Post on 27-Jul-2020
Tratamiento actual del Cáncer Renal.
Daniel Castellano
Servicio de Oncología Médica
Unidad de Tumores Genito-Urinarios
Hospital Universitario 12 de Octubre
Diagnóstico en CCR
Mejor pronóstico en estadios tempranos.
Muchos pts son mts asintomáticos.
25% a 40% son de hallazgo incidental.
Usualmente se diagnostican x MAP/Urologo
> frecuentemente x MAP y Urologo y secundario a síntomas
relacionados: hematuria, astenia, dolor lumbar
Patogenesis de CCR
Patogenesis de CCR a cel. claras
Síndrome Von Hippel-Lindau se caracteriza por
mutación del gen VHL y desarrollo de tumores
vasculares incluido CCR.
La función normal del gen VHL (pVHL) es ayudar a
destruir HIFa dentro de la célula.
Mutación del genVHL (90% somática) conduce a una
pVHL modificada no funcionante que permite
incremento de niveles intracel. de HIFa y b.
Sobre-expresión de HIFa induce expresión de genes
hipoxia tisular.
Sobre-expresión consecuente de VEGF, PDGF,TGF
promueve angiogenesis tumoral y proliferación.
3
Targeting signaling pathways in RCC
Rini, et al. Lancet Oncol. 2009;10:992-1000.
Cirugía en el CCR
Nefrectomía parcial (AUA, EAU) estadios I/II
Nefrectomía radical casos especiales
Tumorectomía en casos seleccionados (NSS)
Tratamiento ablativo (T < 2 cms.)
Nefrectomía citorreductora en estadios IV
Beneficio OS 2 estudios randomizados (SWOG, EORTC)
Doble nefrectomía + diálisis en casos seleccionados
(valorar trasplante con > seguimiento)
Modelos Integrados de Predicción Pronóstica en CCR avanzado
Appropriate treatment selection: modified risk status in clinical trials
MSKCC criteria
Karnofsky PS <80
Low serum hemoglobin
High corrected calcium
High LDH
Time from diagnosis to
treatment <1 year
Motzer RJ, et al. J Clin Oncol 2002; Hudes G, et al. N Engl J Med 2007
5
VEGFR-2
VEGFR-1
PDGFR-α
VEGFR-3 PDGFR-ß c-KitFlt-3
Overview of targeted agents in mRCC1–5
Anti-angiogenesisBevacizumab
VEGF-A
VEGF-B
VEGF-C
VEGF-D
VEGF-E
Pazopanib SorafenibRaf
Sunitinib
Good and Intermediate risk pts N ORR (%)
Median PFS
(months)
Median OS
(months)
Sunitinib vs IFN-a1 750 47 vs 12 P<0.001
11 vs 5 P<0.001
26.4 vs 21.8 P=0.051
Bevacizumab + IFN-a vs IFN-a2,3 649 31 vs 13 P=0.0001
10.2 vs 5.4 P<0.0001
23.3 vs 21.3 P=0.1291
Bevacizumab + IFN-a vs IFN-a4,5 732 26 vs 13 P<0.0001
8.5 vs 5.2 P<0.0001
18.3 vs 17.4 P=0.069
*Pazopanib vs placebo6,7 435 30 vs 3†
P<0.001
11.1 vs 2.8P<0.0001
22.9 vs 20.5†
P=0.224
Poor risk patients
Temsirolimus vs IFN-a8* 626 8.6 vs 4.8 NS
5.5 vs 3.1P<0.001
10.9 vs 7.3 P=0.008
*Poor risk patients (modified MSKCC criteria); †Includes cytokine refractory and treatment-naïve patients
Recommended targeted agents for first-line treatment of mRCC: Results from pivotal trials
1. Motzer RJ, et al. J Clin Oncol 2009; 2. Escudier B, et al. Lancet 2007; 3. Escudier B, et al. J Clin Oncol 2010;
4. Rini BI, et al. J Clin Oncol 2008; 5. Rini B, et al. J Clin Oncol 2010; 6. Sternberg C, et al. J Clin Oncol 2010;
