Nexavar in Patients with Renal
Cell Carcinoma
Naomi B. Haas
October 4, 2007
• Nephrectomy
• Metastectomy
– Solitary lesions
• Cytokine combination
• Combined modalities
– Adjunctive nephrectomy
prio...
BHD=Birt-Hogg-Dubé; FH=fumarate hydratase; VHL=von Hippel-Lindau.
Modified from Linehan WM et al. J Urol. 2003;170:2163-21...
Treatment of Advanced Disease
• Based in part on risk factors
Motzer RJ et al. J Clin Oncol. 2002;20:289-296.
MSKCC Risk Factor Model in
mRCC
0 risk factors (n=80 patients)
1 or 2 risk...
ADVERSE PROGNOSTIC FACTORS FOR
RENAL CELL CARCINOMA Motzer et al, JCO
17:2530-2540, 1999
Risk # Risk Factors Median Surviv...
Do patients with advanced disease
do better with nephrectomy?
Performance status matters
This issue has not been addressed...
Advanced Disease Therapy in
2007
• Multitargeted tyrosine kinase inhibitors
• Mammalian target of rapamycin (mTor)
inhibit...
The molecular profiles associated with the
various histologic RCC subtypes have
identified logical targets
• Pathways asso...
Target Sunitini
b
Sorafe
nib
AG013
736
GW78
6034
ABT-
869
PTK-
787
Bevacizu
mab
Temsirolimus/
Everolimus
Vascular
endothel...
Common Treatment related side effects
Toxicity
Sunitinib
(n= 169)
Sorafenib
(n=451)
Bevacizumab
(n=39)10mg/kg
Temsirolimus...
Bevacizumab for mRCC:
Phase II Study Design
High dose = 10 mg/kg (n=39)
Low dose = 3 mg/kg (n=37)
Placebo (n=40)
Second ra...
Bevacizumab for mRCC:
Summary
• No significant difference in OS between treatment groups
• High dose (10 mg/kg)
– PR = 10%...
Phase III study (AVOREN) of bevacizumab/interferon-
α2a vs placebo/interferon- α2a as first-line therapy in
metastatic RCC...
Sorafenib (Nexavar®)
• Small-molecule receptor TKI1
• Inhibits VEGFR-2, VEGFR-3, FLT-3, PDGFR, c-KIT, Raf
kinases1
• Formu...
Median PFS from randomization
Sorafenib=24 weeks
Placebo=6 weeks
P=.0087
Sorafenib for mRCC: Phase II (RDT)
Progression-Fr...
Sorafenib for mRCC:
Tumor Reduction* (TARGET)
* Investigator assessment. Patients randomized at least 6 weeks before data ...
PFS Median (months)
Sorafenib
Placebo
5.5
2.8
Hazard ratio (S/P) 0.51
Time From Randomization (months)
ProportionofPatient...
Sorafenib for mRCC:
Overall Survival* (TARGET)
OS Median (months)
Sorafenib
Placebo
Not reached
14.7
Hazard ratio (S/P) 0....
Conclusions
• Statistically significant improvement in
progression free survival compared to
placebo in patients with prio...
Sunitinib (Sutent®)
• Small-molecule receptor TKI1
• Inhibits all VEGFRs, PDGFR-a, PDGFR-b, c-KIT, and FLT-
31
• Formulati...
Results
• Median PFS 11 months for sunitinib vs. 5
months for IFN-α (p<0.000001)].
• The objective response rate by third-...
Conclusion
• Statistically significant improvement
in PFS and objective response rate
for sunitinib over IFN-α in first-li...
Targeted Therapy: More Questions Than
Answers
1. First Line:Should we combine these
agents?
Sequentially or concurrently?
...
6. Treatment duration-are these agents purely
angiostatic?
7. Assessment of Response-
Which is more important: RECIST or P...
Sequential Use of
Nexavar and Sunitinib:
Retrospective Analysis in 90 Patients
MKI Sequencing: Study Design
N=90
4 sites in France
RCC patients in
expanded access
programs
Reviewed
• Patient demographi...
MKI Sequencing:
Efficacy of Nexavar→Sunitinib
Sunitinib
Nexavar
PR
n (%)
SD
n (%)
PD
n (%)
NE
n (%)
PR, n 11 2 (18) 7 (64)...
