Transcript Diapositiva 1

TEMSIROLIMUS
Begoña Mellado
Servicio de Oncología Médica. Hospital Clinic. Barcelona
Temsirolimus (CCI-779)
•
•
Ester soluble de rapamicina
Se metaboliza a nivel hepático en sirolimus
• Efecto anti-tumoral sin
efecto immunosupresor:
- fármacocinético: inhibición
función linfos T transitoria y
reversible (24 horas)
Primer agente anti-diana
aprobado por beneficio en
supervivencia en carcinoma
renal
mToR and Cancer
Metilado 30 %
TEMSIROLIMUS
Compite con FKBP-12
Activado 60%
HIF
Efecto anti-angiogénico
Membrane
Amino acid
RTK
PI3K
AKT
mTOR Translation & Stability of HIF-1 transcript
VEGF gene expression
Tumor Angiogenesis
temsirolimus
Efecto antiproliferativo
Growth factor
Amino acids
PI3K
PDK-1
AKT
mTOR
Phosphatases
kinase
temsirolimus
-
Protein stability
P70 S6-K
4E-BP-1
- p27 kip1
- cyclin D1
- others
Protein translation
G1
- ribosomal proteins
- cyclin D1, c-myc
S
Ensayos fase I en monoterapia
• Estudio 100: IV diariamente x 5 días c/ 2 semanas
– 63 pacientes tratados con dosis de 0.75 – 24 mg/m2/día
– De 16 pacientes con RCC (10 evaluables), hubo 1 PR + 1 MR + 6 SD
• Estudio 101: IV semanal
– 24 pacientes tratados con dosis de 7.5 – 220 mg/m2/semana
– De 6 pacientes con RCC (5 evaluables), hubo 1 PR + 3 SD
No una relación dosis-respuesta
Las PR ocurrieron con las dosis de 3,7 mg/m2/día (estudio 100) y de 15
mg/m2/semana (estudio 101)
•
•
Ensayo realizado en pacientes con RCC avanzado,
refractario a tratamiento y multi-pretratado.
Se evaluaron 3 dosis de temsirolimus diferentes:
– 25 mg
– 75 mg
– 250 mg
•
Se evaluó la respuesta según las diferentes dosis y
según la estratificación por criterios pronósticos de
Motzer.
Respuesta según dosis
Dose Group (mg / week) 25 mg
75 mg
250
mg
Total
(ITT)
N
Partial Response
Minor Response
38
3
13
37
3*
11
111
8 (7%)
29 (26%)
36
2
5
Clinical Benefit* n (%) 19 (53) 21 (55) 16 (43)
56 (51)
Time to PD (months;
6.3
6.7
5.2
95%CI) (3.6,7.8) (3.5,8.5) (3.7,7.4)
5.8
Median Survival
(months)
13.8
* Clinical Benefit = PR + MR + SD >=24 weeks
11.0
17.5
(4.5,7.2)
15.0
Supervivencia según grupos de riesgo de Motzer
Risk Group
Number of Patients (%)
200-US (second-line, n=105*)
Favorable
8 (8%)
Intermediate
48 (46%)
Poor
49 (47%)
Overall
111
Median Survival
Months (95% CI)
24 (18, 27)
23 (17, 26)
8.2 (7, 10)
15 (10, 18)
* Pts for whom prognostic factor data available
MSKCC Data (first-line, n=437**)
Favorable
79 (18%)
Intermediate
271 (62%)
Poor
87 (20%)
Overall
** Interferon-based treatments
463
30 (21, 38)
14 (12, 16)
4.9 (4.3, 6.3)
13 (12, 15)
Stratification by:
Geographical Regions:
EU + AU + CA (21%)
US (29%)
Other (50%)
Nephrectomy:
Yes
No
R
A
N
D
O
M
I
S
E
IFN-α escalating to
18 MU SC
3 times weekly (n=207)
Temsirolimus 25-mg IV
once weekly (n=209)
Temsirolimus 15-mg IV once
weekly plus IFN-α 6 MU
3 times weekly (n=210)
Criterios de inclusión
Los pacientes debían tener de 3 a 6 factores de mal pronóstico:
1. Karnofsky 60-70%
2. Hb < LSN
3. Ca corregido > 10 mg/dL
4. LDH > 1.5 LSN
Criterios de Motzer
5. Localización de M1 en > 1 órgano
6. < 1 año desde el diagnóstico
Otros
Hudes et al. N Engl J Med. 2007;356:2271-2281.
Temsirolimus mejora supervivencia
49% Incremento global de
SG respecto IFN
IFN-
TEM
TEM + IFN-
Median OS
7.3 months
10.9 months
8.4 months
Median PFS
1.9 months
3.8 months
3.7 months
Median TTP
1.9 months
3.8 months
2.5 months
ORR
4.8%
8.6%
8.1%
Clinical
benefit*
15.5%
32.1%†
28.1%‡
Outcome
Hudes G et al. N Engl J Med.
2007;356:2271.
No impacto de la nefrectomía en el
beneficio de temsirolimus
IFN-
TEM
HR (95% CI)
TEM vs IFN-
Nefrectomía
7.8 meses
10.4 meses
0.84 (0.63-1.11)
No nefrectomía
6.2 meses
11.5 meses
0.61 (0.41-0.91)
Mediana Sg
P value*
.20
Median PFS
Nefrectomía
3.5 meses
5.3 meses
0.72 (0.55-0.93)
No nefrectomía
2.0 meses
5.7 meses
0.62 (0.43-0.88)
P value*
.47
Note: In each treatment arm, 33% of patients did not receive nephrectomy prior to treatment
* Test of interaction between treatment and nephrectomy status based on unstratified Cox proportional hazard model
Logan T et al. ASCO 2008 Annual Meeting. Abstract 5050.