7. Sternberg C, et al. ESMO 2010; 8. Hudes G, et al. N Engl J Med 2007*Conditionally approved
PFS: Sunitinib > IFN-
0 5 10 15 20 25 30Time (months)
HR=0.538
(95% CI 0.439–0.658)
P<0.000001
SunitinibMedian: 11.0 months(95% CI: 10.7–13.4)
IFN-Median: 5.1 months(95% CI: 3.9–5.6)
Revisión central independiente
No. at risk
Sunitinib: 375 240 156 54 10 1
IFN-: 375 124 46 15 4 0
1.0
0.8
0.6
0.4
0.2
0
Motzer RJ, et al. N Engl J Med 2007; Motzer RJ, et al. ASCO 2007
PF
S p
rob
abili
ty
Supervivencia en pacientes que no recibieron ningún tratamiento post-estudio
HR=0.647
(95% CI: 0.483–0.870)
P=0.0033 (log-rank)
Sunitinib (n=193)
Median 28.1 months
(95% CI: 19.5–NA)
IFN- (n=162)*
Median: 14.1 months
(95% CI: 9.7–21.1)
*Includes 20 patients whocrossed over to sunitinib on study Motzer RJ, et al. J Clin Oncol 2009; Figlin RA, et al. ASCO 2008
Probabilidad de SG
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0Tiempo (meses)
0 3 6 9 12 15 18 21 24 27 30 33 36
Pro
babili
ty o
f surv
ival
Pazopanib vs. Placebo para 1º y 2º linea de CCR avanzado
Eligibility Criteria
• Locally advanced RCC or mRCC
• Predominant clear cell histology
• Measurable disease (≥1 lesion)
• 0 or 1 prior systemic treatment (cytokine based) for locally advanced or mRCC
RANDOMIZATION
2:1
Primary Endpoint: PFS
Final OS data pending
Pazopanib 800 mg/day
n=290
Placebon=145
N=435
• Open-label extension study
(Pazopanib 800 mg; N=71) completed
in April 2009
Sternberg C. ASCO 2009
PFS del grupo global de pts y 1º linea de tratamiento
Treatment naïve subpopulation Overall study population
Sternberg C, et al. J Clin Oncol. 2009;27(Suppl 15s):5021 (Abstract).
Phase III non-inferiority trial of pazopanib vs sunitinib in first-line mRCC (COMPARZ)
www.clinicaltrials.gov (NCT00720941)
*Pazopanib 800 mg/day
Sunitinib50 mg/day
(Schedule 4/2)
Primary endpoint: PFS
Secondary endpoints: OS, ORR, time to response, duration of response, safety, QoL
N=876
Eligibility criteria
Locally advanced
or mRCC with
clear-cell histology
No prior systemic
therapy for
advanced mRCC
R
A
N
D
O
M
I
S
A
T
I
O
N
1:1
*Conditionally approved
COMPARZ primary endpoint: PFS (IRC-assessed)
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)
Pro
po
rtio
n p
rog
ressio
n-f
ree
1.0
0.8
0.6
0.4
0.2
0
MonthsNumber at risk
Pazopinib 557 361 245 136 105 61 46 19 13 1
Sunitinib 553 351 249 147 111 69 48 18 10 3
0 4 8 12 16 20 24 28 32 36 40
Motzer RJ, et al. Presented at ESMO 2012; Abstract LBA8
*Modified MSKCC poor risk; †Stratification by country and nephrectomy status ‡SD 16 weeks; §p=0.0069
IFN 3 MU-18 MU (n=207)
CR + PR – 7%
CR + PR + SD‡ – 29%
Med. OS 7.3 months§
IFN 6 MU + TEM 15 mg QW
(n=210) CR + PR – 11%
CR + PR + SD – 41%
Med. OS 8.4 months
TEM 25 mg QW (n=209)
CR + PR – 9%
CR + PR + SD – 46%
Med. OS 10.9 months§
Randomize†
3/6 Poor Risk Features
• LDH >1.5 x ULN
• Hgb < LLN
• Ca++ (cor) >10
• KPS <70%
• DFI <1 year
