Trattamento delle metastasi ossee

Transcription

Scuola di uro Oncologia
CONTROVERSIE ONCOLOGICHE
L’oncologo risponde all’urologo:
PRIMA LINEA DI TRATTAMENTO
G. Cartenì
Direttore U.O.S.C. di Oncologia
Medica A.O.R.N.
A. Cardarelli Napoli
Roma, 12/13 Luglio 2013
Quali criteri vengono utilizzati per scegliere il farmaco da
utilizzare in prima linea ?
Come monitorizzare la terapia ? Criteri di
successo/insuccesso
La gestione delle complicanze/effetti collaterali
Associazione di farmaci ? terapie sequenziali ?
How to choose first line
treatment
• Prognostic profile (Motzer/Heng)
• Toxicity profile and comorbidities
• Disease characteristics (site/sympthoms)
• Sequential strategies
• Oral/iv administration
• Physician
Ph i i experience
i
• Patient preference
• Biomarkers in development
development…!!
Linee Guida EAU 2010
First-line treatment guidelines for
clear cell mRCC:
ESMO 2012
Risk status
Recommendation
Level of evidence
Favourable or
intermediate
Sunitinib
I, A
Bevacizumab + IFN-α
II, A
Pazopanib
II, A
Poor risk
Temsirolimus
II, A
Escudier B, et al. Ann Oncol 2012;23(Suppl 7):vii65–71
treatment
• Physician
Ph i i experience
i
development…!!
Randomized, Open Label, Phase III Trial of Pazopanib
versus Sunitinib in First-line Treatment of Patients with
Metastatic Renal Cell Carcinoma (mRCC): Results of the
COMPARZ Trial
Robert Motzer1, T. E. Hutson2, James Reeves3, Robert Hawkins4, Jun Guo5,
Paul Nathan6, Michael Staehler7, Paul de Souza8, Jaime R. Merchan9,
Kate Fife10, Jie Jin11, Robert Jones12, Hirotsugu Uemura13, Ugo De Giorgi14,
Ulrika Harmenberg
g15, Jinwan Wang
g16, David Cella17, Lauren McCann18,
Keith Deen18, and Toni K. Choueiri19
1Memorial
Sloan Kettering Cancer Center, NY, NY, USA; 2Baylor Sammons Cancer Center/Texas Oncology, Dallas, TX, USA; 3Florida Cancer Specialists, Fort Myers, FL, USA; 4University
of Manchester and The Christie Hospital
Hospital, NHS Foundation Trust,
Trust Manchester,
Manchester United Kingdom; 5 Renal Cancer and Melanoma Unit
Unit, Peking University Cancer Hospital
Hospital, Beijing
Beijing, China;
6Mount Vernon Hospital, Middlesex, United Kingdom;7 Department of Urology, Interdisciplinary Centre on Renal Tumors, University of Munich, Munich, Germany; 8University of Western
Sydney School of Medicine, MMRG, CRG, Sydney, Australia; 9 University of Miami, Sylvester Cancer Center, Miami, FL, USA:10 Oncology Centre, Addenbrooke's Hospital, Cambridge,
United Kingdom; 11 Peking University First Hospital, Beijing, China; 12Institute of Cancer Sciences University of Glasgow, Glasgow, United Kingdom;13 Department of Urology, Kinki
University Faculty of Medicine, Osaka, Japan; 14IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Meldola, Italy; 15Department of Oncology,
Radiumhemmet Karolinska University Hospital, Stockholm, Sweden; 16 Cancer Hospital, CAMS & PUMC, Beijing, China; 17Robert H. Lurie Comprehensive Cancer Center of Northwestern
University, Chicago, IL , USA; 18GlaxoSmithKline, Inc., Collegeville, PA, USA; 10Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
COMPARZ: PFS (IRC-assessed)
Non-inferiority
Non
inferiority met if upper bound of 95%
CI for HR <1.25 (EMA requested ≤1.223)
PFS (ITT population)
Median PFS, months (95% CI)
HR (95% CI)
PFS (PP population)
l ti )
