emerging options for treatment of metastatic kidney cancer
DESCRIPTION
Emerging Options for Treatment of Metastatic Kidney Cancer. Robert J. Motzer MD Attending Physician Memorial Sloan-Kettering Cancer Center Professor of Medicine Weil Medical College of Cornell University New York, NY. Expert Review Clinical Application of Evolving Treatment Paradigms. - PowerPoint PPT PresentationTRANSCRIPT
Emerging Options for Treatment of Metastatic Kidney Cancer
Robert J. Motzer MDAttending Physician
Memorial Sloan-Kettering Cancer Center
Professor of Medicine
Weil Medical College of Cornell University
New York, NY
Expert Review
Clinical Application of Evolving Treatment Paradigms
Renal Cell Carcinoma (RCC)
• RCC is the most common cancer of the kidney1,2
– Current analyses estimate more than 50,000 new cases and 13,000 deaths in the United States in 20073,4
• Recurrence develops in approximately 40% of patients with localized tumors5
• Approximately 30% of patients with RCC present with metastatic disease1
– 5-year survival rate for patients with metastatic RCC is <10%6
Motzer RJ, et al. N Engl J Med. 2007;356:115-124; 2. Parkin DM, et al. CA Cancer J Clin. 2005;55:74-108; 3. Pickle LW, et al. CA Cancer J Clin. 2007;57:30-42; 4. Jemal A, et al. Ca Cancer J Clin. 2007;57:43-66; 5. Lam
JS, et al. World J Urol. 2005;23:202-212; 6. Motzer RJ, et al. N Engl J Med.1996;335:865-875
Treatment of Advanced/Metastatic RCC
• RCC is highly resistant to chemotherapy
• Cytokines have response rates of 5% to 20% and median OS of 12 months but their use is limited by toxicity1,2
• Therapies targeted to VEGF and PDGF receptors are the new standard of care (e.g., sunitinib and sorafenib)1,3
VEGF = Vascular endothelial growth factor; PDGF = Platelet-derived epithelial growth factor.1. Motzer RJ, et al. N Engl J Med. 2007;356:115-124; 2. Hutson TE, et al. Clin Genitourin Cancer
Suppl.2006;5(Suppl 1):S31-S39; 3. Escudier B, et al. N Engl J Med. 2007;356:125-134.
Pro
port
ion
Sur
vivi
ng
Years From Start of Interferon-α Therapy
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
1.0
0.8
0.6
0.4
0.2
0
Motzer R et al. J Clin Oncol 2002;20:289–296.Reprinted with permission from the American Society of Clinical Oncology.
30 months
14 months5 months
0 risk factors = favorable risk 1/2 risk factors = intermediate risk3–5 risk factors = poor risk
RCC MSKCC Risk Model
Median SurvivalMedian Survival
Clear Cell RCC: VHL Gene Mutation
Elongin B Elongin C
Rbx1
E2
CUL2
Β-domain
VHL complex disrupted
VHL protein
HIFα accumulation
VEGF PDGFGlut1
Mutant α-domain
DeVita. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins. 2005;1826.
RCC Cancer BiologyVHL-HIF Pathway Targets of Agents
DeVita. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins. 2005;1826; Atkins. ASCO. 2006 Plenary session.
Sorafenib, sunitinibaxitinib, pazopanib,
AZD2171
Elongin B Elongin C
Rbx1
E2
CUL2
Β-domainVHL protein
HIFα accumulation
Mutant α-domain
mTOR TemsirolimusEverolimus
Erlotinib, gefitinib,lapatinib
EGFR
TGFα
PDGFR
PDGF
Sorafenib, sunitinibaxitinib, pazopanib
BevacizumabVEGF Trap
KDR
VEGF
mTOR Pathway
Rini. J Clin Oncol. 2005;23:1028, adapted with permission from the American Society of Clinical Oncology; Patel. Br J Cancer. 2006;94:614; Motzer. J Clin Oncol. 2006;24:5601.
