Individualizing Therapy For Patients With Advanced Rcc

Individualizing Therapy for Patients With Advanced RCC

Robert A. Figlin, MDArthur and Rosalie Kaplan Chair in Oncology

Professor and Chair, Medical Oncology and Therapeutics Research

City of Hope National Medical Center and Beckman Research Institute

Associate Director for Clinical ResearchCity of Hope Comprehensive Cancer Center

Duarte, California

Overview

RCC Statistics

• US estimates for 20081

54,390 individuals will be diagnosed with cancer of the kidney and renal pelvis

– Median age at diagnosis: 65 years 13.010 individuals will die from cancer of the kidney and

renal pelvis– Median age at death: 71 years

• Accounts for 3.5% of all cancers in the US2

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

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

1. 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. 2008;58:71.

Stage Distribution

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

Disease Distribution

At Diagnosis5-Year Relative Survival Rate

Localized 56% 89.9%

Regional 19% 61.3%

Distant 20% 9.9%

Unknown 5% 35.5%

Advanced RCC

• 20-30% of patients present with metastatic disease1

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

• Prognosis for patients with metastatic RCC is dismal, with a 5-year survival rate of 9.9%1

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

• Prompted need for rational therapeutic approaches based on disease biology

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.

Biologic Basis of Renal Oncogenesis

Subtypes1-3

Subtype Prevalence Genetic Defect Microscopic Features

Clear cell carcinoma 75–85% VHL

Chromophilic (papillary) carcinomas

10–15% c-Met, fumarate hydratase

Chromophobic carcinomas

5–10% BHD

Oncocytomas Uncommon (≤2%) BHD

Collecting duct tumors (a.k.a. Bellini’s duct)

Very rare

1. Thoenes W et al. Path Res Pract. 1986;181:125. 2. Störkel S, van den Berg E. World J Urol. 1995;13:153.3. Linehan WM et al. J Urol. 2003;170:2163.

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.VHL = von Hippel-Lindau

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


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


Targeting the Molecular Pathways of RCC Oncogenesis

Proposed CME slide


PDGF VEGF EGF

Ras

Angiogenesis/Cell proliferation/Cell survival

RAF PI3K

bevacizumab

gefitinib, cetuximab, erlotinib, panitimumab

AKTMEK

ERK mTOR

Gene expression

rapamycin, temsirolimus, everolimus,

AP23573

CI-1040

sorafenib, ISIS-5132

Endothelial/Tumor cells


sorafenib, sunitinib, PTK/ZK

RCC Prognostic Factors and Risk Stratification

Rationale for RCC Staging

• Predict tumor behavior Patient prognosis

• Stratify patients into risk categories Predict disease recurrence and cancer-related death

• Select treatment approach Choose therapy based on molecular markers expressed by

tumor Predict response to therapy Minimize treatment exposure to avoid unnecessary toxicity

• Standardize inclusion criteria for clinical trials

Leppert JT et al. BJU Int. 2007;99:1208.

Determinants of RCC Prognosis

Anatomic Extent of Disease

Histopathology Clinical Factors

• Tumor size • Fuhrman grade• Performance

status

• Lymph node involvement

• Morphology• Cachexia-related

symptoms

• Metastasis• Microvascular

invasion• Thrombocytosis

• Venous involvement

• Tumor necrosis

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

Integrated Prognostic Models

• Various prognostic models developed that integrate information on anatomic staging, histopathology, and clinical parameters

• Most widely used model is the validated UCLA integrated staging system (UISS)1,2

Uses TNM classification scheme, Fuhrman grade, and ECOG performance status to classify patients into 5 prognostic categories that correlate with post-nephrectomy outcome

1. Zisman A et al. J Clin Oncol. 2001;19:1649.2. Patard JJ et al. J Clin Oncol. 2004;22:3316.

TNM = tumor node metastasisECOG = Eastern Cooperative Oncology Group

UISS and Survival

Zisman A et al. J Clin Oncol. 2001;19:1649.

UISS Stage

TNM Stage

Fuhrman Grade

ECOG PS

5-Year Survival

I I 1, 2 0 94 ± 2.5%

II I 1, 2 ≥ 1 67 ± 6.4%

I 3, 4 Any

II Any Any

III Any 0

III 1 ≥ 1

III III 2-4 ≥ 1 39 ± 2.8%

IV 1, 2 0

IV IV 3, 4 0 23 ± 3.1%

IV 1-3 ≥ 1

V IV 4 ≥ 1 0 ± 4.0%

RCC Prognosis Stratified by UISS Stage

PS = performance status

Biomolecular Prognostic Factors in RCC

Marker Expression Level Predicted Response to Treatment

CAIX1,2 Low Poor survival

Ki673 High Poor survival

p21 (metastatic disease)4 High Poor survival

P535,6 High Higher recurrence rate

VEGF7 (vascular endothelial growth factor)

High serum levels Shorter progression free survival (PFS)

HIF (hypoxia-inducible factor)-18 High Poor survival

B7x9 High Advanced tumor stage

COX (cyclooxygenase)-210 LowNon-response, poor

survival

Hepatocyte growth factor11 High Poor survival

Akt12 High cytoplasmic levels Poor survival

PTEN6,12 Low Poor survival

1. Bui MH et al. Clin Cancer Res. 2003;9:802. 2. Patard JJ et al. Int J Cancer. 2008;123:395.3. Bui MH et al. J Urol. 2004;171:2461. 4. Weiss RH et al. J Urol. 2007;177:63.

