43
“Oltre la prima linea” Dr. Camillo Porta S.C. di Oncologia Medica I.R.C.C.S. Policlinico San Matteo, Pavia
“Oltre la prima linea”
Dr. Camillo PortaS.C. di Oncologia Medica
I.R.C.C.S. Policlinico San Matteo, Pavia
Considering sequences,
the issue is …
Sunitinib
Sorafenib
Pazopanib
Temsirolimus
Bevacizumab + IFN
Everolimus
Axitinib
Even though a number of studies have
already examined different sequences, with
all the active agents we now have, we shall
never be able to test all possible sequences
76 = 117649 possible combinations!!!!
Temsirolimus Axitinib
What I am going to address
• Available evidence
- phase III RCT
- specifically designed sequential studies
- large retrospective series- large retrospective series
• Applying Evidence-Based Medicine to
sequential Tx in RCC
• Take home messages
1st line 2nd line 3rd line
Available evidence for
sequential therapies in RCC
AXIS – Phase 3
(axitinib vs sorafenib)3,4
GOLD – Phase 3
(dovitinib vs sorafenib)11
INTORSECT – Phase 3
(temsirolimus vs sorafenib)5
RECORD-1 – Phase 3
(everolimus vs placebo)1,2
• 1. Motzer RJ et al. Lancet 2008; 372:449–456; 2. Motzer RJ et al. Cancer 2010;116:4256–65; 3. Rini BI et al. Lancet
2011;378:1931–9; 4. Motzer RJ et al. Lancet Oncology 2013;14:552–62 ; 5. Hutson TE et al. J Clin Oncol 2013;32:760–
9; 6. Michel MS et al. ASCO-GU 2014; abstract 393; 7. www.clinicaltrials.gov NCT01613846; 8. Motzer RJ et al. ASCO
2013; abstr 4504; 9. Levy A et al. Eur J Cancer 2013;49:1898–904; 10. Iacovelli R et al. Eur J Cancer 2013;49:2134–42;
11. Motzer RJ et al. Lancet Oncol 2014;15:286–96
SWITCH-1 – Phase 3
(sunitinib-sorafenib vs sorafenib-sunitinib)6
(temsirolimus vs sorafenib)5
Levy A et al – retrospective
(MKI-MKI vs MKI-mTORi)9
Iacovelli R et al – retrospective
(MKI-MKI-mTORi vs MKI-mTORi-MKI)10
RECORD-3 – Phase 2
(everolimus-sunitinib vs sunitinib-everolimus)8
2nd line RCTs
4.9
P
F
S
RECORD-11
AXIS2
1.9
Everolimus
Placebo
p = <0.001
N= 277
N= 139
Three available RCTs in 2nd-line
1. Motzer RJ, et al. Cancer 2010;116:4256–65;
2. Rini BI, et al. Lancet 2011;378:1931–9;
3. Hutson TE, et al. J Clin Oncol 2013 Dec 2. [Epub ahead of print].
(Months)1
5
2
0
0 5 1
0
2
5
6.7
4.7
4.3
3.9
INTORSECT3
Axitinib
Sorafenib
Temsirolimus
Sorafenib
p = <0.0001
p = not significant
N= 361
N= 362
N= 259
N= 253
4.9
P
F
S
6.7
RECORD-11
AXIS2
1.9
Everolimus
Placebo
Axitinib
N= 277
N= 139
N= 361
14.8
20.1
14.4
O
S
OS: p = not significant
OS: p= not
Three available RCTs in 2nd-line
1. Motzer RJ, et al. Cancer 2010;116:4256–65;
2. Rini BI, et al. Lancet 2011;378:1931–9;
3. Hutson TE, et al. J Clin Oncol 2013 Dec 2. [Epub ahead of print].
(Months)1
5
2
0
0 5 1
0
2
5
4.7
4.3
3.9
INTORSECT3
Sorafenib
Temsirolimus
Sorafenib
N= 362
N= 259
N= 253
19.2
12.3
16.6
OS: p= not
significant
OS: p=0.014
statistically significant
Enrolled
N = 416
Stratification
Everolimus 10 mg o.d. + BSC (n = 277)
R
A
N
D
O
M
I
Everolimus RECORD-1 trial:
study design
Final
analysis
Prior VEGFr
TKI: 1 or 2
MSKCC risk group:
favorable,
intermediate,
or poor
matching placebo + BSC (n = 139)
Upon Disease
Progression
Safety Interim
analysis
Efficacy &
Safety Interim
analysis
I
Z
A
T
I
O
N
2:1
Motzer RJ, et al. Lancet 2008;372:449-56.