PI-3 kinase
AktPTENPTEN
S6K 4EBP1
Translation
Extracellularmembrane
Growth Growth ffactorsactors
TemsirolimusEverolimus
Cell division AngiogenesisCell proliferation
PI-3K/Aktactivation
PTEN loss
mTOR
Treatment Naïve mRCC Patients
• First-line therapy - no prior systemic treatment
• Series of phase 3 trials - comparator arm interferon (IFN)-
• Agents investigated:
– Sunitinib
– Temsirolimus
– Bevacizumab
– Sorafenib (phase 2)
Patient CharacteristicsRecent Randomized Trials in Advanced RCC
Treatments Line of Therapy Prior Nephx MSKCC Group Clear Cell
Phase 3 –Sunitinib ± IFN- (n=750)
1st line 90% Favorable = 35%Intermediate = 56%
Poor = 6%
100%
Phase 3 – Temsirolimus ± IFN-α (n=626)
1st line 67% Favorable = 0%Intermediate = 26%
Poor = 74%
80%
Phase 3 – Bevacizumab vs. IFN- (n=649)
Phase 2 - Sorafenibvs. IFN-α (n=189)
1st line
1st line
100%
95%
Favorable = 27%Intermediate = 56%
Poor = 9%
Favorable = 51%Intermediate = 49%
Poor = 0%
100%
100%
1. Motzer R, et al., N Engl J Med 2007, 356:115-124. 2. Hudes G, et al. N Engl J Med 2007;356:2271−2281. 2. Escudier et al. Lancet 2007;370:2103−1211. 3. Szczylik C, et al. ASCO 2007.
Sunitinib vs. InterferonStudy Design
Motzer et al. N Engl J Med 2007;356:115–124.
(N=750)
(n=375)
(n=375)
Sunitinib50 mg PO daily on 4/2
schedule
IFN- 3 MU sc tiw 1st week, 6 MU sc tiw 2nd week, 9 MU sc tiw 3rd week
thereafter
Eligibility Criteria • ≥18 years of age• mRCC• Clear cell histology• No prior systemic treatment• Measurable disease by
RECIST• ECOG PS of 0 or 1• Adequate organ function
RANDOMIZATI
ON
Study Endpoints
• Progression-free survival (PFS)
– 90% power to detect a 35% improvement
– Primary endpoint met atthe pre-planned Interim Analysis 2
• Overall survival (OS)
– 85% power to detect a 35.7% improvement
– 390 events required for the final analysis
• Response rate, safety, patient-reported outcomes
Primary Endpoint
Figlin et al. Abstract 5024, ASCO 2008.
Secondary Endpoints
Best Response
Response (RECIST)Investigator Assessment
IndependentCentral Review
Sunitinib(n=374)
IFN-(n=373)
Sunitinib(n=365)
IFN-(n=346)
No. of patients (%)
Objective response* 174 (46) 45 (12) 142 (39) 29 (8)
Complete response 5 (1) 4 (1) 0 0
Partial response 169 (45) 41 (11) 142 (39) 29 (8)
Stable disease 152 (41) 205 (55) 146 (40) 165 (48)
PD or not evaluable 48 (13) 123 (33) 77 (21) 152 (44)
*Sunitinib vs. IFN-: P<0.000001 ASCO-2007 Update.
Motzer et al. N Engl J Med 2007;356:115–124.
Progression Free Survival (Independent Central Review)
No. at Risk
Sunitinib: 375 240 156 54 10 1IFN-α: 375 124 46 15 4 0
Hazard Ratio=0.53895% CI (0.439, 0.658)P<0.000001
0 5 10 15 20 25 30Time (months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
PF
S p
roba
bilit
y
SunitinibMedian: 11.0 months(95% CI:10.7-13.4)
IFN-Median: 5.1 months(95% CI:3.9-5.6)
Motzer et al. N Engl J Med 2007;356:115–124.
Sunitinib vs. IFN- in First-line mRCC PFS by MSKCC Risk Status
Risk group
Median PFS (95% CI)
N (%)Sunitinib(N=375)
IFN-(N=375)
Favorable (0 risk factors) 264 (35%) 14.5 mo(11.3–16.8)
7.9 mo(7.0–10.5)
Intermediate (1–2 risk factors) 421 (56%) 10.6 mo(8.2–10.9)
3.8 mo(3.6–4.0)
Poor (≥3 risk factors) 48 (6%) 3.7 mo(2.0–9.8)
1.2 mo(1.0–2.4)
Motzer et al. Abstract 5024, ASCO 2007.
Final Overall Survival
Total DeathSunitinib 190IFN-a 200
Figlin et al. Abstract 5024, ASCO 2008.
0 3 6 9 12 15 18 21 24 27 30 33 36Time (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
roba
bilit
y
Hazard Ratio = 0.821(95% CI: 0.673 - 1.001)P =0.051 (Log-rank)
375 44 / 326 38 / 283 48 / 229 42 / 180 14 / 61 4 / 2nDeath/nRisk Sunitinib
375 61 / 295 46 / 242 52 / 187 25 / 149 15 / 53 1 / 1nDeath/nRisk IFN-a
Sunitinib (n=375)Median: 26.4 months(95% CI:23.0–32.9)
IFN-a (n=375)Median: 21.8 months(95% CI:17.9–26.9)
Post-study Treatments
Sunitinib, n (%)(n=323)
IFN-, n (%)(n=359)
Any post-study treatment 182 (56) 213 (59)
Sunitinib 36 (11) 117 (33)
Other VEGF Inhibitors 106 (33) 115 (32)
Cytokines 63 (20) 47 (13)
mTOR Inhibitors 28 (9) 16 (4)
Chemotherapy 21 (6) 20 (6)
*P<0.0001 Figlin et al. Abstract 5024, ASCO 2008.
