type 1Papillary type 1 Papillary type 2 Papillary type 2 ChromophobeChromophobe OncocytomaOncocytoma

Type Type Associated

Associated

mutations

mutations VHL VHL cc--Met Met FHFH BHDBHD BHDBHD

Locus

Locus 3p253p25 7q317q31 1q421q42 17p1117p11 17p1117p11

BHD =

BHD = BirtBirt--HoggHogg--DubDubéé; FH = ; FH = fumaratefumaratehydratase; VHL = von Hippelhydratase; VHL = von Hippel--Lindau.Lindau.

1.

1. Modified from Modified from LinehanLinehanWM, et al: WM, et al: J J UrolUrol170:2163170:2163--2172, 20032172, 2003

2.

2. Kim WY: Kim WY: J J ClinClinOncolOncol22:499122:4991--5004, 20045004, 2004

Incidence (%)

(4)

Clinical Staging and Prognosis in RCC: American

Joint Committee (AJCC) on Cancer Criteria

Modified from Cohen HT, McGovern FJ:

Modified from Cohen HT, McGovern FJ: N N EnglEnglJ MedJ Med353:2477353:2477--2490, 20052490, 2005

Stage I (10-15%)

Tumor ≤≤≤≤7 cm (T1) in greatest dimension and limited to kidney; 5-year survival, ~95%

Stage II (40%)

Tumor >7 cm (T2) in greatest dimension and limited to kidney; 5-year survival, ~88%

Stage III (15-20%)

Tumor in major veins or adrenal gland, tumor within Gerota’s fascia (T3), or 1 regional lymph node involved (N1); 5-year survival, ~59%

Stage IV (25-35%)

Tumor beyond Gerota’s (T4) or >1

regional lymph node involved (N2); distant metastases (M1), 5-year survival, ~20%

Lymph nodes Inferior vena cava Aorta Gerota’s fascia Adrenal gland Kidney

Impact of Stage on Outcome

• An MDACC experience suggested that

25% of pT2 patients went on to develop

metastases

Levy DA et al. J

(5)

Identifying the High Risk Patient

• Histologic subtype

–No difference between Clear Cell, Papillary and Chromophobe1

• Molecular markers

–Early in the development Ki-67, p53 and CA IX have shown some promise

• Nomograms

–Several published from UCLA-MSKCC-Mayo all with fairly good predictive capacity2

1.

1. PatardPatardJJ--J et al. J J et al. J ClinClinOncolOncol2005;23:27632005;23:2763--71.71.

2.

2. CindoloCindoloL Cancer 2005;104:1362L Cancer 2005;104:1362--71.71.

Surgical Management of

Advanced RCC

• The only treatment modality to have a

meaningful impact on advanced disease

• No significant changes in staging and

outcome since Robson’s description 40

years ago

• Surgery alone fails in approximately 30%

of patients

Robson CJJ

(6)

Robson Staging & Outcomes

Robson CJJ

Robson CJJ UrolUrol1969;101:2971969;101:297--301.301.

Survival 0 38 67 60 10 year 5 year 3 year Description Stage 11 25 A – Adjacent organs B – Distant Mets 4 42 59 A – RV or IVC B – Lymphatic

C – Vascular & Lymphatic 3

64 67

Perirenal fat involvement but confined to Gerota’s 2

66 73

Confined to kidney 1

Impact of Mets on Overall Survival

in RCC Patients

Pantuck

Pantuck, et al: , et al: J J UrolUrol20032003

Survival threatened by lymph node and distant metastases Survival threatened by lymph node and distant metastases

(7)

Effect of LND on Outcome with

Localized Disease

• Despite the poor outcomes seen with patients with TxN1-2M0 disease, the impact of a LND is controversial

• There is a prospective RCT being run by the EORTC looking at the effect of a standardized LND in 772 patients

• 5 year data did not show any impact on progression or survival

• Only 11 patients had LN metastases

Blom

BlomJH et al JH et al EurEurUrolUrol1999;36:5701999;36:570--5.5.

