Transcript Sorafenib

Sequential treatment
in metastatic kidney cancer
GIUSEPPE DI LORENZO
Medical Oncology Division
University Federico II of Naples
Bevacizumab + IFN5
Temsirolimus4
High dose interleukin-21
Sorafenib2
1992–2005
Everolimus6
Sunitinib3
2005 2006
2007
Pazopanib7
Tivozanib
2008
2009
2009 2011
2010
2012
IFN-
Axitinib8 (FDA)
1.
2.
3.
4.
5.
6.
7.
8.
Fyfe G et al. J Clin Oncol 1995; 13: 688-696.
Escudier B et al. N Engl J Med 2007; 356: 125-134.
Sutent. Summary of Product Characteristics. 2010.
Hudes G et al. N Engl J Med 2007; 356: 2271-2281.
Escudier B et al. Lancet 2007; 370: 2103-2211.
Afinitor. Summary of Product Characteristics. 2010.
Sternberg CN et al. J Clin Oncol 2010; 28: 1061-1068.
Rini et al. Lancet 2011; 378: 1931-39
1.0
Proportion surviving
0.8
0.6
0.4
0.2
0
0
1
2
3
4
5
6
7
8
9
10
Years from Tx start
Trends in survival for metastatic RCC patients treated
on trials at MSKCC: at 5 years: 20 % vs 5-7% survivors
How to choose first line treatment
Prognostic profile (Motzer/Heng )
Good-intermediate risk :
Standard
Options
sunitinib,pazopanib,beva+IFN, (tivozanib)
sorafenib, HD IL-2,observation
Poor risk:
temsirolimus,sunitinib,BSC
How to choose first line treatment
Toxicity profile, QoL and comorbidities
How to choose first line treatment
Physician experience
How to choose first line treatment
Patient preference
How to choose first line treatment
Histology
First-line and following treatment
Many patients received sunitinib worldwide
The use of pazopanib is limited but growing
SECOND LINE
Second line therapy following prior cytokines: few pts 5-10%
Second line therapy following prior target-therapy:
the maiority
Second line therapy following prior cytokines:
•Sorafenib: level 1 evidence (PFS improvement vs IFN)
•Pazopanib: level 1 evidence (PFS improvement vs placebo)
•Tivozanib: PFS improvement vs sorafenib
SECOND-LINE after TKIs
TKI?
or
MTOR?
Sequential treatment in kidney cancer
RECORD-1 Phase III Study Design: Everolimus vs
Placebo After Progression on a VEGFR-TKI
Stratification
n = 416
 Previous VEGFR-TKI:
1 or 2
 MSKCC risk group
R
A
N
D
O
M
I
Z
A
T
I
O
N
2:1
Everolimus +
Best Supportive
Care (n = 277)
Placebo + Best
Supportive Care
(n = 139)
Motzer RJ, et al. Cancer 2010
RECORD-1
100
Median PFS
Everolimus (n = 277): 4.9 mos
Placebo (n = 139): 1.9 mos
HR: 0.33
95% CI: 0.25-0.43
Log rank P < .001
PFS (%)
80
60
40
20
0
0
2
4
6
8
10
12
Months
Motzer RJ, et al. Cancer 2010
RECORD-1
Central review
Investigator review
MSKCC risk
Favorable
Intermediate
Poor
Previous treatment
Sorafenib only
Sunitinib only
Both
Age
<65 yrs
≥65 yrs
Sex
Male
Female
Region
US and Canada
Europe
Japan and
Australia
0
0.2
0.4
0.6
0.8
In favor of everolimus
1.0
1.2
HR
P Value
N
0.30
0.31
< .0001
< .0001
410
410
0.35
0.25
0.39
< .0001
< .0001
.009
118
231
61
0.29
0.30
0.28
< .0001
< .0001
< .0001
119
184
107
0.32
0.29
< .0001
< .0001
259
151
0.29
0.36
< .0001
.002
317
93
0.24
0.37
0.10
< .0001
< .0001
.001
130
251
29
1.4
In favor of placebo
Motzer RJ, et al. Lancet. 2008;372:449-456.
Everolimus: a real 2nd line?