MKI Sequencing:
Efficacy of Sunitinib→Nexavar
Nexavar
Sunitinib
PR
n (%)
SD
n (%)
PD
n (%)
PR, n 5 1 (20) 2 (40) 2 (40)
SD...
Phase II Trial of Intrapatient
Dose-Escalated-Nexavar in Patients
With Metastatic Renal Cell Cancer
Dose-Escalated Nexavar for RCC:
Study Design
• 1º endpoints: Safety and toxicity
• 2º endpoints: RR, PFS, and OS
Treatment...
Dose-Escalated Nexavar for RCC:
Baseline Patient CharacteristicsN=44
Characteristics N %
Median age, years (range) 50 Rang...
Dose-Escalated Nexavar for RCC:
Baseline Patient Characteristics
(cont’d) N=44
Characteristics N %
Prior systemic therapy ...
Dose-Escalated Nexavar for RCC:
Intensity of Therapy
• At 800-mg dose level:
– 5 patients had dose held between Weeks 2 th...
Dose-Escalated Nexavar for RCC:
Best Response by RECIST
Best Response No. of Patients (%)
Complete response 7 16
Partial r...
Dose-Escalated Nexavar for RCC:
Incidence of Treatment-Related AEs
Cycle 1
Days 1-28 (n=44)
Cycle 2
Days 29-56 (n=41)
Cycl...
Dose-Escalated Nexavar for
RCC: Conclusions
• Dose-escalated Nexavar was well tolerated when
given twice daily by oral adm...
Sorafenib for mRCC:
Tumor Response (TARGET)
Pre-Therapy 8 Weeks Post-Therapy
Image courtesy of Laura Wood, RN, MSN, OCN.
Management of Early-Stage RCC
• Surgery
– Partial or radical
nephrectomy
– Open surgery
– Laparoscopic
– Cryoablation or
r...
Predictors of Relapse
• Prognostic models based on postoperative
score:
– UCLA Integrated Staging System (UISS)
– Leibovic...
Contributors to Prognosis
• Pathologic stage
• Histology
• Fuhrman Grade
• Nuclear grade
• Performance status
• Necrosis
•...
The UCLA Integrated staging system (UISS)
UISS
Survival
1997 TNM
Stage (%)
Fuhrman
Grade
ECOG 2 Yr.
Survival
(%)
5Yr
I 1,2...
Stratify
Risk by TNM
Stage/Grade
Intermediate Risk
High Risk
Histologic
Subtype
Clear cell
Non-clear cell
Performance
stat...
Objectives
Primary Question:
• Can adjuvant therapy with an oral raf
kinase inhibitor/ receptor tyrosine kinase
inhibitor ...
Secondary Objectives
• Overall survival
• Toxicity in the adjuvant setting
• Prospective collection of tumor and biologic
...
Nexavar for 1 year, then
placebo for 2 years
(n=621)
Nexavar in Adjuvant RCC:
MRC SORCE Phase III Trial
• 1º endpoint: Met...
Developments
• ECOG BEST Trial (4 arm) of Doublet
Targeted therapy (tem/bev vs bev vs
sorafenib/bev vs sorafenib/tem
• Tem...
Conclusions
• Surgery remains the most effective therapy
for early RCC and plays a role in advanced
RCC
• New molecular ta...
Common Treatment related side effects
Toxicity
Sunitinib
(n= 169)
Sorafenib
(n=451)
Bevacizumab
(n=39)10mg/kg
Temsirolimus...
Targeted Therapy: More Questions Than
Answers
1. First Line:Should we combine these
agents?
Sequentially or concurrently?
...
6. Treatment duration-are these agents purely
angiostatic?
7. Assessment of Response-
Which is more important: RECIST or P...
Stratify
Risk by TNM
Stage/Grade
Intermediate Risk
High Risk
Histologic
Subtype
Clear cell
Non-clear cell
Performance
stat...
