Targeted Therapy Targeted Therapy for Renal Cell for Renal Cell

CancerCancerDr.MahmoodzadehDr.Mahmoodzadeh

Oncologist-HematologistOncologist-Hematologist

Kidney NeoplasmsKidney Neoplasms Primary or Secondary (metastatic) Primary or Secondary (metastatic) Renal cell carcinoma (RCC) represents 80-Renal cell carcinoma (RCC) represents 80-

85% of primary renal neoplasms85% of primary renal neoplasms Transitional cell carcinoma 8% Transitional cell carcinoma 8% Rare tumors include: Rare tumors include: - Oncocytomas- Oncocytomas- Collecting duct tumorsCollecting duct tumors- Renal sarcomas Renal sarcomas - Nephroblastoma (Wilms’ tumor in children)Nephroblastoma (Wilms’ tumor in children)- Renal medullar carcinoma (Sickle cell Renal medullar carcinoma (Sickle cell

disease)disease)

Pathogenesis of VHLPathogenesis of VHL Von Hippel-Lindau protein, product of Von Hippel-Lindau protein, product of

VHL gene, is a tumor suppressor VHL gene, is a tumor suppressor VHL inhibits hypoxia-inducible genes VHL inhibits hypoxia-inducible genes

involved in angiogenesis such as VEGF, involved in angiogenesis such as VEGF, TGF-a, GLUT-1TGF-a, GLUT-1

VHL destabilizes and promotes VHL destabilizes and promotes ubiquination of HIF-a (hypoxia-inducible ubiquination of HIF-a (hypoxia-inducible factor) factor)

Loss of VHL results in tumor Loss of VHL results in tumor angiogenesis, tumor-cell proliferation angiogenesis, tumor-cell proliferation epithelial cell proliferationepithelial cell proliferation

Advanced RCC Advanced RCC TreatmentTreatment

Primary treatments are systemic therapy Primary treatments are systemic therapy with molecularly targeted therapy or with molecularly targeted therapy or immunotherapy immunotherapy

Surgery is palliative therapy Surgery is palliative therapy - Solitary metastatic siteSolitary metastatic site- Solitary recurrence following Solitary recurrence following

nephrectomynephrectomy- Symptoms related to bulkiness of disease Symptoms related to bulkiness of disease

including pain, nausea, or GI obstruction including pain, nausea, or GI obstruction

Many kidney cancers are associated Many kidney cancers are associated with a kinase mutation responsible for with a kinase mutation responsible for angiogenesis factors overexpressionangiogenesis factors overexpression

TKIs are targeted therapies: TKIs are targeted therapies: increasing response and reducing increasing response and reducing side effects.side effects.

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Why using TKIs for Kidney Why using TKIs for Kidney cancer treatment ?cancer treatment ?

Targeted TherapyTargeted Therapy

Based on advances in the Based on advances in the understanding of the molecular understanding of the molecular biology of RCCbiology of RCC

- Highly vascularlized tumor with Highly vascularlized tumor with increased VEGF and EGFR increased VEGF and EGFR expression expression

- Tumor growth mediated via VEGF Tumor growth mediated via VEGF pathway and mammalian target of pathway and mammalian target of rapamycin (mTOR) pathway rapamycin (mTOR) pathway

What is a tyrosine kinase What is a tyrosine kinase receptor ?receptor ?

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VEGF Pathway InhibitionVEGF Pathway Inhibition

Tyrosine kinase (TK) inhibitors block Tyrosine kinase (TK) inhibitors block the intracellular domain of the VGEF the intracellular domain of the VGEF receptorreceptor

- Sunitinib (Sutent)Sunitinib (Sutent)- Sorafenib (Nexavar)Sorafenib (Nexavar) Monoclonal antibody that binds Monoclonal antibody that binds

circulating VEGF preventing the circulating VEGF preventing the activation of the VEGF receptoractivation of the VEGF receptor

- Bevacizumab (Avastin) - Bevacizumab (Avastin)

SunitinibSunitinib

Two phase II trials evaluating activity and Two phase II trials evaluating activity and safety in previously treated advanced RCC safety in previously treated advanced RCC

- 25-36% of patients had an objective 25-36% of patients had an objective response response

- Progression free survival (PFS) 8.3-8.7 Progression free survival (PFS) 8.3-8.7 monthsmonths