RECORD-1
1st line
2nd line
(3rd line)
EVE
3rd/4th line
n = 108
2 VGFR-TKI ±
1 other prior therapy
79%
1st line
2nd line
EVE
3rd line
n = 219
VEGF-TKI +
1 other prior therapy
most commonly cks
1st line
VGFR-TKI
2nd line
EVE
n = 89
21%
Motzer RJ, et al. Cancer 2010
Axitinib vs Sorafenib as Second-line Therapy
for Metastatic Renal Cell Carcinoma:
Results of the Phase 3 AXIS Trial
Treatment-refractory
metastatic RCC
Primary endpoint: PFS
Secondary analyses:effect of
dose titration and previous firstline treatment duration and
response on axitinib efficacy
R
A
N
D
O
M
I
Z
E
Axitinib 5 mg BID*
Potent and selective
second-generation
inhibitor of VEGFR-1, 2, 3
Sorafenib 400 mg BID
*Starting dose 5 mg BID with option for dose titration to 10 mg BID
Patient Characteristic
Axitinib
(n=361)
Sorafenib
(n=362)
91
91
Lung
76
81
Lymph node
58
56
Bone
33
30
Liver
28
29
Sunitinib
54
54
Cytokines
35
35
Bevacizumab
8
8
Temsirolimus
3
3
Characteristic
Prior nephrectomy, (%)
Sites of disease involvment (%)
Prior Systemic Therapy, (%)
Patient Characteristic
Axitinib
(n=361)
Sorafenib
(n=362)
0 (favorable)
40
40
1 – 2 (intermediate)
54
54
≥ 3 (poor)
2
2
0 (favorable)
18
22
1 – 2 (intermediate)
65
62
≥ 3 (poor)
10
9
Characteristic
MSKCC risk factors1 (%)
Heng et al. risk factors2 (%)
1) Motzer RJ, et al. J Clin Oncol 1999;17:2530-40; 2) Heng DY et al. J Clin Oncol 2009;27:5794-9
Best response by RECIST
(IRC assessment)
Best overall response, %
Axitinib
Sorafenib
Partial response*
19.4
9.4
Stable disease
49.9
54.4
Progressive disease
21.6
21.0
Indeterminate
6.1
11.6
Risk ratio (95% CI)
*Axitinib vs Sorafenib: P = 0.0001
2.1 (1.4-3.0)
Progression-Free Survival (probability)
Progression-free Survival
(IRC Assessment)
1.0
Axitinib
Sorafenib
0.9
mPFS, mo
95% Cl
6.7
4.7
6.3 - 8.6
4.6 - 5.6
0.8
P<0.0001 (log-rank)
Stratified HR 0.665
(95% Cl 0.544-0.812)
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
Subjects at risk, n
Axitinib 361
Sorafenib 362
2
4
6
256
224
202
157
145
100
IRC = Independent Review Committee
8
10
12
Time (months)
14
16
18
20
96
51
20
6
10
3
1
1
0
0
64
28
38
12
PFS by Prior Regimen
Prior Treatment
Regimen
Axitinib
(n=361)
Sorafenib
(n=362)
HR
P
value*
IRC
12.1
6.5
0.464
<0.0001
Investigator
12.0
8.3
0.636
0.005
IRC
4.8
3.4
0.741
0.011
Investigator
6.5
4.5
0.636
0.0002
IRC
10.1
5.3
0.511
0.142
Investigator
2.6
5.7
1.210
0.634
IRC
4.2
4.7
1.147
0.637
Investigator
6.5
4.5
0.753
0.213
Cytokines (n=251)
Sunitinib (n=389)
Temsirolimus (n=24)
Bevacizumab (n=59)
How to select second line therapy?