• Multiple sites of metastases
Metastatic RCC (N=626)
Temsirolimus Fase III en CCR avanzado MSKCC mal pronóstico
Parameter
IFN
Arm 1
(n=207)
TEMSR
Arm 2
(n=209)
TEMSR + IFN
Arm 3
(n=210)
Median survival (mos) 7.3 10.9 8.4
Comparisons Arm 2:Arm 1 Arm 3:Arm 1
Stratified log-rank p 0.0069 0.6912
Parameter
IFN
Arm 1
(n=207)
TEMSR
Arm 2
(n=209)
TEMSR + IFN
Arm 3
(n=210)
Median survival (mos) 7.3 10.9 8.4
Comparisons Arm 2:Arm 1 Arm 3:Arm 1
Stratified log-rank p 0.0069 0.6912
1.0
0.8
0.6
0.4
0.2
0
Su
rviv
al d
istr
ibu
tio
n f
un
cti
on
0 5 10 15 20 25 30 35Time to death
Arm 3: IFN + Temsirolimus
Arm 2: TemsirolimusArm 1: IFN
Hudes G et al. N Engl J Med. 2007;356:2271–2281.
RECORD-3. Study Design*
Everolimus
10 mg/day
Sunitinib
50 mg/day***
2nd Line
*NCT00903175. **Stratified by MSKCC prognostic factors. ***4 weeks on and 2 weeks off.
Primary
• PFS-1st line
Secondary
• Combined PFS
• ORR-1st line
• OS
• Safety
Study
endpoints
Cross-over upon
progression
1 : 1
R
A
N
D
O
M
I
Z
E**
Everolimus
10 mg/day S
C
R
E
E
N Sunitinib
50 mg/day***
1st LineN = 471
22
Primary End Point: First-line PFS
100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 12 15 18 21 24 27 30 33
Time (months)
238
233
164
181
118
145
88
108
68
84
44
55
31
42
23
28
12
15
5
9
0
3
0
0
Number of patients still at risk
Everolimus
Sunitinib
Everolimus (events/N = 182/238)
Sunitinib (events/N = 158/233)Cum
ula
tive e
vent-
free p
robabili
ty (
%)
23
K-M Median PFS (mo)
Everolimus Sunitinib
7.85 10.71
Hazard Ratio = 1.43
Two-sided 95% CI [1.15, 1.77]
Overall Survival
100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Cum
ula
tive e
vent-
free p
robabili
ty (
%)
Time (months)
EVE→SUN (events/N = 108/238)
SUN→EVE (events/N = 96/233)
238
Number of patients still at risk
233
208
220
189
198
165
185
151
164
137
152
103
115
66
71
43
38
15
22
2
6
0
1
0
0
24
K-M Median OS (mo)
EVE→SUN SUN→EVE
22.41 32.03
Hazard Ratio = 1.24
Two-sided 95% CI [0.94, 1.64]
EVE→SUN
SUN→EVE
The challenge of treatment in mRCC
• Benefits of tyrosine kinase inhibitors (TKIs) are
well established; however, there are limitations
– There are few complete responses
– Initial partial responses are followed by progression
– In other cases there is no objective benefit
• Drug resistance remains an ongoing obstacle to
successful treatment of mRCC
– Limits the success of therapy and reduces survival
rates
Motzer RJ, et al. J Clin Oncol 2009; Rini B, et al. J Clin Oncol 2010; Escudier B, et al. J Clin Oncol2010; Escudier B, et al. N Engl J Med 2007; Hudes G, N Engl J Med 2007
Rini, Atkins Lancet Oncology
Resistance to Targeted Therapy in RCC
Clinical trial summary for second-
line therapy after TKIs in RCC
Trial Recruitment Treatment arms
RECORD-1: Phase III, everolimus vs. placebo
after progression to TKIs
410 Everolimus
Placebo
AXIS: Phase III, axitinib vs. sorafenib as
second-line treatment
744 Axitinib
Sorafenib
INTORSECT: Phase III, temsirolimus vs.