Metastatic RCC

•

• 25%

25%

-

30% present with metastases

•

• 30% with localized RCC develop

30% with localized RCC develop

metastasis

•

(8)

Distribution of Metastasis

Metastatic

Metastatic Solitary/SingleSolitary/Single MultipleMultiple

Site

Site OrganOrgan SitesSites

Lung Lung 3030 7575 Lymph Nodes Lymph Nodes 2424 6464 Bone Bone 1515 4343 Liver Liver 55 4141 Brain Brain 88 1111 Adrenal (

Adrenal (ipsilatipsilat)) 33 1919 Adrenal (contra)

Adrenal (contra) <1<1 1212

Saitoh

SaitohH et al: H et al: J J UrolUrol127:1092, 1982127:1092, 1982

Multidisciplinary Approach to

Metastatic

RCC is Optimal

0 12 24 36 48 60 72 84 96 Nx + IMT Nx + IMT 75 100 50 25 0 Months % S u rv iv a l NX NX P<0.05 IMT IMT

UCLA 1989-1999

Pantuck

(9)

Rationale for Cytoreductive

Nephrectomy

•

• PalliationPalliation --PainPain

-- BleedingBleeding

-- ParaneoplasticParaneoplasticsyndromesyndrome

•

• Improve performance statusImprove performance status

•

• Primary tumor rarely responds to systemic therapyPrimary tumor rarely responds to systemic therapy

•

• Enhance response to systemic therapyEnhance response to systemic therapy

•

• Improved survivalImproved survival

•

• Spontaneous regressionSpontaneous regression

• Surgical morbidity/mortality significant

• Spend majority of time left recovering

from surgery

• Delays initiation of systemic therapy to

treat metastatic disease

• Significant disease progression during

post-operative recovery period may

preclude systemic therapy

Argument Against

Cytoreductive Nephrectomy

(10)

Cytoreductive Nephrectomy:

MDACC

No. Patients No. Patients 6666 Received Rx Postop Received Rx Postop 54 (82%)54 (82%) Resected to NED or Refused

Resected to NED or Refused 9 (13.5%)9 (13.5%) Postop

Postop Death or ProgressionDeath or Progression 3 (4.5%)3 (4.5%) 95% of patients eligible for or received systemic

95% of patients eligible for or received systemic

therapy at a median of 40 days post

therapy at a median of 40 days post--nephrectomynephrectomy

Levy, et al:

Levy, et al: J J UrolUrol19981998

1. Modified from

1. Modified from FlaniganFlaniganRC, et al: RC, et al: N N EnglEnglJ Med J Med 345:1655345:1655--1659, 20011659, 2001

2. Modified from

2. Modified from MickischMickischGHJ, et al: GHJ, et al: LancetLancet358:966358:966--970, 2001970, 2001

Cytoreductive Nephrectomy for

Patients with Metastatic RCC: Randomized Trials

0 0 20 20 40 40 60 60 80 80 100 100 S u rv iv a l S u rv iv a l(% ) (% ) Time (months) Time (months) 0 0 2424 4848 7272 9696 8.1 8.1 IFN (n=121) IFN (n=121) 11.1 11.1 IFN + nephrectomy IFN + nephrectomy (n=120) (n=120) Median Median Survival Survival (months) (months) SWOG SWOG P P = .05= .05 0 0 1212 24 3636 0 0 20 20 40 40 60 60 80 80 100 100 Time (months) Time (months) S u rv iv a l (% ) S u rv iv a l (% ) 7.0 7.0 IFN (n=43) IFN (n=43) 17.0 17.0 IFN + nephrectomy (n=42) IFN + nephrectomy (n=42) Median Median Survival Survival (months) (months) EORTC EORTC P P = .03= .03

(11)

IL2 + Nephrectomy in Metastatic RCC

. 0 20 40 60 80 100 0 24 48 72 96 Months Nx + IL-2 Nx + IFN IFN Pantuck

PantuckAJ et al N AJ et al N EnglEnglJ Med 2001;345:1711J Med 2001;345:1711--2.2.