RECORD-1 was the first RCT
conducted after TKIs
50
80
Pro
ba
bil
ity (
%)
60
70
90
100
HR = 0.33 (95% CI 0.25, 0.43)
P<0.001 (log-rank test)
Median PFS (months) (n)
Everolimus 4.90 (277)
Placebo 1.87 (139)
Motzer RJ et al. Lancet 2008; 372:449–456; Motzer RJ et al.
Cancer 2010;116:4256–65.
50
40
30
10
0
Pro
ba
bil
ity (
%)
20
0 2 4 6 9 13Months
101 3 5 7 8 11 12 14
0
0
26
2
51
6
115
15
192
47
Everolimus
Placebo
Patients at risk
277
139
1
0
10
0
Everolimus RECORD-1 trial:
OS
40
60
80
100P
rob
ab
ilit
y,
%
Hazard Ratio = 0.8295 % CI [0.57, 1.17]
Median
0
20
40
0 2 4 6 8 10 12 14 16Months
Pro
bab
ilit
y,
%
Everolimus (n = 277)
Placebo (n = 139)
MedianEverolimus: NA monthsPlacebo: 13.01 months
Logrank P value = 0.137
Patients at RiskEverolimus
Placebo
277 267 236 191 108 52 11 1 0
139 131 114 91 53 19 6 1 0
Everolimus in RECORD-1:
which line of therapy?
1st
line
1st
line
2nd
line
2nd
line
3rd
line
3rd
line
mTOR
4th
line
mTOR
5th
line
4th
line n=82*
n=104* 79%
• Patients received a median of 2 prior antineoplastic medications
Motzer RJ, et al. Cancer 2010;116:4256–65.
mTOR
2nd
line
1st
line
1st
line
2nd
line
mTOR
3rd
line
line
n=141*
n=89* 21%
*Includes patients randomized to everolimus and those randomized to placebo
Everolimus:
better earlier or later?
mTOR
2nd
Line
1st TKI
1st TKI
2nd
TKI
mTOR
3rd
Line
n = 108
n = 308 74%
26%
Beware of
“time-lead bias”:
Calvo E, et al. Eur J Cancer 2012;48:333-39.
“time-lead bias”:
HR is the same!!
The AXIS trial:
Axitinib vs Sorafenib in 2nd line
• The AXIS trial was the first phase III study to report data for sequential TKI therapy
• this open-label study assessed axitinib vs sorafenib in
previously treated patients
• prior therapies included Cytokines, Sunitinib, Bevacizumab, Temsirolimus
• 36.8% of axitinib patients had
a dose escalationSorafenib 400 mg po
bid continuous
R
A
Randomization stratified by ECOG PS and
type of prior treatment
bid continuous
dosing
Axitinib starting
dose of 5 mg bid to
7 mg bid to 10 mg
bid, as tolerated
A
N
D
O
M
I
Z
E
Patients:
• Metastatic RCC with
clear cell histology
• One failed prior
systemic 1st-line
regimen
• ECOG PS 0 or 1
Treatment-
refractory
mRCC
Rini BI, et al. Lancet 2011;378:1931-9.
AXIS trial: PFS results
1.
0
0.
9
0.
8
0.
7
0.
6
0.
5
p<0.0001 (log-rank)
sratified HR 0.665
(95% CI, 0.544–0.812)
Axitinib
Sorafenib
mPFS, mo 95% CI
6.
74.
7
6.3–8.6
4.6–5.6
fre
e s
urv
iva
l (p
rob
ab
ilit
y)
3
6
1
2
5
6
2
0
2
1
4
5
9
6
6
4
3
8
2
0
1
0
1 0
3
6
2
2
2
4
1
5
7
1
0
0
5
1
2
8
1
2
6 3 1 0
Subjects at risk, n
Axitinib
Sorafenib
Rini BI, et al. Lancet 2011;378:1931-9.