sorafenib in patients refractory to sunitinib
480 Temsirolimus
Sorafenib
RECORD-3: Phase II, sequencing sunitinib
after everolimus vs. everolimus after sunitinib
390 Sunitinib
Everolimus
SWITCH: Phase III in sequence of sunitinib
after sorafenib vs. sorafenib and after sunitinib
540 Sunitinib
Sorafenib
NCT00410124; NCT00474786; NCT00678392; NCT00903175; NCT00732914
Agent N ORR (%)
Median PFS
(months)
Median OS
(months)
Everolimus vs placebo410
3.0 % vs
0 %
4.6 vs 1.8
P = .00114.7 vs 14.3
Axitinib vs Sorafenib723
19.4 % vs
9.4 %
6.7 vs 4.7
P < .0001NA
Sorafenib vs placebo 903 10% vs 2%5.5 vs 2.8;
P = .000001NA
*Poor risk patients (modified MSKCC criteria); †Includes cytokine refractory and treatment-naïve patients
Recommended targeted agents for second-line treatment of mRCC: Results from pivotal trials
1. Motzer RJ, et al. J Clin Oncol 2009; 2. Escudier B, et al. Lancet 2007; 3. Escudier B, et al. J Clin Oncol 2010;
4. Rini BI, et al. J Clin Oncol 2008; 5. Rini B, et al. J Clin Oncol 2010; 6. Sternberg C, et al. J Clin Oncol 2010;
7. Sternberg C, et al. ESMO 2010; 8. Hudes G, et al. N Engl J Med 2007*Conditionally approved
Everolimus Estudio Fase III (RECORD-1):
Everolimus + BSC
(n=272)
Placebo + BSC
(n=138)
Upon
disease
progression
Prior treatment
Everolimus
(n=272) %
Placebo
(n=138) %
Nephrectomy
Radiotherapy
VEGFR-TKI therapy
96
31
95
28
Sunitinib 46 44
Sorafenib 28 30
Both 26 26
Other systemic therapy
IFN
IL-2
Chemotherapy
Bevacizumab
50
22
13
9
50
24
16
10
>70
%
R
A
N
D
O
M
I
S
A
T
I
O
N
2:1
Escudier B, et al. ESMO 2008
N=410
Estratificación
Pre VEGFR-TKI:
1 o 2 tratamientos
MSKCC: favorable- vs
intermedio- vs mal
pronóstico
2º Line Treatment
RECORD-1: PFS y OS
0 2 4 6 8 10 12 14
Months
Pro
ba
bili
ty (
%)
Number of patients at risk
Everolimus 277 192 115 51 26 10 1 0
Placebo 139 47 15 6 2 0 0 0
Log rank P value < 0.001
Everolimus (n=277)
Placebo (n=139)
HR=0.33
95% CI [0.25, 0.43]
Median PFS
Everolimus: 4.90 months
Placebo: 1.87 months
PFS*
Analysis on Feb 2008 Data Cut-Off
Motzer R, et al. ASCO GU 2009; Kay et al. EAU 2009
OS
Pro
ba
bili
ty (
%)
100
80
60
40
20
0
Number of patients at risk
Everolimus 277 267 240 204 164 155 131 101 61 30 6 0 0
Placebo 139 131 117 100 86 74 56 43 27 13 3 0 0
0 2 4 6 8 10 12 14 16 18 20 22 24
Months
100
80
60
40
20
0
Log rank P value = 0.177
Everolimus (n=277)
Placebo (n=139)
HR=0.87
95% CI [0.65, 1.17]
Median OS
Everolimus: 14.78 months