Overall Survival Analyses
Pre-specified AnalysesExploratory Analyses
Unstratified StratifiedCrossover pts
censored
Median OS (mos)
26.4 vs. 21.8 26.4 vs. 21.8 26.4 vs. 20.0
HR (95% CI)0.821
(0.673, 1.001) 0.818
(0.669, 0.999)0.808
(0.661, 0.987)
P-value (Log-rank)
0.0510 0.0491 0.0362
P-value (Wilcoxon)
0.0128 0.0132 0.0081*Stratification factors: ECOG PS, LDH, and nephrectomy.
Figlin et al. Abstract 5024, ASCO 2008.
Overall Survival Multivariate Analysis*OS
HR 95% CI P-value
ECOG PS (0 vs. 1) 0.515 0.417 – 0.636 <0.0001
Hemoglobin (≥LLN vs. <LLN) 0.504 0.401 – 0.634 <0.0001
Time from diagnosis to tx (≥1 yr vs. <1 yr) 0.574 0.461 – 0.715 <0.0001
Corrected calcium (≤10 vs. >10 mg/dL) 0.466 0.327 – 0.664 <0.0001
Alkaline phosphatase (≤ULN vs. >ULN) 0.676 0.542 – 0.844 0.0005
LDH (≤1.5 vs. >1.5 x ULN) 0.500 0.337 – 0.742 0.0006
No. of metastatic sites (1 vs. ≥2) 0.664 0.503 – 0.876 0.0037
Treatment (sunitinib vs. IFN-) 0.764 0.623 – 0.936 0.0096
*Treatment comparisons controlling for baseline factors simultaneously from Cox model.
Figlin et al. Abstract 5024, ASCO 2008.
Sunitinib vs. IFN- in First-line mRCC Adverse Events
Event
Sunitinib IFN-
All Grades Grade 3/4 All Grades Grade 3/4
Fatigue 54% 11% 51% 12%/<1%
Diarrhea 60% 8% 13% <1%
Nausea 52% 4% 34% 1%
Stomatitis 30% 1% 3% <1%
Hypertension 30% 12% 2% <1%
Hand-foot Syndrome 29% 8% 1% 0%
Ejection Fraction Decline 13% 3% 3% 1%
Pyrexia 8% 1% 34% 0%
Motzer et al. submitted for publication
Treatment Naïve RCCPoor-risk Patients
• Clinical criteria to define a poor risk population (previously treated vs. untreated) are available
• Use in a clinical trial setting and/or to determine therapy is reasonable
• Validation and development of an international risk classification is underway
• It is unclear whether this group of patients can be defined biologically
*Modified MSK poor risk; †Stratification by Country and Nephrectomy status‡SD 16 weeks; § P=0.0069
IFN 3MU-18MU (n=207)CR + PR – 7%
CR + PR + SD‡ – 29%Med. OS 7.3 months§
IFN 6MU + TEM 15mg QW(n=210) CR + PR – 11%
CR + PR + SD – 41%Med. OS 8.4 months
TEM 25mg QW (n=209)CR + PR – 9%
CR + PR + SD – 46%Med. OS 10.9 months§
Randomize†3/6 Poor RiskFeatures
• LDH>1.5xULN
• Hgb < LLN
• Ca++ (cor) >10
• KPS <70%
• DFI <1 year
• Multiple sites of metastases
Metastatic RCC(N=626)
Temsirolimus (CCI-779)Phase III Trial in Poor Risk RCC*
Hudes et al. ASCO, 2006.
