oncological treatment of renal cell carcinoma · renal clear cell carcinoma (rcc) rcc: most of the...
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Dr. Torday László, MD PhD Assistant professor
University of Szeged
Department of Oncotherapy
Oncological treatment of renal cell
carcinoma
Locations of RCC
Risk factors
Smoking
Obesity
Hypertension
Long term dialysis
Chemical substances: trichlor-acetylen, asbest, cadmium
Occupational risk: leather and shoe industry, iron and steel industry, car sales and gas stations
Drinking pilsen type beer?
Genetical abnormalities as reasons of
RCC
Von Hippel-Lindau (VHL) syndrome
– Rare genetic disease, mutation of the VHL gene
– In 50% of affected patients will develop RCC
Hereditary papillary RCC (HPRC)
– MET-kinase genetic mutations: papillary RCC of both sides
Birt-Hogg-Dubé syndrome
– Rare
Three classical signs
Hematuria
– 60%
Abdominal pain
– 40%
Palpable resistency in the stomach
T Stages
TX Primary tumor cannot be assessed.
T0 No evidence of primary tumor.
T1 Tumor ≤7 cm in greatest dimension, limited to the kidney.
T1a Tumor ≤4 cm in greatest dimension, limited to the kidney.
T1b Tumor >4 cm but not >7 cm in greatest dimension, limited to the kidney.
T2 Tumor >7 cm in greatest dimension, limited to the kidney.
T2a Tumor >7 cm but ≤10 cm in greatest dimension, limited to the kidney.
T2b Tumor >10 cm, limited to the kidney.
T3 Tumor extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota fascia.
T3a Tumor grossly extends into the renal vein or its segmental (muscle containing) branches, or tumor invades perirenal and/or renal sinus fat but not beyond Gerota fascia.
T3b Tumor grossly extends into the vena cava below the diaphragm.
T3c Tumor grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava.
T4 Tumor invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland).
Staging
NX Regional lymph nodes cannot be assessed.
N0 No regional lymph node metastasis.
N1 Metastases in regional lymph node(s).
M0 No distant metastasis.
M1 Distant metastasis.
Stage T N M
I T1 N0 M0
II T2 N0 M0
III T1 or T2 N1 M0
T3 N0 or N1 M0
IV T4 Any N M0
Any T Any N M1
Treatment of Stage I disease
Radical nephrectomy
Simple nephrectomy
Partial nephrectomy (selected patients)
EBRT (palliative)
Arterial embolization (palliative)
Clinical trials.
Treatment of Stage II disease
Radical nephrectomy
Nephrectomy before or after EBRT (selected patients)
Partial nephrectomy (selected patients)
EBRT (palliative)
Arterial embolization (palliative).
Clinical trials.
Treatment of Stage III disease
Radical nephrectomy with renal vein and, as necessary, vena caval resection (for T3b tumors). Radical nephrectomy with lymph node dissection.
Preoperative embolization and radical nephrectomy
EBRT (palliative)
Tumor embolization (palliative)
Palliative nephrectomy.
Preoperative or postoperative EBRT and radical nephrectomy
Clinical trials involving adjuvant interferon-alpha.
Treatment of Stage IV disease
Radical nephrectomy (for T4, M0 lesions).
Cytoreductive nephrectomy
Temsirolimus.
Sunitinib
Pazopanib
Bevacizumab with or without interferon-alpha
Everolimus (for patients who have previously been treated with sunitinib and/or sorafenib)
Sorafenib
Interferon-alpha
IL-2
Palliative EBRT.
Histological subtypes of renal cell
cancer (RCC)
Kidney cancers : 3% of solid tumors
US data: new cases: 64,770, deaths: 13,570
80-85%: renal cell cancer, from this 75% clear cell
Jermann M et al. Cancer Chemother Pharmacol. 2006;57:533-539; Linehan WM et al. J Urol. 2003;170:2163-2172; Motzer RJ et al. N Engl J Med. 1996;335:856-875.
Ttype Clear cell Papillary type 1 Papillary type 12 Chromophob Oncocytoma
75% 5% 10% 5% 5%
Ggene VHL Met FH BHD
Renal Clear Cell Carcinoma (RCC)
RCC: most of the kidney cancers – 33% of patients eare metastatic in the time of
diagnosis1
– Less than 10% of mRCC patients live longer than
5 years2
Limited OS benefit from traditional
treatments
– mRCC: usually chemoresistant3
– Few patients benefitting from cytokines4
1. Lam et al. World J Urol 2005;23:202, 2. National Cancer Institute. SEER Cancer Statistics. Available at: http://seer.cancer.gov/statistics , 3. Lilleby et al. World J Urol 2005;23:175, 4. NCCN Clinical Practice Guidelines in Oncology.