Median PFS, months ((95% CI))
HR (95% CI)
Pazopanib (n
(n=557)
557) Sunitinib (n
(n=553)
553)
8.4 (8.3, 10.9)
9.5 (8.3, 11.1)
1.0466 (0.8982, 1.2195)
P
Pazopanib
ib (n=501)
( 501) Sunitinib
S iti ib (n=494)
( 494)
8.4 ((8.3, 10.9))
10.2 ((8.3, 11.1))
1.069 (0.910, 1.255)
PP, per-protocol
1. GSK. Clinical Study Register. Study 108844. Available at: http://download.gsk-clinicalstudyregister.com/files/ae28e535-6855-4956-8022-084cdeda4d38
(last accessed February 2013); 2. Motzer RJ, et al. Presented at ESMO 2012; Abstract LBA8; 3. Available at
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001141/WC500094275.pdf (last accessed April 2013)
Non-inferiority
Non
HR (95% CI)
PFS (PP population)
l ti )
HR (95% CI)
Pazopanib (n
(n=557)
557) Sunitinib (n
(n=553)
553)
8.4 (8.3, 10.9)
9.5 (8.3, 11.1)
1.0466 (0.8982, 1.2195)
P
Pazopanib
ib (n=501)
( 501) Sunitinib
S iti ib (n=494)
( 494)
8.4 ((8.3, 10.9))
10.2 ((8.3, 11.1))
1.069 (0.910, 1.255)
PP, per-protocol
Non-inferiority
Non
HR (95% CI)
PFS (PP population)
l ti )
HR (95% CI)
Pazopanib (n
(n=557)
557) Sunitinib (n
(n=553)
553)
8.4 (8.3, 10.9)
9.5 (8.3, 11.1)
1.0466 (0.8982, 1.2195)
P
Pazopanib
ib (n=501)
( 501) Sunitinib
S iti ib (n=494)
( 494)
8.4 ((8.3, 10.9))
10.2 ((8.3, 11.1))
1.069 (0.910, 1.255)
PP, per-protocol
COMPARZ study design:
Phase III,, open-label,
p
, noninferiority trial
Enrolment criteria:
•Locally advanced or mRCC
•Clear-cell
Clear cell histology
•No prior systemic therapy
•Measurable disease (RECIST 1.0)
•KPS ≥70
•Adequate
Adequate organ function
Pazopanib 800 mg QD
Continuous daily dosing
Randomised
N=927
1:1
N=1,110
Sunitinib 50 mg QD
Schedule 4/2
Study start: August 2008
VEG108844
Phase III
n=927
VEG113078
Phase II (Asia)
n=183
COMPARZ:
1,110 patients
KPS, Karnofsky Performance Scale; RECIST, Response Evaluation Criteria in Solid Tumors; Schedule 4/2, 4 weeks on treatment, 2 weeks off
www.clinicaltrials.gov (NCT00720941; NCT01147822)
Primary Endpoint: Progression-free
Survival
(independent review)
N
Median PFS (95% CI)
P
Pazopanib
ib
557
8 4 mo (8
8.4
(8.3,
3 10
10.9)
9)
Sunitinib
553
9.5 mo (8.3, 11.1)
HR (95% CI ) = 1.047 (0.898,1.220)
Pazopanib
p
Sunitinib
Interim Analysis of Overall
Survival
N
Median OS (95% CI)
Pazopanib
557
28.4 mos (26.2, 35.6)
Sunitinib
553
29.3 mos (25.3, 32.5)
HR (95% CI ) = 0.908 (0.762,1.082)
P-value = 0.275
Pazopanib
p
Sunitinib
COMPARZ: Timing of
assessments
Sunitinib
Me
ean change
e from base
eline
Pazopanib
Week 6
Week 6
Week 6
Disease assessments
QoL assessments
Week 4
Week 4
Week 4
Time
QoL, quality of life
Motzer RJ, et al. Presented at ESMO 2012; Abstract LBA8
Cella D, et al. Presented at ASCO-GU 2012; Abstract 346
Most Common Adverse Events
(
(treatment-emergent)
g )
Pazopanib (n = 554) % Sunitinib (n = 548) %
Adverse
d e se Event
e ta
Any event b
Diarrhea
Fatigue
Hypertension
N
Nausea
Decreased appetite
ALT increased
Hair color changes
Hand-foot syndrome
Taste Alteration
Thrombocytopenia
a AE
b 2%
All G
Grs
s
Gr 3/4
G
3/
All G
Grs
s
Gr 3/4
G
3/
>99
59/15
>99
57/17
63
9/0
57
7/<1
55
10/<1
63
17/<1
46
15/<1
41
15/<1
45
2/0
46
2/0
37
1/0
37
3/0
31
10/2
18
2/<1
2/
1
30
0/0
10
<1/0
29
6/0
50
11/<1
26
<1/0
36
0/0
10
2/<1
34
12/4
≥30% in either arm
of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 adverse events.