Placebo: 14.39 months
Analysis on Nov 2008 Data Cut-Off
* central radiology review
Phase III study of axitinib versus sorafenib in second-line (AXIS)
Primary endpoints: PFS
Secondary endpoints: OS, ORR, safety and
tolerability, duration of response, patient-reported
outcomes
Axitinib
5 mg BID
Sorafenib400 mg BID
Eligibility
mRCC with clear-cell
histology
Failure of one prior
first-line regimen
containing:
Sunitinib
Bevacizumab +
IFN-α
Temsirolimus
Or cytokines
Stratification by prior
regimen and ECOG
PS
N=717
Rini B, et al. ASCO 2011
R
A
N
D
O
M
I
S
A
T
I
O
N
AXIS: Axitinib significantly prolonged PFS versus sorafenib
361 256 202 145 96 64 38 20 10 1 0
362 224 157 100 51 28 12 6 3 1 0
Subjects at risk, n
Axitinib
Sorafenib
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Time (months)
P<0.0001 (log-rank)
Stratified HR 0.665
(95% CI :0.544–0.812)
0 2 4 6 8 10 12 14 16 18 20
Axitinib
Sorafenib
mPFS, months 95% CI
6.74.7
6.3–8.64.6–5.6
Pro
gre
ssio
n-f
ree
su
rviv
al (p
rob
ab
ility
)
Rini B, et al. ASCO 2011
Beyond the second Line:
Understanding resistance mechanisms can allow identification of optimal treatment strategies
Potential approaches to overcoming resistance include
New pathways
Switch from one TKI to another3
Switch from a TKI to an mTOR inhibitor4
Combination of traditional agents with new agents?
Enhancing Immune Responsiveness
Programmed Death (PD)-1 pathway
PD-1 downregulates T-cell function upon binding to its ligand (PD-L1)
PD-L1 has been shown to be overexpressed in RCC
In patients with mRCC, overexpression of PD-L1 has been shown to
be associated with
Adverse pathology
Aggressive tumour behaviour
Poor survival
APC/
tumour
cell
T-cellT-cell
inactivationPD-1
PD-L1
Thompson RH, et al. Clin Cancer Res 2007
Resolving RCC Lytic Bone Metastasis in
Patient Treated With Anti-PD-1 (10 mg/kg)
3/25/08 4/14/09
B7H1Control Ig
Responses may be
correlated with PD-
L1 expression
3/4 PRs in PDL-1+
tumors,
0/5 PDL-1 negative
Brahmer et al, 2010.
Resolving RCC Lytic Bone Metastasis in
Patient Treated With Anti-PD-1 (10 mg/kg)
3/25/08 4/14/09
B7H1Control Ig
Responses may be
correlated with PD-
L1 expression
3/4 PRs in PDL-1+
tumors,
0/5 PDL-1 negative
Brahmer et al, 2010.
Resolving RCC Lytic Bone Metastasis in
Patient Treated With Anti-PD-1 (10 mg/kg)
3/25/08 4/14/09
B7H1Control Ig
Responses may be
correlated with PD-
L1 expression
3/4 PRs in PDL-1+
tumors,
0/5 PDL-1 negative
Brahmer et al, 2010.
