Transcript Document

Visión Integradora del Tratamiento
del Cáncer Renal Avanzado:
Situación Actual, Nuevos Fármacos
en Investigación y Vías de Progreso
M. Guix y J. Bellmunt
Hospital del Mar, Barcelona
Guadalajara, 18 y 19 Junio 2009
Progress in treatment of mRCC
 Better knowledge of pathology
 Better knowledge of molecular biology
 Many new options with 4 drugs approved in 18 months!!!!
– Sorafenib (Nexavar)
– Sunitinib (Sutent)
– Temsirolimus (Torisel)
– Bevacizumab (Avastin)*
with 4 pivotal studies published the same year
* In EU, in combination with IFN
Sorafenib vs placebo in 2nd line (TARGET)
PFS in 769 patients
Proportion of patients progression free
1.00
Median PFS
Sorafenib = 5.5m
Placebo = 2.8m
0.75
Hazard ratio (S/P) = 0.44 (p<0.001)
Sorafenib improves PFS
Sorafenib
over placebo Placebo
Censored observation
after first line failure
0.50
0.25
0
0
2
4
6
8
10
12
14
16
18
20
Time from randomization (months)
Escudier et al, NEJM 2007
Sunitinib vs IFN in 1st line: PFS
PFS in 750 patients
Sunitinib
1.0
Median PFS = 11 months
PFS probability
IFN-a
Median PFS = 5 months
Sunitinib improves PFS
over IFN in first line MRCC
0.5
Hazard ratio = 0.415
(95% CI: 0.32–0.54)
p<0.000001
0
0
3
6
9
12
15
Time (months)
Motzer R, et al. NEJM 2007
Sunitinib vs IFN in 1st line: OS
Motzer R, et al. JCO 2009
Bev + IFN vs IFN in 1st line (AVOREN): PFS
1.0
PFS in 649 patients
0.9
HR=0.63, p<0.0001
Median progression-free survival:
Probability of being
progression-free
0.8
0.7
Bevacizumab + IFN = 10.2 months
Placebo + IFN = 5.4 months
0.6
0.5
Bevacizumab improves
PFS of IFN in first line
0.4
0.3
0.2
0.1
5.4
0
0
10.2
6
12
Time (months)
18
24
Escudier et al, Lancet 2007
Bev + IFN vs IFN in 1st line (AVOREN): OS
Probability of survival
1.0
Bevacizumab + IFN (n=327)
IFN + placebo (n=322)
HR=0.86 (95% CI: 0.72–1.04)
p=0.1291 (stratified*)
0.8
0.6
0.4
0.2
21.3
0
0
Patients at risk (n)
Bevacizumab + IFN 327
IFN + placebo
322
6
12
278
262
237
216
23.3
18
24
Time (months)
194
177
157
141
30
36
42
124
113
84
78
27
22
*Stratified by Motzer score and region
Escudier et al. ASCO’09 (Abs#5020)
Bev + IFN vs IFN in 1st line
(CALGB 90206): PFS
Bevacizumab improves
PFS of IFN in first line
HR=0.67, p<0.0001
Median progression-free survival:
Bevacizumab + IFN = 8.5 months
IFN = 5.2 months
Rini BI et al, JCO 2008
Bev + IFN vs IFN in 1st line
(CALGB90206): OS
0.8
IFN
BEV/IFN
Stratified log-rank p=0.069
BEV/IFN: Median OS 18.3 months
0.2
0.4
0.6
IFN: Median OS 17.4 months
0.0
Overall Survival (probability)
1.0
Kaplan-Meier Overall Survival Curves by Treatment Arm
0
6
12
18
24
30
36
42
48
54
60
64
94
37
42
10
17
1
2
Time(months)
Number of Patients at Risk
IFN
363 286 221
BEV/IFN 369 314 242
177
190
148
160
118
139
98
116
Rini et al. ASCO’09 (Abs#LBA5019)
AVOREN & CALGB 90206
• Mixed news; Neither study exceeded the
highwater mark of OS set at ASCO 2008 with
sunitinib of 26.4 months (Figlin et al.)