COMPARZ: Common AEs
(treatment-emergent)
Pazopanib
p
(n=554),
(
), % Sunitinib ((n=548),
), % Risk ratio
95% CI
All
grades
Grade 3/4
All
grades
Grade 3/4
Any event†
>99
59/15
>99
57/17
NA
NA
Diarrhoea
63
9/0
57
7/<1
1.09
0.99, 1.20
Fatigue
55
10/<1
63
17/<1
0.87
0.79, 0.96
Hypertension
46
15/<1
41
15/<1
1.14
1.00, 1.31
Nausea
45
2/0
46
2/0
0.98
0.86, 1.11
Decreased appetite
37
1/0
37
3/0
NA
NA
ALT increased
31
10/2
18
2/<1
1.74
1.40, 2.17
Hair colour changes
30
0/0
10
<1/0
NA
NA
HFS
29
6/0
50
11/<1
0.59
0.50, 0.68
Taste alteration
26
<1/0
36
0/0
NA
NA
Thrombocytopenia
10
2/<1
34
12/4
0 30
0.30
0 23 0
0.23,
0.40
40
AE*
*AE ≥30% in either arm; †2% of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 AEs
ALT, alanine transaminase; AST, aspartate transaminase; HFS, hand–foot syndrome; NA, not applicable
All grades
Treatment Duration and Dose
Adjustments
Pazopanib
(n = 554)
Sunitinib
(n = 548)
8.0 (0−40)
7.6 (0−38)
Dose reductions, %
44
51
Discontinuations due to AEs1, %
24
19
Median
M
di d
duration
ti off ttreatment
t
t
(months, range)
1. Most common reason: pazopanib arm (liver event, 6%); sunitinib arm (cytopenia, 3%)
Quality of Life Results (first 6 months1)
Treatment difference : mean change from baseline 2
P ‐value
Fatigue/Total score
2.32
<0.001
Kidney Symptom Index/Total score
1.41
0.018
Physical
0.78
0.027
Emotional
0 05
0.05
0 409
0.409
Treatment Side Effects
0.31
0.033
Functional Well Being
0.31
0.098
Expectations of Therapy
1.41
0.284
Feelings about Side Effects
8.50
<0.001
Satisfaction with Therapy
3 21
3.21
<0 001
<0.001
Worst mouth/throat soreness
0.505
<0.0001
Worst foot soreness
0.204
0.0016
Worst hand soreness
0.267
0.0008
Limitations due to mouth/throat soreness
0.94
<0.001
Limitations due to foot soreness
0.65
0.014
Instrument
FACIT-F
FKSI 19
FKSI-19
Cancer
Treatment
Satisfaction
Questionnaire
(CTSQ)
Supplementary
Q lit off Life
Quality
Lif
Questionnaire
(SQLQ)
1Pre-specified
Domain Description
analysis. HRQoL changes in mean scores over time were analyzed with a repeated measures analysis of
covariance (ANCOVA).