Nexavar in Patients with Renal Cell Carcinoma
Nexavar in Patients with Renal Cell Carcinoma
Nexavar in Patients with Renal Cell Carcinoma
Nexavar in Patients with Renal Cell Carcinoma
Nexavar in Patients with Renal Cell Carcinoma
Nexavar in Patients with Renal Cell Carcinoma
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Nexavar in Patients with Renal Cell Carcinoma

  1. 1. Nexavar in Patients with Renal Cell Carcinoma Naomi B. Haas October 4, 2007
  2. 2. • Nephrectomy • Metastectomy – Solitary lesions • Cytokine combination • Combined modalities – Adjunctive nephrectomy prior to cytokine therapy – Cytokine therapy followed by nephrectomy • Clinical trials Historical Management of Advanced-Stage RCC National Comprehensive Care Network. Clinical Practice Guidelines in Oncology: Kidney Cancer: Version 2. 2006. Jenkintown, PA: National Comprehensive Cancer Network; 2006. Figure adapted from Urban BA, Fishman EK. Radiographics. 2000;20:197-212.
  3. 3. BHD=Birt-Hogg-Dubé; FH=fumarate hydratase; VHL=von Hippel-Lindau. Modified from Linehan WM et al. J Urol. 2003;170:2163-2172. RCC is not one disease Clear cell 75% Type Incidence (%) Associated mutations VHL Papillary type 1 5% c-Met Papillary type 2 10% FH Chromophobe 5% BHD Oncocytoma 5% BHD *2004 WHO lists over 50 different types of kidney cancer (Sarcomatoid variant can occur with any subtype) Undifferentiated type and Collecting duct carcinoma constitute the other 2 types listed in AJCC classification
  4. 4. Treatment of Advanced Disease • Based in part on risk factors
  5. 5. Motzer RJ et al. J Clin Oncol. 2002;20:289-296. MSKCC Risk Factor Model in mRCC 0 risk factors (n=80 patients) 1 or 2 risk factors (n=269 patients) 3, 4, or 5 risk factors (n=88 patients) Risk factors associated with worse prognosis • KPS <80 • Low serum hemoglobin (13 g/dL/11.5 g/dL: M/F) • High corrected calcium (10 mg/dL) • High LDH (300 U/L) • Time from Dx to IFN- <1 yr Time From Start of IFN- (years) ProportionSurviving 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 2 1614131195436 151210876
  6. 6. ADVERSE PROGNOSTIC FACTORS FOR RENAL CELL CARCINOMA Motzer et al, JCO 17:2530-2540, 1999 Risk # Risk Factors Median Survival • Favorable 0 29 mo. • Intermediate 1-2 14 mo. • Poor 3 and + 4 mo.
  7. 7. Do patients with advanced disease do better with nephrectomy? Performance status matters This issue has not been addressed in the era of targeted therapy
  8. 8. Advanced Disease Therapy in 2007 • Multitargeted tyrosine kinase inhibitors • Mammalian target of rapamycin (mTor) inhibitors • Anti VEGF antibodies • VEGF Trap • Other angiogenesis inhibitors- thrombospondin inhibitors, pure PDGFR and VEGFR inhibitors
  9. 9. The molecular profiles associated with the various histologic RCC subtypes have identified logical targets • Pathways associated with EGFR, AKT/mTOR, MAPK/MEK, and VEGF are important in RCC • Drugs available in 2007 – Multitargeted TK inhibitors: • sunitinib, sorafenib, (FDA approved) • GW786034, AG013736,ABT869 – Antibodies: • Bevacizumab – Imids: CC-5013 – mTor inhibitors: temsirilimus, RAD001, rapamycin