Temsirolimus ± IFN-α Maximum Percent Reduction in Tumor Measurement*
*Investigator assessed measurements
Ch
ang
e f
rom
bas
elin
e (%
)
200
100
0
–100IFN
44% 67% 77%
TEMSR IFN + TEMSR
Patients
Temsirolimus ± IFN-
Overall Survival by Treatment
Parameter
IFN Arm 1(n=207)
TEMSR Arm 2(n=209)
TEMSR + IFN Arm 3
(n=210)
Median Survival (mos) 7.3 10.9 8.4
Comparisons Arm 2:Arm 1 Arm 3:Arm 1
Stratified Log-Rank P 0.0069 0.6912
1.0
0.8
0.6
0.4
0.2
0
Sur
viva
l dis
trib
utio
n fu
nctio
n
0 5 10 15 20 25 30 35Time to death
Arm 3: IFN + Temsirolimus
Arm 2: TemsirolimusArm 1: IFN
Temsirolimus vs. IFN-Secondary End Points
ParameterTEMSR 25 mg
(n=209)IFN-
(n=207) Difference (%) P value†
Hazard Ratio (95% CI)†
Median PFS§ by independent reviewMos (95% CI)
5.5(3.9–7.0)
3.1(2.2–3.8)
77 0.00010.66
(0.53–0.81)
Median PFS by investigator reviewMos (95% CI)
3.8(3.6–5.2)
1.9(1.9–2.2)
100 0.00050.69
(0.57–0.85)
Median TTFMos (95% CI)
3.8(3.5–3.9)
1.9(1.7–1.9)
100 <0.00010.61
(0.50–0.74)
ORR% (95% CI)
8.6%(4.8–12.4)
4.8%(1.9–7.8)
79 0.1232 NA
Clinical benefit rate% (95% CI)**
32.1%(25.7–38.4)
15.5%(10.5–20.4)
107 <0.0001 NA†Based on log-rank test stratified by prior nephrectomy and region.‡Based on Cox proportional hazard model stratified by prior nephrectomy and region. #Based on Cochran-Mantel-Haenszel test stratified by prior nephrectomy and region.**CR, PR, or SD for ≥24 weeks. Independent assessment.
1Hudes et al. N Engl J Med 2007;356:2271–2281.
Percent (%) of Patients with Selected Adverse Events
All Grades and Grade 3–4
Temsirolimus Phase III Trial
Adverse Event
IFNn=203
TEMSRn=209
TEMSR + IFNn=209
All Gr 3–4 All Gr 3–4 All Gr 3–4
Asthenia 66 27 54 12 64 30
Nausea 43 5 37 4 42 2
Rash 5 0 37 1 16 2
Dyspnea 28 8 30 9 26 11
Diarrhea 20 2 28 1 27 5
Edema 9 0 27 0 16 2
Vomiting 29 3 21 3 31 2
Stomatitis 3 0 20 1 21 5
Temsirolimus Phase III Trial (cont’d)
Abnormality
IFNn=203
TEMSRn=209
TEMSR + IFNn=209
All Gr 3–4 All Gr 3–4 All Gr 3–4
Anemia 43 24 50 21 66 39
Hyperlipidemia 16 1 28 7 39 2
Hyperglycemia 11 1 26 10 16 4
Hypercholesteremia 5 0 24 1 27 0
Creatinine increase 12 1 16 4 22 2
Thrombocytopenia 8 0 13 1 37 9
Neutropenia 12 8 7 3 25 14
Percent Patients with Laboratory AbnormalitiesAll Grades and Grade 3–4
Phase III Trial Temsirolimus vs. IFN-α Subset Analyses
Median survival
IFN-α TEMSR HR1
Intermediate Risk2 17.7 (n=51) 13.0 (n=64) 1.17
Poor Risk2 6.0 (n=156) 10.2 (n=145) 0.76
Clear Cell 8.2 (n=170) 10.6 (n=169) 0.85
Other 4.3 (n=36) 11.6 (n=37) 0.55
1. HR : hazard ratio; 2 MSK prognostic groups
Dutcher et al. ASCO, 2007.
BevacizumabPhase III Trials in RCC
1Rini, B: letter to CALGB, 7/9/07; 2Escudier et al. Lancet 2007;370:2103−1211.
Patient Population: Metastatic Clear Cell Ca No Prior Systemic Therapy
CALGB 90206N = 732
BO17705 (AVOREN) N = 649
IFN- 9.0 MU TIW
IFN- 9.0 MU TIW +
Bevacizumab 10 mg/kg d1,15
Randomize Randomize
IFN-α 9.0 MU TIW +
Bevacizumab 10 mg/kg d1,15
IFN-α 9.0 MU
TIW +Placebo
CALGB 902061 AVOREN2
Therapy IFN- IFN- + Bev IFN- + Bev IFN- + Placebo
ORR 13.1% 25.5% 31% 13%
PFS (med) 5.2 mos 8.5 mos 10.2 mos 5.4 mos
Pro
babi
lity
of
bein
g pr
ogre
ssio
n-fr
eePFS in Evaluable Patients
AVOREN and CALGB 90206
Time (months)0 6 12 18 24 30 36 42 48
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
05.4 10.25.2 8.5
Bevacizumab + IFN-2a (n=327) = 10.2 months
Placebo + IFN-2a (n=322) = 5.4 monthsBevacizumab + IFN-2b (n=369) = 8.5 months
Placebo + IFN-2b (n=363) = 5.2 months
Median PFS:
Escudier et al. Lancet 2007;370:2103−1211.Rini, et al. JCO in press
AVORENPFS by MSKCC Risk Status*
Median PFS (months)
Risk Group %IFN- + Bev
(n=327)IFN-
(n=322)
Favorable (0 risk factors) 27 12.9 7.6
HR (P value) 0.60 (P=0.004)
Intermediate (1-2 risk factors) 56 10.2 4.5
HR (P value) 0.55 (P<0.0001)
Poor (≥3 risk factors) 9 2.2 2.1
HR (P value) 0.81 (P=0.457)
Risk factors associated with shorter survival are low hemoglobin, high corrected calcium, high LDH, poor performance status, and an interval of <1 yr from diagnosis to treatment.
