New challenges in kidney cancer therapy: Sunitinib

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New challenges in kidney cancer
therapySunitinib

• Olivier Rixe MD, PhD

Université Pierre et Marie Curie, Hôpital
Pitié-Salpêtrière, Paris, France
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Control of Hypoxia-Inducible Factor (HIF) by the
Gene Product of the von HippelLindau Gene (pVHL).
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(No Transcript)
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Sunitinib Mechanism of Action in RCC
Loss of VHL Protein Function
? VEGF
? PDGF
VEGF
PDGF
VEGFR
PDGFR
Pericyte/Fibroblast/ Vascular Smooth Muscle
Vascular Endothelial Cell
Sunitinib
Vascular permeability
Cell survival, proliferation, migration
Vascular formation, maturation
Inhibition of RCC pathogenesis and progression
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Mechanisms of Action of Sunitinib
Sunitinib Potently Inhibits Multiple Targets such
as VEGFR, PDGFR and KIT in Biochemical and
Cellular Assays
NIH-3T3
HUVEC
Mendel et al., Clin Cancer Res, 2003 OFarrell
et al., Blood 2003.
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Phase 1 study from IGR
Total Number of patients DLT Type of
DLTs Dose evaluable/entered at cycle
1 50 mg q2d 2/3 - - 100
mg q2d 1/1 - - 50 mg daily
9/9 2/9 1 G3 edema 1 G4
thrombocytopenia 75 mg daily 11/11
5/11 3 G3 asthenia 1 G3
hypertension 1 G5 tumor necrosis 100 mg
daily 3/3 2/3 1 G3
asthenia 1 G3 hypertension 150 mg daily
1/1 1/1 1 G3 asthenia
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SunitinibPhase I Summary

• Objective response or disease stabilization in
  solid tumors (N 117)

• SD (number of patients)
• CRC (5)
• PC (2)
• NSCLC (1)

• PR (number of patients)
• GIST (4)
• Thyroid (3)
• RCC (4)
• NET (2)
• Sarcoma (2)
• NSCLC (1)
• Melanoma (1)

Demetri et al. Proc Am Soc Clin Oncol.
200322814 Raymond et al. Proc Am Soc Clin
Oncol. 200322192 Rosen et al. Proc Am Soc Clin
Oncol. 200322191.CRC colorectal cancer GIST
gastrointestinal stromal tumor NET
neuroendocrine tumorsPC prostate cancer RCC
renal cell cancer.
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Patient aged 45 with Metastatic renal cell
carcinoma
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Phase II Evaluation of Sunitinib in Metastatic RCC
Two Independent, Single-Arm, Multicenter, Phase
II Studies (Study 014 N63 Study 1006 N106)
Patients with Advanced Disease and Failure of
Prior Cytokine Therapy
Continue Sunitinib Treatment Unless Progression
or Intolerability
Sunitinib
4 weeks on, 2 week off (4/2)
Dosing schedule
Sunitinib
Sunitinib
50mg/day

Dose reduction permitted (to 37.5mg/day and then
to 25mg/day)
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Response (Investigator Assessment) to Sunitinib
in Patients with Metastatic RCC

Study ongoing
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Study Design
Sunitinib 50 mg PO QD (Schedule 4/2)

• Eligibility Criteria
• Clear cell histology
• No prior systemic treatment
• Measurable disease
• ECOG PS of 0 or 1
• Adequate organ function

(n375)
(N750)
RANDOM I Z A T I ON
IFN-a 9 MU SQ TIW
(n375)

• Primary endpoint Progression-free survival
• Secondary endpoints Response rate, overall
  survival, patient-reported outcomes, safety

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Patient Baseline Characteristics
Data missing for 15 pts
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Best Response
Sunitinib vs IFN-? Plt0.000001
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Progression-Free Survival(Independent Central
Review)
a
No. at Risk Sunitinib 375 240
156 54 10
1 IFN-a 375
124 46 15
4 0

