Update on Evolving Therapies for Advanced Kidney Cancer
Nancy A. Dawson M.D.Professor of Medicine
Director, Genitourinary Oncology ProgramLombardi Comprehensive Cancer Center
Washington, DC
Case Study
• 51 yo male presented with headaches, confusion 4/04 MRI- 4 cm frontal mass/1.1 cm occipital mass. Resection frontal mass 4/04. Path – c/w renal cell carcinoma.
• CT chest/abdomen- numerous lung nodules, 8 cm R renal mass
• Whole brain XRT. Gamma knife to occipital mass. R nephrectomy- clear cell carcinoma
Case Study continued• Rx interferon 6/04-12/05 with slow growth of
lung nodules. Initial mild flu symptoms, resolved after 2 months
• 11/05 –two new lesions R occipital lobe, occasional flashing lights. Rx gamma knife
• 1/06 Nexavar 400mg bid started• 3/06 Severe fatigue, diarrhea, hand-foot
syndrome, hypertension requiring initiation of antihypertensive therapy.
• Nexavar decreased to 400mg qAM /200mg qPM with improvement
Case Study continued
• 7/06 Cyberknife to new brain lesion• 4/07 Near resolution all lung nodules. Pulseless
left arm. Nexavar held for subclavian artery bypass graft.
• 5/07 Nexavar X 1 month, poorly tolerated and stopped.
• 7/07 Solitary residual lung nodule resected (clear cell carcinoma). Acute coronary syndrome-emergent stents L main/RCA
Case Study continued
• 7/08 L common iliac artery stent placed• 8/08 Cyberknife to two new brain lesions• 1/09 Patient has been off all systemic therapy
since 6/07. No active cancer. Working full time. STILL SMOKING. Scheduled for stent of L axillary artery, bilateral carotid endarterectomies on 1/30/09
Educational Objectives
• Review pathophsiology of kidney cancer• Review rationale for targetted therapy• Review role of immunotherapy, surgery,
radiotherapy and targetted therapy in the management of metastatic renal cell carcinoma (mRCC)
• Review new targetted agents for mRCC in development
Renal Cell Carcinoma
• Approximately 51,190 new cases diagnosed in US and 12,890 deaths in 2007. Worldwide, 95,000 death annually.
• Kidney cancer has increased by 38% from 1974 to 1990
• About 30% cases present with unresectable disease.
BHD=Birt-Hogg-Dubé, FH=fumarate hydratase, VHL=von Hippel-Lindau.Modified from Linehan WM et al. J Urol. 2003;170:2163-2172.
Histological Classificationof Human Renal Cancers
RCC
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
Clear cell RCC is characterized by VHL gene inactivation
: selected series
Author VHL gene methylation
Herman, 1994 19% (5/26)
Clifford, 1998 15% (7/45)
Kondo, 2002 5.4% (11/202)
Brauch, 2000 7% (10/151)
Total 8% (33/424)
Author VHLgene mutation
Gnarra, 1994 57% (56/98)
Gallou, 1999 56% (73/130)
Brauch, 2000 45% (68/151)
Shuin, 1994&Kondo, 2002
51% (104/202)
Schraml, 2002 34% (38/113)
Total 49% (339/694)
Treatment for mRCC• Surgery: the only modality that appears to
offer cure in RCC.• Radiation: palliative for metastases.• Chemotherapy: low response rate (<10%)• Immunotherapy: 20-30% response,5%
durable CRs with high dose IL-2• Targetted Therapy: Prolonged PFS/OS!!
Solitary metastases• Series N 5yr OS
• Middleton, 1967 59 34%• Skinner, 1971 41 29%• Toli, 1975 19 35%• Kavolius, 1998 94 52%*
* Versus 29% for multiple
Solitary metastases• Site N=94 5yr OS
• Lung 50 54%• LNs 15 63%• Brain 11 18%• Bone 5 40%• Soft tissue 5 75%
Kavolius JP et al JCO 16: 2261, 1998
Interferon
• Meta-analysis on 1600 patients treated with IFN.• Response rate: 15%, CR: 2%• Response duration 6-10 months.• Longer response in patients with good performance
status and non-bulky pulmonary metastases.• Dosage: 3-20x106 units daily, no apparent dose-
response relationship.