No direct comparison between axitinib and everolimus
Toxicity with first-line VEGFi agent
Response or Duration of response with first-line TKI
No data for mTORi  mTORi
PFS
(months)
Axitinib
Sorafenib
Everolimus
Overall
6.7
4.7
4.9
Post sunitinib
4.8
3.4
3.9
Post cytokines
12.1
6.5
_
SECOND-LINE:
Head to head
TKI
VS
MTOR
INTORSECT*: Hutson, Escudier, ESMO 2012
Patients with mRCC
and PD on 1st-line
sunitinib
(N=512)
Stratification factors:
• Duration of sunitinib
therapy (≤ or >6 mo)
• MSKCC risk group
• Histology (clear cell
or non–clear cell)
• Nephrectomy status
R
A
N
D
O
M
I
Z
E
Temsirolimus
25 mg IV weekly†
(n=259)
Sorafenib
400 mg oral BID†
(n=253)
Treat until PD,
unacceptable
toxicity, or
discontinuation
for any other
reason
N=512
112 sites in 20 countries
1:1
First patient randomized: September 25, 2007; last patient randomized: January 31, 2012.
Data cutoff: May 4, 2012. At present, 2 patients are on study.
*ClinicalTrials.gov Identifier: NCT00474786.
†Dose reductions were allowed: temsirolimus (to 20 mg then 15 mg); sorafenib (to 400 mg/day then every other day).
BID, twice daily; IRC, independent review committee; IV, intravenous; mRCC, metastatic renal cell carcinoma;
MSKCC, Memorial Sloan-Kettering Cancer Center; PD, progressive disease; PFS, progression-free survival.
30
INTORSECT: Progression-Free Survival
Median PFS,
95% CI
months
4.01, 5.43
Temsirolimus 4.28
3.91
2.80, 4.21
Sorafenib
1.0
PFS (probability)
0.9
0.8
P=0.1933 (log-rank)
Stratified HR: 0.87
(95% CI: 0.71, 1.07)
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
5
15
20
25
6
5
0
0
Time (months)
Patients at risk, n
Sorafenib
Temsirolimus
10
252
259
72
96
22
28
11
9
CI, confidence interval; HR, hazard ratio; IRC, Independent Review Committee; PFS, progression-free survival.
31
INTORSECT: Overall Survival
Median OS,
95% CI
months
10.13, 14.80
Temsirolimus 12.27
16.64
13.55, 18.72
Sorafenib
Overall Survival (probability)
1.0
0.9
0.8
P=0.014 (log-rank)
Stratified HR: 1.31
(95% CI: 1.05, 1.63)
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
10
30
40
50
13
8
0
0
Time (months)
Patients at risk, n
Sorafenib
253
Temsirolimus 259
20
158
132
74
54
CI, confidence interval; HR, hazard ratio; OS, overall survival.
34
22
32
EUR UROL 2012
Take Home Messages:
Refractory disease
Options:
• Axitinib++
• Everolimus++
• Sorafenib +
• Sunitinib
• Dovitinib?
Choice based on:
• Side-effects with first line +
• Good-risk/poor risk assessment+
• Comorbidity and age+
• Response and duration of first line
• Site of disease
• Histology
Potential factors to customize
second-line
Toxicity profile
Everolimus: adverse events
Everolimus (n = 269)
Adverse event, %
Placebo (n = 135)
All grades
Grade 3
All grades
Grade 3
Stomatitis*
40
3
8
0
Fatigue
20
3
16
<1
Asthenia
18
1
8
<1
Rash
25
<1
4
0
Diarrhea
17
1
3
0
Nausea
15
0
8
0
Mucosal inflammation
14
1
2
0
Cough
12
0
4
0
Infections*
10
2
2
0
Pneumonitis*
8
3
0
0
Dyspnea
8
1
2
0
*Significant difference between sum of grade ¾ events for everolimus and palcebo groups (P < .05)
Motzer RJ, et al. Lancet. 2008;372:449-456.