Phase III Anti-PD-1 study
Patients with advanced RCC, PD to prior 2 VEGF targeted therapy
Anti-PD-1
N=350
-Primary end point: PFS/OS-Prior Cytokines allowed
Study Design: International, Prospective, Randomized, Open-label, Multicenter
Everolimus
n=350
RANDOMIZATION
1:1
3º Line Treatment
Phase III TKI258 (dovitinib)
Patients with advanced RCC, PD to prior VEGF and m-TOR targeted therapy
Dovitinib
n=275
-Primary end point: PFS-Prior Cytokines allowed
Study Design: International, Prospective, Randomized, Open-label, Multicenter
Sorafenib
n=275
RANDOMIZATION
1:1
3º Line Treatment
Negative
Algoritmo CCRm – 2014?Setting Patients Therapy Options
First-line Favourable- or
intermediate-risk
Sunitinib
Pazopanib
Beva - IFN-α
HD IL-2
Cytokines
Sorafenib
Poor-risk Temsirolimus Sunitinib
Second-line Prior cytokine Axitinib
Pazopanib
Sorafenib
Sunitinib
Prior VEGF–TKI Axitinib Sorafenib
Prior VEGF–TKI Everolimus Clinical trial
Adapted from EAU guidelines 2010, ESMO Clinical Recommendations 2012,
NCCN guidelines 2013SOGUG 2010
Algoritmo CCRm – 2014?Setting Patients Therapy Options
First-line Favourable- or
intermediate-risk
Sunitinib
Pazopanib
Beva - IFN-α
HD IL-2
Cytokines
Sorafenib
Poor-risk Temsirolimus Sunitinib
Second-line Prior cytokine Axitinib
Pazopanib
Sorafenib
Sunitinib
Prior VEGF–TKI Axitinib Sorafenib
Prior VEGF–TKI Everolimus Clinical trial
Adapted from EAU guidelines 2010, ESMO Clinical Recommendations 2012,
NCCN guidelines 2013SOGUG 2010
Third-line Prior TKI – TKI Everolimus
Anti-PD1??
Clinical Trial
Prior TKI – mTOR Sorafenib Clinical trial
Achieving a continuum of care in mRCC
• Today, targeted agents are the standard of care for mRCC andlong-term care may be achieved through effective therapymanagement
• But what is the most effective sequencing strategy?
Long-term continuum of care in mRCC
Efficacious
first-line
agents
Efficacious
second-line
agents
Efficacious
third-line
agents
Effective therapy management
INCREASE IN SURVIVAL … >24~36 months
Long-term survival in patients with metastatic renal cell carcinoma (mRCC) in the era of new targeted therapies Five-year follow-up in a single Spanish medical institution
De Velasco G, Sepulveda JM, Ghanem I, Villacampa F, Cortés-Funes H, Castellano D;(Genito-Urinary Tumor Unit, University Hospital 12 de Octubre).
Conclusions: The survival for patients with mRCC who receive multiple lines of targeted therapy has increased to close to 4 years. These results indicate a clear shift in the evolution of mRCC but lack a great deal about what the best sequence.
(days
)
Drug Sunitinib Everolimus Temsirolimus Axitinib Sorafenib Bevacizumab Pazopanib
Pax no.(%) 57(98) 26(45) 9(15) 6(10) 22(38) 13(22) 2(3,5)
Table 2. Drugs
Survival time IC 95%
Media days(months) 1747(58) 1342-2152
Median days Not reached
Favorable risk
Survival time IC 95%
Media days(months) 1248 (41) 1022-1475
Median days 1346 (44) 904-1807
Intermediate risk
Survival time IC 95%
Media days(months) 936 (31) 662-1210
Median 776 (25,8) 157-1394
Poor risk
42
Key Side-effects Associated with Targeted Therapies in mRCC
Gastrointestinal symptoms and oral changes1–6
Fatigue and fatigue-causing side-effects1–6
Hypertension and other cardiovascular toxicities1–6
Skin toxicities1–6
Haematological toxicities1–6
1. Bhojani N, et al. Eur Urol 2008; 2. Kollmannsberger C, et al. Can Urol Assoc J 2007; 3. Pfizer Inc. SUTENT® (sunitinib) Summary of Product Characteristics, February 2009; 4. Bayer Healthcare. Nexavar® (sorafenib) Summary of Product Characteristics, 2008; 5. Wyeth Pharmaceuticals. Torisel® (Temsirolimus) Summary of Product Characteristics, 2009; 6. Roche Products Ltd. Avastin®
(bevacizumab) Summary of Product Characteristics, 2008
The patient’s profile and treatment goals, and the efficacy/toxicity ratio of the targeted agent must be
considered when selecting a first-line strategy in mRCC
43
Most Common Side-effects (≥20%) Reported with the Seven Licensed Agents for mRCC
1. Pfizer Inc. SUTENT® (sunitinib) Summary of Product Characteristics, February 2009; 2. Bayer Healthcare. Nexavar® (sorafenib) Summary of Product Characteristics, 2008; 3. Wyeth Pharmaceuticals. Torisel® (Temsirolimus) Summary of Product Characteristics, 2009; 4. Escudier B, et al. Lancet 2007; 5. Roche Products Ltd. Avastin® (bevacizumab) Summary of Product Characteristics, 2008
Sunitinib/Pazopanib/Sorafenib
Axitinib/Tivozanib
Temsirolimus/Everolimus
Bevacizumab/IFN-α4,5
Fatigue, gastrointestinal disorders, dysgeusia, decreased appetite, hypertension, HFS, skin discolouration, mucosal inflammation, rash
HTA, diarrhea, asthenia, dysphonia.