5
0.
4
0.
3
0.
2
0.
1
0.
00 2 4 6 8 1
0
Time (months)
1
2
1
4
1
6
1
8
2
0
Pro
gre
ssio
n-f
ree
su
rviv
al
(pro
ba
bil
ity
)
In the post Sunitinib subpopulationPFS differences were more limited
Axitinib
(n=361)
Sorafenib
(n=362)P value*
Overall median PFS 6.7 4.7 <0.0001Overall median PFS 6.7 4.7 <0.0001
Prior treatment regimen
Cytokines (n=251) 12.1 6.5 <0.0001
Sunitinib (n=389) 4.8 3.4 0.011
Temsirolimus (n=24) 10.1 5.3 0.142
Bevacizumab (n=59) 4.2 4.7 0.637
Rini BI et al. Lancet 2011;378:1931–9
Axitinib
(n=361)
Sorafenib
(n=362)P value*
Overall median PFS 6.7 4.7 <0.0001
In the post Sunitinib subpopulationPFS differences were more limited
Overall median PFS 6.7 4.7 <0.0001
Prior treatment regimen
Cytokines (n=251) 12.1 6.5 <0.0001
Sunitinib (n=389) 4.8 3.4 0.011
Temsirolimus (n=24) 10.1 5.3 0.142
Bevacizumab (n=59) 4.2 4.7 0.637
Rini BI et al. Lancet 2011;378:1931–9
AXIS: despite PFS advantage,no differences in OS …
Overall population
HR: 0.969 (95% CI: 0.800–1.174)
p=0.3744, one-sided stratified log-rank test
1.0
0.5
0.8
Su
rviv
al d
istr
ibu
tio
n f
un
ctio
n
0.6
0.7
0.9
n Median OS 95% CI
(months)
Axitinib 361 20.1 16.7–23.4
Sorafenib 363 19.2 17.5–22.3
Motzer RJ et al. Lancet Oncology 2013;14:552–62; Rini BI et al. Lancet 2011;378:1931–9
Number at risk
0 2 4 6 8 10 12 14 16 20 22 24 26 28 30 32 34 36
0.5
0.4
0.3
0.1
0
Su
rviv
al d
istr
ibu
tio
n f
un
ctio
n
0.2
18
36
1
36
2
35
1
34
0
32
6
31
8
30
2
29
8
27
3
27
8
25
2
25
9
23
7
24
0
21
4
21
8
19
3
20
2
17
8
18
1
15
2
14
5
12
7
11
8
8
6
8
8
7
0
6
2
4
5
4
1
3
6
2
6
1
4
9
5
4
0
0
Axitinib:
Sorafenib:
Survival time (months)
… even in terms of OS
0.8
Su
rviv
al d
istr
ibu
tio
n f
un
ctio
n
0.6
0.7
0.9
Patients previously treated with sunitinib
1.0
HR: 0.997 (95% CI: 0.782–1.270)
p=0.4902, one-sided stratified log-rank test
n Median OS 95% CI
(months)
Axitinib 194 15.2 12.8–18.3
Sorafenib 195 16.5 13.7–19.2
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
0.5
0.4
0.3
0.1
0
Su
rviv
al d
istr
ibu
tio
n f
un
ctio
n
0.2
0.6
0 2 4 6
194
195
187
183
172
167
157
154
137
140
123
129
114
117
98
106
88
97
80
88
67
66
56
56
38
39
10
5
4
2
0
0
Axitinib:
Sorafenib:
Survival time (months)
p=0.4902, one-sided stratified log-rank test
Number at risk
32
28
22
19
19
12
Motzer RJ et al. Lancet Oncology 2013;14:552–62
Sequences: comparing apples
with pears (don’t do this at home!)
