Sunitinib

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
 Trattamento delle metastasi ossee
 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 experience
• Patient preference
• Biomarkers in development…!
Linee Guida EAU 2010
First-line treatment guidelines for
clear cell mRCC:
ESMO 2012
Risk status
Favourable or
intermediate
Poor risk
Recommendation
Level of evidence
Sunitinib
I, A
Bevacizumab + IFN-α
II, A
Pazopanib
II, A
Temsirolimus
II, A
Escudier B, et al. Ann Oncol 2012;23(Suppl 7):vii65–71
How to choose first line
treatment
• Prognostic profile (Motzer/Heng)
• Toxicity profile and comorbidities
• Disease characteristics (site/sympthoms)
• Sequential strategies
• Oral/iv administration
• Physician experience
• Patient preference
• Biomarkers in 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 Harmenberg15, Jinwan Wang16, 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, NHS Foundation Trust, Manchester, United Kingdom; 5 Renal Cancer and Melanoma Unit, Peking University Cancer Hospital, 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 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)
Median PFS, months (95% CI)
HR (95% CI)
Pazopanib (n=557) Sunitinib (n=553)
8.4 (8.3, 10.9)
9.5 (8.3, 11.1)
1.0466 (0.8982, 1.2195)
Pazopanib (n=501) Sunitinib (n=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)
COMPARZ: PFS (IRC-assessed)
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)
Median PFS, months (95% CI)
HR (95% CI)
Pazopanib (n=557) Sunitinib (n=553)
8.4 (8.3, 10.9)
9.5 (8.3, 11.1)
1.0466 (0.8982, 1.2195)
Pazopanib (n=501) Sunitinib (n=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)
COMPARZ: PFS (IRC-assessed)
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)
Median PFS, months (95% CI)
HR (95% CI)
Pazopanib (n=557) Sunitinib (n=553)
8.4 (8.3, 10.9)
9.5 (8.3, 11.1)
1.0466 (0.8982, 1.2195)
Pazopanib (n=501) Sunitinib (n=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)
COMPARZ study design:
Phase III, open-label, noninferiority trial
Enrolment criteria:
•Locally advanced or mRCC
•Clear-cell histology
•No prior systemic therapy
•Measurable disease (RECIST 1.0)
•KPS ≥70
•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)
Pazopanib
557
8.4 mo (8.3, 10.9)
Sunitinib
553
9.5 mo (8.3, 11.1)
HR (95% CI ) = 1.047 (0.898,1.220)
Pazopanib
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
Sunitinib
COMPARZ: Timing of
assessments
Sunitinib
Mean change from baseline
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)
Pazopanib (n = 554) % Sunitinib (n = 548) %
Adverse Event a
Any event b
Diarrhea
Fatigue
Hypertension
Nausea
Decreased appetite
ALT increased
Hair color changes
Hand-foot syndrome
Taste Alteration
Thrombocytopenia
a AE
All Grs
Gr 3/4
All Grs
Gr 3/4
>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
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
b 2% of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 adverse events.
COMPARZ: Common AEs
(treatment-emergent)
Pazopanib (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
0.23, 0.40
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 duration of treatment
(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
0.409
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
<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
Cancer
Treatment
Satisfaction
Questionnaire
(CTSQ)
Supplementary
Quality of Life
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
0.409
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
<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
Cancer
Treatment
Satisfaction
Questionnaire
(CTSQ)
Supplementary
Quality of Life
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
weeks
Treatment
difference2,3
P
value
Fatigue/Total score
2.5
0.002
Worst mouth/throat soreness
0.38
<0.001
Worst foot soreness
0.08
0.026
Worst hand soreness
0.16
0.005
Limitations due to mouth/throat soreness
0.60
<0.001
Limitations due to foot soreness
0.58
0.003
Domain Description
1. Escudier BJ, et al.. J Clin Oncol 30, 2012 (suppl; abstr CRA4502)
2. Cella D, et al. ESMO Congress 2012 poster 792PD
3. Yellow Font: favors pazopanib
P-value <0.05 is statistically significant
How to choose first line
treatment
• Prognostic profile (Motzer/Heng)
• Toxicity profile and comorbidities
• Disease characteristics (site/sympthoms)
• Sequential strategies
• Oral/iv administration
• Physician experience
• Patient preference
• Biomarkers in development…!
How to choose first line
treatment
• Prognostic profile (Motzer/Heng)
• Toxicity profile and comorbidities
• Disease characteristics (site/sympthoms)
• Sequential strategies
• Oral/iv administration
• Physician experience
• Patient preference
• Biomarkers in development…!
How to choose first line
treatment
• Prognostic profile (Motzer/Heng)
• Toxicity profile and comorbidities
• Disease characteristics (site/sympthoms)
• Sequential strategies
• Oral/iv administration
• Physician experience
• Patient preference
• Biomarkers in development…!
How to choose first line
treatment
• Prognostic profile (Motzer/Heng)
• Toxicity profile and comorbidities
• Disease characteristics (site/sympthoms)
• Sequential strategies
• Oral/iv administration
• Physician experience
• Patient preference
• Biomarkers in development…!