2Yellow Font: favors pazopanib. Blue Font: favors sunitinib. P-value <0.05 is statistically significant
Quality of Life Results (first 6 months1)
Treatment difference : mean change from baseline 2
P ‐value
Fatigue/Total score
2.32
<0.001
Kidney Symptom Index/Total score
1.41
0.018
Physical
0.78
0.027
Emotional
0 05
0.05
0 409
0.409
Treatment Side Effects
0.31
0.033
Functional Well Being
0.31
0.098
Expectations of Therapy
1.41
0.284
Feelings about Side Effects
8.50
<0.001
Satisfaction with Therapy
3 21
3.21
<0 001
<0.001
0.505
<0.0001
Worst foot soreness
0.204
0.0016
Worst hand soreness
0.267
0.0008
0.94
<0.001
0.65
0.014
Instrument
FACIT-F
FKSI 19
FKSI-19
Cancer
Treatment
Satisfaction
Questionnaire
(CTSQ)
Supplementary
Q lit off Life
Quality
Lif
Questionnaire
(SQLQ)
1Pre-specified
Domain Description
analysis. HRQoL changes in mean scores over time were analyzed with a repeated measures analysis of
covariance (ANCOVA).
2Yellow Font: favors pazopanib. Blue Font: favors sunitinib. P-value <0.05 is statistically significant
Quality of Life Results: PISCES1
Randomized double-blind, placebo-controlled, cross-over study in
patients with metastatic renal cell carcinoma
Instrument
FACIT- F
Supplementary
Quality of Life
Questionnaire
Timing
Every 2
weeks
Every 2
E
weeks
Treatment
difference2,3
P
value
Fatigue/Total score
2.5
0.002
0.38
<0.001
Worst foot soreness
0.08
0.026
Worst hand soreness
0.16
0.005
0.60
<0.001
0.58
0.003
Domain Description
1. Escudier BJ, et al.. J Clin Oncol 30, 2012 (suppl; abstr CRA4502)
2 Cella D
2.
D, et al.
al ESMO Congress 2012 poster 792PD
3. Yellow Font: favors pazopanib
P-value <0.05 is statistically significant
treatment
• Physician
Ph i i experience
i
development…!!
treatment
• Physician
Ph i i experience
i
development…!!
treatment
• Physician
Ph i i experience
i
development…!!
treatment
• Physician
Ph i i experience
i
development…!!
treatment
• Physician
Ph i i experience
i
development…!!
Significantly more patients
preferred pazopanib over
sunitinib
iti ib (primary
( i
endpoint)
d i t)1
100
p<0.001
90
80
Patientss (%)
70
60
50
70%
(n=80)
40
30
20
22%
(n=25)
10
8%
(n=9)
0
Preferred pazopanib
Preferred sunitinib
1. Escudier B, et al. J Clin Oncol 2012;30 suppl: abstr CRA4502.
No preference
successo/insuccesso
Valutazione dello stato di malattia in
corso di trattamento con targeted
therapies
Necessario fare riferimento a criteri:
– Diagnostica strumentale
– Clinici
– Laboratorio
Criteri di risposta (RECIST) Criticità
I criteri RECIST rappresentano
pp
lo standard di valutazione di
risposta al trattamento in studi clinici su farmaci antitumorali1
• La risposta
p
p
parziale è
definita come tumor
shrinkage pari al 30%
⇒ Un tumor shrinkage del < 30% è
un risultato positivo per il paziente.
Il controllo del tumore potrebbe
essere un endpoint clinicamente più
rilevante2
• Si basa sulle risposte agli ⇒ Potrebbe non essere appropriato
per valutare la risposta alle targeted
agenti antitumorali
therapies (differente meccanismo
citotossici
d’azione)
• Non si misurano le
necrosi tumorali
⇒ Le targeted therapies possono
determinare necrosi tumorale
piuttosto che tumor shrinkage3
1. Therasse P, et al. J Natl Cancer Inst 2000; 92:205–16
2. Nygren P, et al Acta Oncologia 2008; 47:316–29
3. Abou-Alfa G, et al. J Clin Oncol 2006;24:4293–300
Revisione criteri di risposta
(RECIST v. 1.1)
Principali modifiche proposte:
- Numero delle lesioni valutabili;
- Dimensioni dei linfonodi
f
patologici;
- Conferma della risposta;
- Supporto FDG-PET per valutare le progressioni.