  10. 10. Target Sunitini b Sorafe nib AG013 736 GW78 6034 ABT- 869 PTK- 787 Bevacizu mab Temsirolimus/ Everolimus Vascular endothelial growth factor (VEGF) N N N N N N Y N VEGFR1 (Flt-1) Y N Y Y Y Y N N VEGFR2 (Flk-1/KDR) N Y Y Y Y Y N N VEGFR3 (FLT-4) Y Y Y Y N N Platelet derived growth factor receptor  N N Y N N N PDGFR- Y Y Y Y Y N N N c-kit Y Y Y Y Y N N N FLT-3 Y Y Y U Y N N N Receptor Stem cell factor (SCF) Y N U U N N N RET Y N Y N U N N N FAK (focal adhesion kinase) N N N N U N N N Basic fibroblast growth factor (b- FGF) Y Y Y Y Y N N N B-raf kinase N Y N N N N N N c-raf kinase N Y N N N N N N Mammalian target of rapamycin (MTOR) N N N N N N N Y
  11. 11. Common Treatment related side effects Toxicity Sunitinib (n= 169) Sorafenib (n=451) Bevacizumab (n=39)10mg/kg Temsirolimus (n=212) Fatigue Likely Likely Less likely Likely Hand-Foot Syndrome Less likely Likely ND ND Other Rash Less likely Likely Likely Likely Hypertension Less likely Less likely Likely ND Edema Less likely ND ND Less likely Dyspnea Less likely Less likely ND Likely LVEF decline Rare ND ND ND Anorexia Likely Less likely ND Likely Diarrhea Likely Likely ND Likely Stomatitis Likely Less likely ND Likely Nausea Likely Less likely ND Likely Bleeding Less likely Less likely Less likely Rare Thrombosis Rare Rare Rare ND Hypothyroidism Less likely ND ND ND High AST/ALT Less likely Less likely Less likely Less likely High amylase/lipase Less likely Less likely ND ND High Cholesterol ND ND ND Likely High Triglycerides ND ND ND Likely Low Phosphorus Less likely Less likely ND Likely Neutropenia Less likely Less likely ND Likely Thrombocytopeni a Less likely Less likely ND Likely GI perforation Rare Rare Rare ND
  12. 12. Bevacizumab for mRCC: Phase II Study Design High dose = 10 mg/kg (n=39) Low dose = 3 mg/kg (n=37) Placebo (n=40) Second randomization of placebo group at TTP to low-dose bevacizumab +/- thalidomide. Yang JC et al. N Engl J Med. 2003;349:427-434. • 1° end points: TTP and ORR • 2° end point: OS • Study arms were balanced for demographics mRCC patients (N=116) ECOG PS <2 All patients have prior therapy (mostly IL-2)
  13. 13. Bevacizumab for mRCC: Summary • No significant difference in OS between treatment groups • High dose (10 mg/kg) – PR = 10% (95 CI, 2.9%–24.2%) – Significantly prolonged PFS (median 4.8 months, P<.001) – Moderate toxicity profile – No Grade 4 AE or deaths related to therapy • Proteinuria 64% (any grade) • Hypertension 36% (any grade) • Low dose (3 mg/kg) – Not significant
  14. 14. Phase III study (AVOREN) of bevacizumab/interferon- α2a vs placebo/interferon- α2a as first-line therapy in metastatic RCC Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 3 641 patients + nephrectomy + clear cell RCC IFN (9 MIU 3x weekly) + bevacizumab(10mg/kg) IVq2w (320) IFN (9 MIU 3x weekly) + placebo (321) The addition of BEV to IFN-a2a significantly increased PFS (10.2 vs. 5.4 mo) (HR=0.63; p<0.0001) and objective tumor response rate (30.6% vs. 12.4%; p<0.0001). A trend toward improved OS was observed with the addition of BEV to IFN-a2a (p=0.0670).