P<0.05 S u rv iv a l Retrospective Retrospective

Laparoscopic Cytoreductive Nephrectomy:

The M. D. Anderson Experience

•

• From 2001 From 2001 ––2005, 38 of 191 (2005, 38 of 191 (∼∼∼∼∼∼∼∼20%) cytoreductive 20%) cytoreductive

nephrectomies

nephrectomiesperformed performed laparoscopicallylaparoscopically •

• Operative indicesOperative indices •

• Median OR time 188 minutesMedian OR time 188 minutes

•

• Median estimated blood loss 175 mlMedian estimated blood loss 175 ml

•

• 3 pts (8%) electively converted3 pts (8%) electively converted

•

• 2 pts (5%) major complications 2 pts (5%) major complications

•

• No deathsNo deaths

•

• Length of stay 3.5 daysLength of stay 3.5 days

•

• 97% were eligible for or received systemic therapy 97% were eligible for or received systemic therapy

at a median of 41 days

at a median of 41 days •

• Median survival 18 monthsMedian survival 18 months

Matin

(12)

MDACC Experience with

Cytoreductive Nephrectomy in

the Elderly

• Given the increasing number of elderly

patients aged 75 years and older

presenting to urologists with metastatic

RCC and the difficult management

decisions, we sought to determine if

outcomes were different in elderly

patients as compared to a younger cohort

Kader et al J.

Kader et al J. UrolUrolin pressin press

Patient & Perioperative

Characteristics

0.18 6.0 (1-56) 6.0 (2-14) Length of Stay (d) 0.09 36.0 (7-152) 30.5 (10-97) Time to Therapy (d) 0.61 13.7 (.3-111.3) 16.6 (0-115) Survival Time (m) 0.29 219 (57.6) 157 (41.3) 4 (1.0) 12 (50.0) 11 (45.8) 1 (4.2) ECOG PS - 0 - 1 - 2 <0.01 57 (14-74) 77.5 (75-84) Age P Value Younger N=380 Elderly N=24 Kader et al J.

(13)

Survival Curves Comparing

Younger to Older Cytoreductive

Nephrectomy Patients

0 25 50 75 100 0 50 100 150 Time (months)

≥75 years old < 75 years old

% S u rv iv a l P = 0.89 by log-rank Kader et al J.

Kader et al J. UrolUrolin pressin press

RPLND In Patients With Metastatic

Conventional RCC: MDACC Experience

1990 – 2005 MDACC 352 T_anyN₀M₁ 77 T_anyN_1-2M₁

*All Conventional Histology Median DSS

N₀M₁: 24.6 mos N_1-2M₁(resected): 16.3* mos

N_1-2M₁(not resected): 4.9^ mos (*, ^ p < 0.00001)

(14)

RPLND In N+M1 Conventional

RCC

Time in months 40 30 20 10 0 P ro b a b ili ty o f S u rv iv a l 1.0 .8 .6 .4 .2 0.0 Time in months 40 30 20 10 0 P ro b a b ili ty o f S u rv iv a l 1.0 .8 .6 .4 .2 0.0

Absence of Sarcomatoid Histology p=0.0001

Presence of Sarcomatoid Histology p=0.708 Resected Not resected Resected Not resected Brassell

BrassellS, et al., 2006 submittedS, et al., 2006 submitted

*Risk factors: no prior nephrectomy, KPS <80, low HGB, high corr

*Risk factors: no prior nephrectomy, KPS <80, low HGB, high corrected calcium, high LDH.ected calcium, high LDH. HGB=hemoglobin; KPS=Karnofsky performance status; LDH=lactate de

HGB=hemoglobin; KPS=Karnofsky performance status; LDH=lactate dehydrogenase.hydrogenase. Motzer RJ, et al:

Motzer RJ, et al: J J ClinClinOncolOncol17:253017:2530--2540, 19992540, 1999

Systemic Therapy: Memorial Sloan

-

Kettering

Risk

-

Factor Model for Metastatic RCC

0 risk factors (164 patients, 30 alive) 0 risk factors (164 patients, 30 alive) 1 or 2 risk factors (348 patients, 23 alive) 1 or 2 risk factors (348 patients, 23 alive) 3, 4, or 5 risk factors (144 patients, 1 alive) 3, 4, or 5 risk factors (144 patients, 1 alive)

Years following systemic therapy

S u rv iv a l (% ) S u rv iv a l (% ) 100 100 80 80 60 60 40 40 20 20 0 0 0 0 11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 1515 1616 1717

Greater number of risk factors is associated with worse prognosi

(15)

Cytoreductive Nephrectomy:

Summary

Patient Selection Is Critical To Success:

•

• Favorable performance status (0Favorable performance status (0--1)1)

•

• Future systemic therapy plannedFuture systemic therapy planned

•

• Resection of all intraResection of all intra--abdominal diseaseabdominal disease

Surgical Therapy of

Metastatic Disease

•

• Role of surgery controversialRole of surgery controversial

•

• Is morbidity and mortality acceptable?Is morbidity and mortality acceptable?