Negrier S et al NEJM 338 1272-1278 1998
IL-2 for mRCC: ResponseHD IL-2(720,000 IU/kg)
LD IL-2(72,000 IU/kg)
SC IL-2(250,000 IU/kg d1-
5, 125,000 IU/kg
5x/wk)
Evaluable 96 92 93
CR 6% 1% 2%
PR 15% 10% 8%
Major RR 21% 11% 10%
Yang J et al. J Clin Oncol. 2003;21:3127-3132.
IL-2 for mRCC: SurvivalP
rop
ort
ion
Su
rviv
al
Survival Time (months)
0120
1.0
0.8
0.6
0.4
0.2
24 36 48 60 72 84 96 108 120 132
Comparison P value
HD vs LD
HD vs SC
.38
.34
LD IL-2 (Fail/Total 69/92)
HD IL-2 (Fail/Total 66/95)
SC IL-2 (Fail/Total 73/92)
Yang J et al. J Clin Oncol. 2003;21:3127-3132.
Common Toxicities AssociatedWith Cytokine Therapy
• HD IL-2
– Hypotension
– Capillary leak
– Neurologic
– Hematologic
– Pulmonary
– Renal/electrolytes
– Cardiac
• IFN-α– Constitutional– Neurologic– Hematologic
• IL-2 + IFN-α– Constitutional– Gastrointestinal
McDermott DF et al. J Clin Oncol. 2005;23:133-141.
β pVHL HIF=α
VEGFR EGFRPDGFR
Sunitinib, Sorafenib, AG-013736
Sorafenib
Bevacizumab
RAF
Erlotinib
Kaelin WG. Nat Rev Cancer. 2002;2:673-682.
RCC:Targets of Single Agents
VEGF TGF-αPDGF
RAF
Sorafenib
TemsorilimusEverolimus
Kim KJ, et al. Nature. 1993;362:841-844.Gordon MS, et al. J Clin Oncol. 2001;19:843-850.
Bevacizumab (Avastin)
• Humanized monoclonal anti-VEGF antibody• Binds and neutralizes all biologically active
forms of VEGF• Inhibits angiogenesis in experimental models• Inhibits human xenograft tumor growth in vivo
but not in vitro
Bevacizumab in RCC
Yang JC et al. NEJM 349(5), 2003
RANDOMIZE
BEVACIZUMAB (3 MG/KG) Q 2 WEEKS
(n=37)
PLACEBO Q 2 WEEKS
(n=40)
BEVACIZUMAB (10 MG/KG) Q 2 WEEKS
(n=39)
PD
Treatment-refractory, metastatic RCC
% o
f Pa
tien
ts F
ree
of P
rog
ress
ion
Time to Progression100
80
60
40
20
00 6 12 18 24
Months from On-Study Date
30 36 0 6 12 18 24 30 36
Low-dosePlacebo
High-dosePlacebo
p < 0.001p =0.041
AVOREN: An International Phase III Trial of Interferon Alpha-2a or Interferon Alpha-2a Plus
Bevacizumab in Advanced Renal Carcinoma
RANDOMIZE
IFN-alpha-2a
IFN-alpha-2a +
Bevacizumab 10 mg/kg IV
q 2 weeks
STRATIFY
UNTREATED, ADVANCED RCC; N=649
• 12/06 Planned interim analysis showed improved PFS for the combination, DSMB recommended unblinding of study and all patients offered Avastin
AVOREN
Escudier ASCO June 2008
Placebo BevacizumabInterferon Interferon P-value HR
Response rate 13% 31% <0.0001
PFS (months) 5.4 10.2 <0.0001 0.63
OS (months) 19.8 NR p<.027 0.75
CALGB 90206: A Randomized Phase III Trial of Interferon Alpha-2b or Interferon Alpha-2b Plus
Bevacizumab in Advanced Renal Carcinoma
RANDOMIZE
IFNA 9 MU TIW
IFNA 9 MU TIW +
Bevacizumab 10 mg/kg IV
q d1 and d15
STRATIFY
UNTREATED, METASTATIC CLEAR CELL
RCC
• Patients will be stratified for nephrectomy status and Motzer risk group (0, 1-2 or 3+ risk factors).