  15. 15. Sorafenib (Nexavar®) • Small-molecule receptor TKI1 • Inhibits VEGFR-2, VEGFR-3, FLT-3, PDGFR, c-KIT, Raf kinases1 • Formulation: 200 mg tablets2 • Dosing: 2 tablets bid continuous (1 hr ac or 2 hrs pc)2 • FDA approved December 20, 2005 for advanced RCC3 1. Wilhelm SM et al. Cancer Res. 2004;10:7099-7109. 2. Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA: Onyx Pharmaceuticals, Inc.; 2005. 3. Food and Drug Administration. FDA approves new treatment for advanced kidney cancer. Available at: www.fda.gov/bbs/topics/NEWS/2005/NEW01282.html. Accessed January 24, 2006. N H N H O O O N CI CF3 NH CH3
  16. 16. Median PFS from randomization Sorafenib=24 weeks Placebo=6 weeks P=.0087 Sorafenib for mRCC: Phase II (RDT) Progression-Free Survival Time From Randomization (days) ProportionofPatients Progression-Free 1.00 0.75 0.50 0.25 0 12-week period 84 0 100 200 300 400 500 Ratain MJ et al. Presented at: ASCO; May 13-17, 2005; Orlando FL. Sorafenib (n=33) Placebo (n=32) Censored
  17. 17. Sorafenib for mRCC: Tumor Reduction* (TARGET) * Investigator assessment. Patients randomized at least 6 weeks before data cut-off of May 31, 2005. Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France. Sorafenib (n=451)Placebo (n=452) Tumor Reduction Tumor Reduction PR (30% or reduction, RECIST). ChangeFromBaseline(%)* 25% 76% ChangeFromBaseline(%)* 0 50 100 150 -50 -100 0 50 100 150 -50 -100 PD (20% increase, RECIST);
  18. 18. PFS Median (months) Sorafenib Placebo 5.5 2.8 Hazard ratio (S/P) 0.51 Time From Randomization (months) ProportionofPatients ProgressionFree 0 0.25 0.50 0.75 1.00 0 4 10 202 6 8 12 14 16 18 Sorafenib for mRCC: Progression-Free Survival* (TARGET) * Investigator assessment. Independent assessment at planned interim analysis (ASCO 2005) demonstrated doubling of PFS for sorafenib vs placebo (24 vs 12 weeks, P<.000001). Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France. Censored observation Placebo (n=452) Sorafenib (n=451)
  19. 19. Sorafenib for mRCC: Overall Survival* (TARGET) OS Median (months) Sorafenib Placebo Not reached 14.7 Hazard ratio (S/P) 0.72 P=.018 Censored observation Placebo (n=452) Sorafenib (n=451) Time From Randomization (months) ProportionofPatients OverallSurvival 0 0.25 0.50 0.75 1.00 0 4 10 202 6 8 12 14 16 18 *Interim analysis. Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France.
  20. 20. Conclusions • Statistically significant improvement in progression free survival compared to placebo in patients with prior cytokine therapy • Improvement in OS may have been affected by crossover and was not achieved in final analysis
  21. 21. Sunitinib (Sutent®) • Small-molecule receptor TKI1 • Inhibits all VEGFRs, PDGFR-a, PDGFR-b, c-KIT, and FLT- 31 • Formulation: 12.5 mg, 25 mg, 50 mg capsules2 • Dosing: 50 mg qd ± food (4 wks on, 2 wks off)2 • FDA approved January 26, 2006 for advanced RCC 1. Pietras K, Hanahan D. J Clin Oncol. 2005;23:939-952. 2. Sutent [package insert]. New York, NY: Pfizer Inc.; 2006. H3C CH3 F O O CH3 CH3 N H N H N N H
  22. 22. Results • Median PFS 11 months for sunitinib vs. 5 months for IFN-α (p<0.000001)]. • The objective response rate by third-party independent review was 31% for sunitinib vs. 6% for IFN-α (p<0.000001). • 8% withdrew from the study due to adverse event on sunitinib arm vs. 13% on IFN-α arm.
  23. 23. Conclusion • Statistically significant improvement in PFS and objective response rate for sunitinib over IFN-α in first-line treatment of patients with metastatic RCC
  24. 24. Targeted Therapy: More Questions Than Answers 1. First Line:Should we combine these agents? Sequentially or concurrently? Vertical inhibition or horizontal inhibition? 2. Which Type of Agent should be used first? mTKI or mTor inhibitor? 3. At Progression Dose escalation of mTKI vs other mechanism?