•

• Response rate to systemic therapy is improving, Response rate to systemic therapy is improving, stimulating the interest in the

stimulating the interest in the neoadjuvantneoadjuvant or or adjuvant approach

(16)

Nephrectomy and Resection

of Solitary Metastasis

Study

Study PatientsPatients 55--yr Survivalyr Survival

Middleton, 1967

Middleton, 1967 5959 34%34%

Tolia

Tolia & Whitmore, 1975& Whitmore, 1975** 1919 35%35% Klugo

Klugo et al, 1977et al, 1977 1010 50%50% O

O’’Dea et al, 1978Dea et al, 1978 4444 16%16% Golimbu

Golimbu et al, 1986et al, 1986 2121 33%33% Kavolius

Kavolius et al, 1998et al, 1998 141141 44%44%

Pulmonary

Metastectomy

N N 5 yr Survival5 yr Survival Wilkins et al, 1961 Wilkins et al, 1961 1616 31%31% Skinner et al, 1971 Skinner et al, 1971 2020 25%25% DeKernion

DeKernionet al, 1978et al, 1978 1212 25%25% Katzenstein et al, 1978

Katzenstein et al, 1978 1616 38 mo mean38 mo mean Mountain et al, 1978

Mountain et al, 1978 1616 50%50% Morrow et al, 1980

Morrow et al, 1980 2525 24%24%

Jett et al, 1983

Jett et al, 1983 4444 33 mo mean33 mo mean Tanguey

Tangueyet al, 1996et al, 1996 5151 61% alive at 43 mo61% alive at 43 mo Piltz

Piltzet al, 2002*et al, 2002* 105105 43 mo median43 mo median

* Improved survival associated with P0 (p = 0.002) and N0 status

(17)

Resection of Metastatic RCC

•

• 278 patients at MSKCC278 patients at MSKCC

•

• Quality of resectionQuality of resection

–

– Complete vs incomplete: 44% vs 14% 5Complete vs incomplete: 44% vs 14% 5--year survivalyear survival

•

• Favorable featuresFavorable features

–

–DFI >12 vs DFI >12 vs ≤≤≤≤≤≤≤≤12 months: 55% vs 9%, p < 0.000112 months: 55% vs 9%, p < 0.0001

–

–Solitary vs multiple sites: 54% vs 29%, p < 0.001Solitary vs multiple sites: 54% vs 29%, p < 0.001

–

–Age < 60 years: 49% vs 35%, p < 0.05Age < 60 years: 49% vs 35%, p < 0.05

Kavolius

KavoliusJP et al JP et al J J ClinClinOncolOncol16:2261, 199816:2261, 1998

Surgical Management of Metastatic RCC

•

• Cytoreductive nephrectomy Cytoreductive nephrectomy

–

– Improves survival of selected patients treated in a Improves survival of selected patients treated in a multidisciplinary fashion

multidisciplinary fashion

•

• Resection of metastatic diseaseResection of metastatic disease

–

– Possible improved survival especially with single lung Possible improved survival especially with single lung mets

mets

•

• Combination therapy with “Combination therapy with “newernewer””agents may agents may improve results

improve results

•

• NeoadjuvantNeoadjuvant strategy may identify candidates for strategy may identify candidates for surgical consolidation

(18)

Surgical Management of Metastatic

RCC

Approach in a state of evolution

Systemic Therapy of Advanced RCC

•

• RCC is generally resistant to standard RCC is generally resistant to standard chemotherapy (response <10%)

chemotherapy (response <10%)11

•

• Cytokine therapy (IL-Cytokine therapy (IL-2 or IFN2 or IFN--αααααααα) became the ) became the standard of care for

standard of care for metastaticmetastatic RCC with RCC with response rates of approximately 15% response rates of approximately 15%

•

• However:However:

–

– only a minority of patients experience clinical benefitonly a minority of patients experience clinical benefit –

– adverse events can be problematicadverse events can be problematic –

– secondsecond--line treatment with alternative cytokines line treatment with alternative cytokines produces responses in <5% of patients

produces responses in <5% of patients

1.