CALGB 90206
ASCO GU Symposium 2/08
Placebo BevacizumabInterferon Interferon P-value
Response rate 13.1% 25.5% <0.0001
(95%CI,9.5-17.3) (95%CI, 20.9-30.6)
TTP (months) 5.2 8.5 <0.0001
(95%CI, 3.1-5.6) (95%CI,7.5-9.7)
OS (months) NR NR
CALGB 90206Toxicity
DSMB review 6/22/2007
Placebo Bevacizumab Interferon Interferon
Hypertension 0% 9%
Anorexia 8% 17%
Fatigue 28% 35%
Proteinuria 0% 13%
Riedl B, et al. Proc Am Soc Clin Oncol. 2001;20:83a.
Wilhelm S, et al. Cancer Res. 2004;64:7099–7109.
Sorafenib (Nexavar)
• Sorafenib selectively inhibits B-RAF, VEGFR-2, VEGFR-3, PDGFR-β, FLT-3, and c-KIT
• Originally identified through inhibitory effects on RAF-1, a serine-threonine kinase
• Inhibits angiogenesis in experimental models• Inhibits growth of human renal cell carcinoma
xenografts
>25% Tumor
shrinkage
-25% to +25%Tumor
stabilization
>25%Tumor growth
Sorafenib12-weekrun-in
Continuesorafenib
Continue sorafenib12 weeks
Placebo12 weeks
Off study
16 (50%) SD at
24 weeks
6 (18%) SD at
24 weeks
SD = Stable Disease Ratain MJ, et al. ASCO 2005, abstract 4544.
Randomized Discontinuation Trial:Patient Outcome
Randomized Discontinuation Trial:
Progression-Free Survival (PFS)
Ratain MJ, et al. ASCO 2005, abstract 4544.
0.00
0.25
0.50
0.75
1.00
Su
rviv
al D
istr
ibu
tio
n
Fu
nct
ion
–84 0 50 100 150 200 250 300 35012 -week
run -in period Days from Randomization
450400
Median PFS from randomization:
Placebo = 6 weeks
Sorafenib = 24 weeks
p = 0.0087
Sorafenib (n=32)
Placebo (n=33)
Censored
SorafenibSorafenib400 mg bid400 mg bid Major end points
• Survival (α=0.04)
• PFS (α=0.01)
Escudier B, et al. NEJM 2007;356:125-134.
Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGETs):Study Design and Objectives
PlaceboPlacebo
(1:1) Randomization
N=903
Eligibility criteria
• Histologically/cytologically confirmed, unresectable and/or metastatic disease
• Clear cell histology
• Measurable disease
• Failed one prior systemic therapy in last 8 months
• ECOG PS 0 or 1
• Good organ function
• No brain metastasis
• Poor-risk MSKCC group excluded
Stratification• MSKCC criteria
• Country
Objective Responses by Investigator Assessment
* Patients randomized at least 6 weeks before data cut-off of May 31, 2005
Sorafenib (n=451)*
Placebo (n=452)*
Complete Response (CR) 1 (<1) 0 (0)
Partial Response (PR) 43 (10) 8 (2)
Stable Disease (SD) 333 (74) 239 (53)
Progressive Disease (PD) 56 (12) 167 (37)
Missing 18 (4) 38 (8)
Best Response (RECIST)
Number of Patients (%)
Escudier B, et al. NEJM, 2007;356:15-134..
TARGETsProgression-Free Survival Benefit*
* Based on investigator assessment
Pro
po
rtio
n o
f P
atie
nts
Pro
gre
ssio
n-F
ree
Time from Randomization (Months)
0
0.25
0.50
0.75
1.00
0 4 10 202 6 8 12 14 16 18
Sorafenib
Censored observation
Placebo
Median PFS
Sorafenib = 5.5 months
Placebo = 2.8 months
Hazard ratio (S/P) = 0.51
Escudier B, et al. Presented at: ECCO 13 – the European Cancer Conference, October 30-November 3, 2005; Paris, France. abstract 794.
TARGETsMedian Overall Survival
Escudier B, et al. NEJM, 2007;356:15-134.