*Escudier, et al. Lancet. 2007;370:2103-2111.
AVOREN and CALGB 90206Selected Grade 3/4 Adverse Events
AVOREN CALGB
IFN + placebo(n=304)
Bev + IFN(n=337)
IFN(n=349)
Bev + IFN(n=366)
Any grade 3/4 event 137 (45) 203 (60) 213 (61) 289 (79)
Fatigue/asthenia 46 (15) 76 (23) 104 (30) 134 (37)
Proteinuria 0 (0) 22 (6.5) 1 (<1%) 56 (15)
Hypertension 2 (0.7) 13 (3.9) 0 (0) 36 (10)
Hemorrhage 1 (0.3) 11 (3.3) 1 (<1) 5 (1.4)
Venous thromboembolism 2 (0.7) 6 (1.8) 3 (1) 6 (2)
Gastrointestinal perforation 0 (0) 5 (1.5) 0 (0) 1 (<1)
Arterial ischemia 1 (0.3) 4 (1.2) 0 (0) 5 (1.4)
*Stratified by Motzer score and region category; unstratified analysis HR=0.79, p=0.067; prespecified level of significance P=0.0056 †Not reached
AVOREN Trial Interim Analysis of Overall Survival
(251 of 450 Scheduled Events)
HR=0.75 (95% CI: 0.58–0.97), p<0.0267*Median overall survival:
Bevacizumab + IFN = NR†
Placebo + IFN = 19.8 months
Pro
babi
lity
of s
urvi
val
Time (months)0 6 12 18 24 30
1.00.90.80.70.60.50.40.30.20.1
019.8
Number ofpatients at risk Placebo + IFN 322 262 176 53 1 0Bevacizumab+ IFN 327 275 197 60 2 0
Selected Serious Adverse Events (Grade 3/4) Associated With Sunitinib, Bevacizumab and Temsirolimus
Treatment setting First-line First-line First-line*
Adverse event (AE, %) Sunitinib1 Bevacizumab + IFN-α2 Temsirolimus3
Anorexia − 3 3
Asthenia 4 10 11
Diarrhea 5 2 1
Dyspnea − <1 9
Fatigue 7 12 −
Hand–foot syndrome 5 − −
Hyperglycemia 5 − 11
Hypertension 8 3 −
Anemia 4 3 20
Neutropenia 12 4 3
Thrombocytopenia 8 2 1
Leukopenia 5 − 1
Discontinuations due to AEs 19 28 7
1. Motzer RJ, et al. N Engl J Med 2007;356:115–124;2. Escudier B, et al. Lancet 2007;370:2103–2111; 3. Hudes G, et al. N Engl J Med 2007;356:2271−2281;
4. Escudier B, et al. N Engl J Med 2007;356:125−134.
*Poor risk patients – stratified according to modified MSKCC criteria plus number of metastatic sites
Phase IISorafenib vs. IFN-α in Treatment Naïve Advanced RCC
Szczylik et al. J Clin Oncol 2007;25(suppl):5025, abstract.
Eligibility Criteria
• Clear-cell histology
• No prior systemic therapy
• ECOG PS of 0 or 1
• All MSKCC risk groups
Randomization
1:1
N=189
Stratification• MSKCC
prognostic score
PrimaryEnd Point• PFS
Dis
eas
e p
rog
ress
ion
Sorafenib 600 mg bid
n=44
Sorafenib 600 mg bid
n=44
Period 1 Period 2
Sorafenib 400 mg bid
n=50
Sorafenib 400 mg bid
n=50
End Points (Investigator Assessment)
Sorafenib (n=97) IFN- (n=92)
Median PFS (mos) 5.7 5.6
CR + PR (%) 5% 9%
Stable Disease (%) 74% 55%
Sorafenib400 mg bid
n=97
Sorafenib400 mg bid
n=97
IFN-9 MU tiw
n=92
IFN-9 MU tiw
n=92
Sorafenib vs. IFN- in Treatment Naïve mRCC Patients: PFS
Adapted from Szczylik C et al. Presented at ASCO Annual Meeting;June 1-5, 2007; Chicago, IL.