Kidney Cancer. V2 2009
Historical treatment
Medián OS: 13 hónap N = 463 pts
Motzer RJ, et al. J Clin Oncol. 2002;20:289-296.
OS
(%
)
Arm A: MPA (123)
Arm B: IFN (122)
Arm C: IL-2 (125)
Arm D: IFN + IL-2 (122)
0
20
40
60
80
0 6 12 18 24 30 36 42 48
100
Time from randomization (months)
Median OS
Arm A: 14.9 month (95% CI: 11.7–19.2)
Arm B: 15.2 month (95% CI: 12.8–19.9)
Arm C: 15.3 month (95% CI: 13.3–20.0)
Arm D: 16.8 month (95% CI: 14.0–18.9)
The PERCY QUATTRO Study:
the end of immunotherapy
“Pharmacoptosis”:
Progreammed death of IFN and IL-2
…tried my very best…
P. Schöffski
…tried my very best…
The 1971 hypothesis of Folkman
Theoretical bases of therapy
Folkman J. N Engl J Med 1971;285:1182–6
‘Without vascularisation solid tumors remain in a dormant stage and their
size not more than 2–3mm3; this is the size
which is determined by the intratumorous
diffusional capacity of oxygen and nutrients”
The tumor and its environment
induces VEGF expression
EGF
IGF-1 PDGF
IL-8
bFGF
Hypoxia
COX-2
NO
Oncogenes
VEGF release Binding to VEGF receptor
Activation of VEGF receptor
H2O2
Proliferation Survival Migration
ANGIOGENESIS Permeability
Overexpression
(MMP, tPA, uPA, uPAr,
eNOS, etc.)
– P
– P
P–
P–
IGF = insulin-like growth factor; PDGF = platelet-derived growth factor
VEGF: vascular endothelial
growth factoe
Angiogenic schwitch
Bergers G, et al. Nature 2002;3:401–10
Small tumor (1–2mm)
• Avascular
• Hided
Bigger tumor
• Vascularised
• Metasztatic
potential
Angiogenic „switch”
Overexpression of elements of
Signal transduction (pl. VEGF)
Role of angiogenesis in tumor formation,
growth and metastasis
Poon RT-P, et al. J Clin Oncol 2001;19:1207–25
Stages of tumorous progression: role of angiogenesis
Premalignant stage
Malignant tumor
Tumor growth
Vascular invasion
Dormant mikro- metastasis
„Living” metastasis
Avascular tumor
Angiogenic switch
Vascularised tumor
Tumor cell invasion
Metastasis to distant organs
Secondary angiogenezis
Effect of anti-VEGF treatment on
tumor vasculature
Baluk, et al. Curr Opin Genet Dev 2005; Inai, et al. Am J Pathol 2004; Erber, et al. FASEB J 2004
Tong, et al. Cancer Res 2004; Jain. Nat Med 2001; Jain. Science 2005; Lee, et al. Cancer Res 2000
Willett, et al. Nat Med 2004; Gerber, et al. Cancer Res 2005; Warren, et al. J Clin Invest 1995
Early effecgt Long term effect
Normalisation of remaining
tumorous microvasculature
1
2
Decrease of tumorous
microvasculature Decrease of new
tumorous
microvasculature
3
Scientific facts
The RCC is a hypervascularised tumor-3
–Angiogenesisi is needed fro tumorous growth
over1-2 mm3
Inactivated VHL tumor supresor gene1-3
–Overproduction of „hypoxia inducible factor”
(HIF), transcription of HIF
target genes
–„Vascular endothelial growth
factor” (VEGF)
–„Transforming growth
factor” (TGF)-α
–„Platelet-derived
growth factor” (PDGF)
RCC=renal cell carcinoma; mm=millimeter; VHL=von Hippel-Lindau; VEGFR-TKI=vascular endothelial growth factor receptor-tyrosine kinase.
Rini BI, Atkins MB. Lancet Oncol. 2009;10:992-1000; Decker HJH et al. Cancer Genetics Cytogenet. 1997;93:74-83; Costa LJ, Drabkin HA. Oncologist. 2007;12:1404-1415.