– patient mix of prognostic factors (and expertise of
treating MD’s?) may explain the difference
– Subsequent therapies appear to alter the OS
behaviour of mRCC (ie sorafenib crossover in the
TARGET trial)
Temsirolimus vs IFN in 1st line poor risk mRCC
Probability of Survival
1.00
0.75
Parameter
IFN
Arm 1
TEMSR
Arm 2
TEMSR + IFN
Arm 3
n
207
209
210
survival
7.3
10.9
8.4
Comparisons
Arm 2:Arm 1
Arm 3:Arm 1
Log-Rank p
0.0069
0.6912
Arm 2: Temsirolimus
Temsirolimus improves OS
over IFN in poor risk
mRCC
OS in
626 patients
0.50
Arm 1: IFN
0.25
Arm 3: IFN + Temsirolimus
0
0
5
10
15
20
25
30
35
Time from Randomization (Months)
Hudes G et al. NEJM 2007
Phase III Trial of Pazopanib in Locally
Advanced and/or Metastatic Renal
Cell Carcinoma (Sternberg ASCO 2009)
Patients with advanced RCC
(N = 435)
Stratification
• ECOG PS 0 vs 1
• Prior nephrectomy
• Rx-naive (n = 233) vs 1 cytokine
failure (n = 202)
Study Design
Randomization
2:1
Pazopanib 800 mg qd
(n = 290)
Matching Placebo
(n = 145)
Option to receive pazopanib via an open-label study at progression
PFS in Overall Study Population
Proportion Progression-Free
1.0
Hazard Ratio = 0.46
95% CI (0.34, 0.62)
P value < 0.0000001
0.8
Median PFS
Pazopanib: 9.2 mo
Placebo:
4.2 mo
0.6
0.4
0.2
Pazopanib
Placebo
0.0
0
5
10
Months
15
20
Sternberg et al. ASCO’09 (Abs#5021)
But now, how to deal with all these
options in real life?
 Can we establish a treatment algorithm?
 Should we use MSKCC in routine?
 Is histology important to decide therapy?
 Should we use combination or sequential
therapy?
Algorithm: 2008/2009
RCC Treatment Algorithm: 2008/2009
Setting
Patients
Therapy
(level 1)
Other Options
(≥ level 2)
Untreated
Good or
Intermediate risk
Sunitinib
Bevacizumab +
IFN
Pazopanib ????
HD IL-2
Sorafenib
Clinical trial
Observation
Poor risk
Temsirolimus
Sunitinib
Clinical trial
Cytokine
Sorafenib
Sunitinib,
Bevacizumab
VEGF; mTOR
Everolimus
Clinical trial
Everything
Refractory
*Adapted from M Atkins, ASCO 2006 & R Bukowski ASCO 2007
But now, how to deal with all
these options in real life?
•
•
•
•
Can we establish a treatment algorithm?
Should we use MSKCC in routine?
Is histology important to decide therapy?
Should we use combination or sequential
therapy?
Proportion surviving
mRCC: prognostic factors
1.0
All (670 patients, 57 alive)
Median survival: 10 months
CI: (9, 11)
0.8
0.6
0.4
0.2
0
Age
Motzer score
LDH
Hb
Ca++
Prior history of nephrectomy
ECOG status
Nuclear grade 1 through 4 tumours
Stage
Histology
0 1
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Years following systemic therapy
MSKCC
risk group
Favourable
Number of poor Patients
prognostic features
(%)
Median OS
(months)
0
25
20
Intermediate
1–2
53
10
Poor
≥3
22
4
MSKCC risk factor model
Motzer RJ, et al J Clin Oncol 1999;17:2530–2540
Comparison of Risk Factor Criteria for RCC:
Memorial Sloan-Kettering Cancer Center (MSKCC) and
Cleveland Clinic Foundation (CCF)
MSKCC Criteria 2002
Factor
Time from diagnosis to
Poor Prognostic
Factor
< 12 months
treatment with IFN-alfa
CCF Criteria 2005
Factor
Time from diagnosis to
Poor Prognostic
Factor
<12 months
treatment with IFN-alfa
Hemoglobin
< lower limit of
laboratory’s reference
range
Hemoglobin
< lower limit of
laboratory’s reference
range
Lactate dehydrogenase
> 1.5 X the upper limit
of laboratory’s range
Lactate dehydrogenase
> 1.5 X the upper limit
of laboratory’s range
Corrected serum
calcium
> 10.0 mg/dL
Corrected serum
calcium
> 10.0 mg/dL
Karnofsky Performance
Status
< 80
Prior radiotherapy
Yes
Presence of hepatic,
lung, or retroperitoneal
node metastases
Yes (2 or 3)
Risk groups are defined as follows:
Favorable: 0 risk factors present
Intermediate: 1 or 2 risk factors
Poor: 3,4, or 5 risk factors
Motzer RJ, et al. J Clin Oncol. 2002; 20:289-296. Mekhail TM, et al. J Clin Oncol. 2005;23:832-841.