Time from randomization (months)
0 5 10 2515 200
0.25
0.50
0.75
1.00
Su
rviv
al d
istr
ibu
tio
n f
un
ctio
n
Median OS
Placebo = 15.9 months
Sorafenib = 19.3 months
Hazard ratio = 0.77 (95% CI: 0.63, 0.95)
p-value = 0.02
Incidence of Treatment-Emergent Adverse Events* in ≥2% patients
Sorafenib (n=451) Placebo (n=451)Any grade Grades 3/4 Grades 3/4Any grade
Diarrhea 195 (43%) 11 (2%) 58 (13%) 3 (1%)
Hypertension 76 (17%) 16 (4%) 8 (2%) 2 (<1%)
Fatigue 165 (37%) 22 (5%) 125 (28%) 16 (4%)
Hand–foot skin reaction 134 (30%) 25 (6%) 30 (7%) –
Decreased hemoglobin 34 (8%) 12 (3%) 33 (7%) 20 (4%)
Tumor pain 29 (6%) 13 (3%) 24 (5%) 8 (2%)
Bone pain 34 (8%) 3 (1%) 35 (8%) 15 (3%)
Dyspnea 65 (14%) 16 (4%) 52 (12%) 11 (2%)
*NCI-CTC Version 3.0Escudier B, et al. Presented at: ECCO 13 – the European Cancer Conference, October 30-November 3, 2005; Paris, France. abstract 794.
Grade 3 Hand-foot syndrome Improved to Grade 1
Hand-Foot Syndrome
*Sorafenib 400 mg bid.
Image courtesy of Laura Wood, RN, MSN, OCN.
Sunitinib (Sutent)
• Oxindole TK inhibitor • Orally bioavailable small
molecule• Selective multitarget
inhibition of:– PDGF-R– VEGF-R– Kit– Flt-3
• Plasma half-life ≈ 40 hours
NH
O
NH
F
H3C
CH3
NH
O
N
CH3
CH3
Mendel et al. Clin Cancer Res 9, 2003
Sunitinib Phase 2 Studies: Best Response by RECIST
* 1 patient with change in cancer diagnosis excluded from analysis
Motzer RJ, et al. Presented at: 4th International Kidney Cancer Symposium of the Kidney Cancer Association, October 21-23, 2005; Chicago, IL.
Response Trial 1 N (%)
Trial 2* N (%)
Patients 63 105
Overall response (OR) 25 (40) 46 (44)
Complete response (CR) 0 1 (1)
Partial response (PR) 25 (40) 45 (43)
Stable disease (SD) > 3 mos 17 (27) 24 (23)
Progression, SD < 3 mos, or not evaluable
21 (33) 35 (33)
Progression-Free Survival Trials 1 and 2 Combined
Sunitinib Therapy (Months)
Pro
po
rtio
n o
f P
atie
nts
Pro
gre
ssio
n-F
ree 1.0
0.8
0.7
0.6
0.5
0
0 9 15 18 24
0.9
0.3
0.2
0.1
0.4
3 6 12 21
Median PFS: Trial 1: 8.7 monthsTrial 2: 8.1 months
Combined: 8.2 months(95% CI: 7.8, 10.4)
27
Motzer RJ, et al. Presented at: 4th International Kidney Cancer Symposium of the Kidney Cancer Association, October 21-23, 2005; Chicago, IL.
Sunitinib Phase 2 Studies: Treatment-Related Adverse Events
Incidence (%)Grade 2 Grade 3
Adverse Event Trial 1 Trial 2 Trial 1 Trial 2
Fatigue 27 17 11 11
Diarrhea 21 17 3 3 Nausea 16 13 3 0 Stomatitis 17 9 2 5
Dermatitis 6 8 2 7
LVEF Decline 9 3 2 4
Hypertension 3 10 2 6
Motzer RJ, et al. Presented at: 4th International Kidney Cancer Symposium of the Kidney Cancer Association, October 21-23, 2005; Chicago, IL.
Phase III trial of IFNA vs Sunitinib
Untreated, metastatic RCC (n=750)
Sunitinib(50 mg/day x4weeks q 6 weeks)
IFNA 9 MU TIW
Response rate 8% (P<0.001) 39%
PFS (months) 5 (P<0.001) 11
OS (months) 21.8 p=0.051 26.4
*Motzer R et al. NEJM 2007;356:115-124, Figlin ASCO 2008
*
0 3 6 9 12 15 18 21 24 27 30 33 36
Time (months)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Ove
rall
Su
rviv
al P
rob
abili
ty Sunitinib (n=193) Median 28.1 months (95% CI: 19.5 - NA)IFN-α (n=162) Median 14.1 months (95% CI: 9.7 - 21.1)
Hazard Ratio = 0.647(95% CI: 0.483 - 0.870)p =0.0033 (Log-rank)
Figlin et al. ASCO 2008. Abstract 5024.