22
HIF-1α
HIF-1α
Ubiquitination and degradation
HIF-1β Mutáns pVHL
X
Angiogenesis
The VHL protein not binds to HIF-1α, which avoyds proteolysis
Increased
transcription
X
Well differentiated RCC, low VEGF-expression: good prognosis
Poorly differentiatedRCC, high VEGF-expression: poor prognosis
Rini BI, Atkins MB. Lancet Oncol. 2009;10:992-1000. 23
Firts line treatment: scientific
considerations
Strategies of anti-angiogenesis1-3
– Anti-VEGF antibody (bevacizumab)
– VEGFR-TKI (sunitinib)
– „Mammalian target of rapamycin” (mTOR) inhibitor (temsirolimus)
– Cytokine therapy
RCC=renal cell carcinoma; mm=millimeter; VHL=von Hippel-Lindau; VEGFR-TKI=vascular endothelial growth factor receptor-tyrosine kinase.
1. Rini BI, Atkins MB. Lancet Oncol. 2009;10:992-1000; 2. Decker HJH et al. Cancer Genetics Cytogenet. 1997;93:74-83; 3. Costa LJ, Drabkin HA. Oncologist. 2007;12:1404-1415.
MSKCC risk factors
KPS = Karnofsky PS; LDH = lactate dehydrogenase; LLN = lower limit of normal; MSKCC = Memorial Sloan-Kettering Cancer Center; ULN = upper limit of normal.
1. Motzer RJ, et al. J Clin Oncol. 2002;20:289-296; Motzer RJ, et al. J Clin Oncol. 2004;22:454-463
MSKCC Criteria 20021
KPS <80
Time from
dignosis to
treatment
<12 hónap
Hemoglobin <LLN
LDH >1.5 x ULN
Corrected serum
calcium >10.0 mg/dL
0 risk factor = favorable prognosis
1 or 2 risk factor = intermediate
prognosis
≥3 risk factor = ppoor prognosis
Prognosis of mRCC: MSKCC risk
model (cytokin éra)
favorable : 19.9 months (n = 164)
intermediate: 10.3 months (n = 348)
poor: 3.9 months (n = 144)
Time from the start of systemic treatment
OS
, %
100
80
60
40
20
0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Motzer RJ, et al. J Clin Oncol. 1999;17:2530–2540.
Median OS
mRCC prognosis: risk factor model:
TKI era
1.0
0.8
0.6
0.4
0.2
0.0 0 10 20 30 40 50
good: 0 factor (OS NR months)
intermediate: 1–2 factor (OS 27 months)
poor: 3–6 factor (OS 8.8 months)
Months from the start of the treatment
pro
babili
ty
p<0.0001
Heng DYC, et al. J Clin Oncol. 2009; 27:5794–5799.
OS
*Prognostic factors : Time from diagnosis to treatment <1 év, KPS <80%, low hemoglobin, High corrected calcium, high neutrophil count , high platelet count
Mechanism of action: bevacizumab
Molecular target
– Monoclonal
antibody against
VEGF
Effects
– Block the
binfding of VEGF
to its own
receptor
– Decrease the
proliferation of
endothelial cells
– Decrease the
VEGFR-induced
proliferation of
endothelial cells
Rini BI, Atkins MB. Lancet Oncol. 2009;10:992-1000.
Bevacizumab: Phase III studies in
mRCC
Patient population: mRCC, no previous tretament
CALGB 90206
N = 732
BO17705 (AVOREN)
N = 649
IFN- 9.0 MU TIW
FN- 9.0 MU TIW + Bevacizumab
10 mg/kg d1,15
Randomised Randomised
IFN-α 9.0 MU TIW + Bevacizumab
10 mg/kg d1,15
IFN-α 9.0 MU TIW + Placebo
CALGB 902061 AVOREN2
Terápia IFN- IFN- + Bev IFN- + Bev IFN- + placebo
ORR 13.1% 25.5% 31% 12%
PFS (median) 4.9 months 8.4 months 10.4 months 5.5 months
1. Rini B, et al. J Clin Oncol. 2009;27(Suppl 15s) (Abstract LBA5019). 2. Escudier B, et al. J Clin Oncol. 2009;27(Suppl 15s):5020 (Abstract).
0 6 12 18 24
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Patient number
Bevacizumab + IFN 327 196 107 18 0
IFN + placebo 322 137 59 15 0
AVOREN: PFS P
rob
ab
ilit
y o
f p
rog
ress
ion
Time (months)
Bevacizumab + IFN
IFN + placebo
5.4 10.2
Escudier B, et al. Lancet 2007;370:2103–11.
HR=0.63; p<0.0001
Mechanism of action: sunitinib
Molekular targets
– TKI
– VEGFR, PDGFR,
KIT, FLT3, CSF-1R,
RET
Effects
– Blocks the signal
transduction of
target molecules
– Decrease
vascularisation and
endothelial
proliferation
Rini BI, Atkins MB. Lancet Oncol. 2009;10:992-1000.