Axitinib Sorafenib Everolimus Placebo
Overall PFS (mos) 6.7
(+43%)
4.7 4.9 1.9
PFS Sunitinb 4.8 3.4 3.9 1.8
RECORD-1AXIS
PFS Sunitinb
subgroup (mos)
4.8
(+41%)
3.4 3.9
(4.6 in 2nd line)
1.8
ORR (%) 19.4
(+86%)
9.4 2 0% of pts in >2nd line 0 79
Median n. of prior Tx 1 3Discontinuation due
to AEs (%)
3.9 8.2
(+106%)
13.1 1.5
No of intolerant pts 0 0 50 131. Motzer RJ, et al. Lancet 2008;372:449-56; 2. Rini BI, et al. Lancet 2011;378:1931-9.
Sequences: comparing apples
with pears (don’t do this at home!)
Axitinib Sorafenib Everolimus Placebo
Overall PFS (mos) 6.7
(+43%)
4.7 4.9 1.9
PFS Sunitinb 4.8 3.4 3.9 1.8
RECORD-1AXIS
PFS Sunitinb
subgroup (mos)
4.8
(+41%)
3.4 3.9
(4.6 in 2nd line)
1.8
ORR (%) 19.4
(+86%)
9.4 2 0% of pts in >2nd line 0 79
Median n. of prior Tx 1 3Discontinuation due
to AEs (%)
3.9 8.2
(+106%)
13.1 1.5
No of intolerant pts 0 0 50 131. Motzer RJ, et al. Lancet 2008;372:449-56; 2. Rini BI, et al. Lancet 2011;378:1931-9.
INTORSECT: no PFS differences,
but OS advantage
Stratified HR: 1.31 (95% CI 1.05–1.63)
p=0.01 (2-sided log-rank)
Temsirolimus
Sorafenib
Median OS 95% CI
(months)
12.3 10.1–14.8
16.6 13.6–18.7INTORSECT was the first head-
to-head study of 2nd-line TKI vs
mTORi
Hutson TE et al. J Clin Oncol 2013;32:760–7
Failed to meet the primary
endpoint of prolonging PFS with
temsirolimus vs sorafenib
Patients had received prior
sunitinib only
INTORSECT:
post-progression treatments
Anti-neoplastic agent, n (%)
Temsirolimus
(n=249)
Sorafenib
(n=252)
Surgery 0 (0) 6 (2.4)
Radiation therapy 5 (2.0) 12 (4.8)~10% patients Any non-study medication* 14 (5.6) 16 (6.3)
Bevacizumab 0 (0) 1 (0.4)
Everolimus 2 (0.8) 12 (4.8)
IFN-α 3 (1.2) 1 (0.4)
Sorafenib 9 (3.6) 1 (0.4)
Temsirolimus 0 (0.0) 2 (0.8)
*Includes medications started after the last dose of randomized study medication. Information collected up to 30 days
after study completion Patients may have received ≥2 different agents
Hutson TE et al. ESMO 2012; abstr LBA22_PR
~10% patients
received subsequent
treatments
in INTORSECT
3rd line trial
GOLD: first phase III study of 3rd-line
treatment in mRCC
Eligibility criteria
• clear cell mRCC
• 1 previous VEGF-
targeted therapy
AND 1 previous
Dovitinib
(FGFR- and
VEGFR–MKI)N=550
R
A
N
D
O
M
I
Z
• Motzer RJ et al. Lancet Oncol 2014;15:286–96
AND 1 previous
mTOR inhibitorSorafenib
• Primary endpoint: PFS (central radiology assessment)
• Secondary endpoints included: OS, PFS (investigator assessed), overall response
rate, safety, patient-reported outcomes
Z
A
T
I
O
N
GOLD: trial failed to show any PFS
advantage with dovitinib vs sorafenibn Median PFS 95% CI
(months)
Dovitinib 284 3.7 3.5–3.9
Sorafenib 286 3.6 3.5–3.7
HR: 0.86 (95% CI: 0.72–1.04)
p=0.063 (1-sided)
• Median follow-up: 11·3 months
• (IQR 7·9–14·6)
• Motzer RJ et al. Lancet Oncol 2014;15:286–96
Sequential trials
SWITCH-1:
the first phase III sequencing study
Sorafenib
Sunitinib50 mg
once daily*
Randomization
1:1
365 patients• mRCC unsuitable for
cytokines and no prior
systemic therapy
• Age >18 and ≤85 years
Primary
endpointIf total PFS**
is superior with
So−Su
vs Su−So
Progression
or
intolerable
toxicity
Sunitinib
Sorafenib400 mg
twice daily
Sorafenib 400 mg
twice daily
• Age >18 and ≤85 years
• ECOG PS 0/1
• ≥1 measurable lesion
vs Su−SoSunitinib
50 mg
once daily*
• *In cycles of 4 weeks on, 2 weeks off. **From randomization to confirmed progression or death during 2nd-line (or 1st-line for
patients who did not receive 2nd-line). ***For patients who discontinued for reasons other than disease progression.
