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Renal cell carcinoma: what does the future hold?

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Title: Renal cell carcinoma: what does the future hold?


1
Renal cell carcinoma what does the future hold?
Rome, November 23-24, 2007

                                                                                                                    
  • Floriana Morgillo, MD PhD
  • Second University of Naples

2
Epidemiology 2007
  • 51,190 diagnosis
  • 12,890 deaths
  • Incidence increased of 2 per year
  • 5-year survival from 5 to 10 in advanced stage

3
What did the past give?
  • Cytoreductive nephrectomy

4
What did the past give?
  • The Cytokine Era

5
THE ROLE OF VEGF IN RENAL CELL CARCINOMA
Motzer JR J Clin Oncol 2006
6
THE ROLE OF VHL IN RENAL CELL CARCINOMA
7
THE ROLE OF GFR IN RENAL CELL CARCINOMA
HIF1
8
Monotherapy Trials
Study population No. patients PFS ORR ()
Bevacizumab vs placebo 2nd Line 116 4.8 vs 2.5 mo 10 vs 0
Bevacizumab erlotinib 1st Line 104 8.5 vs 9.9 mo 13 vs 14
Sorafenib vs placebo 2nd Line 905 5.5 vs 2.8 mo 2 vs 0
Sorafenib vs IFN-a 1st Line 189 5.7 vs 5.6 mo DS 79 vs 64
Sunitinib 2nd Line 63 8.7 mo 40
Sunitinib 2ndLine 106 8.1 mo 44
Sunitinib vs IFN-a 1st Line 750 11 vs 5 mo 31 vs 6
9
Combination Therapy
  • Preclinical rationale
  • PDGF-A, PDGF-B, TGF-a, EPO are overexpressed in
    pericytes and renal epithelial cancer cells
  • Targeting VEGF, VEGFR-2 and Tie2 with
    immunotherapy (dendridic cells) lead to
    synergistic activity
  • IFN-a has demonstrated an antiangiogenic activity
  • Sorafenib and sunitinib reduced immunosuppressive
    T regulatory cell

10
Addition of Bevacizumab to IFN-a
Response Interferon with Placebo (n289) Interferon with Bevacizumab (n306)
Overall Response Rate () 13 31
Complete Response 2 1
Partial Response 11 30
Median Duration of Response (mo) 11 13
Median Duration of Stable Disease (mo) 7 10
Escudier B, ASCO Annual Meeting Proceedings 2007
11
Addition of Bevacizumab to IFN-a
Outcome Interferon with Placebo (n289) Interferon with Bevacizumab (n306) Hazard Ratio P
Median PFS (mo) 5.4 10.2 0.63 lt.0001
Escudier B, ASCO Annual Meeting Proceedings 2007
12
Rini BI, CALGB 90206
13
Addition of Sorafenib to IFN-a
From ASCO 2006
  • Gollob et al.
  • Phase II
  • 1-2 line
  • Sorafenib 400 mg po bid
  • plus
  • IFN- 10MU sc. tiw
  • 24 pts evaluable
  • RR 42

Ryan et al. SWOG Phase II 1st line
Sorafenib 400 mg po bid plus IFN- 10MU sc.
3/wk 58 pts evaluable RR 19
14
Combination therapy in RCC
15
Addition of Bevacizumab to Sorafenib or Sunitinib
Study design Dose Status Investigator
Phase I/II trial of bevacizumabsorafenib (solid tumors) MTD Bevacizumab5-10 mg/kg sorafenib200 mg bid Ongoing Kohn, NCI, Bethesda
Phase I/II trial of bevacizumabsorafenib Dose escalation design Ongoing Sosman, Vaderbilt-Ingram Cancer Center Nashville
Phase I trial of bevacizumabsunitinib (solid tumors) Dose escalation design Ongoing Rini, Cleveland Clinic Taussing Cancer Center
Phase I trial of bevacizumabsunitinib (RCC) Dose escalation design Ongoing Motzer, MSKCC
16
Combined blockade of EGFR and VEGF
bFGF IL-8 VEGF FGF-a
EGF TGF-a
EGFR
Endothelial cell growth Permeability
Tumor
Endothelial cells
17
Addtion of Bevacizumab to erlotinib
104 pts Low and Int risk (MSKCC) RANDIMIZE
Bevacizumab Placebo (n53) Bevacizumab Erlotinib (n50)
Median PFS (months) 8.5 9.9
ORR () 13 14 P.999
Bev 10 mg/kg
Bev 10 mg/kg Erlotinib 150 mg
Median PFS (months) Median PFS (months)
IFN-a Bev
Low risk 8.3 13.1
Intermediate risk 5.1 7.3
Bukowski RM, J Clin Oncol 2007
18
Mammalian target of rapamycin (MTOR) Inhibitors
19
(No Transcript)
20
Promising agents
Agent Target Clinical Development
Lapatinib EGFR/ErbB2 TKI Phase II
Pazopanib Multitarget TKI (VEGFRs, PDGFRs and c-Kit Phase III
Axitinib VEGFR-2, PDGFR-ß TKI Phase II
Everolimus MTOR Phase III
VEGF-trap VEGF Phase II
Lenalidomide angiogenesis inhibitor Phase II
21
Sequenced therapy
Progression Disease
22
Clinical end-points
  • RECIST
  • Block the tumor growth rather than tumor
    regression
  • Response-independent survival benefit
  • PFS

23
Patients selection
  • Non-clear cell carcinoma

Median OS (months) Median OS (months) Median PFS (monts) Median PFS (monts)
IFN-a TEMSR IFN-a TEMSR
Clear cell 8.2 10.6 3.8 5.5
Other 4.3 11.6 1.8 7
24
Predictive biomarkers of response
25
  • Predictive biomarkers of response

Sunitinib
Sorafenib
26
  • Risk group

Median Survival (months) Median Survival (months) Median Survival (months)
Risk (MSKCC risk model) Good Intermediate Poor
IFN-a 29.6 13.8 4.9
Tensirolimus 23.8 22.5 8.2
27
From the past to the future
Pre-selection of pts by hystology Risk
class Prognostic biomarkers Clinical end-point
Front-line
ORR ()
PFS (mts)
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