1st line sunitinib vs. IFN-α:
Phase 3 trial design
101 australian, brasilian, canadian, european and USA center
N = 750
n = 375
n = 375
Sunitinib
50 mg/day, per os
4 weeks on, 2 weeks off
IFN-α
3 MU sc. TIW week 1,
6 MU sc. TIW week 2
9 MU sc. TIW after week 3
Inclusion criteria
• Older than 18 years
• mRCC
• Clear cell histology
• No previous systemic treatment
• Measurable disease by RECIST
• ECOG PS 0 or 1
• Adequate organ functions
RANDOMISATION
Motzer RJ, et al. N Engl J Med 2007;356:115–124.
RECIST = response evaluation criteria in solid tumors; SC = subcutaneously; TIW = three times weekly.
Primary endpoint: PFS
Sunitinib vs. IFN-α: efficacy data
Best tumor response
Sunitinib (n=375) IFN- (n=375)
Response N % N %
ORR 176 47 46 12
CR 11 3 4 1
PR 165 44 42 11
SD 150 40 202 54
PD 26 7 69 18
Motzer RJ, et al. J Clin Oncol 2009;27:3584–90.
Sunitinib vs. IFN-α: PFS
No. at Risk
Sunitinib: 375 240 156 54 10 1
IFN-α: 375 124 46 15 4 0
Motzer RJ, et al. N Engl J Med. 2007;356:115-124; Motzer RJ, et al. J Clin Oncol. 2007;20(Suppl 18s):5024 (Abstract).
HR = 0.538 95% CI (0.439, 0.658)
P<0.00001
0 5 10 15 20 25 30
Time, months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
bab
ilit
y o
f P
FS
Sunitinib,
Median: 11.0 months,
95% CI:10.7–13.4)
IFN-
Median: 5.1 months
(95% CI:3.9–5.6)
HR = hazard ratio.
Primary endpoint
Sunitinib vs. IFN-α: OS
Total deaths
Sunitinib: 190
IFN-: 200
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
Pro
ba
bil
ity o
f O
S (
%)
HR = 0.821 (95% CI: 0.673–1.001)
P=0.051 (logrank)
0 / 375 44 / 326 38 / 283 48 / 229 42 / 180 14 / 61 4 / 2
nDeath/nRisk Sunitinib
0 / 375 61 / 295 46 / 242 52 / 187 25 / 149 15 / 53 1 / 1
nDeath/nRisk IFN-
Sunitinib (n = 375)
Median: 26.4 months
(95% CI: 23.0–32.9)
IFN- (n = 375)
Median: 21.8 months
(95% CI:17.9–26.9)
Motzer RJ, et al. J Clin Oncol. 2009;27:3584-3590.
Sunitinib vs. IFN-α: OS of patients not
receiving post-study treatment
*Includes 20 patients who crossed over to sunitinib on study.
Figlin RA, et al. J Clin Oncol. 2008;26 (May 20 suppl) [Abstract 5024].
HR = 0.647
(95% CI: 0.483–0.870)
P=0.0033 (logrank)
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
Pro
ba
bil
ity o
f O
S
Sunitinib (n = 193)
Median: 28.1 months
(95% CI:19.5–NA)
IFN- (n = 162)
Median: 14.1 months
(95% CI:9.7–21.1)
Pazopanib vs. placebo in the first and
second line treatment of mRCC
Inclusion criteria
• Locally advanced or mRCC
• Primarily clear cell histology
• Measurable disease (≥1 lesion)
• 1 previous systemic treatment (cytokine based)*
R
A
N
D
O
M
I
Z
A
T
I
O
N
2:1
Primary endpoint: PFS
No OS data available yet
Pazopanib 800 mg/day
Placebo N = 400
• Open-label extension study (Pazopanib 800 mg; N = 71)
*Patients with no prior treatment were also permitted to enroll in the study
Sternberg C, et al. J Clin Oncol. 2010 ;28:1061–1068.
Pazopanib* vs Placebo: tumor
response: independent review
Independent review
Pazopanib* (n=290)
Placebo (n=145)
No. of patients (%) CR 1 (<1) 0 (0) PR 87 (30) 5 (3)
SD 110 (38) 59 (41)
PD 51 (18) 58 (40)
ORR (CR + PR) 88† (30) 5 (3)
†P < .001, based on Fischer’s exact test comparison of treatment arms.
CR=complete response; PR=partial response.
Sternberg CN, et al. J Clin Oncol. 2010;28:1061-1068.
Pazopanib vs. placebo: PFS
Patients not receiving prior therapy Every ITT patient
Sternberg C, et al. J Clin Oncol. 2010 ;28:1061–1068.