Pro
gres
sion
-Fre
e S
urvi
val (
% p
atie
nts) 100
80
60
40
20
0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Time From Randomization (months)
Median PFS (121 events/189 patients)
Sorafenib = 5.7 months
IFN = 5.6 months
Hazard Ratio = 0.883 p = 0.504 (log-rank test)
Treatment Refractory mRCC Patients
• Refractory to cytokines
• Refractory to non-cytokine regimens
• Refractory to angiogenesis inhibitors
Escudier et al. Presented at: ECCO 13 – the European Cancer Conference, October 30-November 3, 2005; Paris, France. Abstract 794.
Treatment Approaches in Renal Cancer Global Evaluation Trial
(TARGETs)
Sorafenib400 mg bidORR 10%SD 74%
PFS 5.5 mo Major end points
• PFS (α=0.01)
• OS (α=0.04) Placebo*ORR 2%SD 53%
PFS 2.8 mo
(1:1) Randomization
n~905
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
Secondary end point: ORR
*Crossover - initiated 6/05
*Based on investigator assessment.
Pro
port
ion
of P
atie
nts
Pro
gres
sion
Fre
e
0
0.25
0.50
0.75
0 4 10 202 6 8 12 14 16 18
1.00
Time From Randomization (months)
Sorafenib in Second-Line mRCC: PFS Benefit*
Escudier. N Engl J Med. 2007;356:124.
Median PFSSorafenib=5.9 monthsPlacebo=2.8 monthsHR=0.51P<0.001
Censored observationPlaceboSorafenib
Phase III TARGETs Trial: Response and Maximum Percent Reduction in Tumor Measurement*
*Independently assessed measurements available for 574 patients.
Placebo
Best response
Sorafenib
Best response
74%20%
Max
imum
Per
cent
Re
duct
ion
inT
umo
r M
easu
rem
ent
PR – 0%
SD – 55%
PR – 2%
SD – 78%
100
80
60
40
20
0
–20
–40
–60
–80
–100
Patient number
50 100 150 200 250
Patient number
50 100 150 200 250
Summary OS: Sorafenib PlaceboFinal Analysis (9/06) 17.8 mos 15.2 mosCensored Analysis (6/05) 17.8 mos 14.3 mos
TARGETsFinal OS Analyses
TARGET: Per-protocol OS Analysis at 561 deaths
TARGET: Preplanned Secondary Analysis† OS Data for Placebo Patients Censored
0 4 8 12 16 20 24 28 32 36 40
Months for randomization
Pro
por
tion
of p
atie
nts
surv
ivin
g
1.00
0.75
0.50
0.25
0.00
● 216/452 placebo recipients crossed over to sorafenib
● 615 of all drug taken on placebo arm was sorafenib
● 216/452 placebo recipients crossed over to sorafenib
● 615 of all drug taken on placebo arm was sorafenib
SorafenibPlacebo
HR=0.88*CI: 0.74–1.04
SorafenibPlacebo
HR=0.88*CI: 0.74–1.04
*Non-significant (P=0.146); †Planned analysis prior to unblinding of the OS data; O’Brien-Fleming threshold for statistical significance =0.037
0 4 8 12 16 20 24 28 32 36 40
Months for randomizationP
rop
ortio
n of
pa
tient
s su
rviv
ing
1.00
0.75
0.50
0.25
0.00
HR (sor/pla)=0.78*95% CI: 0.62–0.97p=0.0287*
HR (sor/pla)=0.78*95% CI: 0.62–0.97p=0.0287*
Sorafenib (N=451)Placebo (N=452)Sorafenib (N=451)Placebo (N=452)
Bukowski et al. ASCO, 2007.
Phase II Evaluation of Sunitinib in mRCC
Sunitinib
4 weeks on, 2 week off (4/2)
50 mg/day*
SunitinibDosing schedule
Sunitinib
Two Independent, Single-arm, Multicenter, Phase II Trials (Trial 014: N=63; Trial 1006: N=106)1,2
*Dose reduction permitted(to 37.5 mg/day and then to 25 mg/day).
1. Motzer RJ, et al. J Clin Oncol 2006;24:16–24.2. Motzer RJ, et al. JAMA 2006;295:2516–2524
Patients with advanced disease
and failure of prior cytokine therapy
Continue sunitinibtreatment unless
progression or intolerability
34.0
8.3
40.0
27.0
8.70.0
5.0
10.0
15.0
20.0
25.0
30.0
35.0
40.0
45.0
Objectiveresponse rate
(%)
Progression-freesurvival(months)
Partial response(%)
Stable disease ≥3 months (%)
Progression-freesurvival(months)
Sunitinib: Phase II Efficacy
1. Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology 2006;24:16–24.
2. Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in Patients with metastatic renal cell carcinoma. Journal of the American Medical Association 2006;295:2516–2524.
Sunitinib has been studied in two Phase II trials in cytokine-refractory patients with advanced RCC
Motzer et al. JAMA 2006
N=106
Motzer et al. JCO 2006
N=63
Everolimus (RAD001) in mRCC
• Everolimus is an oral agent that is an inhibitor of mTOR
• Responses were observed in previously treated and untreated metastatic RCC patients1
• Phase III trial was initiated in patients who progressed on VEGFR TKI therapy
1. Jac et al. ASCO, 2007. Abstract 5107.
Phase III Trial of Everolimus vs. Placebo Everolimus vs. Placebo
• Primary endpoint: PFS
• Secondary endpoints: OS, safety, response,patient-reported outcomes
Motzer. ASCO, 2008. Abstract LBA5026.
(n = 410)
RANDOMIZE
Eligibility criteria:
• Metastatic RCC with clear cell histology
• Measurable disease
• Refractory to TKIs – sunitinib and/or sorafenib
• Prior bevacizumab and cytokines permitted
Stratify by:
• MSKCC risk group (favorable vs. intermediate vs. poor)
Everolimus 10 mg/day p.o. BSC
Placebo 10 mg/day p.o. BSC
2:1
Study Design
Phase III Trial of Everolimus vs. Placebo Efficacy/Results
Everolimus(n = 272)
Placebo(n = 138) P Value
Overall Response Rate 1% 0
NRComplete response % 0 0
Partial response % 1% 0
Stable Disease Rate 63% 32%
Median PFS* 4.0 months 1.9 months <0.001
6-month PFS Rate 26% 2% NR
Median OS† Not reached 8.8 months 0.233
*Central review†81% of the patients receiving placebo crossed over at progression Abbreviation: NR = not reported
Motzer. ASCO, 2008. Abstract LBA5026.
RECORD 1 TrialPFS in Everolimus and Placebo Patients
Pro
babi
lity
(%)
0 2 4 6 8 10 12
Hazard ratio = 0.31
95% CI [0.23, 0.41]
Median PFS
Everolimus: 4.6 moPlacebo: 1.8 mo
p<0.001
Everolimus (n = 272)
Placebo (n = 138)
Independent Review Investigator Assessment
Months
100
80
60
40
20
00 2 4 6 8 10 12
Hazard ratio = 0.30
95% CI [0.22, 0.40]
Median PFS
Everolimus: 4.0 moPlacebo: 1.9 mo
P<0.001
Everolimus (n = 272)
Placebo (n = 138)
Months
Pro
babi
lity
(%)
100
80
60
40
20
0
Motzer et al. ASCO, 2008.
RECORD 1 Trial Maximum % Change in Target Lesions and ORR*
NE = not evaluable*Central Radiology Review
100%
75%
50%
25%
0%
–25%
–50%
–75%
–100%
Everolimus Placebo
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)
Phase III Trial of Everolimus vs. Placebo Grade 3/4 Adverse Events
Everolimus(n = 269)
Placebo(n = 135)
Lymphopenia 15% 5%
Hyperglycemia 12% 1%
Anemia < 10% 5%
Hypophosphatemia 4% 0
Hypercholesterolemia 3% 0
Stomatitis 3% 0
Asthenia/Fatigue 3% 1%
Infections 3% 0
Pneumonitis 3% 0
Motzer. ASCO, 2008. Abstract LBA5026.
Reported Phase II/III Datafor Clear Cell RCC Therapy
Setting Phase III Phase II
1st-line Therapy
Good and intermediate risk
SunitinibBevacizumab + IFN-
HD IL-2
Poor risk* TemsirolimusSunitinib
2nd-lineTherapy
Prior cytokine Sorafenib Sunitinib or bevacizumab
Prior VEGFR inhibitor Everolimus
Prior mTOR inhibitor No data available
Atkins et al. ASCO 2006 Plenary session; Figlin et al. Clin Adv Hematol Oncol 2007;5:35; Escudier et al. Drugs 2007;67:1257; Cho et al. Clin Cancer Res 2007;13:761s; Atkins et al. Clin Cancer Res
2005;11:3714. Motzer et al. Abstract LBA5026, ASCO 2008
*MSKCC risk status
Investigational Agents
Regimen Setting Phase N ORR (CR)
VEGF/VEGFR Inhibition
AxitinibCytokine-refractory
mRCCII 52 46% (0%)
Pazopanib mRCC II 225 27% (0%)
AZD2171 First-line mRCC II 32 38% (0%)
mTOR Inhibition
Everolimus mRCC II 371 14% (0%)
ERBB Inhibition
Lapatinib vs Hormone Therapy
Second-line mRCC III 417TTP
HR: 0.94 P=0.6
Chemotherapy
Ixabepilone mRCC II 87 13% (1%)
Rini. ASCO. 2005 (abstr 4509); Hutson. ASCO. 2007 (abstr 5031); Sridhar. ASCO. 2008 (abstr 5047); Jac. ASCO. 2008 (abstr 5113); Ravaud. ASCO. 2006 (abstr 4502); Huang. ASCO. 2008 (abstr 5053).
