Renal Cell Carcinoma by pptfiles


									Targeted Therapy for
 Renal Cell Cancer
            Kidney Neoplasms
n Primary or Secondary (metastatic)
n Renal cell carcinoma (RCC) represents 80-85% of
  primary renal neoplasms
n Transitional cell carcinoma 8%
n Rare tumors include:
- Oncocytomas
- Collecting duct tumors
- Renal sarcomas
- Nephroblastoma (Wilms’ tumor in children)
- Renal medullar carcinoma (Sickle cell disease)
          Pathogenesis of VHL
n   Von Hippel-Lindau protein, product of VHL
    gene, is a tumor suppressor
n   VHL inhibits hypoxia-inducible genes involved
    in angiogenesis such as VEGF, TGF-a, GLUT-1
n   VHL destabilizes and promotes ubiquination of
    HIF-a (hypoxia-inducible factor)
n   Loss of VHL results in tumor angiogenesis,
    tumor-cell proliferation epithelial cell
       Advanced RCC Treatment
n   Primary treatments are systemic therapy with
    molecularly targeted therapy or immunotherapy
n   Surgery is palliative therapy
-   Solitary metastatic site
-   Solitary recurrence following nephrectomy
-   Symptoms related to bulkiness of disease
    including pain, nausea, or GI obstruction
    Why using TKIs for Kidney cancer
              treatment ?

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

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

             Targeted Therapy
n   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)
What is a tyrosine kinase receptor ?

     VEGF Pathway Inhibition
n Tyrosine kinase (TK) inhibitors block the
  intracellular domain of the VGEF receptor
- Sunitinib (Sutent)

- Sorafenib (Nexavar)

n Monoclonal antibody that binds circulating
  VEGF preventing the activation of the VEGF
- Bevacizumab (Avastin)
n   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
n   Side effects include fatigue, HTN, nausea,
    diarrhea, mucositis, and hypothyroidism
      n   Phase III trial 750 pts
          with untreated stage IV
          RCC Sunitinib vs.
      n   Sunitinib showed
          prolonged median PFS
          11 vs. 5m and higher
          response rate of 31%
          vs. 6%

      Motzer RJ, et al. NEJM. 2007;356:115-124
       SUTENT Efficacy and Safety Were
    Demonstrated Using a 50-mg Starting Dose

                  SUTENT dose may be easily adjusted in 12.5-mg increments

n    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)

n   Phase II and phase III trials in advanced RCC
n   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
n   Side effects include HTN, fatigue, rash, hand-
    foot syndrome, diarrhea, nausea
Marco Antonio Arap, New directions in the management of renal cell carcinoma
Kinase profile of Pazopanib

   Kinase affinity profile
                    Ki app (nM)
VEGFR-1                  10
VEGFR-2                  4
VEGFR-3                  6
PDGFR-a                  2
PDGFR-b                  5
 C-Kit                   15
 Sora                  Suniti     Pazop
 feni                   nib        anib
  b                                       17
                  PDGF-a/b          VEGFR- VEGF-C
               PDGFR                         VEGFR-3

                       Pz             Pz



         Clinical trial of Pazopanib
n   Patient with metastasic RCC

n   800mg once a day

n   No treatment holiday

n   versus placebo

n   Half patient naïve and half with prior cytokine treatment

   Primary endpoints:
    ◦ PFS: Progression free survival

 Overview of clinical trial results
              Treatment naïve           Cytokine Refractory      OS

                      PFS                      PFS

                    5,8 mos.
Sorafenib                                    5,9 mos.         10,7 mos*.
              (Phase II results only)

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

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

            * : Cross-over                                                 20
n Phase II trial of 116 pts, Bevacizumab increased TTP
  4.8 vs. 2.5m for placebo group.
-No difference in median survival
n 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

n Not FDA approved, but can be used as second-line
    mTOR Pathway Inhibition
n Temsirolimus (TMSR) is a rapamycin analog
  that inhibits mTOR kinase
n 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
         RECENTIN : Cediranib
n   AstraZeneca

n   Oral inhibitor of the :
    n VEGF-R 1/2/3
    n C-kit

    n PDGF-R

n   Efficacy Racenta vs Placebo
       Axitinib (Bayer, AG013736)
   Inhibs specifically: VEGFR 1-2-3 and PDGFR

   Low effects on C-kit or flt-3

   No cross resistance with sorafenib

        The ideal kinase inhibiting profile in
The perfect tyrosine kinase inhibitor treating RCC

§   should inhib:
    o   VEGFR 1-2-3
    o   PDGFR a-b
    o   Raf

§   Without inhibiting
    ◦   FLT-3
    ◦   C-kit
n   Immunotherapy with IL-2 activates immune response
    against RCC resulting in tumor remission rates 10-20%
    with median duration of 19-91 months
n   Severe toxicity including hypotension, capillary leak
    syndrome, MI, renal insufficiency, pulmonary edema,
    hepatic dysfunction, CNS dysfunction
n    Treatment requires ICU monitoring
n   Used for patients that can tolerate side effects
n   RCC is only minimally responsive to
n   83 clinic trials involving over 4000 pts, overall
    response rate is only 6%
n   On-going clinical trials of combination
    chemotherapy including Gemcitabine and 5-FU
n   Limited data reveals some response in non-clear
    cell RCC to Carboplatin, Cisplatin plus
             Radiation Therapy
n   RCC relatively radioresistant

n   XRT has limited use in metastatic disease
-   Painful bone or recurrent abdominal metastases
-   Brain metastases
n   RCC is relatively rare but increasing incidence
n   Associated with tobacco and inherited disorders
n   Surgery is the only curative modality for Stage I,
    II, and III
n   Stage IV disease holds poor prognosis despite
    advancements in molecular understanding
n   IL-2, Sorafenib, Sunitinib, and Temsirolimus are
    FDA approved treatments for advanced RCC
Thanks for your attention


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