Come valutare la risposta al
trattamento nell’era delle
targeted therapies?
• I criteri RECIST e la loro più recente revisione non
tengono conto di:
g g funzionale come la PET o la RMN
• Tecniche di imaging
• Valutazione anatomica volumetrica del tumore
• Necessità di nuove metodiche di immagine atte a
studiare la vascolarizzazione e la necrosi tumorale
FDG-PET
DCE-US
DCE-MRI
Imaging funzionale con DCE-US
Valutazione della risposta a
sorafenib
f ib
• Abdominal lymph node from an RCC in a 37 year-old
woman (good
(
d responder)
d ) treated
t t d with
ith sorafenib
f ib
DCE-US
before treatment shows
contrast uptake
throughout the tumour
estimated at 81%
DCE-US after 3 weeks
of treatment
shows contrast uptake
estimated at 48%
Lamuraglia et al.EJC 2006
DCE-US after 6 weeks
of treatment shows
contrast uptake
estimated at 31%
identifying patients with progression
progression-free
free survival of >250
250 days
sensitivity
specificity
MASS
criteria
86%
100%
SACT
criteria
75%
100%
CONCLUSION: Assessment of metastatic RCC target lesions on CECT for changes in morphology,
attenuation, size, and structure by MASS Criteria is more accurate than response assessment by
SACT Criteria, RECIST, or modified Choi Criteria. Furthermore, the use of MASS Criteria for imaging
response assessment showed high interobserver agreement and may predict disease outcome in
patients with metastatic RCC on targeted therapy
Smith AD, Shah SN, Rini BI, Lieber ML, Remer EM. Morphology, Attenuation, Size, and Structure (MASS) criteria: assessing response
and
predicting clinical outcome in metastatic renal cell carcinoma on antiangiogenic targeted therapy. AJR Am J Roentgenol. 2010
Jun;194(6):1470-8
Valutazione dello stato di malattia in
corso di trattamento con targeted
therapies
Necessario fare riferimento a criteri:
– Diagnostica strumentale
– Clinici
– Laboratorio
Criteri clinici
Esame obiettivo
Performance status
Sintomi tumore-correlati
Perdita di peso
Consumo di analgesici
Qualità di vita del paziente
Criteri di laboratorio
Emocromo completo
Funzionalità epatica
Funzionalità renale
LDH
Calcemia
Tossicità o progressione di malattia?
Quando finisce Q
d fi i
p
una prima linea di trattamento ?
trattamento ?
In assenza di una sicura progressione In
assenza di una sicura progressione
obiettiva, i criteri clinici che depongono per un beneficio per il paziente, devono sempre orientare verso la prosecuzione p
p
del trattamento con l’agente target in corso
E viceversa….
•
Sintomi all’esordio
– Ematuria
– Anemia – Dolori addominali – Calo ponderale
– Astenia – Dispnea
– Il paziente viene trasportato a braccia alla visita
•
•
•
•
Emoglobina: 9.0 gr/dl
LDH 920
PS: sec Karnofsky 70%
Pluri‐metastatico
22.01.2010
•
Maggio 2010
– Praticati due cicli di Sutent
– Netto miglioramento delle condizioni cliniche
Netto miglioramento delle condizioni cliniche
– Molto ridotto il dolore addominale
– Astenia quasi assente
– Hgb 11 g/dl
– Calcemia 8.6 mg/dl
– LDH 650
LDH 650
– Karnofsky 80%
18.05.2010
27.07.2010
11.11.2010
04.02.2011
successo/insuccesso
ccRCC
Predictive markers of
Predictive markers of target therapy
• Bio‐Clinical
– Hypertension (>90 mm/hg DBP)
yp
(
/ g
)
– LDH
– Hypothiroidism (increased TSH)
Hypothiroidism (increased TSH)
Hypertension Biomarker of Efficacy with Sunitinib B Rini, J Natl Cancer Inst 2011; 103:763-773.
Diastolic blood pressure Biomarker of efficacy with axitinib in solid tumors
OS with landmark at 8 weeks.
