Targeted Therapy for Renal Cell Cancer

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Targeted Therapy for Renal Cell Cancer

• Dr.Mahmoodzadeh
• Oncologist-Hematologist

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Kidney Neoplasms

• Primary or Secondary (metastatic)
• Renal cell carcinoma (RCC) represents 80-85 of
  primary renal neoplasms
• Transitional cell carcinoma 8
• Rare tumors include
• - Oncocytomas
• Collecting duct tumors
• Renal sarcomas
• Nephroblastoma (Wilms tumor in children)
• Renal medullar carcinoma (Sickle cell disease)

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Pathogenesis of VHL

• Von Hippel-Lindau protein, product of VHL gene,
  is a tumor suppressor
• VHL inhibits hypoxia-inducible genes involved in
  angiogenesis such as VEGF, TGF-a, GLUT-1
• VHL destabilizes and promotes ubiquination of
  HIF-a (hypoxia-inducible factor)
• Loss of VHL results in tumor angiogenesis,
  tumor-cell proliferation epithelial cell
  proliferation

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Advanced RCC Treatment

• Primary treatments are systemic therapy with
  molecularly targeted therapy or immunotherapy
• Surgery is palliative therapy
• Solitary metastatic site
• Solitary recurrence following nephrectomy
• Symptoms related to bulkiness of disease
  including pain, nausea, or GI obstruction

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Why using TKIs for Kidney cancer treatment ?

• Many kidney cancers are associated with a kinase
  mutation responsible for angiogenesis factors
  overexpression
• TKIs are targeted therapies increasing response
  and reducing side effects.

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Targeted Therapy

• Based on advances in the understanding of the
  molecular biology of RCC
• Highly vascularlized tumor with increased VEGF
  and EGFR expression
• Tumor growth mediated via VEGF pathway and
  mammalian target of rapamycin (mTOR) pathway

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What is a tyrosine kinase receptor ?
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VEGF Pathway Inhibition

• Tyrosine kinase (TK) inhibitors block the
  intracellular domain of the VGEF receptor
• Sunitinib (Sutent)
• Sorafenib (Nexavar)
• Monoclonal antibody that binds circulating VEGF
  preventing the activation of the VEGF receptor
• - Bevacizumab (Avastin)

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Sunitinib

• Two phase II trials evaluating activity and
  safety in previously treated advanced RCC
• 25-36 of patients had an objective response
• Progression free survival (PFS) 8.3-8.7 months
• Median survival 16.4 months
• Side effects include fatigue, HTN, nausea,
  diarrhea, mucositis, and hypothyroidism

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Sunitinib

• Phase III trial 750 pts with untreated stage IV
  RCC Sunitinib vs. INFa
• Sunitinib showed prolonged median PFS 11 vs. 5m
  and higher response rate of 31 vs. 6
• Motzer RJ, et al. NEJM. 2007356115-124

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SUTENT Efficacy and Safety Were Demonstrated
Using a 50-mg Starting Dose
SUTENT dose may be easily adjusted in 12.5-mg
increments

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

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Sorafenib

• Phase II and phase III trials in advanced RCC
• Phase III TARGET study of 903 previously tx pts
  w/ stage IV RCC randomized to Sorafenib vs.
  placebo
• Sorafenib improved median PFS 5.5 vs. 2.8m
• No statistically significant survival benefit,
  median survival of 17.8 vs. 15.2 m
• Side effects include HTN, fatigue, rash,
  hand-foot syndrome, diarrhea, nausea

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Therapeutic scheme before Pazopanib
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Therapeutic scheme before Pazopanib
Marco Antonio Arap, New directions in the
management of renal cell carcinoma 2007
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Kinase profile of Pazopanib
Kinase affinity profile Kinase affinity profile
Ki app (nM)
VEGFR-1 10
VEGFR-2 4
VEGFR-3 6
PDGFR-a 2
PDGFR-b 5
C-Kit 15
Sunitinib
Sorafenib
Pazopanib
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Scheme of action, Pazopanib
VEGF-A/B
VEGF-C
PDGF-a/b
VEGFR-1/2
Pz
PDGFR
VEGFR-3
Pz
Pz
Pz
Pz
Pz
Pz
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Clinical trial of Pazopanib

• Patient with metastasic RCC
• 800mg once a day
• No treatment holiday
• versus placebo
• Half patient naïve and half with prior cytokine
  treatment
• Primary endpoints
• PFS Progression free survival

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Overview of clinical trial results
Treatment naïve Cytokine Refractory OS
PFS PFS
Sorafenib 5,8 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
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Bevacizumab

• Phase II trial of 116 pts, Bevacizumab increased
  TTP 4.8 vs. 2.5m for placebo group.
• -No difference in median survival
• Phase III AVOREN trial of 648 untreated pts
• INFa plus Avastin or placebo
• Avastin group resulted in PFS of 10.2 vs. 5.4 m.
• Unclear activity as single agent however
• Not FDA approved, but can be used as second-line
  therapy

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mTOR Pathway Inhibition

• Temsirolimus (TMSR) is a rapamycin analog that
  inhibits mTOR kinase
• Phase III trial 626 untreated poor-prognosis pts
  with stage IV RCC tx w/ TMSR, TMSR INFa, or
  INFa.
• - TMSR prolonged survival compared to INFa (10.9
  vs. 7.3m) and prolonged PFS (3.8 vs. 1.9m)
• Benefit greater in non-clear cell RCC

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RECENTIN Cediranib

• AstraZeneca
• Oral inhibitor of the
• VEGF-R 1/2/3
• C-kit
• PDGF-R
• Efficacy Racenta vs Placebo
• Phase II, active, not recruiting

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Axitinib (Bayer, AG013736)

• Inhibs specifically VEGFR 1-2-3 and PDGFR b
• Low effects on C-kit or flt-3
• No cross resistance with sorafenib

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The ideal kinase inhibiting profile in RCC

• The perfect tyrosine kinase inhibitor treating
  RCC
• should inhib
• VEGFR 1-2-3
• PDGFR a-b
• Raf
• Without inhibiting
• FLT-3
• C-kit

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Immunotherapy

• Immunotherapy with IL-2 activates immune response
  against RCC resulting in tumor remission rates
  10-20 with median duration of 19-91 months
• Severe toxicity including hypotension, capillary
  leak syndrome, MI, renal insufficiency, pulmonary
  edema, hepatic dysfunction, CNS dysfunction
• Treatment requires ICU monitoring
• Used for patients that can tolerate side effects

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Chemotherapy

• RCC is only minimally responsive to chemotherapy
• 83 clinic trials involving over 4000 pts, overall
  response rate is only 6
• On-going clinical trials of combination
  chemotherapy including Gemcitabine and 5-FU
• Limited data reveals some response in non-clear
  cell RCC to Carboplatin, Cisplatin plus
  Gemcitabine

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Radiation Therapy

• RCC relatively radioresistant
• XRT has limited use in metastatic disease
• Painful bone or recurrent abdominal metastases
• Brain metastases

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Summary

• RCC is relatively rare but increasing incidence
• Associated with tobacco and inherited disorders
• Surgery is the only curative modality for Stage
  I, II, and III
• Stage IV disease holds poor prognosis despite
  advancements in molecular understanding
• IL-2, Sorafenib, Sunitinib, and Temsirolimus are
  FDA approved treatments for advanced RCC

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Thanks for your attention