Multivariable Analysis:
645 patients, 7 center collaboration
Independent Predictors of Poor OS
Median overall survival was updated
for each of the risk group
–
–
–
Favorable risk: 37 months
Intermediate risk: 28.5 months
Poor risk: 9.4 months
p<0.0001
Median follow-up 25 months
Prognostic factors for overall survival in patients with metastatic renal cell carcinoma
treated with VEGF-targeted agents: Results from a large multicenter study.
Heng & Choueiri ASCO 2009 (#5041)
Final multivariate analysis of baseline
characteristics predictive for overall survival to
sunitinib and IFN-a
IFN-a
Sunitinib
Variable
Hazard ratio
P-value
Hazard ratio
P-value
LDH (natural log scale)*
2.009
<0.0001
1.797
0.0013
Corrected calcium*
1.557
<0.0001
1.339
0.0161
Time from diagnosis to treatment (≥1 vs. <1 yr)*
1.704
0.0008
1.632
0.0028
Hemoglobin*
0.135
0.0008
0.031
<0.0001
ECOG status (0 vs. 1)*
1.524
0.0085
-
-
Bone metastases (no vs. yes)
1.462
0.015
1.632
0.0019
Lymph node metastases (no vs. yes)
-
-
1.954
<0.0001
ANC
-
-
1.113
0.001
Gender (male vs. female)
-
-
1.712
0.0013
Note: for continuous variables, a hazard ratio >1 = risk reduction when the value decreases and a hazard ratio <1 = risk reduction
when the value increases; for binary variables, a hazard ratio >1 = risk reduction for the first category and a hazard ratio <1 = risk
reduction for the second category.
LDH = lactate dehydrogenase; ECOG = Eastern Cooperative Oncology Group; ANC = absolute neutrophil count.
*Prognostic factors included in Memorial Sloan-Kettering Cancer Center risk-group stratification (Motzer RJ et al. J Clin Oncol
2002;20:289).
Prognostic Factors for Overall Survival with Sunitinib as First-line Therapy in Patients with
Metastatic Renal Cell Carcinoma S Patil, & RJ Motzer Abstract 5042 ASCO 2009
But now, how to deal with all these
options in real life?
 Can we establish a treatment algorithm?
 Should we use MSKCC in routine?
 Is histology important to decide therapy?
 Should we use combination or sequential
therapy?
Overall Survival by Histologic Subtype
(ITT Population)
IFN
Temsirolimus
IFN + Temsirolimus
Variable
ITT Population
N
OS1 (CI)2
N
OS (CI)
HR
P
N
OS (CI)
HR
P
207
7.3
(6.1-8.8)
209
10.9
(8.6-12.7)
0.78
0.0252
210
8.4
(6.6-10.3)
0.93
0.4902
Histologic subtype
Clear cell
170
8.2
(6.6-10.4)
169
10.6
(8.5-13.0)
0.85
0.1304
16
3
10.1
(7.9-12.0)
0.86
0.2493
Other
36
4.3
(3.2-7.3)
37
11.6
(8.9-15.0)
0.55
0.0095
43
4.4
(2.5-6.6)
0.96
0.7683
1
2
Median Overall Survival in months
95% Confidence Interval
Data on file, Wyeth Pharmaceuticals Inc.
Do sarcomatoid features
influence response?
ECOG 8802: Phase II trial of doxorubicin
and gemcitabine in metastatic renal cell
carcinoma with sarcomatoid features.
N Haas, ASCO 2009 (Abs#5038)
• Insufficient data on most patients to determine %
• Responders (RR16% n=38, PFS 3.6m, OS 8.8m)
– 3 PR had >75% sarcomatoid features
– 2 PR unknown
– 1 CR 100% sarcomatoid features
But now, how to deal with all these
options in real life?
 Which is the best first line in good or
intermediate risk?
 Should we use MSKCC in routine?
 Is histology important to decide therapy?
 Should we use combination or sequential
therapy?
Is sequential better than
combination?
• Sequential allows full dose of each drug
• Avoids safety issues
• Has been shown active in different situations:
– TKIs post cytokines
– TKIs post bevacizumab
– mTOR post TKIs
• But design and feasibility of such studies are
difficult
Prospective Trials of Sequential Targeted Agents
Agent
N
OR / TS
PFS
Phase II:
Bevacizumabrefractory
62
23% / 75%
7.1 months
Phase II: Sorafenibrefractory
52
23% / 55%
7.4 months
Phase II:
Bevacizumab or
sunitinib-refractory
26
each
3% / 38%
3.8 months
Everolimus
Phase III:
(RECORD 1 trial) TKI-refractory (vs.