Axitinib: Adverse events*
Axitinib (%)
Event
Sorafenib (%)
All grade
Grade 3/4
All grade
Grade 3/4
Diarrhea
55
11
53
7
Hypertension
40
16
29
11
Fatigue
39
11
32
5
Nausea
32
3
22
1
Vomiting
24
3
17
1
Hypothyroidism
19
<1
8
0
Stomatitis
15
1
12
<1
Hand-foot syndrome
27
5
51
16
Rash
13
<1
32
4
Alopecia
4
0
32
0
Potential factors to customize
second-line
good/poor prognosis
GOOD PROGNOSIS: generally able to
undergo multiple lines of therapies
TKI
POOR PROGNOSIS: no multiple lines
MTOR
Potential factors to customize
second-line
Age
Hazard Ratios for PFS by Prognostic Factors
and Baseline Characteristics
Baseline factor
n
Axitinib
benefit
Sorafenib
benefit
ECOG performance status 1
ECOG performance status 0
Sunitinib-containing regimen
Bevacizumab-containing regimen
Temsirolimus-containing regimen
Cytokine-containing regimen
White
Non-white
Male
Female
Age <65 years
327
396
389
59
24
251
547
176
523
200
476
Age ≥65 years 247
306
MSKCC favorable
MSKCC intermediate/poor
417
Asia 152
Europe
357
North America
186
Other region
28
0.0
1.0
2.0
Hazard Ratio (95% Cl)
3.0
Incidence in elderly patients and the total study population
of adverse events and laboratory abnormalities (all grades)*
Age ≥65 yrs
Adverse event, %
Stomatitis
Cough
Infection
Asthenia
Rash
Peripheral edema
Diarrhea
Fatigue
Anorexia
Nausea
Dyspnea
Pyrexia
Vomiting
Mucosal inflammation
Headache
Epistaxis
Dysgeusia
Pneumonitis
Pain in extremity
Pruritus
Dry skin
Age ≥70 yrs
All patients
Everolimus
plus
BSC (n = 111)
Placebo
plus
BSC (n = 39)
Everolimus
plus
BSC (n = 52)
Placebo
plus
BSC (n = 20)
Everolimus
plus
BSC (n = 274)
Placebo
plus
BSC (n = 137)
42
36
36
33
32
32
32
29
28
25
23
22
21
21
16
16
14
11
10
10
9
5
21
15
26
13
10
8
26
10
13
8
5
10
0
5
0
3
0
13
10
3
46
40
33
37
33
37
38
37
27
27
23
27
21
25
15
15
17
10
14
10
8
0
20
10
25
0
20
10
20
10
15
5
0
15
0
0
0
5
0
15
15
5
44
30
37
33
29
25
30
31
25
26
24
20
20
19
19
18
10
14
10
14
13
8
16
18
23
7
8
7
27
14
19
15
9
12
1
9
0
2
0
7
7
5
BSC = best supportive care.
*Regardless of relation to treatment, occurring in >10% of all patients in the everolimus arm.
Dose reductions, dose interruptions and concomitant
medications in elderly patients and the total study population
Age ≥65 yrs
N. of dose reductions/interruptions, %
0
1
>1
Reasons for dose reductions/interruption,
%
Adverse event
Dosing error
Laboratory test abnormality
Scheduling conflict
Treatment duration, d
Median (min, max)
Dose intensity, mg/d
Mean (min, max)
No. of concomitant
medications*
Mean
Median (min, max)
Age ≥70 yrs
All patients
Everolimus
plus
BSC (n = 111)
Placebo
plus
BSC (n = 39)
Everolimus
plus
BSC (n = 52)
Placebo
plus
BSC (n = 20)
Everolimus
plus
BSC (n = 274)
Placebo
plus
BSC (n = 137)
56 (50.5)
30 (27.0)
26 (22.5)
34 (87.2)
5 (12.8)
0
23 (44.2)
13 (25.0)
16 (30.8)
18 (90.0)
2 (10.0)
0
147 (53.6)
75 (27.4)
52 (19.0)
116 (84.7)
15 (10.9)
6 (4.4)
44 (39.6)
13 (11.7)
6 (5.4)
2 (1.8)
3 (7.7)
1 (2.6)
1 (2.6)
0
27 (51.9)
4 (7.7)
3 (5.8)
2 (3.8)
2 (10.0)
0
0
0
107 (39.1)
27 (9.9)
7 (2.6)
7 (2.6)
12 (8.8)
7 (5.1)
3 (2.2)
1 (0.7)
157.0 (20, 451)
84.0 (21, 284)
150.0 (28, 402)
111.0 (25, 237)
141.0 (19, 451)
60.00 (21, 295)
9.03 (2.7,
10.0)
9.96 (9.3, 10.0)
8.69 (2.7,
10.0)
9.97 (9.4, 10.0)
9.18 (2.7,
10.0)
10.01 (5.0, 20.0)
15.1
14 (2, 41)
13.3
11 (2, 34)
15.2
14 (4, 39)
12.0
11.5 (2, 27)
13.8
12 (1, 46)
14.2
12 (1, 55)
Potential factors to customize
second-line
Prior response to TKI
INVESTIGATING TREATMENT SEQUENCES:
A STEP
FORWARD
Third line
Clin Genitourin Cancer. 2013 Jan 16.
