Understanding Renal Cell Carcinoma

Ronald M. Bukowski, MD

Emeritus Staff, Consultant

Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio

Overview

RCC Statistics

• US estimates for 20071

51,190 individuals diagnosed with cancer of the kidney and renal pelvis

12,890 individuals died from cancer of the kidney and renal pelvis

• 3rd most common genitourinary cancer after prostate cancer and bladder cancer2

• Median age at diagnosis: 65 years (2000-2004)1

• Median age at death: 71 years (2000-2004)1

• An estimated 240,266 US individuals with a history of kidney and renal pelvis cancer were alive in 20041

• 5-year survival has improved3

50.9% in 1975-1977; 65.7% in 1996-20031. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2008.

2. Jemal A et al. CA Cancer J Clin. 2007;57:43. 3. Ries LAG et al. SEER Cancer Statistics Review, 1975-2004;2007.

US Yearly Kidney and Renal Pelvis Cancer Incidence and Mortality

0123456789

101112131415

1975 1980 1985 1990 1995 2000Year

Rat

e P

er 1

00,0

00 I

nd

ivid

ual

s

Incidence

Mortality

Ries LAG et al. SEER Cancer Statistics Review, 1975-2004;2007.

US Kidney and Renal Pelvis Cancer in Comparison With Other Cancers

1. Jemal A et al. CA Cancer J Clin. 2007;57:43.

• Accounts for 3.5% of all cancers in the US1

7th most common cancer in men 9th most common cancer in women

Cancers in Men New Cases

% of all

Cancers in Women New Cases

% of all

Prostate 218,890 29 Breast 178,480 26

Lung & Bronchus 114,760 15 Lung & bronchus 98,620 15

Colon & rectum 79,130 10 Colon & rectum 74,630 11

Urinary bladder 50,040 7 Uterine corpus 39,080 6

NHL 34,200 4 NHL 28,990 4

Melanoma 33,910 4 Melanoma 26,030 4

Kidney & renal pelvis 31,590 4 Thyroid 25,480 4

Leukemia 24,800 3 Ovary 22,430 3

Oral cavity & pharynx 24,180 3 Kidney & renal pelvis 19,600 3

Pancreas 18,830 2 Leukemia 19,440 3

All sites 766,860 100 All sites 678,060 100

NHL = non-Hodgkins lymphoma

Historical Overview of Treatment

Surgery for Localized RCC

• Nephrectomy Radical: entire kidney removed Partial: only the cancerous portion of the kidney removed

along with a margin of healthy tissue

• Potentially curative for patients with early-stage disease (ie, stage I, II, or III)

Ongoing surveillance in these individuals is critical, as 25-50% will develop disease recurrence1

• May be used for palliation or in combination with other treatment modalities in metastatic disease

1. Janzen N et al. Urol Clin North Am. 2003;30:843.

Advanced RCC

• 20-30% of patients present with metastatic disease1

Another 25-50% of individuals treated for localized disease experience recurrence2

• Additional treatment options aside from surgery Radiotherapy

– Not an effective option Chemotherapy

– Not an effective option Immunotherapy

– Limited/some benefit Targeted therapy

– Clinical benefit; active area of research and further refinement

1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2008.2. Janzen N et al. Urol Clin North Am. 2003;30:843.

Radiotherapy

• RCC characterized as radioresistant No effect on survival when administered pre- or postsurgery

1. Finney R. Br J Urol. 1973;45:258. 2. Juusela H et al. Scand J Urol Nephrol. 1977;11:277.

3. Stein M et al. Radiother Oncol. 1992;24:41.4. Janzen N et al. Urol Clin North Am. 2003;30:843.

StudyNumber of

Patients

5-Year Survival

SurgerySurgery +

Radiotherapy

Finney 19731 100 44% 36%

Juusela et al. 19772 88 63% 47%

Stein et al. 19923 147 40% 55%

* Radiotherapy administered postsurgery in Finney & Stein studies; administered presurgery in Juusela study

• Radiotherapy may have some benefit for1

Painful bone metastases Brain metastases Painful recurrences in renal bed

Chemotherapy

• RCC has intrinsic resistance to conventional chemotherapy

Literature review of 33 chemotherapy agents tested in 1347 patients in 51 phase II trials found no justification for using any drugs as single agents based on poor response rates1

– 23 trials reported response rates of 0%– 38 trials reported response rates ≤6%

Chemotherapy ineffective even when multidrug resistance modifiers (eg, cyclosporine A, tamoxifen) are used to try and sensitize tumors to therapy1

– Response rates ≤11% seen in all 15 trials assessing this approach

• As such, chemotherapy is rarely used in RCC

1. Motzer RJ, Russo P. J Urol. 2000;163:408.

Immunotherapy

• RCC considered to be an immunogenic disease Spontaneous regression of metastatic lesions observed1

Prolonged stabilization of disease without systemic treatment is seen2,3

Tumor-infiltrating lymphocytes present at site of lesions4-6

Durable responses can be elicited with cytokine therapy7

• As such, immunotherapy has long been the principal treatment modality for managing advanced RCC8

1. de Reise W et al. Int Urol Nephrol. 1991;23:13. 2. Motzer RJ et al. N Engl J Med. 1996;335:865. 3. Whang, YE, Godley PA Curr Opin Oncol. 2003;15:213. 4. Schoof DD et al. Cell Immunol. 1993;150:114.