• ECOG PS, Eastern Cooperative Oncology Group Performance Status; MSKCC, Memorial Sloan-Kettering Cancer Center.
• www.clinicaltrials.gov NCT00732914
• Michel MS et al. ASCO-GU 2014;abstract 393.
• Patients enrolled in Germany, Austria, and The Netherlands
• Stratified by MSKCC prognostic group (favourable or intermediate)
• Efficacy assessed every 12 weeks (RECIST v1.0), and at treatment end***
SWITCH-1:
no differences in PFS for Su-So vs So-Su
n
Median (95% CI) PFS, months
So–Su 182 12.5 (9.9, 15.9)
Su–So 183 14.9 (9.7, 17.4)
HR: 1.01 (one-sided 95% CI: <1.27)
p value for superiority = 0.54
PF
S p
rob
ab
ilit
y (
%)
60
80
10
0
50
70
90
• Intent-to-treat population
• CI, confidence interval; HR, hazard ratio; So = sorafenib; Su = sunitinib
• Michel MS et al. ASCO-GU 2014;abstract 393.
PF
S p
rob
ab
ilit
y (
%)
Months from randomization
0
10
20
40
30
0 5 10 15 20 25 30 35 40 45 50
No. patients
So–Su 18
2
12
7
83 66 45 30 17 14 7 6
Su–So 18
3
11
6
85 62 43 26 19 16 10 9
n
Median (95% CI) OS,
months
So–Su 182 31.5 (>23.3, <36.9)
Su–So 183 30.2 (>23.6, <50.1)HR: 1.00 (one-sided 95% CI: <1.30)
p value for superiority = 0.49
Su
rviv
al
pro
ba
bil
ity
(%
)
60
80
10
0
50
70
90
SWITCH-1:
no differences in OS for Su-So vs So-Su
• Intent-to-treat population
• OS, overall survival
• Michel MS et al. ASCO-GU 2014;abstract 393.
Su
rviv
al
pro
ba
bil
ity
(%
)
Months from randomization
0
10
20
40
30
0 5 10 15 20 25 30 35 40 45 50 55
No. patients
So–Su 18
2
14
8
12
3
10
5
79 58 36 25 17 9 6
Su–So 18
3
14
7
11
9
95 80 59 37 29 18 12 7
Phase 2 RECORD-3
randomized, open-label, non-inferiority study
of mTORi-MKI vs MKI-mTORi
Everolimus10 mg PO QD
Eligible patients
• Treatment naïve
• Karnofsky PS ≥70
On disease progression
Sunitinib50 mg PO QD schedule 4/2
R
A
N
D
O
M
mRCC, metastatic renal cell carcinoma; mTORi, mammalian target of rapamycin inhibitor; OS, overall survival; PFS, progression-free
survival; PO, by mouth; MKI, multikinase inhibitor; PS, performance status; QD, once daily; RCC renal cell carcinoma;
Motzer RJ et al. ASCO 2013; abstr 4504; www.clinicaltrials.gov NCT00903175
• N=460
• Primary endpoint: first-line PFS (non-inferiority)
• Key secondary endpoints: second-line PFS; OS; objective response rate; safety
Sunitinib50 mg PO QD schedule 4/2
• Karnofsky PS ≥70
Everolimus10 mg PO QD
M
I
Z
E
1:1
Phase 2 RECORD-3 failed to show
non-inferiority of mTORi-MKI vs MKI-mTORi
EveSu (n=238) SuEve (n=233) HR
(95% CI)Mean
(months)95% CI
Mean
(months)95% CI
Median PFS 1.43
Median PFS
after 1st-
line
7.9 5.6–8.2 10.7 8.2–11.51.43
(1.15–1.77)
Combined
PFS*21.1 – 25.8 –
1.28
(0.94–1.73)
Median OS 22.4 19.7–NA 32.0 20.5–NA1.24
(0.94–1.64)
*combined PFS composite endpoint linking both lines of treatment
CI, confidence interval; Eve, everolimus; HR, hazard ratio; mTORi, mammalian target of rapamycin inhibitor;
