Renal Cell Carcinoma (RCC): Molecular Basis of Therapeutic Approaches

ModeratorMichael A. Carducci, MDProfessor of Oncology and UrologyJohns Hopkins Medical InstitutionsBaltimore, Maryland

Faculty William G. Kaelin Jr., MDProfessor of MedicineHarvard Medical SchoolDana-Farber Cancer Institute Boston, Massachusetts

Hans-Joerg Hammers, MD, PhDAssistant Professor of Urologic OncologyJohns Hopkins Medical InstitutionsBaltimore, Maryland

Overall Goal

The goal of this educational activity is to review the molecular pathways for choosing therapies based on the molecular biology of kidney cancer

Role of VHL Gene in RCC

• Inactivation of the VHL tumor-suppressor protein• Accumulation of HIF transcription factor• Overexpression of a number of genes, including

VEGF

VHL = von Hippel Lindau; HIF = hypoxia-inducible factor; RCC = renal cell cancer; VEGF = vascular endothelial growth factor

Review of Published Literature - VHL Gene Inactivation

StudyVHL gene mutation

in clear-cell RCCVHL gene mutation in nonclear-cell RCC

Gnarra,[a] 1994 57% (63/110) Not reportedShuin,[b] 1994 56% (22/39) 0% (0/8)Gallou,[c]1999 56% (73/130) 0% (0/21)Schraml,[d] 2002 34% (38/113) Not reportedYao,[e] 2002 52% (98/187) Not reportedvan Houwelingen,[f] 2005

61% (114/187) 15% (7/48)

aGnarra JR, et al. Nat Genet. 1994;7:85-90. bShuin T, et al. Cancer Res. 1994;54:2852-2855.cGallou C, et al. Hum Mutat. 1999;13:464-475. dSchraml P, et al. J Pathol. 2002;196:186-193.eYao M, et al. J Natl Cancer Inst. 2002;94:1569-75. fvan Houwelingen KP, et al. BMC Cancer. 2005;5:57.

VEGF and mTOR Inhibitors

VEGF inhibitors•Bevacizumab – Neutralizing antibody against VEGF

•Sunitinib•Sorefenib Small molecules inhibitors•Pazopanib against the VEGF receptor, KDR (VEGF-R2)

mTOR kinase inhibitors•Temsirolimus•Everolimus

KDR = kinase domain receptor; mTOR = mammalian target of rapamycin

VEGF Correlated With Poorer Overall Survival

Jacobsen J, et al. BJU Int. 2004;93:297-302.

VEGF Signaling Mechanisms

Antibodies to VEGFor VEGFR

mTORinhibitors

Tyrosine kinase inhibitors

Adapted from Rini BI, et al. J Clin Oncol. 2005;23:1028-1043.

Erk = extracellularly regulated kinase; MAPK = mitogen-activated protein kinase; MEK = MAP/Erk kinase; PKB = protein kinase B; VEGFR = VEGF receptor

Relationships Between VHL and mTOR

• Direct relationship between VHL loss and increased VEGF activity

• mTOR indirectly affects HIF and VEGF• Not clear which mTOR activities are relevant to

kidney cancer• Inhibition of mTOR with rapamycin-like drugs can

activate upstream kinases

RAPTOR

HIFHIF

HIF

TemsirolimusEverolimus

RAPTOR

mTOR

TemsirolimusEverolimus

mTORPI3K AKT

KDR Endothelial Cell

VEGF

Cancer Cell

Extracellular Space

SunitinibSorafenibPazopanib

Bevacizumab

Roles of VEGF and mTOR Inhibitors

pVHL

Transcription/Synthesis Destruction

Courtesy of William G. Kaelin Jr., MD

Effectiveness of Current TherapiesVEGF inhibitors as monotherapy are not curativeCombination therapies • Must have different mechanisms of action• Should not be cross-resistantOngoing clinical trials address• VEGF inhibitors with mTOR inhibitors– Bevacizumab, sorafenib, and temsirolimus in patients with metastatic

RCC[a]

– Everolimus and vatalanib in treating patients with advanced solid tumors[b]

– Phase 1b, open-label, dose-finding study to evaluate the safety of tivozanib (AV-951) in combination with temsirolimus in subjects with metastatic RCC[c]

aClinicaltrials.gov. Available at: http://clinicaltrials.gov/ct/show/NCT00378703bClinicaltrials.gov. Available at: http://clinicaltrials.gov/ct/show/NCT00303732cClinicaltrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00563147

Questions That Remain Unanswered

• Is the combination of these agents actually adequate for all patient populations?• Can we stratify patients to these treatments with

some patient groups benefiting more from the combinations than others? • What are the potential mechanisms of resistance to,

for example, VEGF-based agents?• Will combinations with mTOR inhibitors break this

resistance?