  25. 25. 6. Treatment duration-are these agents purely angiostatic? 7. Assessment of Response- Which is more important: RECIST or PFS? 8. Predictors of Response Blood flow/ vascularity histology Imaging- PET/CT, DCE/MRI, CT 9. Role of agents-Adjuvant?, First-line? Before or after cytokines? 10. Exposure to agent- drug levels of sunitinib correlated with response 11. Dose escalation of agent –some patients can tolerate dose escalation at the time of progression 12. How to treat non clear cell and other variants
  26. 26. Sequential Use of Nexavar and Sunitinib: Retrospective Analysis in 90 Patients
  27. 27. MKI Sequencing: Study Design N=90 4 sites in France RCC patients in expanded access programs Reviewed • Patient demographics • MSKCC • No. of metastatic sites Efficacy • OS • PFS • Best response • Safety Retrospective review of sequential therapy with MKIs in RCC Nexavar → Sunitinib n=68 Sunitinib → Nexavar n=22 MKI=multikinase inhibitor. Adapted from Sablin MP et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
  28. 28. MKI Sequencing: Efficacy of Nexavar→Sunitinib Sunitinib Nexavar PR n (%) SD n (%) PD n (%) NE n (%) PR, n 11 2 (18) 7 (64) 2 (18) – SD, n 45 6 (13) 24 (53) 11 (25) 4 (9) PD, n 10 2 (20) 3 (30) 4 (40) 1 (10) NE, n 2 – 1 – 1 Adapted from Sablin MP et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
  29. 29. MKI Sequencing: Efficacy of Sunitinib→Nexavar Nexavar Sunitinib PR n (%) SD n (%) PD n (%) PR, n 5 1 (20) 2 (40) 2 (40) SD, n 12 1 (8) 7 (58) 4 (34) PD, n 5 0 3 (60) 2 (40) Adapted from Sablin MP et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
  30. 30. Phase II Trial of Intrapatient Dose-Escalated-Nexavar in Patients With Metastatic Renal Cell Cancer
  31. 31. Dose-Escalated Nexavar for RCC: Study Design • 1º endpoints: Safety and toxicity • 2º endpoints: RR, PFS, and OS Treatment continues until PD or intolerance Target accrual: 44 patients. Response assessed by RECIST every 8 weeks. DLT=dose-limiting toxicities; Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL. Eligibility • Metastatic RCC, component of clear-cell • ≤1 prior cytokine therapy • Adequate PS • Adequate pancreatic and cardiac function After 4 weeks, patients with no DLT (grade 3/4) increase dose After 4 weeks, patients with no DLT (grade 3/4) increase dose Nexavar 800 mg po bid Days 57+ Nexavar 400 mg po bid Days 1-28 Nexavar 600 mg po bid Days 29-56
  32. 32. Dose-Escalated Nexavar for RCC: Baseline Patient CharacteristicsN=44 Characteristics N % Median age, years (range) 50 Range 43-79 Male/female 37/7 84/16 Zubrod PS, (0/1) 39/5 89/11 Clear Cell (CC) 35 80 Other histology 9 20 CC/Sarcomatoid 7 CC/Focal Rhabdoid 1 CC/Papillary 1 Prior nephrectomy 42 95 Prior radiation therapy 10 23 MSKCC Risk Factors 0 18 41 1 17 38 2 6 14 3 3 7 Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
  33. 33. Dose-Escalated Nexavar for RCC: Baseline Patient Characteristics (cont’d) N=44 Characteristics N % Prior systemic therapy 19 43 IL-2 15 RAD001 2 Interferon 1 cG250 1 Best response to prior systemic CR/PR 3/2 16/11 Total number of metastatic sites 1 26 59 2 11 25 ≥3 7 16 CR=complete response; IL-2=interleukin 2; PR=partial response. Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
  34. 34. Dose-Escalated Nexavar for RCC: Intensity of Therapy • At 800-mg dose level: – 5 patients had dose held between Weeks 2 through 4 – 3 patients were dose reduced • Doses were escalated to 1200 mg in 41 of 44 patients • Doses were escalated to 1600 mg in 32 of 41 patients – 25 patients maintained dose – 7 patients were dose reduced • Summary – 41 patients were able to receive 1200 or 1600 mg per day of Nexavar – 3 patients were unable to be dose escalated – Those with early toxicity have difficulty with dose escalation Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
  35. 35. Dose-Escalated Nexavar for RCC: Best Response by RECIST Best Response No. of Patients (%) Complete response 7 16 Partial response 17 39 Stable disease ≥6 months 9 20 Progression defined as ≤4 months 11 25 Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