Sunitinib vs. Interferon in First-Line Treatment of mRCC: OS
(Patients Received No Post-Study Treatments)
Biomarker Analysis and Final Efficacy and Safety Results of a Phase II Renal Cell Carcinoma Trial With Pazopanib
(GW786034), a Multi-Kinase Angiogenesis Inhibitor
TE Hutson,1 ID Davis,2 JH Machiels,3 PL de Souza,4 K Baker,5 L McCann,5 W Bordogna,5 JP Hodge,5 R Westlund,5
L Pandite,5 RA Figlin6
1Baylor-Sammons/Texas Oncology PA, Dallas, TX, USA; 2Austin Hospital, Melbourne, VIC, Australia; 3Centre du Cancer, Cliniques Universitaires St.-Luc, Brussels, Belgium; 4Cancer Center, St. George Hospital, Sydney, NSW, Australia; 5GlaxoSmithKline, Research Triangle Park, NC, USA; 6City of Hope National
Medical Center, Duarte, CA, USA
Original Study Design (N = 225)
IDMC Recommendations at the Interim Analysis• Based on robust clinical activity observed in the first 60 patients enrolled
– Randomization was discontinued– Patients on placebo were crossed over to pazopanib– The study continued as an open-label, single-arm study
CR = Complete response; PR = Partial response; SD = Stable disease; PD = Progressive disease; IDMC = Independent data monitoring committee.
Treatment12 weeks pazopanib 800 mg once daily
orally
CR/PR Continue pazopanib
SD
PD
RANDOMIZE
Pazopanib
Placebo
Maximum Decrease in Target Lesion Diameters: Independent Review
*Patients with non-target new lesions at the same time point as the recorded maximum decrease in sum of the longest diameters for target lesions.
Progression-Free Survival:Randomized Comparison (n = 55)
Independent Review
When the randomized phase was stopped because of IDMC recommendation, patients crossing over to open-label pazopanib were not censored.
Investigator-Assessed Treatment-Related AEs (> 10% of Patients)
Patients, n (%)(N = 225)
Any grade Grade 3 Grade 4*
Patients with any treatment-related AE, n (%)† 215 (96) 77 (34) 16 (7)
Diarrhea 133 (59) 9 (4) 0 (0)
Hair color changes 96 (43) 0 (0) 0 (0)
Hypertension 90 (40) 19 (8) 0 (0)
Nausea 83 (37) 1 (<1) 0 (0)
Fatigue 83 (37) 9 (4) 0 (0)
Dysgeusia 52 (23) 0 (0) 0 (0)
Anorexia 39 (17) 2 (<1) 0 (0)
Vomiting 33 (15) 1 (<1) 0 (0)
Alanine aminotransferase (ALT) 30 (13) 12 (5) 2 (<1)
Aspartate aminotransferase (AST) 26 (12) 7 (3) 2 (<1)
Rash 28 (12) 2 (<1) 0 (0)
Hand-foot syndrome 28 (12) 4 (2) 0 (0)
Abdominal pain 22 (10) 4 (2) 0 (0)
Alopecia (hair thinning) 23 (10) 0 (0) 0 (0)AE = Adverse event.*Two grade 5 drug-related AEs: large bowel perforation and dyspnea.†Safety data are presented on all 225 patients with a median exposure of 36 weeks (0.30 to 130 weeks); AEs led to treatment discontinuation in 15% of patients.
No Correlation Demonstrated Between VHL Status and Clinical Response
Best response assessment, n (%)
Evaluable patients*(N = 78)
Methylation or mutation(n = 70)
Wild-type (n = 8)
Complete response 1 (1) – 1 (13)
Partial response 31 (40) 29 (41) 2 (25)
Stable disease 31 (40) 28 (40) 3 (38)
Progressive disease 7 (9) 6 (9) 1 (13)
Not evaluable 8 (10) 7 (10) 1 (13)
VHL mutations or methylation found in 70 patients (90% of 78 assessed). Literature: VHL mutations ~47% to 70%.