Are Tyrosine Kinase Inhibitors Still Active in Patients With Metastatic Renal Cell
Carcinoma Previously Treated With a Tyrosine Kinase Inhibitor and Everolimus?
Experience of 36 Patients Treated in France in the RECORD-1 Trial.
Blesius A, Beuselinck B, Chevreau C, Ravaud A, Rolland F, Oudard S, Escudier B.
BACKGROUND:
This study evaluated the efficacy of TKI re-treatment in patients with disease progression
after a TKI-everolimus sequence.
PATIENTS AND METHODS:
Data were reviewed for patients enrolled in RECORD-1 (Renal Cell Cancer Treatment With
Oral RAD001 Given Daily) at French sites. Response, progression-free survival (PFS), and
overall survival were evaluated in patients treated with a TKI-everolimus-TKI sequence.
RESULTS:
Thirty-six patients received a TKI after everolimus: sunitinib in 17 patients, sorafenib in 15,
and dovitinib (TKI258) in 4. The response rate with TKI re-treatment was 8%, and the
disease-control rate (response plus stable disease) was 75%. The median PFS with each
component of the TKI-everolimus-TKI sequence was 10.7 months , 8.9 months , and 8.2
months , respectively. The median overall survival from the start of everolimus was 29.1
months (95% CI 21.1 to not reached months), which suggests a benefit in using TKI in this
setting.
CONCLUSIONS:
Administration of a TKI-everolimus-TKI sequence may be associated with clinical benefit
and should be prospectively investigated.
PFS and OS in patients receiving 3 TTs
for mRCC.
281 pts (13%)
2065 pts
•
•
•
•
•
•
•
•
•
•
Fondazione IRCCS INT, Milano.
Sapienza University of Rome.
Università Politecnica delle Marche, Ancona.
Università Federico II Napoli.
San Camillo-Forlanini Hospital Rome.
Istituto per la Ricerca e la Cura del Cancro,
Candiolo.
Azienda Ospedaliero Universitaria, Modena.
Niguarda Cà Grande Hospital, Milano .
Ospedali Riuniti di Bergamo.
Istituto Clinico Humanitas, Milano.
Baseline characteristics
Pts with at least 3 lines of
treatement
m Age
60 yr
Male
73%
Prior Nephrectomy
96 %
Metastasis at diagnosis
38 %
Motzer score
Good
48 %
Intermediate
47 %
Poor
5%
Endpoints: PFS, OS, TTSF (Time to Strategy Failure: time from start of 1st to end of 3rd line)
Iacovelli et al ESMO 2012
53
Results: Sequences by drug 1/2.
SUSOEVE
Mean
(months)
TTSF
OS
SUEVESO
p-value
95% CI
Mean
(months)
95% CI
42.1
31.8 – 52.4
30.4
26.3 – 35.4
0.006
NR
-
35.6
31.6 – 39.6
<0.001
TTSF
OS
p<0.001 log-rank test
p=0.006 log-rank test
SUSOEV
E
SUEVES
O
SUSOEV
E
SUEVES
O
Results: Sequences by drug 2/2
SOSUEVE
Mean
(months)
TTSF
OS
SUEVESO
p-value
95% CI
Mean
(months)
95% CI
46.7
42.1 – 51.2
30.4
26.3 – 35.4
<0.001
55.8
46.7 – 64.8
35.6
31.6 – 39.6
<0.001
TTSF
OS
p<0.001 log-rank test
p<0.001 log-rank test
SOSUEV
E
SUEVES
O
SOSUEV
E
SUEVES
O
Iacovelli R et al ESMO 2012
Clin Cancer Res. 2013 Jan
Phase I Study of Dovitinib (TKI258), an Oral FGFR, VEGFR, and PDGFR Inhibitor, in
Advanced or Metastatic Renal Cell Carcinoma.