NA, not available; PFS, progression-free survival; OS, overall survival; Su, sunitinib; MKI, multikinase inhibitor
Motzer RJ et al. ASCO 2013; abstr 4504
Primary endpoint not reached
Phase 3 SWITCH-2 will provide
additional 1st- and 2nd-line sequential data
Sorafenib400 mg PO BID
Eligibility criteria
• Treatment-naïve patients
with metastatic/advanced
RCC who are unsuitable for
Disease progression/
unacceptable toxicity
R
A
N
D
O
M
Pazopanib800 mg PO BID
• BID, twice daily; OS, overall survival; PFS, progression-free survival; PO, by mouth; QD, once daily; RCC renal cell carcinoma;
SoPaz, sorafenib → pazopanib;
• PazSo, pazopanib → sorafenib. www.clinicaltrials.gov NCT01613846
• N=544
• Primary endpoint: PFS from randomization to progression/death on 2nd-line therapy
• Key secondary endpoints: time from randomization to progression on 2nd-line therapy;
PFS with 1st-line and 2nd-line treatment; OS (data cut-off same as for primary endpoint)
• Estimated study completion date: June 2016
Pazopanib800 mg PO QD
RCC who are unsuitable for
cytokine therapy
unacceptable toxicityM
I
Z
E
1:1
Sorafenib400 mg PO BID
Retrospective series
Retrospective studies:
the IGR experiencePatients treated from January 2005 to December 2009
Total patients(N=251)
Su (N=127) So (N=60) Bev (N=61) mTORi (N=3)1st
line
100%
N=2/2• MKI (100%)
Levy A et al. Eur J Cancer 2013;49:1898–904
N=24 (19%)
• CR (4)• SD (5)• Current (15)• NA (1)
59%
N=61/103• MKI (56%)• mTORi (44%)
N=2 (3%)
• CR (1)• Current (1)
52%
N=30/58• MKI (80%)• mTORi (17%)• Other (3%)
N=13 (21%)
• CR (2)• SD (6)• Current (3)• Refusal (2)
79%
N=38/48• MKI (100%)
N=1 (33%)
• Current (1)
line
Non-eligible
(n=40)
2nd
line
(n=101)
0
.
6
0
.
8
1
.
0
Cum
ula
tive s
urv
ival
Median OS p-value
(months)*
20.8 0.12
16.6MKI (n=98)
mTORi (n=32)
2nd line therapy
Retrospective studies:
the IGR experience
*from the start of 2nd-line treatment
Levy A et al. Eur J Cancer 2013;49:1898–904
MKI 98 24 5
mTORi 32 5
OS (months)
0 2
4
4
8
7
2
0
0
.
2
0
.
4
6
Cum
ula
tive s
urv
ival
No. patients at risk
2065 patients with
clear-cell mRCC
281 (13%) had 3
Patients treated from August 2006 to June 2011
Retrospective studies:
the Italian experience
• Iacovelli R et al, Eur J Cancer 2013;49:2134–2142
281 (13%) had 3
TTs
152 (54%) had
VEGFi→VEGFi
→mTORi
34 (13%) had
other
sequences
95 (33%) had
VEGFi→mTORi
→VEGFi
71 (25%)
had
Su→So→E
v
44 (16%)
had
So→Su→E
v
56 (20%)
had
Su→Ev→S
oClinical outcomes assessed: PFS and OS
Sequences 1
Sequences 1
Retrospective studies:
the Italian experience
VEGFiVEGFimTORi (n=152) VEGFimTORiVEGFi (n=95) P value
Mean
(months)
95% CI
Mean
(months)
95% CI
PFS 36.5 30.5–42.6 29.3 23.6–34.9 0.059
OS 50.7 40.6–60.8 37.8 34.2–41.5 0.004
Both studies
on the same side,
Iacovelli R et al, Eur J Cancer 2013;49:2134–2142
VEGFi–
VEGFi–
mTORiVEGFi–
mTORi–
VEGFi
Sequences
by class
Total PFS
(months)
0 2
4
4
8
7
2
9
6
1
2
0
0
0
.