• VHL mutations were located in Exons 1, 2, and 3 in 40%, 37%, and 23% of patients, respectively
• Types of mutations included frameshifts (48%), missense (30%), nonsense/stop (9%), splices (9%), and inframe deletions or insertions (4%)
• All except for 1 missense mutation occurred in evolutionarily conserved regions and all occurred in a domain of the protein critical for VHL function (a and b domain)
• Therefore, all amino acid changes may have a functional impact on the protein
*Patients for whom PGX data were available.
Axitinib in Cytokine-Refractory mRCC: Trial Design
• Primary end point: Response rate
• Secondary end points: Duration of response, TTP, OS, safety
Patients with mRCC (refractory to cytokine)
N=52
Axitinib:5 mg, bid, q4wks
Assess
Rini et al. Lancet Oncology 2007;8:975-84.
Single-Agent Axitinib in Cytokine-Refractory RCC Maximum Reduction in Target Lesions (ORR = 44%)
Rini et al. Lancet Oncology 2007;8:975-84.
Max
imu
m r
edu
tio
n in
tar
get
lesi
on
s
-100
-80
-60
-40
-20
0
20
Excludes 4 patients without a post-baseline scan
0
0.25
0.50
0.75
1.00
0 3 6 9 12 15 18 21 24 27 30 33
Cytokine-Refractory RCC Time to Progression (Median = 15.7 months)
N=50, excludes 12 patients without a post-baseline scan due to study withdrawal (Discontinued due to adverse events or withdrawal of consent) B.I. Rini,1 G. Wilding,2 G. Hudes,3 W.M. Stadler,4 S. Kim,5 J.C. Tarazi,5 P.W. Bycott,5 K.F. Liau,5 J.P. Dutcher6
Time (months)
Tim
e-to
-pro
gre
ssio
n p
rob
abili
ty
mTOR Inhibitors in the Treatment of Renal Cell
Cancer
mTOR Is a Novel Cancer Target
• mTOR is an intracellular serine-threonine kinase activated by mutations in cancer
• mTOR is downstream of growth factor and nutrient signalling
• mTOR is a central regulator of protein synthesis
• Everolimus and Temsorilimus are amultifunctional inhibitors of:
– cell growth and proliferation
– angiogenesis
– cancer cell metabolism (bioenergetics)
Nutrients Growth Factors
IGF, EGF, VEGF etc
PI3KPI3K
glucose, amino acids, etc
Mutations in cancer
AKTAKT
S6k eif-4e
Protein Synthesis
Growth &Proliferation
Cell Metabolism
Angiogenesis
Podsypanina K, et al. PNAS. 2001;98:10320-10325.
Licun W, et al. Cancer Res. 2005;65:2825-2831.
Temsorilimus(CCI-779, Torisel)
• Water-soluble ester of sirolimus• Novel mammalian target of rapamycin
(mTOR) kinase inhibitor• Exhibits immunosuppressive and anti-tumor
activity• Reduces tumor growth in PTEN +/- mice
Phase III Study of Temsirolimus and IFN in Advanced RCC: Study Design
Eligibility Criteria
• Histologically confirmed, measurable (RECIST) advanced (stage IV or recurrent) RCC
• No prior systemic therapy
• Karnofsky PS ≥60
• Fasting serum cholesterol ≤350 mg/dL, triglycerides ≤400 mg/dL
• Minimum of 3 poor-risk features required*
(n=207)
(n=209)
(n=210)
IFN escalating to 18 MU SC tiw
Temsirolimus25 mg IV qw
+Temsirolimus
15 mgIV qw
IFN 6 MU SC tiw
Primary end point: OS
Hudes et al. N Engl J Med. 2007;356:2271.
(N=626)
*Risk Factors• LDH >1.5 × ULN• Hgb <LLN• Corrected calcium >10 mg/dL• Time from diagnosis to first treatment <1 y• Karnofsky PS 60-70• Multiple organ sites of metastasis
RANDOMIZATION
Lam JS, et al. J Urol. 2005;173:1853-1862.