(19)

Systemic Therapy of

Advanced RCC

A) Hormone Therapy - Medroxyprogesterone B) Immunologic Therapy

Cytokine Therapy – IL2/IFN Adoptive Immunotherapy – LAK

Tumor Vaccines - Oncophage® _HSP-96 C) Chemotherapy

D) Anti-Angiogenic Therapy - Thalidomide

E) Targeted therapy - Small Molecule Kinase Inhibitors - Monoclonal Antibody Therapy

Targeted Therapy

•

• VHL pathway

VHL pathway

–

–inactivated in over 80% of sporadic clear cell inactivated in over 80% of sporadic clear cell RCC

RCC

•

• Altered pathway results in overexpression of

Altered pathway results in overexpression of

hypoxia

-

inducible genes

•

• increasedincreasedTGF, VEGF and PDGF, stimulating TGF, VEGF and PDGF, stimulating angiogenesis and cellular proliferation

angiogenesis and cellular proliferation

•

(20)

HIF

-1

-

1 α

α

Pathway

NORMAL O₂

HIF-1αααα

OH

Ubiquitin Mediated Degradation

VHL _{E3 Ligase}

HIF-1αααα

OH

Clear Cell RCC Targeted Therapy

VHL MUTATION

Transcriptional Activation of HIF Target Genes No HIF Degradation CAIX VEGF VEGFR PDGF PDGFR TGF EGFR Bevacisumab Sunitinib Sorafenib Erlotinib Gefitinib Cetuximab G250 HIF-1αααα OH VHL E3 Ligase LOW O₂ HIF-1αααα OH

(21)

100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 0 0 66 1212 1818 2424 3030 3636 Time (months) Time (months) P a ti e n ts f re e P a ti e n ts f re e o f tu m o r p ro g re s s io n ( % ) o f tu m o r p ro g re s s io n ( % )

Bevacizumab in Metastatic RCC:

Progression

Progression-

-Free Survival

Free Survival

Adapted from Yang JC, et al:

Adapted from Yang JC, et al: N N EnglEnglJ MedJ Med349:427349:427--434, 2003434, 2003

3.0 (

3.0 (PP<.041)<.041)

Low

Low--dose bevacizumab dose bevacizumab (3 mg/kg) (3 mg/kg)(n=37)(n=37) 2.5 2.5 Placebo (n=40) Placebo (n=40) 4.8 ( 4.8 (PP<.001)<.001) High

High--dose dose bevacizumab bevacizumab(10mg/kg) (10mg/kg) (n=39) (n=39) Median PFS Median PFS (months) (months)

Multitargeted Approaches in

Metastatic RCC: Sunitinib (SU11248)

•

• SmallSmall--molecule receptor tyrosine kinase inhibitormolecule receptor tyrosine kinase inhibitor11

•

• Inhibits all Inhibits all VEGFRsVEGFRs, PDGFR, PDGFR--αααααααα//ββββββββ, and c, and c--KITKIT11

•

• Oral administrationOral administration11

•

• Both antitumor and antiangiogenic activityBoth antitumor and antiangiogenic activity11

•

• FDA approved January 26, 2006 for treatment of advanced RCCFDA approved January 26, 2006 for treatment of advanced RCC22

10 10 PDGFR PDGFR 15 15 VEGFR VEGFR--11 10 10 VEGFR VEGFR--22 10 10 c c--KitKit 880 880 FGFR FGFR--11 8900 8900 EGFR EGFR IC IC₅₀50nMnM Receptors Receptors F F H H33CC O O O O CH CH33 CH CH33 CH CH33 N N H H N N N N H H N N H H

(22)

Front Line Therapy: Phase III

Trial of

Sunitinib

vs

IFN

•

• Randomized, openRandomized, open--label, international multicenter triallabel, international multicenter trial

•

• Primary end point: progressionPrimary end point: progression--free survivalfree survival •

• Secondary end points: overall survival, toxicity, and Secondary end points: overall survival, toxicity, and

response rate

response rate •

• Trial completed accrual July 2005Trial completed accrual July 2005 1:1

Randomization N = 730

Previously untreated patients Only clear-cell histology

Sunitinib: 50 mg administered daily (Schedule 4/2)