5. Shvarts O et al. J Urol. 2005;173:725. 6. Kim HL et al. J Urol. 2005;173:1496.7. Bukowski RM et al. ASCO 2007; Abstract 5023. 8. Klatte T et al. Clin Cancer Res. 2007;13:7388.

9. Thompson RH et al. ASCO 2008; Abstract 5052. 10. Kim H et al. ASCO 2008; Abstract 16015.11. Tanimoto S et al. J Med Invest. 2008;55:106. 12. Pantuck AJ et al. Cancer. 2007;109:2257.

CAIX Expression

Bui MH et al. Clin Cancer Res. 2003;9:802.

Factor HR (95% CI) P Value

Low CAIX staining 3.17 (2.07-4.86) <.001

ECOG PS 1.62 (1.18-2.24) .003

Grade 1.52 (1.15-2.01) .004

Tumor stage 1.44 (1.12-1.87) .005

Nodal status 1.32 (1.02-1.71) .033

Predicting Response to Treatment Based on

Molecular/Genetic Markers

Molecular Marker Expression Level Predicted Response to Treatment

CAIX1 High Good response to immunotherapy

COX-21 High Good response to immunotherapy

HIF-1/HIF-22 High Good response to sunitinib

Genetic Marker Predicted Response to Treatment

Various nsSNPs3 Significant sunitinib toxicity

Loss of chromosomes 4, 9, or 17p4 Non-response to interleukin-2 (IL-2)

VHL loss-of-function mutation5 Good response to VEGF therapy

nsSNPs: nonsynonymous single nucleotide polymorphisms

1. Kim HL et al. J Urol. 2005;173:1496. 2. Patel PH et al. ASCO 2008. Abstract 5008.3. Faber PW et al. ASCO 2008. Abstract 5009. 4. Jaeger E et al. ASCO 2008. Abstract 5043.

5. Choueiri TK et al. J Urol. 2008; [Epub ahead of print].

Poor-Risk Clinical Features of Advanced RCC

MSKCC Criteria 20041 CCF Criteria 20052

Hemoglobin≤13.0 g/dL men,

≤11.5 g/dL womenHemoglobin

<lower limit of normal

Corrected serum calcium

≥10.0 mg/dLCorrected serum calcium

>10.0 mg/dL

Karnofsky performance status

<80%Lactose dehydrogenase

>1.5 x upper limit of normal

Time from diagnosis to interferon (IFN)-

<12 months

Prior radiotherapy Yes

Presence of metastasis*

Yes

* In liver, lungs, or retriperitoneal lymph nodesMSKCC = Memorial Sloan Kettering Cancer CenterCCF = Cleveland Clinic Foundation

1. Motzer RJ et al. J Clin Oncol. 2004;22:454. 2. Mekhail TM et al. J Clin Oncol. 2005;23:832.

Comparison of MSKCC1 and CCF2 Criteria

1. Motzer RJ et al. J Clin Oncol. 2004;22:454. 2. Mekhail TM et al. J Clin Oncol. 2005;23:832.

MSKCC Criteria CCF Criteria

Risk GroupProportion,

%Median OS,

moProportion,

%Median OS,

mo

Favorable 42 22 37 26

Intermediate 35 11.9 35 14.4

Poor 23 5.4 28 73

MSKCC risk groups• Favorable: 0 risk factors• Intermediate: 1 risk factor• Poor: 2-3 risk factors

CCF risk groups• Favorable: 0-1 risk factor• Intermediate: 2 risk factors• Poor: ≥3 risk factors

OS = overall survival

Individualizing Therapy for Metastatic RCC

Rationale for Individualizing Therapy

• RCC has a highly variable natural history with no available systemic cure

• No one therapy predicted to be uniformly active in all patient populations

• Individualizing therapy offers patients the best chance of disease control balanced with the best possible quality of life

Issues to Consider

• Overall goals of treatment for metastatic RCC Delay life-threatening burden of disease Optimize chance of long-term disease control Maximize quality of life and patient convenience

• Weigh benefits vs risks to identify optimal therapeutic for a given patient

• Most patients will likely receive a sequence of several agents to help control disease

• Development of targeted agents has outpaced an understanding of their optimal use

Broad approval ≠ broad activity

Clinically Available Targeted

Agents for Advanced RCC

Agent Target Efficacy in Randomized Phase III Trials

Comparison No. Treated

ORR TTP (mos)

Bevacizumab VEGFBevacizumab + IFN- vs placebo (PBO) + 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 PBO4 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 Engl J Med. 2007;356:2271.ORR = overall response rateTTP = time to progression

When Should Systemic Therapy Be Started?