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Progression-Free Survivalby MSKCC Risk Status
Independent Central Review
MSKCC Risk Factors 0 (Favorable)
MSKCC Risk Factors 12 (Intermediate)
MSKCC Risk Factors 3(Poor)
1.0 0.8 0.6 0.4 0.2 0
1.0 0.8 0.6 0.4 0.2 0
1.0 0.8 0.6 0.4 0.2 0
Sunitinib (n209)Median 11 months(95 CI
1111)
Sunitinib (n23)Median 4 months(95 CI 110)
IFN-? (n212)Median 4 months (95 CI 34)
IFN-? (n25)Median 1 month (95 CI 12)
Hazard ratio0.534(95 CI 0.2311.234)
Progression-free survival probability
Sunitinib (n143)Median not reached
IFN-? (n121)Median 8 months (95 CI 7NA)
Hazard ratio0.388(95 CI 0.2810.537)
Hazard ratio0.371(95 CI 0.2140.643)
0 2 4 6 8 10 12 14
0 2 4 6 8 10 12 14
0 2 4 6 8 10 12 14
Time (months)
Time (months)
Time (months)
Motzer et al. J Clin Oncol 200220289-296
excludes 17 pts from IFN-? with missing data
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Multivariate Analysis of Pretreatment Features
Predictive of Progression-free Survival to
Sunitinib
Outcome by investigator assessment
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Progression-free Survival According to Risk
Factors Derived from Sunitinib Treated Patients
Outcome by investigator assessment
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Laboratory Abnormalities
Comparison between sunitinib and IFN-?
significant (Plt0.05) for the sum of grade 3 and 4
adverse events
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Treatment-Related Adverse Events
Comparison between sunitinib and IFN-?
significant (Plt0.05) for the sum of grade 3 and 4
adverse events
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Probability of PR or CR in mRCC Increased with
Mean Daily Sunitinib Exposure
1.0
Mean 95 CI
0.8
0.6
Probability of a response
0.4
P0.023 for AUC
0.2
0.0
0.5
1.0
1.5
2.0
AUCss sunitinib (ughr/mL)
HOUK et al, ASCO 07
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Longer TTP and OS in mRCC Patients with the
Highest Sunitinib Exposure
Time to tumor progression
Overall survival
AUCgtMedian (N120)
AUCgtMedian (N120)
AUCltMedian (N117)
AUCltMedian (N117)
1.0
1.0
0.8
0.8
0.6
0.6
Historical placebo median
Fraction of patientsnot progressed
Fraction of patientssurviving
Historical placebo median
0.4
0.4
0.2
0.2
P0.014 Relative risk 0.49
P0.001 Relative risk 0.52
0.0
0.0
500
500
600
0
100
200
300
400
0
100
200
300
400
Days
Days
HOUK et al, ASCO 07
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Similar TTP and OS for 37.5 mg/day CDand 50
mg/day 4/2 Schedules
Time to tumor progression
Overall survival
50 mg/day 4/2 (N188) 37.5 mg/day CD (N49)
50 mg/day 4/2 (N188) 37.5 mg/day CD (N49)
1.0
1.0
0.8
0.8
0.6
0.6
Fraction of patientsnot progressed
Fraction of patientssurviving
0.4
0.4
0.2
0.2
0.0
0.0
500
500
600
0
100
200
300
400
0
100
200
300
400
Time (days)
Time (days)

• Caveats for grouping patients by treatment
  regimen
• dose titration
• dose escalation
• unscheduled dose interruptions

HOUK et al, ASCO 07
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Future challenges
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Sunitinib DCE-MRI Evaluation
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Sunitinib CT Scan Perfusion
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Sunitinib CT Scan Perfusion
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Sunitinib and brain metastases
Thibault et al, J Neuro Oncol., 2007
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Cross resistance

• Sunitinib after Sorafenib failure
• N22 pts
• PR 22.7
• median TTP 22 weeks.

SABLIN MP et al, ASCO 07
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Predictive factors?
RIXE O. et al, Annals Oncol, 2007
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Clinical trials

• Adjuvant phase III study in a selected high-risk
  population (sunitinib vs placebo, 1-year)
  S-TRAC
• Neoadjuvant phase II study in inoperable disease
• Ancillary studies
• Biomarkers
• Imaging

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Summary and Conclusions

• Patients with mRCC receiving sunitinib
  experienced a significantly longer
  progression-free survival than those receiving
  IFN-? (Plt0.001)
• all prognostic sub-groups benefited from
  sunitinib
• The objective response rate was significantly
  higher in the sunitinib than in the IFN-? group
  (Plt0.001)
• Sunitinib treatment was associated with an
  acceptable safety profile
• Drugging the renal cancer kinome is validated by
  these results
• Sunitinib is a new treatment option providing
  hope for patients with mRCC, and should be
  considered one of the reference standard for the
  first-line treatment of mRCC