IFN-αααα: (9M IU) administered TIW

Progression

-

Free Survival

No. at Risk

No. at Risk SunitinibSunitinib:: 235235 9090 3232 22

No. at Risk IFN

No. at Risk IFN--αααααααα:: 152152 4242 1818 00

0 0 11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 Time (Months) Time (Months) 0 0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 P ro g re s s io n F re e S u rv iv a l P ro b a b il it y P ro g re s s io n F re e S u rv iv a l P ro b a b il it y SunitinibSunitinib Median: 11 months Median: 11 months (95% CI: 10 (95% CI: 10––12)12) IFN IFN--αααααααα Median: 5 months Median: 5 months (95% CI: 4 (95% CI: 4––6)6) Hazard Ratio = 0.415 Hazard Ratio = 0.415 (95% CI: 0.320 (95% CI: 0.320––0.539)0.539) P P<0.000001<0.000001

(Independent Central Review)

(23)

Motzer RJ, et al:

Motzer RJ, et al: Paper presented at ASCO; May 13Paper presented at ASCO; May 13--17, 2005; Orlando, FL17, 2005; Orlando, FL

Sunitinib in

Metastatic

RCC

•

• Approved for treatment of advanced RCC

Approved for treatment of advanced RCC

•

• Sunitinib is more effective than IFN for the

Sunitinib is more effective than IFN for the

first line treatment of metastatic RCC

•

• Most adverse events were mild to

Most adverse events were mild to

moderate

•

• Grade 3/4 toxicities were generally

Grade 3/4 toxicities were generally

managed with dose interruption or

reduction

Sorafenib

Sorafenib: Mechanism of Action

: Mechanism of Action

•

• SmallSmall--molecule receptor tyrosine kinase inhibitormolecule receptor tyrosine kinase inhibitor11 •

• Inhibits Inhibits VEGFRVEGFR--22, FLT, FLT--3, c3, c--KIT, PDGFRKIT, PDGFR--ββββββββ

and

and RafRafkinaseskinases11 •

• Oral administrationOral administration11 •

• FDA approved December 20, 2005, for treatment FDA approved December 20, 2005, for treatment of advanced RCC of advanced RCC22 90 90±±1515 VEGFR VEGFR--22 6 6±±33 Raf Raf--11 58 58±±2020 Flt Flt--33 68 68±±2121 c c--KITKIT 580 580±±100100 FGFR1 FGFR1 >10,000 >10,000 EGFR EGFR IC IC₅₀₅₀nMnM±±SDSD Receptors Receptors 1. Wilhelm SM, et al:

1. Wilhelm SM, et al: Cancer Cancer ResRes10:709910:7099--7109, 20047109, 2004

2. 2. http://www.fda.gov/bbs/topics/NEWS/2005/NEW01282.html. http://www.fda.gov/bbs/topics/NEWS/2005/NEW01282.html. N N H H N N H H O O O O O O N N CI CI CF CF₃₃ NH NH CH CH₃₃

(24)

n = 451

n = 452

Sorafenib

in Metastatic RCC:

TARGET Phase III Study Design

•

• Primary end point: overall survivalPrimary end point: overall survival •

• Secondary end points include response rates, Secondary end points include response rates, progression free survival, safety, health

progression free survival, safety, health--related related quality of life quality of life Sorafenib Sorafenib (400 mg BID) (400 mg BID) Placebo Placebo R R A A N N D D O O M M I I Z Z A A T T I I O O N N Unresectable and/or Unresectable and/or metastatic RCC metastatic RCC Clear

Clear--cell histologycell histology 1 prior systemic therapy

1 prior systemic therapy

in last 8 months in last 8 months n = 903* n = 903* ECOG PS 0/1 ECOG PS 0/1

*Out of 905 patients randomized by February 15, 2005 *Out of 905 patients randomized by February 15, 2005

Escudier

EscudierB, et al: Paper presented at The European Cancer B, et al: Paper presented at The European Cancer

Conference; October 30

Conference; October 30--November 3, 2005; Paris, FranceNovember 3, 2005; Paris, France

Sorafenib

in Metastatic RCC:

TARGET Phase III Overall Survival

Time from randomization (months) Time from randomization (months)