Angevin E, Lopez-Martin J, Lin CC, Gschwend JE, Harzstark A, Castellano D, Soria JC, Sen P, Chang
J, Shi MM, Kay A, Escudier B.
PURPOSE:
Signaling through the fibroblast growth factor (FGF) pathway may account for tumor resistance to antiangiogenic
therapies targeting the vascular endothelial growth factor (VEGF) pathway. Here, dovitinib (TKI258), a potent oral
inhibitor of FGF receptor, VEGF receptor (VEGFR), and platelet-derived growth factor receptor tyrosine kinases, is studied
in a dose-escalation trial.
EXPERIMENTAL DESIGN:
Patients with advanced or metastatic renal cell carcinoma (RCC) with predominant clear cell histology were treated with
oral dovitinib 500 or 600 mg/day (5-days-on/2-days-off schedule).
RESULTS:
Twenty heavily pretreated patients (median 3 prior regimens) were enrolled, with 16, 11, and 12 patients having
previously received at least 1: VEGFR inhibitor, mammalian target of rapamycin (mTOR) inhibitor, and immunotherapy,
respectively. Fifteen and 5 patients were treated in 500-mg and 600-mg cohorts, respectively. Three patients experienced
dose-limiting toxicities: grade 2 bradycardia (500 mg), grade 4 hypertensive crisis (600 mg), and grade 3 asthenia with
grade 2 nausea and vomiting (600 mg). The most common adverse events related to dovitinib were nausea (75%),
diarrhea (70%), vomiting (70%), and asthenia (50%), the majority of which were mild (grade 1 or 2), with grade 3 events
≤5% (except asthenia, 15%) and only 1 grade 4 event (hypertensive crisis). Two patients achieved a partial response (500
mg), and 12 patients had stable disease, including 2 patients with long-lasting disease stabilizations (>1 year) in 500-mg
cohort.
CONCLUSIONS:
Dovitinib was tolerable and demonstrated antitumor activity at a maximum tolerated dose of 500 mg on a 5-days-on/2days-off schedule in heavily pretreated RCC patients.
Conclusions (1):
A CONTINUED EFFORT TO INVESTIGATE
SEQUENTIAL TREATMENTS IN LARGE
PHASE III TRIALS IS REQUIRED
T-cell checkpoints: PD‐1 and CTLA-4
targeting in cancer immunotherapy
CTLA-4
Cancer
pages n/a-n/a, 5 OCT 2012 DOI: 10.1002/cncr.27832
http://onlinelibrary.wiley.com/doi/10.1002/cncr.27832/full#fig1
Phase III trial following 1-2 VEGFR
TKIs: Everolimus vs. PD-1 inhibition
Key Eligibility Criteria:
• Advanced or metastatic cc RCC
• Progression on or after most
recent therapy and within 6 months
of study enrollment
• One or 2 previous anti VEGF
• No mTOR inhibitor
R
A
N
D
O
M
I
Z
E
BMS-936558
3 mg/kg IV Q2 wk s
Everolimus
10 mg PO QD
n = 822
Primary endpoint: Overall Survival
Conclusions (2)
FURTHER PREDICTIVE VARIABLES SHOULD BE
IDENTIFIED
•biological markers, POLYMORPHISMS (IL8, HIF1A,
VEGFA, VEGFR 1,2,3), germline variants in
angiogenesis, exposure-related genes (pazopanib);
• imaging techniques ( MASS criteria, PET-role and
everolimus, DCE-RM).
Take Home Messages:
Refractory
disease
No determined
algorithm
Options:
• Axitinib++
• Everolimus++
• Sorafenib +
• Sunitinib
• Dovitinib?
Always
i
looks
the
patient
and
Choice based on:
disease
• Side-effects with first line
• Good-risk/poor risk assessment
• Comorbidity and age
• Response and duration of first line
Thanks!!!