Pro
po
rtio
n S
urv
ivin
g
Years Following Systemic Therapy
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Risk factors are:• no prior nephrectomy• KPS < 80• low HGB• high corrected calcium• high LDH
0 risk factors (164 patients, 30 alive)
1 or 2 risk factors (348 patients, 23 alive)3, 4, or 5 risk factors (144 patients, 1 alive)
Survival by the Memorial Sloan-Kettering Cancer Center Risk Factor Model
Phase III Study of Temsirolimus and IFN in Advanced RCC: OS by Treatment Arm
Hudes et al. N Engl J Med. 2007;356:2271.
nMedian OS
(mo)
IFN 207 7.3
Temsirolimus 209 10.9
Temsirolimus + IFN 210 8.4
0
0.25
0.50
0.75
1.00
0 5 10 15 20 25 30 35Months
Pro
po
rtio
n s
urv
ivin
g
P=0.008 P=0.70
RAD001
Phase 2 in Metastatic RCC (Amato)
• Single-arm, 2-stage design, RAD001 10 mg/d orally (28-day cycle)– 41 patients
• Primary end point: TTP– Secondary end point: RR (RECIST, q 12 wks); OS
• Results: - 12/37 PR (32%), 14 SD (38%) > 6 months duration- PFS 11.17+ (2.00-31.53+) months - Overall survival 24.17+ months
Jac ASCO 2007, #5107
Progression Free Survival
0 10 20 30 400
25
50
75
100
Time (Months)
Perc
en
t P
rog
ressio
n F
ree
N=37
Median = 11.17+( 2.00 – 31.53+) Months
RAD001 Phase 2 in Metastatic RCC (Amato)
Jac ASCO 2007, #5107
Overall Survival
0 10 20 30 400
25
50
75
100
Time (Months)
Percen
t su
rviv
al
Median = 24.17 + Months
N = 39
RAD001 Phase 2 in Metastatic RCC (Amato)
Jac ASCO 2007, #5107
Non-Hematologic Adverse Events
0 10 20 30 40
Population (Percent)
Diarrhea
Nausea
Rash
Stomatitis
Anorexia
Vomiting
Pneumonitis
G3
G2
G1
RAD001 Phase 2 in Metastatic RCC (Amato)
Jac ASCO 2007, #5107
60
Late-Breaking Abstract # 5026
RECORD-1: RAD001 (Everolimus) + Best Supportive Care (BSC) vs BSC + Placebo in Pts With Metastatic RCC After Progression
on VEGFr-TKI Therapy
R. Motzer, B. Escudier, S. Oudard, C. Porta, T. Hutson, S. Bracarda, R. Figlin, J. Thompson,
V. Grünwald, N. Hollaender, G. Urbanowitz, A. Kay, A. Ravaud, for the RECORD-1 Study Group
Supported by Novartis Pharmaceuticals
Key Eligibility Criteria
• Metastatic RCC with clear cell component
• Measurable disease
• Progressive disease on or within 6 mos of treatment with sunitinib, sorafenib, or both
• Prior bevacizumab and cytokines permitted
• Adequate performance status, blood counts and serum chemistry
Study Conduct
• 410 patients randomized September 2006 and October 2007
• Second interim analysis cut-off: October 15, 2007, based on 191 PFS events
• Independent Data Monitoring Committee recommended termination of study
RRAANNDDOOMMIIZZAATTIIOONN
2:12:1
Placebo + BSC(n = 138)(n = 138)
Upon Disease Progression
Interim analysis
Interim analysis
N = 410
Stratification
• Prior VEGFrTKI: 1 or 2
• MSKCC risk group: favorable, intermediate,
or poor
=Finalanalysis
Everolimus + BSC(n = 272)(n = 272)
Progression-Free Survival by Treatment Central Radiology Review
Patients at Risk Everolimus 272 132 47 8 2 0 0 Placebo 138 32 4 1 0 0 0
100
80
60
40
20
0
0 2 4 6 8 10 12
Pro
bab
ility
, %
Hazard ratio = 0.30 95% CI [0.22, 0.40]
Median PFSEverolimus: 4.0 moPlacebo: 1.9 mo
P value < 0.001 Everolimus (n = 272) Placebo (n = 138)