Mechanism of action: sorafenib
Molecular targets – TKI
– Like sunitinib —
VEGFR, PDGFR, RAF,
KIT, FLT3
Effects – Inhibits downstream
signal transduction
– Decreases
vascularisation and
endothelial cell
proliferation
Rini BI, Atkins MB. Lancet Oncol. 2009;10:992-1000.
Sorafenib vs. IFN-α in first line:
Phase II
Escudier B, et al. J Clin Oncol. 2009;27:1280–1289.
Sorafenib
600 mg BID
(n = 44)
Sorafenib
400 mg BID
(n = 50)
Inclusion criteria:
Clear cell histology
No prior systemic therapy
ECOG PS 0 or 1
Every MSKCC prognostic groups
Randomisation:1:1
N = 189
Stratification: MSKCC prognostic categories
Pro
gre
ss
ion
Sorafenib
400 mg BID
(n = 97)
IFN-α
9 MU TIW
(n = 92)
1. period 2. period
BID = twice daily
Sorafenib vs. IFN: Median PFS P
rog
ressio
n-f
ree S
urv
ival (%
pati
en
ts)
100
80
60
40
20
00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Time 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)
Escudier B, et al. J Clin Oncol. 2009;27:1280–1289.
The PI3K/AKT/mTOR signal transduction
pathway in the tumor: aberrant activation mTOR activity ofter
increased in cancer
cells :
– Increased EGFR, IGF-1R,
és VEGFR signal
transduction1,2
– Appearance of function
modifying mutationse.g.
In PI3K, Ras/Raf, erbB
receptors, and Abl2-4
– Loss of function of
negative regulators (e.g.
PTEN és TSC1/2)3
1. Harris TE, et al. Sci STKE. 2003;(212):re15; 2. Humar A, et al. FASEB J. 2002;16:771-780; 3. Huang S, et al. Cancer Biol Ther. 2003;2:222-232; 4. Edinger and Thompson. Mol Biol Cell. 2002;13:2276-2288.
Temsirolimus phase III study on RCC
patients with poor prognosis
Inclusion criteria
• Locally advanced or mRCC
• Primarily clear cell histology
• 3/6 poor risk sign
• LDH >1.5 x ULN
• Hgb < LLN
• Corrected Ca++ >10
• KPS <70
• DFI <1 year
• Multiple organ metasteses)
RANDOMISATION
Primary andpoint: OS
TEM 25 mg QW
(n = 209)
IFN 6 MU + TEM 15 mg QW (n = 210)
N = 626
IFN 3 MU-18 MU
(n = 207)
*Modified MSKCC poor risk; †Stratification by country and nephrectomy status.
DFI = disease-free interval.
Hudes G et al. N Engl J Med. 2007;356:2271–2281.
*Modified MSKCC poor risk; †Stratification by country and nephrectomy status.
Temsirolimus vs. IFN: OS
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
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
Hudes G et al. N Engl J Med. 2007;356:2271–2281.
Toxicity profiles of drugs used in first
line (Grade 3/4) Sunitinib1,2 Bev + IFN-α3 Sorafenib4 Pazopanib5 Temsirolimus6
AE (%)
Phase III
1st line
Phase III
1st line
Phase II
1st line
Phase III
1st line
Phase III*
1st line
Anorexia – 3 0 2 3
Asthenia 4 10 – 3 11
Diarrhea 5 2 6 4 1
Dyspnea – <1 0 – 9
Fatigue 7 12 5 2 –
Hand-foot szindróma 5 – 11 – –
Hyperglycemia 5 – – <1 11
Hypertension 8 3 2 4 –
Anemia 4 3 – – 20
Neutropenia 12 4 – 2 3
Thrombocytopenia 8 2 – 2 1
Leukopenia 5 – – 0 1
Tretament interruption due to
AE
19 28 11 16 7
*Poor prognostic patients based on MSKCC criteria (+ metasztatically involved organs)
1. Motzer RJ, et al. N Engl J Med. 2007;356:115–124. 2. Figlin RA, et al. J Clin Oncol. 2008;26(Suppl. 15S):5024 (Abstract). 3. Escudier B, et al. J Clin Oncol. 2009;27:1280–1289. 4. Escudier B, et al. Lancet. 2007;370:2103–2111. 5. Sternberg C, et al. J Clin Oncol. 2010 ;28:1061-1068. 6. Hudes G, et al. N Engl J Med. 2007;356:2271−2281.
Hand-foot skin reaction
Relapse or metastatic disease or irresectable
Clear cell histology
Level 1 evidence*
– Sunitinib
– Bevacizumab + IFN-α
– Pazopanib
– Temsirolimus (for patients with poor prognosis)
NCCN Guidelines: 1st line treatment
* Level 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials) and there is uniform NCCN consensus.