(Motzer et al. ASCO 2008)
placebo)
410
Temsirolimus
Phase III:
Sunitinib-refractory
(vs. sorafenib)
440
Axitinib (AXIS
trial)
Phase III: Any frontline refractory (vs.
sorafenib)
540
Sunitinib
(Rini et al. JCO (in press))
Axitinib
(Rini et al. ASCO 2007)
Sorafenib
(Sheppard et al. ASCO 2008)
Population
RECORD-1
Study Conduct
N = 410
Stratification
• Prior VEGF-r
TKI: 1 or 2
• MSKCC risk
group: favorable,
intermediate,
or poor
R
A
N
D
O
M
I
Z
A
T
I
O
N
2:1
Everolimus + BSC
(n = 272)
Upon
Disease
Progression
Placebo + BSC
(n = 138)
Interim
analysis
Final
Interim
=
analysis
analysis
• 410 patients randomized between September 2006 and October 2007
• Second interim analysis cut-off: October 15, 2007
• Independent Data Monitoring Committee recommended termination of study
Rini et al. ASCO’08 (Abs#LBA5026)
RECORD 1: PFS by Treatment
Central Radiology Review
100
Hazard ratio = 0.30
95% CI [0.22, 0.40]
Probability, %
80
Median PFS
Everolimus: 4.0 mo
Placebo: 1.9 mo
60
Log rank P value < 0.001
Everolimus (n = 272)
Placebo (n = 138)
40
20
0
Patients at Risk
Everolimus
Placebo
0
2
4
272
138
132
32
47
4
6
Time, mo
8
1
8
10
12
2
0
0
0
0
0
A Prospective Randomised Phase III Trial of Temsirolimus vs
Sorafenib in Advanced Renal Cell Carcinoma as 2nd line
Therapy in Patients Who Have Failed Sunitinib 1st line
Study Design: International, prospective, randomised, open-label, outpatient,
multicentre study
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
years
R
A
N
D
O
M
I
S
A
T
I
O
N
Temsirolimus 25 mg IV q week
n=220
Sorafenib 400 mg PO BID
n=220
Primary endpoints: PFS, safety and tolerability
Secondary endpoints: RR (CR & PR), OS, SD at 12, 24, 36 wks, clinical benefit (CR+PR+SD
at > 24 wks), duration of response and best tumour shrinkage
NCT00474786 www.clinicaltrials.gov
Axitinib Second-line Phase III Trial in Patients with
mRCC Refractory to First-line Therapy (AXIS)
Histologically-confirmed
mRCC with clear-cell
component
Failure of one prior firstline regimen containing:
• Sunitinib
• Bevacizumab + IFN-a
• Temsirolimus or
• Cytokine(s)
Stratification by prior
regimen and ECOG PS
(0 vs 1)
Start date: June 2008
Completion date: December 2011
N=540
R
A
N
D
O
M
I
S
A
T
I
O
N
Axitinib 5 mg bid
(4-week cycles)
Sorafenib 400 mg bid
(4-week cycles)
Primary endpoint: PFS
Secondary endpoints: OS, ORR,
safety/tolerability, duration of
response, patient-reported
outcomes
NCT00678392 www.clinicaltrials.gov
RECORD-3:
Phase II Sequence Trial of RAD001 and Sunitinib
 First-line treatment of patients with previously untreated
mRCC
 Stratified by MSKCC risk criteria
 Primary endpoint: PFS of sequence
 Secondary endpoint: Overall survival, safety, efficacy,
quality of life (QoL)
S
C
R
E
E
N
Sunitinib
50 mg/day,
4 wk on/2 wk off
RAD001
10 mg/day
Randomized
1:1
Start date:
2Q 09
Disease
progression
Sunitinib
50 mg/day,
4 wk on/2 wk off
RAD001
10 mg/day
SWITCH: randomised, phase III,
non-inferiority study
Treatment-naïve
patients with
mRCC
Stratification by
MSKCC score

sunitinib
Discontinuation
due to PD
or toxicity
sunitinib
sorafenib
total PFS
Secondary endpoints:
–
–
–
–
–
–

n=270
sorafenib
Primary endpoint
–

n=270
total TTP
OS
time to first-line treatment failure
PFS for first and second-line treatment
DCR for first and second-line treatment
safety
Estimated duration: January 2009–September 2012
Principal Investigator: M-S Michel
NCT00732914
Sequential therapy: summary
 Current data indicate that there may be only limited
cross-resistance to targeted agents
• responses seen in several different sequences
 Further studies are still necessary to optimize sequences
• prospective trials are in progress (i.e.: Tms/Axitinib vs So)