- Median survival 16.4 months Median survival 16.4 months Side effects include fatigue, HTN, nausea, Side effects include fatigue, HTN, nausea,

diarrhea, mucositis, and hypothyroidism diarrhea, mucositis, and hypothyroidism

SunitinibSunitinib Phase III trial 750 Phase III trial 750

pts with untreated pts with untreated stage IV RCC stage IV RCC Sunitinib vs. INFaSunitinib vs. INFa

Sunitinib showed Sunitinib showed prolonged median prolonged median PFS 11 vs. 5m and PFS 11 vs. 5m and higher response higher response rate of 31% vs. 6% rate of 31% vs. 6%

Motzer RJ, et al. NEJM. Motzer RJ, et al. NEJM. 2007;356:115-1242007;356:115-124

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SUTENT Efficacy and Safety Were SUTENT Efficacy and Safety Were Demonstrated Using a 50-mg Demonstrated Using a 50-mg

Starting DoseStarting Dose

No dose adjustment is recommended based on age, race, gender, No dose adjustment is recommended based on age, race, gender, body weight, creatinine clearance, ECOG performance status body weight, creatinine clearance, ECOG performance status score, or hepatic impairment (Child-Pugh Class A or B)score, or hepatic impairment (Child-Pugh Class A or B)

SUTENT dose may be easily adjusted in 12.5-mg incrementsSUTENT dose may be easily adjusted in 12.5-mg increments

SorafenibSorafenib Phase II and phase III trials in advanced Phase II and phase III trials in advanced

RCCRCC Phase III TARGET study of 903 previously Phase III TARGET study of 903 previously

tx pts w/ stage IV RCC randomized to tx pts w/ stage IV RCC randomized to Sorafenib vs. placeboSorafenib vs. placebo

- Sorafenib improved median PFS 5.5 vs. Sorafenib improved median PFS 5.5 vs. 2.8m 2.8m

- No statistically significant survival benefit, No statistically significant survival benefit, median survival of 17.8 vs. 15.2 m median survival of 17.8 vs. 15.2 m

Side effects include HTN, fatigue, rash, Side effects include HTN, fatigue, rash, hand-foot syndrome, diarrhea, nausea hand-foot syndrome, diarrhea, nausea

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Marco Antonio Arap, Marco Antonio Arap, New directions in the management of renal cell carcinomaNew directions in the management of renal cell carcinoma20072007

Kinase profile of PazopanibKinase profile of Pazopanib

1717

SuniSunitinibtinib

SoSorafrafenienibb

PazoPazopanipani

bb

Kinase affinity profile

Ki app (nM)

VEGFR-1 10

VEGFR-2 4

VEGFR-3 6

PDGFR- 2

PDGFR- 5

C-Kit 15

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PzPz PzPz

PzPz

PzPz

PzPz

PzPz

VEGF-A/BVEGF-A/BVEGF-CVEGF-CPDGF-PDGF-

PDGFPDGFRR

VEGFR-VEGFR-1/21/2

VEGFR-3VEGFR-3

PzPz

Patient with metastasic RCCPatient with metastasic RCC

800mg once a day800mg once a day

No treatment holidayNo treatment holiday

versus placeboversus placebo

Half patient naïve and half with prior cytokine Half patient naïve and half with prior cytokine treatmenttreatment

Primary endpoints:Primary endpoints:◦ PFS: Progression free survivalPFS: Progression free survival

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Clinical trial of PazopanibClinical trial of Pazopanib

Overview of clinical trial results

Treatment naïveCytokine

RefractoryOS

PFS PFS

Sorafenib5,8 mos.

(Phase II results only)5,9 mos. 10,7 mos*.

Sunitinib 11 mos. 8,7 mos. 26,4 mos.

Pazopanib 11,1 mos. 7,4 mos. 21.1 mos.

* : Cross-over* : Cross-over20

Phase II trial of 116 pts, Bevacizumab Phase II trial of 116 pts, Bevacizumab increased TTP 4.8 vs. 2.5m for placebo group. increased TTP 4.8 vs. 2.5m for placebo group.

-No difference in median survival -No difference in median survival Phase III AVOREN trial of 648 untreated ptsPhase III AVOREN trial of 648 untreated pts- INFa plus Avastin or placeboINFa plus Avastin or placebo- Avastin group resulted in PFS of 10.2 vs. 5.4 Avastin group resulted in PFS of 10.2 vs. 5.4

m. m. - Unclear activity as single agent however Unclear activity as single agent however Not FDA approved, but can be used as Not FDA approved, but can be used as

second-line therapy second-line therapy

BevacizumabBevacizumab

mTOR Pathway mTOR Pathway InhibitionInhibition

Temsirolimus (TMSR) is a rapamycin Temsirolimus (TMSR) is a rapamycin analog that inhibits mTOR kinase analog that inhibits mTOR kinase

Phase III trial 626 untreated poor-Phase III trial 626 untreated poor-prognosis pts with stage IV RCC tx w/ prognosis pts with stage IV RCC tx w/ TMSR, TMSR +INFa, or INFa. TMSR, TMSR +INFa, or INFa.