† Poor prognosis patients, defined as those with ≥3 predictors of short survival.
NCCN = National Comprehensive Cancer Network; RT = radiation therapy.
Kidney Cancer, NCCN v.2.2010 Clinical Practice Guidelines in Oncology. Available at www.NCCN.org.
Everolimus: Post-TKI Therapy (RECORD-1)
RCC=renal cell carcinoma; RECIST=Response Evaluation Criteria in Solid Tumors; PS=performance status; VEGFR-TKI=vascular endothelial growth factor receptor tyrosine kinase inhibitors; MSKCC=Memorial Sloan-Kettering Cancer Center; qd=every day; BSC=best supportive care. IFN-α=interferon alfa.
1. Motzer RJ, et al, for the RECORD-1 Study Group. Lancet. 2008;372:449-456; 2. Motzer RJ, et al, for the RECORD-1 Study Group. Cancer. 2010 ;116(18):4256-4265.
Inclusion criteria
Metastatic clear cell RCC
Progression on sunitinib, or sorafenib, or 6 months after finishing sunitinib/sorafenib treatment
Measurable disease (RECIST)
Karnofsky PS ≥70%
Adequate bone marrow, liver and kidney function
Stratification
Prior VEGFR-TKI: 1 vs 2
MSKCC risk: good, intermediate, poor
R A
N D
O M
I ZA
TIO
N Everolimus 10 mg qd + BSC
(n=277)
Placebo + BSC (n=139)
Cross over to everolimus in
case of progression
2:1
Primary endpoint Progression free survival (PFS)
Secondary endpoints Objective response rate(ORR), Overall survival (OS), Toxicity (AE-s), Quality of life (QoL)
RECORD-1: PFS
PFS improved in every MSKCC risk groups, independently from the type of previous VEGFR-TKI therapy
100
80
60
40
20
0
0 2 4 6 8 10 14
Pro
bab
ilit
y,
%
Everolimus (median PFS: 4.90 months) Placebo (median PFS: 1.87 months)
Hazard Ratio = 0.33
95% CI: 0.25, 0.43
Log-Rank P Value <0.001
Time, months 12
PFS=progression-free survival
Reprinted from Motzer RJ, et al, for the RECORD-1 Study Group. Cancer. 2010;116(18):4256-4265.
0
Time, months
30
40
50
60
70
80
90
100
Pro
bab
ilit
y, %
Everolimus (n=277; Kaplan-Meier Median: 14.8 hó)
Placebo (n=139; Kaplan-Meier Median: 14.4 hó)
20 2 4 6 8 10 12 14 16 18 22
Motzer RJ, et al, for the RECORD-1 Study Group. Cancer. 2010;116(18):4256-4265.
RECORD-1 OS
The real evaluation of OS is biased by the cross-over of 81% of placebo treated patients to everolimus arm after progression
Sorafenib
400 mg bid ORR 10%
SD 74%
PFS 5.5 months
Priary endpoint
• PFS (P=0.01)
• OS (P=0.04)
Secondary
endpoint
• ORR
TARGET: Phase III, sorafenib vs.
placebo, 2nd line
Placebo* ORR 2%
SD 53%
PFS 2.8 months
1:1
randomisation
n~905
Inclusion criteria
• Histologically confirmed
non-resectable or
metastatic disease
• Clear cell histology
• Measurable disease
• Failure of at least one prior
therapy
• ECOG PS 0 or 1
• Good organ functions
• No brain metastasis
• Poor prognostic group
excluded
Stratification
MSKCC criteria
Country
*Crossover initiated 6/05.
Escudier B, et al. N Engl J Med. 2007;356:125–134; Bukowski R, et al. Am J Clin Oncol. 2007;30:220–227.
OS Sorafenib Placebo
Final analysis 17.8 hó 15.2 hó
Censored analysis 17.8 hó 14.3 hó
TARGET: OS analysis TARGET: 561 death
OS analysis defined by protocol TARGET: pre-planned secondary analysis†:
data of censored sorafenib receiving patients excluded
0 4 8 12 16 20 24 28 32 36 40
Months after randomisation
Pro
po
rtio
n o
f th
e liv
ing
pati
en
ts 1.00
0.75
0.50
0.25
0.00
● 216/452 patient receiving placebo changed to sorefenib
● 61% of patients of placebo arm has received sorefenib
Sorafenib
Placebo
HR = 0.88*
95% 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 after randomisation
Pro
po
rtio
n o
f th
e liv
ing
pa
tie
nts
1.00
0.75
0.50
0.25
0.00
HR = 0.78*
95% CI: 0.62–0.97
P=0.0287*
Sorafenib (N = 451)
Placebo (N = 452)
Escudier B, et al. N Engl J Med. 2007;356:125–134. Bukowski R, et al. Am J Clin Oncol. 2007;30:220–227.