5. Kowalczyk D et al. Br J Urol. 1997;80:543. 6. van den Hove LE et al. Clin Ex Immunol. 1997;109:501.7. Coppin C et al. Cochrane Database Syst Rev. 2005;(1):CD001425.

8. Bukowski RM. Oncology. 1999;13:801.

Immunotherapy

• 2 immunotherapies used, either alone or in combination Recombinant human interleukin-2 (IL-2) Recombinant human interferon -2b (IFN-)

• IL-2 Stimulates growth of immune cells and activates them to destroy

tumor cells Common sides effects: flu-like symptoms, nausea, diarrhea,

hypotension, decreased urine production• IFN-

Increases antigen presentation on the surface of cancer cells, thereby increasing their susceptibility to attack by the immune system

Common side effects: flu-like symptoms, nausea, fatigue, depression

Immunotherapy

• IL-2 and IFN- have limited benefit in RCC Meta-analysis of 58 randomized trials of immunotherapy

conducted in 6880 patients with advanced RCC1

– ORR of immunotherapy vs active controls: 12.4% vs 2.4%– Mean OS with immunotherapy vs active controls: 13 vs 9.5

months– Efficacy of IFN- vs controls: mean increase in OS of 3.8

months, 44% reduction in 1-year mortality, 26% reduction in 2-year mortality

– Efficacy of high-dose IL-2 vs controls: RR as high as 23% observed, but this conferred no improvement in OS

• Toxicity of these agents often outweighs the potential benefits

1. Coppin C et al. Cochrane Database Syst Rev. 2005;(1):CD001425.OS = overall survivalRR = response rate

Unmet Treatment Needs

• Prognosis for patients with metastatic RCC is dismal, with a 5-year survival rate of 9.5%1

Surgery is generally not an option for cure RCC resistant to radiotherapy and chemotherapy Immunotherapy results in limited benefit with

marked toxicity

• Significant unmet treatment needs for patients with advanced RCC prompted research into biologic basis of renal oncogenesis to guide rational therapeutic approaches

1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2008.

Biologic Basis of Renal Oncogenesis

Angiogenesis

• Angiogenesis is a key determinant in the pathophysiology of RCC1

• RCCs are the most vascularized of all solid tumors2

1. Izawa JI, Dinney CP. CMAJ. 2001;164:662.

2. Cristofanilli M et al. Nat Rev Drug Discov. 2002;1:415.

Map of Blood Flow to a Metastatic RCC Lesion

Growth Factors

• Vascular endothelial growth factor (VEGF) is a key growth factor involved in angiogenesis1,2

VEGF mRNA expression correlates with vascularization

VEGF is overexpressed in most clear-cell RCCs

• Other growth factors that play a role in angiogenesis and oncogenesis include platelet-derived growth factor (PDGF) and epidermal growth factor (EGF)

1. Cristofanilli M et al. Nat Rev Drug Discov. 2002;1:415. 2. De Mulder PH. Ann Oncol. 2007;18:ix98.

Role of VEGF in Angiogenesis

1. Cristofanilli M et al. Nat Rev Drug Discov. 2002;1:415.

Angiogenesis

• Molecular mechanisms leading to angiogenesis1-3

Disruption of von Hippel-Lindau (VHL) gene function Disruption of mammalian target of rapamycin (mTOR)

signal transduction pathway

1. Stadler WM. Cancer. 2005;104:2323. 2. Seeliger H et al. Cancer Metastasis Rev. 2007;26:611.

3. Faivre S et al. Nat Rev Drug Discov. 2006;5:671.

VHL and RCC

• VHL is a tumor suppressor gene located on chromosome 3p25

• Loss of heterozygosity of VHL gene locus detected in ~85-95% of clear-cell RCCs1,2

• VHL genetic abnormalities present in 60-90% of patients with sporadic RCC1,2

VHL mutated in 52-71% of patients with sporadic RCC VHL silenced by hypermethylation in an additional 5-20%

• Inactivation of VHL thought to be a very early event in clear-cell RCC tumorigenesis

1. Shuin T et al. Cancer Res. 1994;54:2852. 2. Brauch H et al. Cancer Res. 2000;60:1942.3. Yao M et al. J Natl Cancer Inst. 2002;94:1569. 4. Banks RE. Cancer Res. 2006;66:2000.