B Rini, Clin Cancer Res; 17(11); 3841–9.2011
Serum LDH Biomarker with Temsirolimus Andrew J Armstrong et al, J Clin Oncol 30:3402-3407. 2012
Hypothyroidism (increased TSH)
Biomarker of activity with TKI in solid y
tumors
Objective
Obj
ti R
Remission
i i A
According
di tto R
Response E
Evaluation
l ti
C
Criteria
it i iin S
Solid
lid Tumors
T
Based
B
d
on Increased Thyroid-Stimulating Hormone Levels
Schmidinger M, Cancer 2011
Implicazioni cliniche
Implicazioni cliniche
• Trattiamo FINO alla tossicità ?
• Trattiamo LA tossicità ?
Trattiamo LA tossicità ?
• Ruolo dei farmaci per la tossicità ?
Take home messages
Take home messages
• Metodi di valutazione e misure profilattiche verso gli effetti collaterali possono confondere questi risultati
• Gran parte dei risultati derivano da studi retrospettivi G
t d i i lt ti d i
d t di t
tti i
(validazione in studi prospettici)
• I I ‘potenziali
potenziali benefici
benefici’ derivanti dalla somministrazione derivanti dalla somministrazione
contemporanea di medicinali devono essere considerati
• Nessuno di questi marcatori Nessuno di questi marcatori ideale: il marcatore ideale ideale: il marcatore ideale
predittivo valutabile prima del trattamento, piuttosto che durante il trattamento
successo/insuccesso
Key Factors for Successful
Therapy Management in mRCC
D i
Dosing
Side-effect
Management
Optimum
Efficacy
y
Schedule
Treatment
Duration
successo/insuccesso
Zoledronic acid significantly extended (A) the time to first skeletal
complication compared with placebo and (B) the time to first pathologic fracture compared with placebo
pathologic fracture compared with placebo
Rosen et al. Cancer 2004; 100: 2613‐21
mRCC patients: 74 total
reduction of skeletal complications: 74% (ZA) vs 37% (placebo) (p=0.015)
absolute reduction: 37%
ti
time to First On‐Study SRE:
t Fi t O St d SRE 424 days vs 72 days (p=0.007)
424 d
72 d
( 0 007)
Rosen et al. Cancer 2004; 100: 2613‐21
Three Identical International, Randomized, Double‐Blind Active‐Controlled Trials
Double‐Blind, Active‐Controlled Trials
Key Inclusion Criteria
• Adults with breast, prostate,
other solid tumors, or multiple
myeloma and ≥1 bone metastasis
Key Exclusion Criteria
• current or prior IV bisphosphonate
administration
• creatinine clearance <30 mL/min
R
A
N
D
O
M
I
Z
A
T
I
O
N
Denosumab 120 mg SC and
Placebo IV* every 4 weeks
(n=2862)
Zoledronic acid 4 mg IV* and
Placebo SC every 4 weeks
( 2861)
(n=2861)
E
N
D
O
F
S
T
U
D
Y
Recommended: Daily supplementation with calcium
(≥500 mg) and vitamin D (≥400 U)
Primary Endpoint: Time to first on-study skeletal-related event (SRE) (Non-inferiority)
Lipton A, Fizazi K, Stopeck A, et al. Eur J Cancer 2012
Baseline Characteristics
Baseline Characteristics
Ch
Characteristics, n (%) or Median (Q1, Q3)
i i
(%) M di (Q1 Q3)
Denosumab
(n=2862)
Zoledronic Acid
(n=2861)
1026 (36)
1020 (36)
Prostate
950 (33)
951 (33)
Non small cell lung
Non‐small cell lung
350 (12)
350 (12) 352 (12)
352 (12)
Multiple myeloma
87 (3)
93 (3)
Renal
70 (2) 85 (3) Small cell lung 61 (2) 48 (2) Bladder 28 (1)
35 (1) Rectal
Rectal 25 (1)
25 (1) 35 (1)
35 (1) Colon 30 (1) 29 (1)
Other§
449 (16)
445 (16)
Tumor type†
Breast
Primary Endpoint: Time to Fi t O St d SRE
First On‐Study SRE
Proportion without SR
RE
1.0
HR 0.83 (95% CI: 0.76, 0.90)
P<0.001 (Superiority)
17%
Risk Reduction
0.8
0.6
KM Estimate of Median Months 0.4
0.2
0
0
Denosumab
27.66
Z l d i A id
Zoledronic Acid 19 45
19.45
6
12
18
24
30
570
522
197
178
22
26
Month
Patients at Risk:
Denosumab
2862
Zoledronic Acid 2861
1666
1596
1077
991
Time to First and S b
Subsequent On‐Study SRE
t O St d SRE
Cumulative Mean Number of S
SRE
2.0
HR 0.82 (95% CI: 0.75, 0.89)
P<0.001 (Superiority)
18%
Risk Reduction
Total Number of Events 1.5
1.0
Denosumab
1360
Z l d i A id
Zoledronic Acid
1628
0.5
0
0
3
6
9
12
15
18
21
Month
24
27
30
33
36
successo/insuccesso
Combination or Sequential Therapy
Why Combine?