Kaelin WG Jr. Cancer. 2009;115(10 Suppl):2262-2272.

Targets: HIF-Responsive Gene Products

CA = carbonic anhydrase; c-Met = mesenchymal-epithelial transition factor; CTGF = connective tissue growth factor; CXCR = CXC chemokine receptor; HDAC = histone deacetylases; MMP = matrix metalloproteinase; PDGF = platelet-derived growth factor; pVHL = VHL protein; SDF = stromal cell-derived factor; TGF = transforming growth factor

Pazopanib

RAPTORmTOR

PI3K

AKT

RTKIntracellular

Torc1 complex (rapalog sensitive)

RICTORTorc2 complex(rapalog insensitive)

Additional oncogenic functions

Extracellular

Inhibition of TORC1 and TORC2 Complexes

HIFCourtesy of William G. Kaelin Jr., MD

Temsirolimus and everolimus are rapalogs

pVHL Activity in Physiologic and Pathologic States

Rathmell WK, Chen S. Exp Rev Anticancer Ther. 2008;8:63-73.

Brugarolas J. N Engl J Med. 2007;356:185-187.

PDGFR = PDGF receptor; PTEN = phosphatidylinositol phosphate 3'-phosphatase; FKBP = FK binding protein; TSC = tuberous sclerosis complex

Molecular Pathways and Targeted Therapies

McDermott DF. Clin Cancer Res. 2007;13:716s-720s.

US Food and Drug Administration-approved high-dose IL-2• Durable responses in carefully selected patients• Toxic• Substituting with lower dose or adding interferon produced

fewer tumor regressions

Predictors of response to IL-2 therapy• Patients with clinical features of a good or intermediate

prognosis• Tumors with clear-cell histology

Responses With High-Dose IL-2

IL = interleukin

Immunologic Agents in Clinical Development

• Antibodies to CTLA4– Phase 2 study with iplilimumab[a]

– Response was 4% to 27% by RECIST in IL-2 nonresponders

• Antibodies to PD1– Phase 1/2 trial of MDX-1106 in solid tumors– Clinical activity against RCC and melanoma with

intermittent dosing at 10 mg/kg – No serious toxicity

aYang JC, et al. J Immunother. 2007;30:825-830.bBrahmer JR, et al. J Clin Oncol. 2009;27(15s):3018.

CTLA4 = cytotoxic T-lymphocyte-associated protein 4; RECIST = response evaluation criteria in solid tumors

MET in RCC• MET signaling has been shown to be important in

RCC[a]

• MET can cooperate with epidermal growth factor receptor[b]

• MET mutations drive the pathology in hereditary papillary kidney cancer[a] • Papillary kidney cancer is an ideal RCC tumor for the

study of MET-targeted therapies[a]

• The rational design and development of MET inhibitors has produced a number of potent and selective agents[a]

• MET is an HIF target gene and therefore a potential target in clear-cell RCC[a]

aGiubellino A, et al. Expert Rev Anticancer Ther. 2009;9:785-793.bInoue K, et al. Virchows Arch. 1998;433:511-515.

MET Signaling Pathway

Abounader R, et al. Oncogene. 2004;23:9173-9182.GRB = growth factor receptor binding protein; PLC = phospholipase C

Potential Predictors of Outcome

• Histology: Tyrosine kinase inhibitors promise longer progression-free survival in clear-cell histology• Clinical prognostic factors combined with histologies

can help guide treatment selection in poor-risk patients

– Poor-risk patients can also benefit from tyrosine kinase inhibitors

Waterfall Plots of Primary Tumor Responses: Size Response to Sorafenib Therapy

Cowey CL, et al. J Clin Oncol. 2010;28:1502-1507.