2
0
.
4
0
.
6
0
.
8
1
.
0
Cu
mu
lati
ve
su
rviv
al p=0.059 log-
rank test
No. patients at
riskVEGFi–VEGFi–mTORi 152 110 35 1
VEGFi–mTORi–VEGFi 95 46 10 2 1
VEGFi–
VEGFi–
mTORiVEGFi–
mTORi–
VEGFi
Sequences
by class
p=0.004 log-
rank test
Overall
survival
(months)
0 2
4
4
8
7
2
9
6
1
2
0
0
0
.
2
0
.
4
0
.
6
0
.
8
1
.
0
Cu
mu
lati
ve
su
rviv
al
No. patients at
riskVEGFi–VEGFi–mTORi 152 121 46 2
VEGFi–mTORi–
VEGFi 95 55 11 2 1
1
on the same side,
but highly biased
Applying Evidence-Based criteria
to all the above
mTOR
inhibitor
TKI/VEGF
inhibitor
Level of evidence: 1,
Grade of recommendation: A1
?
Probably, Sorafenib and Sunitinib
are both effective in this setting3,4
Level of evidence: 2,
Grade of recommendation: B
TKI-TKI-mTORI or TKI-mTORI-TKI?
TKI/VEGF
inhibitor
TKI/VEGF
inhibitor
Level of evidence: 1,
Grade of recommendation: A2
mTOR
inhibitor
Level of evidence: 1,
Grade of recommendation: A1
We do now know that Everolimus is at least as effective
after 1 TKI, as it is after both1
1. Motzer RJ, et al. Lancet 2008;372:449-56; 2. Rini BI, et al. Lancet 2011;378:1931-9;
3. Di Lorenzo G, et al. Eur Urol 2010;58:906-11; 4. Paglino C, et al. Anticancer Res 2013;33:4999-5004.
mTOR
inhibitor
TKI/VEGF
inhibitor
Level of evidence: 1,
Grade of recommendation: A1
TKI/VEGF
inhibitor
Level of evidence: 1,
Grade of recommendation: A3
From the GOLD study3
TKI-TKI-mTORI or TKI-mTORI-TKI?
TKI/VEGF
inhibitor
TKI/VEGF
inhibitor
Level of evidence: 1,
Grade of recommendation: A2
mTOR
inhibitor
Level of evidence: 1,
Grade of recommendation: A1
We do now know that Everolimus is at least as effective
after 1 TKI, as it is after both1
1. Motzer RJ, et al. Lancet 2008;372:449-56; 2. Rini BI, et al. Lancet 2011;378:1931-9;
3. Motzer RJ, et al. Lancet Oncol 2014 Feb 14. [Epub ahead of print].
We can make the difference …
“… Even though Physics tells us that chaos can be, and often is, a property of
very simple systems, meaning that simple questions usually have complicated
answers , our only way out could be found turning upside-down this concept: in
a complex system (e.g., kidney cancer) we should look for an easy – and credible
– answer to our doubts. And such an answer probably is Chris Ryan’s ‘simplified
algorythm’ statement: “choose any agent You want. Use it well” … A shortcut, for
sure, but a smart one, and also a glowing glance of simplicity to move out from
the fogs of chaos”. Porta C. Eur Urol 2011;60:1171-2 (Editorial).
We can make the difference …
“… Even though Physics tells us that chaos can be, and often is, a property of
very simple systems, meaning that simple questions usually have complicated
answers , our only way out could be found turning upside-down this concept: in
a complex system (e.g., kidney cancer) we should look for an easy – and credible
– answer to our doubts. And such an answer probably is Chris Ryan’s ‘simplified
algorythm’ statement: “choose any agent You want. Use it well” … A shortcut, for
sure, but a smart one, and also a glowing glance of simplicity to move out from
the fogs of chaos”.
Porta C. Eur Urol 2011;60:1171-2 (Editorial).