Why Combine?
Why Sequence?
y Seque ce?
Mechanistically
Mechanisticallyy
• “Vertically” block a pathway
• “Horizontally” block multiple pathways
Goals
• increase response rates and prolong PFS
• target resistant pathways upregulated by prior therapy
Goals
• maintain prolonged disease stability
• decrease toxicity by diminishing drug d
t i it b di i i hi d
interactions
What are we looking for
?
1 Maior increases in response rate over
monotherapy
2 Ability to achieve a CR from therapy or in
conjunction with metastasectomy
3 Relative tolerability
Combination Therapy
Antiangiogenic therapy combinations
‐
Sorafenib plus bevacizumab (Sosman et al. JCO 2006)
‐
Sorafenib and AMG 386 (Rini et al. JCO 2011)
‐
Sunitinib plus Bevacizumab (Feldman et al. JCO 2009)
Antiangiogenic therapy‐mTOR inhibitor combinations
‐
Sunitinib plus Temsirolimus (Patel et al. Clin Genitourinary Cancer 2009)
‐
Bevacizumab plus Temsirolimus (Merchan et al JCO 2007 abstract 5034; Escudier et al. JCO 2011 abstract 4516 )
Immunotherapy‐Antiangiogenic therapy combinations
‐
Sunitinib+IFN (Motzer et al. Clin Genitourinary Cancer 2009)
‐
Sorafenib+ IFN (Jonasch et al. Cancer 2010)
‐
Bevacizumab+ IFN (Rini et al, JCO 2008)
Combinations of Targeted
Agents in mRCC:
Sunitinib Combinations
Agents in mRCC:
Sorafenib Combinations
Agents in mRCC:
Bevacizumab Combinations
Sequenzial therapy:
goals
1 Maximize efficacy and duration of first-line
agent
2 Minimize toxicity
3 Choose both initial and subsequent
therapy on the basis of robust predictive
biomarkers
RECORD‐1 vs AXIS: trial design discrepancies
RECORD‐1 RECORD
1
(everolimus)
AXIS
(axitinib)
12/2006‐10/2007
12/2006
10/2007
9/2008‐7/2010
9/2008
7/2010
Placebo
Sorafenib
2 or more prior therapies (TKI)
2 or more prior therapies (TKI)
26%
0%
MSKCC poor‐risk
14%
33%
Allowed TKI intolerant patients
Allowed TKI‐intolerant patients
Yes
No
Allowed crossover
Yes
No
Allowed dose esclation
ll
dd
l i
No
Yes
N=43, 13% of pts
N=194, 26% of pts
Accrual disease
Accrual disease
Comparator
Only prior sunitinib
Attenzione ai confronti indiretti!
[TITLE]
Presented By Thomas Powles, MD at 2013 ASCO Annual Meeting
[TITLE]
[TITLE]
[TITLE]
[TITLE]
TKI
TKI
mTOR
TKI
TKI
TKI
mTOR
mTOR
TKI
mTOR
Ongoing clinical trials will solve all our doubts …

Trattamento delle metastasi ossee

Transcription

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