Presentación - Foro de Debate en Oncologia

Presentación - Foro de Debate en Oncologia

Personalización del tratamiento en
Cáncer Renal: Enfoque actual
Xavier García del Muro Solans
Unidad de Cáncer Genitourinario y Sarcomas
Institut Català d’Oncología L’Hospitalet. Barcelona
•
There was a significant improvement in OS for advanced RCC patients treated in the targeted therapy
era (N= 12,330) compared to those treated in the pre-targeted therapy era (N=11,565) (med. OS 20 m.
vs. 15 m., p= 0.0006)
•
Multivariate analysis revealed that the pre-targeted therapy time period, age over 65 years, black race,
and lack of nephrectomy were predictors of a shorter OS
Phase III randomized trials with targeted
agents in metastatic RCC
Year
Investig. agent
Comparator
Setting
2007
Sunitinib
IFN
First-line
2007
Sorafenib
Placebo
Second-line (prior CK)
2007
Temsirolimus
IFN
First-line / Poor risk
2007
Bevaciz. + IFN
IFN
First-line
2008
Bevaciz. + IFN
IFN
First-line
2008
Everolimus
Placebo
Second-line (prior TKI)
2010
Pazopanib
Placebo
First-line (and prior CK)
2011
Axitinib
Sorafenib
Second-line (prior TKI or CK)
2012
Pazopanib
Sunitinib
First-line
2012
Tivozanib
Sorafenib
First-line (and prior CK)
2012
Temsirolimus
Sorafenib
Second-line (prior TKI)
2012
Bevaciz + Tems
Bevaciz + IFN
First-line
Heng et al. Ann Oncol 2014
Potential predictive biomarkers in metastatic RCC
Are clinicopathological features useful in
selecting therapy in advanced RCC
patients?
Phase III Study of Temsirolimus and IFN-a in
Advanced RCC: Study Design
Phase III Study of Temsirolimus and IFN-a in
Advanced RCC: Study Design
Eligibility Criteria
• Histologically confirmed, measurable
(RECIST) advanced (stage IV or
recurrent) RCC
• No prior systemic therapy
• Karnofsky PS ≥60
(N=626)
• Fasting serum cholesterol ≤350 mg/dL,
triglycerides ≤400 mg/dL
• Minimum of 3 poor-risk features
required*
*Risk Factors
•
•
•
•
•
•
LDH >1.5× ULN
Hb < LLN
Corrected calcium >10 mg/dL
Time from diagnosis to first treatment <1 y
Karnofsky PS 60-70%
Multiple organ sites of metastasis
R (n=207)
A
N
D
O
M (n=209)
I
S
A
T
I
(n=210)
O
N
IFN
escalating to
18 MU SC tiw
Temsirolimus
25 mg/m2 IV qw
Temsirolimus
15 mg/m2 +
IV qw
IFN
6 MU
SC tiw
Primary end point: OS
Hudes G. NEJM 2007
Hudes G. NEJM 2007
Everolimus versus sunitinib prospective evaluation in metastatic
non-clear cell RCC (The ESPN Trial):
A multicenter randomized phase 2 trial
Tannir NM. ASCO 2014
Personalized therapy in advanced RCC:
Optimization of dosing, treatment
duration and toxicity management
Relationship between exposure to sunitinib and efficacy
and tolerability endpoints in patients with cancer: results
of a pharmacokinetic/pharmacodynamic meta-analysis
Overall survival (OS)
1.0
1.0
0.8
0.8
OS probability
TTP probability
Time to tumour progression (TTP)
0.6
0.4
0.2
0.6
0.4
0.2
High AUCss (n=67)
Low AUCss (n=79)
0
0
100 200 300 400 500
Time (days)
High AUCss (n=67)
Low AUCss (n=79)
0
0
100 200 300 400 500 600
Time (days)
Houk B et al, Cancer Chemother Pharmacol 2010
Therapy management: Appropriate
treatment duration
 Objective response may be increased by long-term
exposure to targeted agents
Analysis
Sunitinib
n=374
Duration,
ORR, %
months (range)
IFN-α
n=373
Duration,
months (range)
p-value
ORR, %
Interim
Central
6 (1–15)
31
4 (1–13)
6
<0.001
Invest.
6 (1–15)
37
4 (1–13)
9
<0.001
11 (<1–41)
47
4 (<1–40)
12
<0.001
Final
Invest.
Motzer et al. N Engl J Med 2007; Motzer et al. J Clin Oncol 2009
FALLO A LA 1ª LÍNEA DE TRATAMIENTO DE TERAPIAS DIRIGIDAS
EN LOS ENSAYOS PIVOTALES
Fármaco
Progresión (%)
Toxicidad (%)
SUN vs. INF-α
TEM vs. INF-α vs. INF-α + TEM
BEV + INF-α vs. INF-α + Placebo
PAZO vs. placebo
60 vs. 68
74 vs. 58 vs. 48
46 vs 70
51 vs. 77
19 vs. 23
7 vs. 14 vs. 20
28 vs. 12
14 vs. 3
Rini B. JNCI 2011
Common Adverse Events of TKI in RCC treatment
Adverse Event
Sunitinib
Beva+INF
Pazopanib Sorafenib
Asthenia
++
++
+
+
Hypertension
++
++
++
++
Hand-foot synd.
++
-
+
++
Diarrhea
+
+
+
+
Stomatitis
+
+
-
-
Myelosuppression
+
+
+
-
Liver toxicity
-
-
++
-
Bleeding
-
+
-
-
Thrombosis
-
+
-
-
Proteinuria
-
+
-
-
Clinical Outcomes in Metastatic Renal Cell Carcinoma Patients
Treated with Alternative Sunitinib Schedules
BJ Atkinson, S Kalra, X Wang, T Bathala, P Corn, NM Tannir, E Jonasch
J Urol, March 2014
Clinical Outcomes in Metastatic Renal Cell Carcinoma Patients
Treated with Alternative Sunitinib Schedules
BJ Atkinson, S Kalra, X Wang, T Bathala, P Corn, NM Tannir, E Jonasch
J Urol, March 2014
Selected proposed predictive molecular and imaging biomarkers in advanced RCC
CONCLUSIONES
• La heterogeneidad del cáncer renal y la disponibilidad de
diferentes fármacos permite una personalización del tratamiento
dirigida a la optimización de los resultados
• Las características clínico-patológicas de los pacientes pueden ser
útiles en la selección de la terapia. La exposición prolongada al
tratamiento, a dosis adecuadas, con un correcto manejo de la
toxicidad puede contribuir a mejorar los resultados. Las pautas
alternativas de administración pueden ser útiles para conseguirlo
• Es necesario profundizar en la investigación de biomarcadores
predictivos (tisulares, circulantes y dependientes del huésped) que
conduzcan a una mejor selección del tratamiento adecuado