How to choose first line
treatment
• Prognostic profile (Motzer/Heng)
• Toxicity profile and comorbidities
• Disease characteristics (site/sympthoms)
• Sequential strategies
• Oral/iv administration
• Physician experience
• Patient preference
• Biomarkers in development…!
Significantly more patients
preferred pazopanib over
sunitinib (primary endpoint)1
100
p<0.001
90
80
Patients (%)
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
 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
 Trattamento delle metastasi ossee
 Associazione di farmaci ? terapie sequenziali ?
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 lo standard di valutazione di
risposta al trattamento in studi clinici su farmaci antitumorali1
• La risposta 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 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:
• Tecniche di imaging funzionale come la PET o la RMN
• 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
• Abdominal lymph node from an RCC in a 37 year-old
woman (good responder) treated with sorafenib
DCE-US
before treatment shows
contrast uptake
throughout the tumour
estimated at 81%
DCE-US after 3 weeks
of treatment
shows contrast uptake
throughout the tumour
estimated at 48%
Lamuraglia et al.EJC 2006
DCE-US after 6 weeks
of treatment shows
contrast uptake
throughout the tumour
estimated at 31%
identifying patients with progression-free survival of >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
una prima
linea di
trattamento ?
In assenza di una sicura progressione
obiettiva, i criteri clinici che depongono
per un beneficio per il paziente, devono
sempre orientare verso la prosecuzione
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
– Molto ridotto il dolore addominale
– Astenia quasi assente
– Hgb 11 g/dl
– Calcemia 8.6 mg/dl
– LDH 650
– Karnofsky 80%
18.05.2010
27.07.2010
11.11.2010
04.02.2011
 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
 Trattamento delle metastasi ossee
 Associazione di farmaci ? terapie sequenziali ?
ccRCC
Predictive markers of
target therapy
• Bio-Clinical
– Hypertension (>90 mm/hg DBP)
– LDH
– 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
tumors
Objective Remission According to Response Evaluation Criteria in Solid Tumors Based
on Increased Thyroid-Stimulating Hormone Levels
Schmidinger M, Cancer 2011
Implicazioni cliniche
• Trattiamo FINO alla tossicità ?
• Trattiamo LA tossicità ?
• Ruolo dei farmaci per la tossicità ?
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
(validazione in studi prospettici)
• I ‘potenziali benefici’ derivanti dalla somministrazione
contemporanea di medicinali devono essere considerati
• Nessuno di questi marcatori •ideale: il marcatore ideale
predittivo •valutabile prima del trattamento, piuttosto che
durante il trattamento
 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
 Trattamento delle metastasi ossee
 Associazione di farmaci ? terapie sequenziali ?
Key Factors for Successful
Therapy Management in mRCC
Dosing
Side-effect
Management
Optimum
Efficacy
Schedule
Treatment
Duration
 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
 Trattamento delle metastasi ossee
 Associazione di farmaci ? terapie sequenziali ?
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
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%
time to First On-Study SRE: 424 days vs 72 days (p=0.007)
Rosen et al. Cancer 2004; 100: 2613-21
Three Identical International, Randomized,
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)
E
N
D
O
F
Zoledronic acid 4 mg IV* and
Placebo SC every 4 weeks
(n=2861)
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
Characteristics, n (%) or Median (Q1, Q3)
Denosumab
(n=2862)
Zoledronic Acid
(n=2861)
1026 (36)
1020 (36)
Prostate
950 (33)
951 (33)
Non-small cell lung
350 (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
25 (1)
35 (1)
Colon
30 (1)
29 (1)
Other§
449 (16)
445 (16)
Tumor type†
Breast
Lipton A, Fizazi K, Stopeck A, et al. Eur J Cancer 2012
Primary Endpoint: Time to
First On-Study SRE
Proportion without SRE
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
Denosumab
27.66
Zoledronic Acid
19.45
0
0
6
12
18
24
30
570
522
197
178
22
26
Month
Patients at Risk:
Denosumab
2862
Zoledronic Acid 2861
1666
1596
1077
991
Lipton A, Fizazi K, Stopeck A, et al. Eur J Cancer 2012
Time to First and
Subsequent On-Study SRE
Cumulative Mean Number of 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
Denosumab
1360
Zoledronic Acid
1628
1.0
0.5
0
0
3
6
9
12
15
18
21
Month
24
27
30
33
36
Lipton A, Fizazi K, Stopeck A, et al. Eur J Cancer 2012
 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
 Trattamento delle metastasi ossee
 Associazione di farmaci ? terapie sequenziali ?
Combination or
Sequential Therapy
Why Combine?
Why Sequence?
Mechanistically
Mechanistically
• “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
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
Combinations of Targeted
Agents in mRCC:
Sorafenib Combinations
Combinations of Targeted
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
(everolimus)
AXIS
(axitinib)
12/2006-10/2007
9/2008-7/2010
Placebo
Sorafenib
2 or more prior therapies (TKI)
26%
0%
MSKCC poor-risk
14%
33%
Allowed TKI-intolerant patients
Yes
No
Allowed crossover
Yes
No
Allowed dose esclation
No
Yes
N=43, 13% of pts
N=194, 26% of pts
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 …