Months
Subgroup Analysis of Progression-Free Survival Central Radiology Review
1. Motzer et al. J Clin Oncol. 2004;22:454-463.
HR NCentral Review 0.30 410Investigator Review 0.31 410MSKCC RiskFavorable 0.35 118Intermediate 0.25 231Poor 0.39 61Prior TxSorafenib Only 0.29 119Sunitinib Only 0.30 184Both 0.28 107Age< 65 yrs 0.32 259≥ 65 yrs 0.29 151SexMale 0.29 317Female 0.36 93RegionU.S. & Canada 0.24 130Europe 0.37 251Japan & Australia 0.10 29
0 0.4 1.0 1.4
Hazard Ratio
Everolimus benefit Placebo benefit
1.20.80.60.2
1
−100%
−75%
−50%
−25%
0%
25%
50%
75%
100%
Best Response n (%)
PR 3 (1) Stable 171 (63) PD 53 (20) NE 45 (16)
Best Response n (%)
PR 0 Stable 44 (32) PD 63 (46) NE 31 (22)
Maximum % Change in Target Lesions and Objective Response Rate*Everolimus Placebo
NE = not evaluable
* Central Radiology Review
Treatment-Related Adverse Events*
Everolimus%, (n = 269)
Placebo%, (n = 135)
All Grades Grade 3 All Grades Grade 3
Stomatitis† 40 3 8 0
Asthenia / fatigue 37 3 24 1
Rash 25 < 1 4 0
Diarrhea 17 1 3 0
Anorexia 16 < 1 6 0
Nausea 15 0 8 0
Mucosal inflammation 14 1 2 0
Vomiting 12 0 4 0
Cough 12 0 4 0
Edema peripheral 10 0 3 0
Infections† 10 3 2 0
Pneumonitis† 8 3 0 0
Dyspnea 8 1 2 0
*≥ 10% of everolimus patients and additional selected AEs.†Significant difference between sum of grade 3/4 events for everolimus and placebo groups (P < .05) .
Overall Survival by Treatment
Hazard ratio = 0.8395% CI [0.50, 1.37]
Median OSEverolimus: not reachedPlacebo: 8.8 mo
Log rank P value = 0.233 Everolimus (n = 272)Placebo (n = 138)
81% of pts with PD on placebo crossed-over to everolimus
100
80
60
40
20
0
0 2 4 6 8 10 12
Pro
bab
ility
, %
MonthsPatients at Risk Everolimus 272 229 126 61 9 1 0 Placebo 138 111 62 25 9 1 0
Outcome Summary
End Point Everolimus Placebo
Median PFS, mo (95% CI) 4.0 (3.7, 5.5) 1.9 (1.8,1.9)
Hazard ratio (95% CI) 0.30 (0.22, 0.40)
6 Month PFS 26% 2%
Benefit across all subgroups
MSKCC risk1 Yes —
Prior VEGFr-TKI Yes —
Secondary end points
Safety Acceptable —
Patient-reported outcomes Acceptable —
1. Motzer et al. J Clin Oncol. 2004;22:454-463
Adjuvant Immunotherapy
• Two large randomized clinical trials of interferon vs placebo and IL-2 vs placebo in high risk resected disease failed to show a survival benefit to adjuvant immunotherapy
Intergroup Adjuvant TrialArms/Regimens:Patients minimum 6 weeks post radical nephrectomy will be randomized to receive Arm A Nexavar 400mg po BID versus Arm B
Sutent 50 mg qd for 28days q 6weeks vs Arm C placebo, All for 12 months
StratifyDisease Stage: II T2 Grade 3,4III T1,N1, M0T2,N1,M0T3aN0-1, M0T3bN0-1,M0T3cN0-1,M0IV T4 anyN M0
AnyT, N2,M0Histologic SubtypeClear cellNon-clear cell
Arm A Sorafenib (Nexavar)
Arm C Placebo
Randomize
Arm B Sunitinib (Sutent)
Standards for RCC Therapy by Phase III Trial
ASCO 2008
Setting Phase III
Treatment- naive
Good or intermediate risk*
Sunitinib
Bevacizumab + IFN-α
Poor risk* TemsirolimusSunitinib
Previously treated
Prior cytokine Sorafenib
Prior VEGFr-TKI Everolimus
Prior mTOR inhibitor
*MSKCC risk status.