Subanálisis de
grupos
IFN-
TEM
HR (95% CI)
TEM vs IFN-
Clear cell
8.2 months
10.6 months
0.85 (0.64-1.06)
Other
4.3 months
11.6 months
0.55 (0.33-0.90)
<65 yrs
6.9 months
12.0 months
0.67 (0.52-0.87)
≥65 yrs
8.3 months
8.6 months
1.15 (0.78-1.68)
17.7 months
13.0 months
1.17 (0.74-1.84)
6.0 months
10.2 months
0.70 (0.55-0.89)
Median OS, by
Subgroup
Histology type
Age
Risk group
Intermediate
Poor
30/36
30/36 en
en IFN
IFN
c. papilar
25/37 en TEM
CÉLULAS CLARAS
CARCINOMA PAPILAR
Analysis of PTEN and HIF-1alpha and correlation with efficacy in
patients with advanced renal cell carcinoma treated with TEM vs
INF
Figlin et al. Cancer 2009
Análisis exploratorio del estudio Global
IH
416 pts
HIF-1
HIF
PTEN 51%
HIF 60%
PTEN +
81
11,3
0,81
PTEN -
31
10,7
0,62
HIFalfa +
56
9,5
0,74
HIFalfa -
75
10,7
0,56
Transcriptional Profiles in Peripheral Blood Mononuclear Cells
Prognostic of Clinical Outcomes in Patients with Advanced Renal
Cell Carcinoma Michael E. Burczynski et al. Clin Cancer Res 2005
Fig. 1 Unsupervised hierarchical clustering of RCC patient PBMC profiles using all expressed genes present in at least
one sample and possessing a frequency of >10 ppm in at least one sample (5,424 genes total)
Most Common Temsirolimus Toxicities
Associated With 25-mg Dose
Category
AE
All Grades
Grade 3/4
Systemic
Fatigue/asthenia
51%
11%
Cardiac
Hypertension
7%
--
Respiratory
Dyspnea
28%
9%
Gastrointestinal
Nausea
37%
2%
Anorexia
32%
3%
Diarrhea
27%
<1%
Abdominal pain
21%
4%
Vomiting
19%
2%
Altered taste
15%
0%
Bhojani N et al. Eur Urol. 2008..
Most Common Temsirolimus Toxicities
Associated With 25-mg Dose (Cont.)
Category
AE
Cutaneous
Laboratory
All Grades
Grade 3/4
Rash
47%
4%
Mucositis/stomatitis
41%
3%
Edema
35%
3%
Pruritis
19%
1%
Anemia
45%
20%
Thrombocytopenia
14%
1%
Neutropenia
7%
3%
Hypertriglyceridemia
27%
4%
Hypercholesterolemia
24%
1%
Hyperglycemia
26%
11%
Elevated creatinine
14%
3%
Hypophosphatemia
8%
5%
Bhojani N et al. Eur Urol. 2008..
TEM y en combinación con agentes anti- VEGF
SUNITINIB
stop por toxicidad
SORAFENIB
Aumento del síndrome mano-pie, HTA, proteinuria
25 respuestas in 48 pacientes (52%)
BEVACIZUMAB (fase I/II)
12 (RCC células claras)
7 PR y SD
DLT Hipertrigliceridemia Gº 3
Mucositis Grado º 3
Dosis recomendada: TEM 25 mg/semana+ bevacizumab 10 mg/kg c/2 sem
Phase I study of TEM and bryostatin in patients with
metastatic renal cell carcinoma. Wong et al. ASCO 2009
TEM (10-37,5 MG) + BRYO 20 MCG/m2
Tox GIII: neumonitis, hematológica,
trombosis
TEM
BRYO
Se observan respuestas y estabilizaciones
duraderas en CCR
Estudio 3311
•Tx 1a línea
RCC de células claras
(n=800)
R
A
N
D
O
M
I
Z
E
Endpoint primario: PFS
Temsirolimus + Bevacizumab
25 mg IV QW 10 mg/kg IV Q2W
(n = 400)
Bevacizumab + INF-α
10 mg/kg IV Q2W
9MU SC TIW
(n = 400)
Estudio 404
•Fallo a Sunitinib
• Tx 2a línea
(n=440)
R
A
N
D
O
M
I
Z
E
Temsirolimus
25 mg IV QW
(n=220)
Sorafenib
400 mg PO BID
(n=220)
Endpoint primario: PFS, Tolerabilidad
Ongoing Studies in Metastatic RCC
Treatment
Patient Population
Trial
Phase
Treatment-naïve advanced
RCC
III
TEM vs sorafenib (SOR)
Advanced RCC, failure on 1stline sunitinib (SUN)
II/III
TEM
Asian patients with advanced
RCC
II
Treatment-naïve metastatic
RCC
II
Advanced RCC
II
Metastatic or unresectable
RCC
I/II
Metastatic RCC
Ib
TEM + bevacizumab (BEV) vs BEV + IFN 
TEM + BEV vs BEV + IFN -2a vs SUN
TEM vs BEV vs BEV + SOR vs TEM + SOR
TEM + BEV
TEM + AV-951 (a VEGF receptor inhibitor)
Gracias