 Patients are likely to benefit from the multiplicity of agents
available
• options for several lines of therapy
• potential for improved survival outcomes
 Everolimus significantly prolongs PFS versus placebo across risk
groups in TKI-refractory RCC
Combination therapy
Combination therapy with
targeted agents in mRCC
Monotherapy
Standard cytokine
regimen(s): IL-2, IFNa
Targeted
agent
Metronomic
chemotherapy
1) Capecitabine
2) Gemcitabine
3) Others
Vertical and horizontal inhibition
with other targeted agents
1) VEGF inhibitors
2) EGFR inhibitors
3) mTOR inhibitors
Adapted from R. Bukowski
Combination with approved drugs
in randomized trials
• 4 important comparative (II/III) studies:
– BeST study phase II (6 arm trial of
Combination Targeted Therapy With
Bevacizumab, Sorafenib and Temsirolimus)
– TORAVA study phase II
– IFN-Bev vs TEMS-Bev phase III
– IFN-Bev vs EVER-Bev phase II
Temsirolimus and Avastin (TORAVA) study
(Phase II)
2:1:1
Metastatic RCC
patients (n=160)
Avastin + temsirolimus
(n=80)
PD
Avastin + IFN-a2a
(n=40)
PD
Sunitinib
(n=40)
PD
• Objectives
– primary: PFS
– secondary: safety, ORR (independently assessed), OS
– tertiary: circulating endothelial cells, functional imaging
Review of Other Ongoing and Planned
Trials (Phase II/III)
Randomized phase III trial of
temsirolimus + bevacizumab vs
IFN-α + bevacizumab in mRCC
Patients
with mRCC
R
A
N
D
O
M
I
S
E
Randomized phase II trial of
everolimus + bevacizumab vs
IFN-α + bevacizumab in mRCC
Temsirolimus +
bevacizumab
Patients
with mRCC
IFN-α +
Bevacizumab
R
A
N
D
O
M
I
S
E
Everolimus +
bevacizumab
IFN-α +
Bevacizumab
Adjuvant Studies in RCC
Trial title
N
Start
date
Completion
date
S-TRAC: Adjuvant SUTENT® vs Placebo in
Patients with high-risk renal cell cancer
290
Sept
2007
Nov 2009
ASSURE: Adjuvant Sorafenib or Sunitinib
for Unfavorable Renal Carcinoma
1332
May
2006
April 2010
SORCE: Sorafenib vs Placebo in Patients
With Resected Primary RCC at
High/Intermediate Risk
1656
June
2007
Aug 2012
Any other News at ASCO 2009 in RCC?
• Combinations of Targeted Agents
– Sunitinib + everolimus (VEGF + mTOR)
•
•
•
•
Kroog GS Abs#5037
Phase I
20mg RAD001 weekly + sunitinib 37.5mg 4w on 2w off
3/5 pts PR, responses both in clear cell and other histologies
– bevacizumab + temsirolimus (VEGF + mTOR)
• Merchan JR Abs#5039
• Phase II in RTKI refractory pts
• N=35 pts RR 16%
– sorafenib/gem/capecitabine (VEGF + chemo)
• Bellmunt J Abs#5040
• Phase II 1st line
• n=40 pts RR 47% PFS 10.2m
Drugs in development (I)
• TKIs
– BAY 73-4506
•
•
•
•
T. Eisen, ASCO 2009 (abs#5033)
Oral multikinase inhibitor (VEGFR1-3, c-kit, RET, FGFR, PDGFR)
Phase II trial 1st line
N=49 pts PFS n/a RR 27%
– AV-951 Tivozanib
•
•
•
•
P. Bhargava ASCO 2009 (abs#5032)
Oral multikinase inhibitor (VEGFR1-3, c-kit, PDGFR)
Phase II randomized discontinuation trial, placebo controlled, 1st line
N=274 pts PFS 11.8m RR 24%
– ABT-869
•
•
•
•
N. Tannir ASCO 2009 (abs#5036)
Oral multikinase inhibitor (VEGFR, PDGFR)
Phase II, 2nd line after sunitinib failures
N=53 pts PFS 5.4m RR 9.4%
Drugs in development (II)
• Other targeted agents:
– Integrin inhibitors:
• Volociximab (M200)
– c MET inhibitors
• AMG 102
• XL 880
• ARQ 197
– Akt / MAPK / JNK pathway inhibitors
• Perifosine
– NJ Vogelzang, ASCO 2009 abs#5034
– Phase II 2nd line after VEGFR inhib or mTOR inhib
– N=46 pts PFS 15w RR 5%
Conclusions
• RCC is a very active area for clinical trials
• Many drugs have been approved recently,
and many more drugs are in development
• There is an urgent need for better
understanding mechanisms of resistance
and synergy to better develop current and
future drugs