• Immediately start treatment or delay therapy to offset treatment burden?

• Evidence suggests that treatment benefit may be preserved even if treatment initiation is delayed in asymptomatic patients

Randomized phase II discontinuation trial of sorafenib vs placebo

28 patients initially randomized to placebo arm subsequently received sorafenib upon disease progression at a median of 7 weeks

Median PFS = 24 weeks– PFS identical to that of patients in original sorafenib arm

Ratain MJ et al. J Clin Oncol. 2006;24:2505.

Which Agent Is Best?

Rini BI, Bukowski RM. Oncology (Williston Park). 2008;22:388.

Agent Pros ConsSunitinib • Highest ORR

• Oral dosing• Survival advantage

• Long-term disease control may not be robust

Temsirolimus • Survival advantage• Active in patients with poor-risk

disease

• Activity appears to be restricted to patients with poor-risk disease

• Requires infusion

Bevacizumab • Favorable toxicity profile • Requires infusion• Often requires combination therapy

with IFN-

Sorafenib • Active in cytokine-refractory disease

• Oral dosing• Favorable toxicity profile

• Less efficacy in front-line setting

High-dose IL-2 • Higher ORR in patients with high CAIX expression – requires clinical trial confirmation

• Only active in a subset of patients• Considerable toxicity• Requires infusion

Which Agent Is Best?

Hutson TE, Figlin RA. Cancer J. 2007;13:282.

Setting Therapy

First-line therapy

Low + intermediate risk

Sunitinib Bevacizumab ± IFN- High-dose IL-2

Poor risk Temsirolimus

Second-line therapy

Prior cytokine therapy Sorafenib, Sunitinib

Prior VEGF therapy Everolimus

NCCN Practice Guidelines in Oncology:

Kidney Cancer

Relapse or Stage IV and medically or surgically unresectable

Predominant clear cell histology

Clinical trial orSunitinib (category 1)or Temsirolimus for poor-prognosis patients* (category 1)orBevacizumab + IFNor High-dose IL-2 for selected patientsor Sorafenib for selected patientsandBest supportive care

FIRST-LINE THERAPY

* Temsirolimus indicated for poor-prognosis patients, defined as those with ≥3 predictors of short survival

Best supportive care can include palliative radiation therapy (RT), metastasectomy or biphosphonates for bony metastasis NCCN Clinical Practice Guidelines in Oncology. 2007;v.1.2008.


Kidney Cancer

Relapse or Stage IV and medically or surgically unresectable

Clinical trial (preferred)or

Temsirolimus* (category 1 for poor-prognosis, category 2A for other risk groups)orSorafenib or Sunitinibor Chemotherapy (category 3):

gemcitabine or capecitabine or floxuridine or 5-FU or doxorubicin (in sarcomatoid only)and Best supportive care

FIRST-LINE THERAPY (cont.)

Non clear cell histology

* Temsirolimus indicated for poor-prognosis patients, defined as those with ≥3 predictors of short survival

Best supportive care can include palliative RT, metastasectomy or biphosphonates for bony metastasis NCCN Clinical Practice Guidelines in Oncology. 2007;v.1.2008.


Kidney Cancer

Clinical trial (preferred)orSorafenib (category 1 following cytokine therapy and category 2A following TKI)or Sunitinib (category 1 following cytokine therapy and category 2A following TKI)or Temsirolimus (category 2A following cytokine therapy and category 2B following TKI)or IFN (category 2B)orHigh dose IL-2 (category 2B)orLow dose IL-2 + IFN (category 2B)or BevacizumabandBest supportive care*

SUBSEQUENT THERAPY (use crossover regimen)

Progression

* Best supportive care can include palliative RT, metastasectomy or biphosphonates for bony metastasis

NCCN Clinical Practice Guidelines in Oncology. 2007;v.1.2008.

Does the Sequence of Agents Matter?

• Use of sequential targeted agents has become the de facto treatment approach in metastatic disease

Ideal sequence of agents unknown

• Many unresolved issues Is immunotherapy active after targeted therapy? Does the biology of a tumor change after exposure to an

agent? Does this affect the effectiveness of subsequent therapy? What are the mechanisms of drug resistance? Does the toxicity profile of 1 agent affect the tolerability of

subsequent agents?

Factors to Consider When Individualizing Therapy

• Risk status Extent of disease Histopathology Clinical factors

• Tumor molecular characteristics• First-line, second-line, subsequent lines of therapy• Patient preference

Regarding start of treatment Desired clinical outcomes Acceptable/unacceptable toxicities

Summary

• Accurately predicting patient outcomes is important for individualizing therapy

Enables patients to be informed about their prognosis Enables educated decision-making regarding treatment

• RCC staging will evolve as factors defining patient prognosis are better understood

• Patient prognosis will become more accurate as molecular marker information is incorporated into staging systems

• Additional molecular marker research needed to better facilitate individualized therapy selection

Current goal of individualized therapy is to maximize treatment effectiveness and minimize toxicity

Health & Medicine

Individualizing Therapy For Patients With Advanced Rcc