- TMSR prolonged survival compared to - TMSR prolonged survival compared to INFa (10.9 vs. 7.3m) and prolonged INFa (10.9 vs. 7.3m) and prolonged PFS (3.8 vs. 1.9m) PFS (3.8 vs. 1.9m)

- Benefit greater in non-clear cell RCCBenefit greater in non-clear cell RCC

AstraZenecaAstraZeneca

Oral inhibitor of the :Oral inhibitor of the : VEGF-R 1/2/3VEGF-R 1/2/3 C-kitC-kit PDGF-RPDGF-R

Efficacy Racenta vs PlaceboEfficacy Racenta vs Placebo

Phase II, active, not recruitingPhase II, active, not recruiting

RECENTIN : CediranibRECENTIN : Cediranib

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Inhibs specifically: VEGFR 1-2-3 and Inhibs specifically: VEGFR 1-2-3 and PDGFR PDGFR

Low effects on C-kit or flt-3Low effects on C-kit or flt-3

No cross resistance with sorafenibNo cross resistance with sorafenib

Axitinib (Bayer, Axitinib (Bayer, AG013736)AG013736)

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The perfect tyrosine kinase inhibitor treating RCCThe perfect tyrosine kinase inhibitor treating RCC

should inhib:should inhib:o VEGFR 1-2-3VEGFR 1-2-3o PDGFR PDGFR o RafRaf

Without inhibitingWithout inhibiting◦ FLT-3FLT-3◦ C-kitC-kit

The ideal kinase inhibiting The ideal kinase inhibiting profile in RCCprofile in RCC

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ImmunotherapyImmunotherapy

Immunotherapy with IL-2 activates immune Immunotherapy with IL-2 activates immune response against RCC resulting in tumor response against RCC resulting in tumor remission rates 10-20% with median duration remission rates 10-20% with median duration of 19-91 months of 19-91 months

Severe toxicity including hypotension, Severe toxicity including hypotension, capillary leak syndrome, MI, renal capillary leak syndrome, MI, renal insufficiency, pulmonary edema, hepatic insufficiency, pulmonary edema, hepatic dysfunction, CNS dysfunctiondysfunction, CNS dysfunction

Treatment requires ICU monitoringTreatment requires ICU monitoring Used for patients that can tolerate side effectsUsed for patients that can tolerate side effects

Chemotherapy Chemotherapy

RCC is only minimally responsive to RCC is only minimally responsive to chemotherapychemotherapy

83 clinic trials involving over 4000 83 clinic trials involving over 4000 pts, overall response rate is only 6%pts, overall response rate is only 6%

On-going clinical trials of combination On-going clinical trials of combination chemotherapy including Gemcitabine chemotherapy including Gemcitabine and 5-FUand 5-FU

Limited data reveals some response Limited data reveals some response in non-clear cell RCC to Carboplatin, in non-clear cell RCC to Carboplatin, Cisplatin plus Gemcitabine Cisplatin plus Gemcitabine

Radiation TherapyRadiation Therapy

RCC relatively radioresistant RCC relatively radioresistant

XRT has limited use in metastatic XRT has limited use in metastatic diseasedisease

- Painful bone or recurrent abdominal Painful bone or recurrent abdominal metastasesmetastases

- Brain metastasesBrain metastases

SummarySummary

RCC is relatively rare but increasing incidence RCC is relatively rare but increasing incidence Associated with tobacco and inherited Associated with tobacco and inherited

disordersdisorders Surgery is the only curative modality for Stage Surgery is the only curative modality for Stage

I, II, and III I, II, and III Stage IV disease holds poor prognosis despite Stage IV disease holds poor prognosis despite

advancements in molecular understandingadvancements in molecular understanding IL-2, Sorafenib, Sunitinib, and Temsirolimus IL-2, Sorafenib, Sunitinib, and Temsirolimus

are FDA approved treatments for advanced are FDA approved treatments for advanced RCC RCC

Thanks for your Thanks for your attentionattention

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