  36. 36. Dose-Escalated Nexavar for RCC: Incidence of Treatment-Related AEs Cycle 1 Days 1-28 (n=44) Cycle 2 Days 29-56 (n=41) Cycle 3 Days 57+ (n=32) Adverse Events G1 G2 G3 G1 G2 G3 G4 G1 G2 G3 Hand-foot syndrome 13 2 2 18 4 2 — 21 2 1 Diarrhea 11 — 1 13 2 — — 16 4 — Fatigue 9 1 — 11 — — — 13 1 1 Nausea 9 — 1 4 — — — 6 2 — Rash 7 2 1 7 — — — 7 — — Hypertension 5 3 — 7 2 — — 6 3 — Stomatitis 5 — — 8 — — — 18 — — Alopecia 4 — — 10 — — — 17 — — Anorexia 4 — — 8 — — — 6 — — Dry skin 2 — — 4 1 — — 4 1 — Stomatitis 1 — — — — — — — — — Anemia 16 — — 16 — — — 14 — 1 ALT/AST 6 — — 7 1 1 1 9 3 1 Amylase/lipase 5 — 3 3 — 1 — 6 1 1 Hypophosphatemia — 12 6 10 3 — — 2 8 9 AEs=adverse events; ALT=alanine aminotransferase; AST=aspartate aminotransferase. Adapted from Amato RJ et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
  37. 37. Dose-Escalated Nexavar for RCC: Conclusions • Dose-escalated Nexavar was well tolerated when given twice daily by oral administration • 93% of patients were able to be dose escalated to either 1200 or 1600 mg per day • A high level of antitumor activity was demonstrated by a 55% complete and partial response rate in patients with metastatic RCC • Follow-up trials are in progress to verify these data Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
  38. 38. Sorafenib for mRCC: Tumor Response (TARGET) Pre-Therapy 8 Weeks Post-Therapy Image courtesy of Laura Wood, RN, MSN, OCN.
  39. 39. Management of Early-Stage RCC • Surgery – Partial or radical nephrectomy – Open surgery – Laparoscopic – Cryoablation or radiofrequency ablation • Adjuvant Tx – No benefit from adjuvant interleukin2 or interferon – No benefit from radiation therapy – Benefit from adjuvant targeted therapy is unknown • Neoadjuvant- investigational National Comprehensive Care Network. Clinical Practice Guidelines in Oncology: Kidney Cancer: Version 2. 2006. Jenkintown, PA: National Comprehensive Cancer Network; 2006. Figure adapted from Urban BA, Fishman EK. Radiographics. 2000;20:197-212.
  40. 40. Predictors of Relapse • Prognostic models based on postoperative score: – UCLA Integrated Staging System (UISS) – Leibovich Model – Frank Model (SSIGN) – Kattan Model • Prognostic Models based on preoperative score: – Yaycioglu – Cindolo
  41. 41. Contributors to Prognosis • Pathologic stage • Histology • Fuhrman Grade • Nuclear grade • Performance status • Necrosis • Size • Clinical Presentation
  42. 42. The UCLA Integrated staging system (UISS) UISS Survival 1997 TNM Stage (%) Fuhrman Grade ECOG 2 Yr. Survival (%) 5Yr I 1,2 96 94 II I I II III III 1,2 3,4 Any Any I 1 Any Any 0 1 or more 89 64 III III IV 2-4 1,2 1 or more 0 66 39 IV IV 3,4 1-3 0 1 or more 42 23 V IV 4 1 or more 9 0
  43. 43. Stratify Risk by TNM Stage/Grade Intermediate Risk High Risk Histologic Subtype Clear cell Non-clear cell Performance status Surgery Open vs laparoscopic Arm B Sorafenib 800mg daily for 1 year Arm C Placebo Daily for 1 year R A N D O M I Z E Non- Metastatic Kidney Cancer That meets radiologic criteria to be clinically  T1bNany (resectable) M0 disease S U R G E R Y Arm A Sunitinib 50 mg daily for 1 year R E G I S T R A T I O N 1 R E G I S T R A T I O N 2 A.S.S.U.R.E. (ECOG 2805)
  44. 44. Objectives Primary Question: • Can adjuvant therapy with an oral raf kinase inhibitor/ receptor tyrosine kinase inhibitor (Sorafenib) or pure receptor tyrosine kinase inhibitor (Sunitinib) improve disease-free survival in locally advanced RCC over placebo after surgical resection? • Primary endpoint is DFS
  45. 45. Secondary Objectives • Overall survival • Toxicity in the adjuvant setting • Prospective collection of tumor and biologic specimens /Correlatives: - Measures of angiogenesis - Mutational analyses (oncogenes/TSG) - Hypermethylation - Polymorphisms
  46. 46. Nexavar for 1 year, then placebo for 2 years (n=621) Nexavar in Adjuvant RCC: MRC SORCE Phase III Trial • 1º endpoint: Metastasis-free survival • 2º endpoints: RCC-specific survival time, toxicity, QoL, and biomarkers (1.5:1.5:1)Randomization (N=1656) High and intermediate risk, resected RCC Nephrectomy Placebo for 3 years (n=414) Nexavar for 3 years (n=621) MRC=Medical Research Council; QoL=quality of life; SORCE=SOrafenib versus placebo in patients with Resected primary renal CEll carcinoma.