Asthenia, anemia, rash, gastrointestinal, disorders, oedema, metabolic disorders,
dyspnea, pain, cough, bacterial infections
Anorexia, fatigue/asthenia, hemorrhage, hypertension, influenza-like illness,
headache, diarrhea
• Mecanismo de acción diferente a QT Toxicidad diferente a QT.
• Mecanismo de acción diferente entre ellos Toxicidades diferentes.
• Son tratamientos prolongados Mayor riesgo de toxicidad.
• La toxicidad es muy frecuente, pero pocos G3-4 y reversibles.
• Hay que conocer la toxicidad y optimizar su manejo.
• No reducciones de dosis ni suspensiones prematuras.
Pazopanib/
/
Manejo de Efectos Secundarios
45
Mucositis funcional
Sínd. Mano-Pie
Rash Cutaneo
Baseline
Month 12
Month 5
Month 11
Pneumonitis with Everolimus Therapy
18
Possible areas of unmet medical need
Currently approved treatments are not curative, and patientsdevelop progressive disease
Evolving need for effective therapeutics with unique
mechanisms of action for patients who progress
Non clear cell histologies
Few studies are available to determine efficacy
Biomarkers, new pathways, gene profile,mechanisms of resistance !!!
Molecular Marker Expression Level Predicted Response to TKI-s1
Hypertension High Good response/PFS-OS
Hormonal syndrome Low Good response/PFS
H-Foot syndrome High Good response/PFS-OS
Clinical Marker Predicted Response to mTOR´s
Pneumonitis Good response/PFS
Lymphopenia PFS?
Castellano D, et al. Cancer T Reviews 2012.
Predicting Response to Treatment Based on Clinical Markers
Predicting Response to Treatment Based on Molecular/Genetic Markers
Molecular Marker Expression Level Predicted Response to Treatment
CAIX1 High Good response to immunotherapy
COX-21 High Good response to immunotherapy
HIF-1/HIF-22 High Good response to sunitinib
Genetic Marker Predicted Response to Treatment
Various nsSNPs3-6 Significant sunitinib toxicity/PFS
Loss of chromosomes 4, 9, or 17p4 Non-response to interleukin-2 (IL-2)