0 0 22 44 66 88 1010 1212 1414 1616 1818 2020 0 0 0.25 0.25 0.50 0.50 0.75 0.75 1.00 1.00 O v e ra ll s u rv iv a l O v e ra ll s u rv iv a l Censored observation Censored observation Placebo Placebo Sorafenib Sorafenib Not reached Not reached 14.7 14.7 Sorafenib Sorafenib(n = 451)(n = 451) Placebo (n = 452) Placebo (n = 452) 0.72 0.72 Hazard ratio (S/P) Hazard ratio (S/P) P P = .018= .018 Median (months) Median (months) OS OS Escudier

EscudierB, et al: Paper presented at The European Cancer B, et al: Paper presented at The European Cancer Conference; October 30

(25)

Effect of

Effect of Sorafenib

Sorafenib

Pre Treatment – Biopsy Showed High Grade Conventional RCC Post Treatment – Final pathology extensive necrosis with dense inflammatory infiltrate

57 yo man with a T1 G4 Conventional RCC metastatic to LN and bone treated with neoadjuvant sorafenib followed by lap cytoreductive nephrectomy. 36 retroperitoneal lymph nodes

harvested at the time of dissection

Sorafenib

in Metastatic RCC: Summary

•

• Approved for treatment of advanced RCC

Approved for treatment of advanced RCC

•

• Most frequent adverse events leading to

Most frequent adverse events leading to

dose reduction (12%) are hand

-

foot

syndrome and diarrhea

•

• Improved overall survival in patients

Improved overall survival in patients

compared with placebo in randomized

Phase III study

(26)

Main

Toxicities

+ + +++ +++ + + Hypertension Hypertension 0 0 +(

+(colorcolor change)change) + (

+ (alopeciaalopecia)) Hair

Hair changeschanges

0 0 + + +++ +++ Hand

Hand--footfoot

0 0 + + ++ ++ Skin Skin + + +++ +++ + + Stomatitis Stomatitis 0 0 ++ ++ +++ +++ Diarrhea Diarrhea + + +++ +++ + + Fatigue Fatigue Avastin Avastin Sunitinib Sunitinib Sorafenib Sorafenib Toxicity Toxicity

mTOR Pathway

PI PI--3 3 KinaseKinase A Aktkt

mTOR

PTEN PTEN S6K S6K 4EBP14EBP1 HIF

HIF--11αααααααα, HIF, HIF--22αααααααα

overexpression overexpression PTEN Loss Translation Translation PI-3K/AKT Activation cMyc cMyc overexpression overexpression extracellular extracellular membrane membrane Cyclin D1 Cyclin D1 overexpression overexpression Temsirolimu s Temsirolimu s Temsirolimu s 52 Growth

(27)

Phase III Trial of CCI

Phase III Trial of CCI-

-779

779 in Metastatic RCC

in Metastatic RCC

First-line therapy in metastatic RCC N=600 (200 per arm) Sites ~165 Mostly clear cell

Primary end point: Survival Primary end point: Survival

R A N D O M I Z A T I O N CCI-779 25 mg IV q Wk CCI-779 15 mg IV q Wk + IFN-αααα6M IU SC TIW IFN-ααααescalating as tolerated

to 18M IU SC TIW

*Stage 4 or recurrent disease *Stage 4 or recurrent disease

Available at:

Available at: http://www.clinicalhttp://www.clinicaltrial.gov/ct/show/NCT00065468?order=1trial.gov/ct/show/NCT00065468?order=1

CCI

CCI-

-779 vs. IFN: Overall Survival

779 vs. IFN: Overall Survival

Arm 3: IFN + Temsirolimus

Arm 2: Temsirolimus

Arm 1: IFN

Time from Randomization, Months

P ro b a b il it y o f S u rv iv a l 0.6912 0.0069 Log-Rank p 8.4 10.9 7.3

Median overall survival

TEMSR + IFN Arm 3 TEMSR Arm 2 IFN Arm 1

(28)

CCI

-

779 in Metastatic RCC: Summary

•

• Most frequent adverse events leading to dose

Most frequent adverse events leading to dose

reduction rash,

mucositis

, nausea, malaise

•

(29)