Response evaluation criteria in solid tumors: partial response criteria designated by lower dashed line at −30% and progressive disease criteria designated by upper dashed line at 20%.LD = longest dimension

Maximum percentage of tumor decrease for target lesions by RECISTZero represents baseline (no change), -100% represents potential complete response, ~ 30% represents potential partial response

Axitinib Treatment for Cytokine-Refractory mRCC: Phase 2 Study

Rixe O, et al. Lancet Oncol. 2007;8:975-984.

Axitinib - Investigational KDR inhibitor

Improving Response?

• Does HIF-1-alpha status affect the response to VEGF inhibitors?

• Will the use of a pharmacodynamic biomarker (hypertension) provide more effective dosing?

• Which VEGF inhibitor has good potential in combination therapy?

Resistance Mechanisms

• IL-8 contributing to VEGF resistance[a]

• Acquired or transient resistance[b]

aHuang D, et al. Cancer Res. 2010;70:1063-1071.bMotzer RJ, et al. J Clin Oncol. 2009;27:3584-3590.

Toxicity of Sunitinib Plus Bevacizumab

CharacteristicIndex Patient

1Index Patient

2Index Patient

3Other Patients With

RCC (n = 8)

Age 57 60 69 Median 55 (range, 46-83)

Sex Female Male Male 7 male/1 female

Histology Chromophobe Clear cell Papillary 7 clear cell†/1 papillaryPrevious nephrectomy Yes Yes Yes Yes (100%)

Baseline blood pressure, mm Hg 114/77 140/86 146/80 Median 142/81

Peak blood pressure, mm Hg 157/102 180/104 190/111 Median 167/99

Hemoglobin baseline/nadir, g/dL

11.7/9.8 15.7/12.4 15.2/15.2 Median 13.4/12.6

Rini BI, Garcia JA. J Clin Oncol. 2010;28:e284-e285.

Characteristics of patients in whom TMA developed compared with characteristics of patients with RCC

TMA = thrombotic microangiopathy; LDH = lactate dehydrogenase; HFS = hand-foot syndrome; S = sunitinib; B = bevacizumab

Toxicity of Sunitinib Plus Bevacizumab (cont)Characteristic

Index Patient 1

Index Patient 2

Index Patient 3

Other Patients With RCC (n = 8)*

Platelet baseline/nadir, K/μL 490/59 273/76 158/72 Median 219/78

Creatinine baseline/peak, mg/dL 0.9/1.1 1.3/1.4 1.5/2.2 Median 1.3/1.6

Haptoglobin baseline/nadir, mg/dL 393/< 20 209/< 20 118/< 20 NA†

LDH baseline/peak, U/L 324/392 173/310 585/324 Median 170/396

Peak reticulocyte count, % 2.9 2.7 2.2 NA†

Grade 3 toxicity Hypertension/fatigue

Hypertension/HFS Hypertension

Hypertension: 6 pts HFS: 3 ptsProteinuria: 2 ptsFatigue: 1 ptLow platelets: 1 pt

Tumor burden change, % −48 −36 −66 Median −39 (range, −4 to −73)‡

*Dose levels for other patients with RCC included S 25 mg/B 5 mg/kg (1 pt), S 37.5 mg/B 5 mg/kg (3 pts), S 37.5/B 10 mg/kg (1 pt), and S 50 mg/B 10 mg/kg (3 pts). † Two pts with papillary features and 1 pt with sarcomatoid features. ‡ Baseline haptoglobin and reticulocyte count not be measured in the majority of patients enrolled in initial cohort. No patient with haptoglobin < 20 on any measurement. § Two pts unevaluable due to lack of postbaseline scans. Rini BI, Garcia JA. J Clin Oncol. 2010;28:e284-e285.

Adjuvant Therapy for Those at High Risk for Relapse

Bleumer I, et al. Can J Urol. 2006; Suppl 2:57-62.Jonasch E, Tannir NM. Cancer J. 2008;14:315-319.de Reijke TM, et al. Eur J Cancer. 2009;45:765-773.

There is no evidence for benefit of adjuvant therapy in clear-cell RCC at this time

• Should it be given before or after nephrectomy?• Will molecular markers be better able to identify

high-risk patients?• Adjuvant therapy

– Sunitinib, sorafenib, bevacizumab– Temsirolimus and everolimus– Immunotherapy with CTLA-4 and PD-1 antibodies

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