  47. 47. Developments • ECOG BEST Trial (4 arm) of Doublet Targeted therapy (tem/bev vs bev vs sorafenib/bev vs sorafenib/tem • Temsirolimus versus sunitinib trial for non clear cell RCC • mTKI to mTOR vs mTor to mTKI trial • Adjuvant trials SORCE and ASSURE are ongoing
  48. 48. Conclusions • Surgery remains the most effective therapy for early RCC and plays a role in advanced RCC • New molecular targets have been identified which are critical to the pathogenesis of different types of RCC and new targeted therapies are replacing traditional biologic therapies • The ultimate role that these agents will play in RCC has yet to be decided
  49. 49. Common Treatment related side effects Toxicity Sunitinib (n= 169) Sorafenib (n=451) Bevacizumab (n=39)10mg/kg Temsirolimus (n=212) Fatigue Likely Likely Less likely Likely Hand-Foot Syndrome Less likely Likely ND ND Other Rash Less likely Likely Likely Likely Hypertension Less likely Less likely Likely ND Edema Less likely ND ND Less likely Dyspnea Less likely Less likely ND Likely LVEF decline Rare ND ND ND Anorexia Likely Less likely ND Likely Diarrhea Likely Likely ND Likely Stomatitis Likely Less likely ND Likely Nausea Likely Less likely ND Likely Bleeding Less likely Less likely Less likely Rare Thrombosis Rare Rare Rare ND Hypothyroidism Less likely ND ND ND High AST/ALT Less likely Less likely Less likely Less likely High amylase/lipase Less likely Less likely ND ND High Cholesterol ND ND ND Likely High Triglycerides ND ND ND Likely Low Phosphorus Less likely Less likely ND Likely Neutropenia Less likely Less likely ND Likely Thrombocytopeni a Less likely Less likely ND Likely GI perforation Rare Rare Rare ND
  50. 50. Targeted Therapy: More Questions Than Answers 1. First Line:Should we combine these agents? Sequentially or concurrently? Vertical inhibition or horizontal inhibition? 2. Which Type of Agent should be used first? mTKI or mTor inhibitor? 3. At Progression Dose escalation of mTKI vs other mechanism?
  51. 51. 6. Treatment duration-are these agents purely angiostatic? 7. Assessment of Response- Which is more important: RECIST or PFS? 8. Predictors of Response Blood flow/ vascularity histology Imaging- PET/CT, DCE/MRI, CT 9. Role of agents-Adjuvant?, First-line? Before or after cytokines? 10. Exposure to agent- drug levels of sunitinib correlated with response 11. Dose escalation of agent –some patients can tolerate dose escalation at the time of progression 12. How to treat non clear cell and other variants
  52. 52. Stratify Risk by TNM Stage/Grade Intermediate Risk High Risk Histologic Subtype Clear cell Non-clear cell Performance status Surgery Open vs laparoscopic Arm B Sorafenib 800mg daily for 1 year Arm C Placebo Daily for 1 year R A N D O M I Z E Non- Metastatic Kidney Cancer That meets radiologic criteria to be clinically  T1bNany (resectable) M0 disease S U R G E R Y Arm A Sunitinib 50 mg daily for 1 year R E G I S T R A T I O N 1 R E G I S T R A T I O N 2 A.S.S.U.R.E. (ECOG 2805)

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