Adjuvant Therapy for Locally Advanced

Renal Cell Carcinoma: E2805

Locally Advanced RCC Locally Advanced RCC 1. T2N0M0 Grade 3 1. T2N0M0 Grade 3--44 2. T3a 2. T3a--cN0M0cN0M0 3. T4N0M0 3. T4N0M0 4. TanyN1 4. TanyN1--2M02M0 Surgery to remove Surgery to remove

all visible disease

R R A A N N D D O O M M I I Z Z E E Placebo Placebo Pathology Pathology confirmed confirmed Sunitinib Sunitinib50mg50mg

for one year for one year 4wks on/2wks off 4wks on/2wks off

All RCC

All RCC histologieshistologiesincludedincluded

Sorafenib

Sorafenib400mg BID400mg BID for one year for one year

1332 patients (444/arm)

--80% power to detect 33% improvement in RFS80% power to detect 33% improvement in RFS

Future Directions

•

• Continued early detection

Continued early detection

•

• Better identification of high risk patients

Better identification of high risk patients

and thus target for

neoadjuvant

and

adjuvant therapy

•

• Continued development of

Continued development of

targetted

therapies

•

• Evaluation of these agents in the adjuvant

Evaluation of these agents in the adjuvant

setting, in combination strategies, and as

front

(30)

Advanced RCC Summary

•

• Multidisciplinary approach for locally

Multidisciplinary approach for locally

advanced disease under evaluation

•

• Response rates to cytokine and

Response rates to cytokine and

chemotherapy in metastatic setting low

•

• Paradigm shift in the therapy of metastatic

Paradigm shift in the therapy of metastatic

RCC

–

targeted therapy based upon biology

2000 2016

Potential Improved Survival in

the Future

Molecular Profiling & Targeted Therapy

(31)

Acknowledgements

• RCC Team

–Christopher Wood –Surena Matin –David Swanson

• Colin Dinney

• Xifeng Wu

Trends of Incidence Over Time

Chow W

Chow W--H et al. JAMA 1999;281:1628H et al. JAMA 1999;281:1628--31.31.

Age-Adjusted (1970 US Standard) Incidence Rates Per 100,000 Person-Years for Renal Cell Carcinoma by Sex, Race, and Tumor Stage at Diagnosis--SEER, 1975-1977 to 1993-1995

Localized Regional Distant Unstaged white men black men

(32)

1.

1. MotzerMotzerRJ, et al: RJ, et al: N N EnglEnglJ MedJ Med335:865335:865--870, 1996870, 1996

2. National Comprehensive Cancer Network:

2. National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology: Kidney Clinical Practice Guidelines in Oncology: Kidney Cancer: Version 1, 2006

Cancer: Version 1, 2006; Jenkintown, PA.; Jenkintown, PA.

Surgical Management of RCC

•

• Surgery is the primary approach for Stage 1 and 2 RCCSurgery is the primary approach for Stage 1 and 2 RCC11

–

– Partial vs radical nephrectomyPartial vs radical nephrectomy –

– Laparoscopic vs open surgeryLaparoscopic vs open surgery –

– Minimally invasive approaches or expectant managementMinimally invasive approaches or expectant management

•

• Surgical resection of locally advanced RCC (Stage 3) is associatSurgical resection of locally advanced RCC (Stage 3) is associated ed

with high recurrence

with high recurrence11

–

– 20%–20%–30% recur post30% recur post--radical nephrectomy, usually within 3 yearsradical nephrectomy, usually within 3 years –

– Adjuvant therapy has not been proven to be effective in reducingAdjuvant therapy has not been proven to be effective in reducing risk of relapse

risk of relapse

•

• Surgical resection of Stage 4 RCC is a deSurgical resection of Stage 4 RCC is a de--bulking procedure, but bulking procedure, but

improves survival in select patients

MDACC Experience with

Cytoreductive Nephrectomy in

the Elderly

• Western society is aging

• Furthermore, life expectancy is increasing

• The incidence of RCC increases with age and peaks in those aged 75 to 85

• There is an increase in presentation of advanced RCC

• Elderly patients with advanced malignancy are often not offered standard therapy

(33)

Nephrectomy and Resection of

Solitary Metastases

Site Resected

Site Resected N N 55--year Survival Rateyear Survival Rate Lung Lung 5050 56%56% Gland Gland 1111 63%63% Skin Skin 1010 38%38% Visceral Visceral 2323 30%30% Appendicular bone Appendicular bone 2727 18%18% Brain Brain 1111 18%18% Bone Bone 55 40%40%