Pazopanib vs. placebo: 2nd line
Inclusion criteria
• Locally advanced or mRCC
• Primarily clear cell histology
• Measurable disease (≥1 lesion)
• 1 prior systemic treatment (cytokine based)*
R
A
N
D
O
M
I
Z
A
T
I
O
N
2:1
Primary endpoint: PFS
Pazopanib 800 mg/day
Placebo N = 400
• Open-label extension study (Pazopanib 800 mg; N = 71)
*Patients with no prior treatment were also permitted to enroll in the study
Sternberg C, et al. J Clin Oncol. 2010 ;28:1061–1068.
Pazopanib PFS on cytokine pretreated
patients HR = 0.54
95% CI (0.35, 0.84)
P value <0.001
Median PFS
Pazopanib: 7.4 hónap
Placebo: 4.2 hónap
1.0
0.8
0.6
0.4
0.2
0.0 0 5 10 15 20
Months
Pro
po
rtio
n p
rog
ress
ion
fre
e
Patients receiving treatment
Pazopanib 135 75 37 18 5
Placebo 67 16 7 Sternberg C, et al. J Clin Oncol. 2009;27(Suppl 15s):5021 (Abstract).
Less potent
More potent
Pote
ncy: IC
50 (
nM
)
Figure modified using data from Chow LQM, Eckhardt SG. J Clin Oncol. 2007 Eskens FALM, et al. AACR 2008. Abstract LB-201; Hu-Lowe DD, Clin Cancer Res 2008
VEGFR-1
VEGFR-2
VEGFR-3
Motesanib AMG-706
Sunitinib ABT-869 *Pazopanib Sorafenib Vatalanib PTK787
Vandetanib Cediranib Axitinib Tivozanib AV-951
1,000
100
10
1
0.1
0.01
Relative potencies of VEGF TKI-s
AXIS: Fázis III, axitinib vs. sorafenib,
2nd line
Primary endpoint: PFS
Secondary endpoint: OS, ORR
Axitinib 5 mg BID
Sorafenib 400 mg BID
Inclusion criteria
mRCC with clear cell histology
Failure of one prior treatment:
Sunitinib
Bevacizumab + IFN-α
Temsirolimus
Or cytokin
Stratification: Prior treatment, ECOG PS
N=717
Rini B, et al. ASCO 2011
R
A
N
D
O
M
I
S
A
T
I
O
N
AXIS: Az axitinib szignifikánsan
megnyújtja a PFS-t
361 256 202 145 96 64 38 20 10 1 0
362 224 157 100 51 28 12 6 3 1 0
Betegszám
Axitinib
Sorafenib
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Idő (hónap)
P<0.0001 (log-rank)
Stratified HR 0.665
(95% CI :0.544–0.812)
0 2 4 6 8 10 12 14 16 18 20
Axitinib
Sorafenib
mPFS, hónap 95% CI
6.7 4.7
6.3–8.6 4.6–5.6
Pro
gre
sszió
me
nte
s tú
lélé
s
Rini B, et al. ASCO 2011
PFS and prior treatments
Prior treatment
Axitinib
(n=361)
Sorafenib
(n=362) HR P value*
Cytokines (n=251)
IRC
Investigator
12.1
12.0
6.5
8.3
0.464
0.636
<0.0001
0.005
Sunitinib (n=389)
IRC
Investigator
4.8
6.5
3.4
4.5
0.741
0.636
0.011
0.0002
Temsirolimus (n=24)
IRC
Investigator
10.1
2.6
5.3
5.7
0.511
1.210
0.142
0.634
Bevacizumab (n=59)
IRC
Investigator
4.2
6.5
4.7
4.5
1.147
0.753
0.637
0.213
*One-sided log-rank test stratified by ECOG PS Rini B, et al. ASCO 2011
The ORR of axitinib is better
Best tumor response, % Axitinib Sorafenib
Partial response*
Stable disease
Progressive disease
Not defined
19.4
49.9
21.6
6.1
9.4
54.4
21.0
11.6
Risk ratio (95% CI) 2.1 (1.4–3.0)
*Axitinib vs. sorafenib: P = 0.0001
Rini B, et al. ASCO 2011
Results of treatment of cytokin
refrakter mRCC
Study
n
ORR (%)
Median
PFS/TTP (mos)
Median
OS (mos)
Sorafenib (vs. placebo)1 903 10 vs. 2 5.5 vs. 2.8 17.8 vs. 15.2
Pazopanib (vs. placebo)4 202 29 vs. 3 7.4 vs. 4.2 NA
Sunitinib2 106 34 8.3 23.94
Sunitinib3 63 40 8.7 16.4
Axitinib5 52 44 15.7 29.9
1. Escudier B, et al. N Engl J Med. 2007;356:125–134. 2. Motzer RJ, et al. J Urol. 2007;178:1883-1887. 3. Motzer RJ, et al. J Clin Oncol. 2006;24:16–24. 4. Sternberg C, et al. J Clin Oncol. 2009;27(Suppl 15s):5021 (Abstract). 5. Rixe O, et al. Lancet Oncol. 2007;8:975–984.