Normal VHL Function

Stadler WM. Cancer. 2005;104:2323.

O2

VEC

Cul2

VHL

Rbx1

NEDD8

Elongin B Elongin C OH

HIF-1

OH

x

Degradation by

proteasome

Hypoxia Response:• Angiogenesis• Glycolysis• Erythropoiesis

• pH• Cell adhesion• ECM assembly

Ub

Mutant VHL

Stadler WM. Cancer. 2005;104:2323.

O2

VEC

Cul2

Mutant VHL

Rbx1

NEDD8

Elongin B Elongin C

Degradation by proteasome

X

XHIF-1

X

Mutant VHL mimics conditions of hypoxia

HIF-1HIF-1

mRNA transcription

VEGF PDGF TGF- EGFR

Ub

Pathways Activated by HIF-11,2

1. Stadler WM. Cancer. 2005;104:2323.2. Vignot S et al. Ann Oncol. 2005;16:525.

Endothelial/Tumor cellsPDGF VEGF EGF

Ras

RAF

MEK

Erk

Angiogenesis/Cell proliferation

PLC

RAC

P38MAPK

Cell migration

PKC

Cell proliferationCell survival

PI3K

AKT/PKB

AngiogenesisCell survival

SRC

JAK

STAT

Cell survival

Upregulation in response to HIF-1 transcription

mTOR Pathway

Seeliger H et al. Cancer Metastasis Rev. 2007;26:611.

Growth Factor

PI3K

AKT

mTOR

S6K1

Growth factors = insulin,IGF, VEGF, IL-2

PTEN

HIF-1

Protein synthesis eIF-4E

Upregulation in response to HIF-1 transcription

Rational Approaches to Treating RCC Based on Disease Biology

Targeting the Molecular Pathways of RCC Oncogenesis

Stadler WM. Cancer. 2005;104:2323.

PDGF VEGF EGF

Ras

Angiogenesis/Cell proliferation/Cell survival

RAF PI3K

bevacizumab

gefitinib, cetuximab, erlotinib, panitumumab

AKTMEK

ERK mTOR

Gene expression

rapamycin, temsirolimus, everolimus,

AP23573

CI-1040

sorafenib, ISIS-5132

Endothelial/Tumor cells

Upregulation in response to HIF-1 transcription

sorafenib, sunitinib, PTK/ZK

Clinically Available Targeted Agents for Advanced RCC

• 4 targeted agents available for advanced RCCAgent Target Efficacy in Randomized Phase III Trials

Comparison No. Treated

ORR TTP (mos)

Bevacizumab VEGFBevacizumab + IFN- vs

Placebo + IFN-1 649 31% vs 13%

10.2 vs 5.4;

P = .0001

Bevacizumab + IFN- vs IFN-2 732 26% vs 13%

8.5 vs 5.2;

P < .0001

SunitinibVEGF

receptorSunitinib vs IFN-3 750 37% vs 9%

11.1 vs 5;

P = .00001

SorafenibVEGF

receptorSorafenib vs Placebo4 903 10% vs 2%

5.5 vs 2.8;

P = .000001

Temsirolimus mTORTemsirolimus vs IFN- vs

both agents5 626 9% vs 7% vs 11%3.7 vs 1.9 (IFN-);

P = .001

1. Escudier B et al. Lancet. 2007;370:2103. 2. Rini BI et al. 2008 ASCO Genitourinary Cancers Symposium. Abstract 350.3. Motzer RJ et al. N Engl J Med. 2007;356:115. 4. Escudier B et al. N Engl J Med. 2007;356:125.

5. Hudes G et al. N EngJ Med. 2007;356:2271.

Summary

• RCC accounts for 3.5% of all cancers in US 7th most common cancer in men 9th most common cancer in women

• Incidence of RCC has steadily increased over past 30 years, likely due to increased rate of incidental detection

• Treatment of RCC Surgery potentially curative for early-stage RCC RCC resistant to chemotherapy and radiotherapy Immunotherapy produces limited benefit in advanced RCC Targeted therapy proving to be a promising approach to

treatment of advanced RCC

Summary

• Insight into biologic basis of RCC has led to rational development of targeted therapies

RCC angiogenesis driven by loss of VHL function and disruption of mTOR pathway

Key growth factors involved in angiogenesis include VEGF, PDGF, and EGF

• 4 targeted agents available for advanced RCC Bevacizumab, sunitinib, and sorafenib all target VEGF

pathway Temsirolimus targets mTOR pathway

• Landscape of RCC treatment continues to evolve with more new targeted agents on the horizon