VHL loss-of-function mutation5 Good response to VEGF therapy
nsSNPs: nonsynonymous single nucleotide polymorphisms
1. Kim HL et al. J Urol. 2005;173:1496. 2. Patel PH et al. ASCO 2008. Abstract 5008.
3. Faber PW et al. ASCO 2008. Abstract 5009. 4. Jaeger E et al. ASCO 2008. Abstract 5043.
5. Choueiri TK et al. J Urol. 2008; [Epub ahead of print].
6. Garcia-Donas J. Lnacet Oncology 2011. Estudio SUTREN (SOGUG)
Estudios Fase III en Adyuvancia
Estudios Fase III en Adyuvancia
Immunotherapy ref year Numberofpts Medianfollowup
Outcomes Pvalue
IFNvsobservation Pizzocaroetal 2001 247 N/A5-yrOS:66.5%vs66.0%
NS
IFNvsobservation Messingetal 2003 283 124.0MedianOS:5.1vs7.4years
NS
High-doseIL-2vsobservation
Clarketal 2003 69 N/AMedianDFS:19.5vs36.0mo
NS
Tumorcellvaccinevsobservation
Jochametal 2004 558N/A 5-yrPFS:77.4%
vs67.8%0.02
IL-2+IFN+FUvsobservation
Atzpodienetal 2005 203 51.08-yrRFS:39%vs49%
NS
HSPPC-96vsobservation
Woodetal 2006 818 21.01.9-yrRFS:62.3%vs60.2%
NS
IL-2+IFN+FUvsobservation
NCT00053807 2006 550 N/APhaseIIIcompletedresultspending
N/A
Prior immunotherapy trials:IFN and IL2 trials
G. Pizzocaro, et al. Interferon adjuvant to radical nephrectomy in Robson stages II and IIIrenal cell carcinoma: a multicentric randomized study. J Clin Oncol, 19 (2001),p. 425E.M.Messing, etal. Phase IIIstudy of interferon alfa-NL as adjuvant treatmentfor resectable renal cell carcinoma: an Eastern Cooperative Oncology Group/Intergroup trial. J Clin Oncol, 21(2003),p. 1214J.I.Clark, et al. Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial J Clin Oncol, 21(2003),p. 3133D. Jocham, et al. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial. Lancet, 363(2004),p. 594J. Atzpodien, et al. Adjuvant treatment with interleukin-2- and interferon-alpha2a-based chemoimmunotherapy in renal cell carcinoma post tumour nephrectomy: results of a prospectively randomised trial of theGerman Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN)Br J Cancer, 92(2005),p. 843C. Wood, et al. An adjuvant autologous therapeutic vaccine (HSPPC-96;vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial. Lancet, 372(2008),p. 145
Phase II Neoadjuvant vs. Adjuvant PD-1 Blockade inNon-metastatic RCC (ECOG 1813)
• Does the preoperative dosing induce greater tumor CD8+ T cell infiltration?
– 54 pts randomized 2:186% power to detect 100% increase
• Address the need for preop doses in a larger phase III trial
Assess:
•
•
T cell infiltratePD-L1 expression
R
a
n
d
o
m
i
z
e
Baselineprimarytumorbiopsy
*Serum samples at baseline, dose 2, dose 4 in arm B,and at nephrectomy
Primary EP: safety/tolerabilitySecondary endpoints:
-CD8 T cell: Treg infiltration of kidney-CD4 T cell: Treg ratio-Tumor PD-L1 expression
Anti-PD13mg/kg x 3 doses
q 2 wks
Partial or RadicalNephrectomy
2: 1n=54
Partial or RadicalNephrectomy
Anti-PD13mg/kg x 3 doses
q 2 wks
Conclusiones La secuenciación de fármacos es la mejor opción terapéutica
en cáncer renal avanzado.
TKI´s son la 1º opcion en 1º linea de MSKCC pronóstico bueno
e intermedio. Temsirolimus en MSKCC pobre pronóstico.
Axitinib y Everolimus son opciones de 2º linea.
Unidad multidisciplinar de diagnóstico y tratamiento
Identificar nuevos factores moleculares asociados a eficacia y/o
toxicidad> Investigación básica y traslacional
Uso adecuado y/o individualizado del arsenal terapéutico> Línea de trabajo asistencial e investigacional
Aplicación real de guías terapéuticas> Generar grupos de expertos para su gestión y aplicación
KIDNEY PROSTATE BLADDERTOXICITIES
RARE TUMORSTRASLATIONAL
Chair : Daniel Castellano
Co-Chair : Nuria Lainez
Executive Secretary: Ignacio Durán
Treasurer : Arantxa González del Alba
Working Groups/Grupos de Trabajo
Grupos Colaboradores/Miembros SOGUG
Collaborate Groups/SOGUG members
Spanish Oncology Genito Urinary Group
X. García
del MuroM.A. Climent A. Font
J. García-
Donás J.L. Perez G.
EDUCATIONAL COMMITTEE/ DOCENCIA
V Symposium SOGUG-2013
Madrid19-21 de noviembre
¡ Estais todos invitados !
Muchas Gracias