Phase 3 Trial of Pazopanib vs. Sunitinib in First-line Treatment for Metastatic RCC
1:1 RandomizationN = 876
Pazopanib 800 mg
Sunitinib 50 mg
First-line treatment naïve advanced or metastatic RCC patientsPrimary endpoint: PFS
Secondary endpoint(s): OS, ORR, Safety parameters, PRO measures
RANDOMIZE
Study scheduled to open August 2008; International with Predominant USA Site and Patient Recruitment
*Accrual goal.†Arm to be added when phase II doses are available from ongoing phase I trials.
• Primary endpoint: PFS• Secondary endpoints: ORR, OS, and correlates (dynamic contrast-enhanced MRI,
biomarkers)
Phase II Trial: ECOG BeST
Bevacizumab 10 mg/kg IV every 2 weeks (days 1 and 15)
Advanced RCC
Stratified by:Prior therapy
(cytokine/vaccine vs no cytokine)
Motzer risk category (low, intermediate, or high)
(N=360*)
Bevacizumab 10 mg/kg IV every 2 weeks (days 1 and 15) +
Sorafenib 400 mg bid
Bevacizumab 10 mg/kg IV every 2 weeks (days 1 and 15) +
Temsirolimus 25 mg IV weekly (days 1, 8, 15, and 22)
Sorafenib bid +Temsirolimus IV weekly (days 1, 8, 15, and 22)†
Temsirolimus vs Sorafenib in Advanced Renal Cell Carcinoma as Second-Line Therapy in Patients
Who Have Failed First-Line Sunitinib Therapy
Patients with advanced RCC, PD by RECIST criteria while receiving 1st line sunitinib therapy, at least 1 measureable lesion, at least 2 wks since prior treatment with sunitinib, palliative radiation therapy, and/or surgery, and resolution of all toxic effects of prior therapy, age ≥ 18
Temsirolimus 25 mg IV q week n=220
Primary end points: PFS, safety and tolerabilitySecondary endpoints: RR (CR & PR), OS, SD at 12, 24, 36 wks, clinical benefit (CR+PR+SD at > 24 wks), duration of response and best tumor shrinkage
Study Design: International, Prospective, Randomized, Open-label, Outpatient,Multicenter Study
Sorafenib 400 mg PO BID n=220
RANDOMIZATION
AG-013736 (axitinib) As Second-Line Therapy For Metastatic Renal Cell Cancer
Primary end point: Compare PFS of patients receiving AG-013736 versus sorafenib in mRCC after disease progression to one prior systemic first-line regimen containing one or more of the following agents: sunitinib, bevacizumab + IFN alfa, temsirolimus or cytokine(s).
Secondary end point: OS, ORR, evaluate safety and tolerability, DR, compare symptoms’ severity
RANDOM
IZATI
ON Sorafenib (2 x 200 mg) BID
Axitinib 5 mg BID
1:1
Patients after disease progression to one prior systemic first-line treatment (N=540)
RAD001 10 mg/d + Bevacizumab 10 mg/kg IV q 2 wks
• Patients with previously untreated metastatic RCC
• RAD001 + bevacizumab vs. interferon-α + bevacizumab
• Open label, randomized, group sequential design
RECORD-2Phase II First-line in RCC: RAD001 + Bevacizumab
SCREEN Interferon dose escalation SQ +
bevacizumab 10 mg/kg IV q 2 wks
Prim Endpt:
• PFS
Sec Endpts:
• Response
• Survival
• Safety
• QoL
1 : 1
Randomize
Adjuvant Therapy Ongoing Phase III Trials
*Planned accrual.
Nephrectomy Sorafenib
Placebo
Non-mRCC
(N=1332*)
SunitinibECOG E2805
NephrectomySorafenib x 1 year then placebo
x 2 years
Placebo x 3 years
Non-mRCC
(N=1656*)
Sorafenib x 3 yearsSORCE
NephrectomyPlacebo
Non-mRCC
(N=228*)
SunitinibSTAR
Emerging Options for Treatment of Metastatic Kidney Cancer
Concluding Remarks
Expert Review
Clinical Application of Evolving Treatment Paradigms