* Date presented are not from comparative trials!
NCCN Guidelines: 2nd line treatments
Clear cell histology
• Clinical study
• Sunitinib (1* after cytokine treatment, 2A† after other TKI treatment)
• Sorafenib (1 after cytokine treatment, 2A after other TKI treatment)
• Pazopanib (1 after cytokine treatment, 3§ after other TKI treatment)
• Everolimus (1 after TKI treatment)
Level 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials) and there is uniform NCCN consensus.
† Level 2A: Uniform NCCN consensus based on lower-level evidence, including clinical experience, that the recommendation is appropriate.
§ Level 3: Recommendation is based on any level of evidence but reflects major disagreement.
Kidney Cancer, NCCN v.2.2010 Clinical Practice Guidelines in Oncology. Available at www.NCCN.org.
Europen mRCC treatment
landscape
Patient group Treatment Option
No prior treatment
MSKCC: good
or intermediate
Sunitinib Bevacizumab
+ IFNα Pazopanib
HD IL-2
MSKCC: poor
Temsirolimus Sunitinib
Second-line patient
Cytokine
refracter
Sorafenib Pazopanib Sunitinib
VEGF/VEGFR
TKI refracter Everolimus
Sequential TKI or VEGF
inhibitor
Treatment of mRCC in Hungary
AVOREN ASCO 2009
Figlin ASCO 2008
Multiple studies
Hudes 2007
Gore ASCO 2008
Kane 2006
5.3
Improving PFS in the 1st line treatment
of mRCC
Time (months)
Best supportive care
INF-α+ IL-2+5-FU
Temsirolimus
Sunitinib
Bevacizumab + INF-α
Sorafenib
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
11.0
5.5
5.7
2–3
10.4
Nexavar PI
Kane et al. Clin Cancer Res. 2006;12:7271; Gore et al. ASCO 2008; Hudes et al. N Engl J Med 2007;356:2271; Nexavar PI; Rini et al. ASCO 2009; Escudier et al. ASCO 2009; Figlin et al. ASCO 2008; Sternberg et al. ASCO 2009.
Bevacizumab + INF-α CALGB 90206 ASCO 2009
INF-α alone 3–5
8.4
Fro
m 2
00
5 u
ntil re
ce
ntly
Pazopanib ASCO 2009 Pazopanib 1.1
Improving OS in the 1st line treatment
of mRCC
1. Kane et al. Clin Cancer Res 2006;12:7271; 2. Hudes et al. N Eng J Med 2007;356:2271; 3. Escudier et al. N Engl J Med 2007;356:125; 4. Gore et al. ASCO 2008. Abstract 5039; 5. Escudier. ASCO 2008. Abstract 5025; 6. Rini et al. J Clin Oncol 2010;28:2137–2143;
7. Escudier et al. J Clin Oncol 2010; 28:2144–2150; 8. Figlin et al. ASCO 2008. Abstract 5024.
Fro
m 2
00
4 u
ntil re
ce
ntly
Best supportive care1
Temsirolimus2
IFN-α + IL-2 + 5-FU4,5
CALGB6
AVOREN7
Sunitinib8
Kane 2006
IFN
Figlin ASCO 2008
Gore ASCO 2008 IFN
Bevacizumab + IFN
Temsirolimus IFN
IFN
IFN Bevacizumab + IFN
Primary goal in the treatment of
mRCC: improving efficacy
Before targeted therapies the ORR was low (~2–13%), and median OS was 13.3 months
Effect of targeted therapies:
– In contrast to palliation we can count on long OS
– Comparing to cytokine based therapies PFS and OS significantly increased
1. Rini et al. J Clin Oncol 2008; 26:5422; 2. Escudier et al. Lancet 2007;370:2103; 3. Escudier. Cancer J 2008;14:325; 4. Escudier et al. N Engl J Med 2007;357:203;
5. Motzer et al. J Clin Oncol 2009; 27:3584; 6; Coppin et al. Cochrane Collaboration, 2006; 7. Motzer et al. N Engl J Med 2007;356:115; 8. Heng et al. Cancer 2009;115:776