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Evidencia y criterios de eficacia para la
selección del tratamiento de 1ª línea: Sunitinib
Hospital Universitario Central de Asturias, Oviedo Emilio Esteban González
Evidencia actual en cáncer renal
¿Recomendaciones de
tratamiento?
Importancia de la maximizacion
de la primera línea de
tratamiento
Eficacia: factor clave en la
secuencia de tratamiento
¿Como se translada a la
práctica clínica habitual?
Relapse or stage 4 and medically or surgically unresectable Predominant clear-cell histology
• Level 1 evidence*
– Sunitinib
– Bevacizumab + IFN-α
– Pazopanib
– Temsirolimus (for poor prognosis† patients)
• Level 2A evidence‡
– Clinical trial
– High-dose IL-2 (for selected patients)
– Sorafenib (for selected patients)
– Best supportive care§
• Level 2B evidence**
– Temsirolimus (for selected patients of other risk groups)
2014 NCCN guidelines for clear-cell mRCC: First-line therapy
* Level 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials) and there is uniform NCCN consensus. † Poor prognosis patients, defined as those with ≥3 predictors of short survival. ‡ Level 2A: Uniform NCCN consensus based on lower-level evidence, including clinical experience, that the recommendation is appropriate. § Best supportive care can include palliative RT, metastasectomy, biphosphonates or RANK ligand inhibitors for bony metastases.
**Level 2B: Non-uniform NCCN consensus (but no major disagreement), based on lower-level evidence, including clinical experience, that the
recommendation is appropriate.
NCCN = National Comprehensive Cancer Network; RT = radiation therapy.
Kidney Cancer, NCCN v.2.2014 Clinical Practice Guidelines in Oncology. Available at www.NCCN.org.
1. Motzer RJ, et al. J Clin Oncol. 2009;27:3584–3590; 2. Escudier B, et al. J Clin Oncol. 2009;27(Suppl. 15S):5020 (Abstract);
3. Rini B, et al. J Clin Oncol. 2009;27(Suppl. 15S):LBA5019 (Abstract); 4. Sternberg C, et al. J Clin Oncol. 2010;28:1061–1068;
5. NICE final appraisal determination 2010; 6. Hudes G, et al. N Engl J Med. 2007;356:2271–2281;
7. Motzer RJ et al. N Engl J Med. 2013;369:722–731; 8. Escudier B, et al. J Clin Oncol. 2009;27:1280–1289.
First-line treatment landscape Study N Median PFS (months) Final Median
OS (months)
Phase III
Sunitinib vs. IFN-α1 750 11 vs. 5 p<0.001
26.4 vs. 21.8 p=0.051
Bev + IFN-α vs. IFN-α2 649 10.4 vs. 5.5
p<.0001
23.3 vs. 21.3
p =0.1291
Bev + IFN-α vs. IFN-α3 732 8.4 vs. 4.9 p<0.0001
18.3 vs. 17.4 p =0.069
Pazopanib vs. placebo4 233 11.1 vs. 2.8
p<0.0000001
22.9 vs. 23.55
p=0.525
Temsirolimus vs. IFN-α6
626 5.5 vs. 3.1
p<0.001
10.9 vs. 7.3
p=0.0069
Pazopanib vs. sunitinib7
1110 8.4 vs. 9.5
Non-inferior
28.4 vs. 29.3
Non-inferior
Phase II
Sorafenib vs. IFN-α8 189 5.7 vs. 5.6 p =0.504
NA
COMPARZ study design:
Phase III, open-label, non-inferiority trial
Motzer RJ, et al. N Engl J Med. 2013;369:722–731.
Pazopanib 800 mg QD
Continuous daily dosing Enrolment criteria:
•Locally advanced or mRCC
•Clear-cell histology
•No prior systemic therapy
•Measurable disease (RECIST 1.0)
•KPS ≥70
•Adequate organ function
N=927
Sunitinib 50 mg QD
Schedule 4/2
Randomised
1:1
Study start: August 2008
VEG108844
Phase III
n=927
VEG113078
Phase II (Asia)
n=183
COMPARZ:
1,110 patients
N=1,110
COMPARZ study: Timing of assessments M
ea
n c
ha
ng
e fro
m b
ase
line
Time
Sunitinib
Pazopanib
Disease assessments
QoL assessments
Week 4
Week 6 Week 6 Week 6
Week 4 Week 4
Motzer RJ, et al. N Engl J Med. 2013;369:722–731.
COMPARZ Study: PFS At a Glance
http://www.gsk-clinicalstudyregister.com/result_detail.jsp?protocolId=108844&studyId=A1C548E6-186D-405F-B1D6-
853A51D9376B&compound=pazopanib
HR: 1.069 (0.910–1.255)
HR: 1.07 (0.81–1.42)
HR: 1.05 (0.90–1.22)
8.4 8.4 8.4
11.1
10.29.5
0
2
4
6
8
10
12
AnálisisEstudioAsiá co(IRC)AnálisisPorProtocolo(IRC) AnálisisITT(IRC)
Pazopanib Sutent
Asian substudy
analysis
Per protocol
analysis
ITT analysis
Pazopanib Sunitinib
Motzer RJ, et al. N Engl J Med. 2013;369:722–731; Guo et al. J Clin Oncol 31, 2013 (suppl 6; abstr 366)
Motzer RJ, et al. N Engl J Med 2013;369(8):722–731
COMPARZ Study: AEs Leading To Drug Discontinuation
COMPARZ: HRQoL assessments
FACIT-F and FKSI-19 only validated HRQoL assessments scales
reported1
Although differences were statistically significant, they were not
clinically meaningful2–4
Difference (favouring
pazopanib if >0)2 p-value Minimally important
difference*
FACIT-F 2.32 <0.001 3‒43
FKSI-19 total 1.41 0.02 2‒34
*Smallest difference in score in the domain of interest that patients perceive as important in
either benefit or harm and that would lead clinicians to consider a change in patients therapy
1. Cella. Oncologist 2011; 2. Motzer et al. NEJM 2013;
3. Cella et al. J Rheumatol 2005; 4. Cella et al. Value Health 2007
Risk status Recommendation Level of evidence
Favorable or
intermediate
Sunitinib
Bevacizumab + IFN-α
Pazopanib
I, A
II, A
II, A
Poor risk Temsirolimus II, A
First-line treatment guidelines for clear-cell mRCC: ESMO 2013
Escudier B, et al. Ann Oncol. 2012;23(Suppl 7):vii65–71.
Gore et al , Lancet Oncol 2009
n %
Total 4,371pts**
Age, median (range) 59 (19-89)
Age >65yrs 1,418 32%
Prior nephrectomy 3,873 89%
Pts + brain mets 321 7%
PS 2-4 582 13%
Nonclear cell 588 13%
1 metastatic site 833 19%
>2 metastatic site 3,489 80%
Prior cytokine 2,974 68%
Prior antiangogenic 238 5%
*characteristics +/- prior cytokine similar
* * 4,371 / 4,564pts received 1 cycle
Uso expandido sunitinib: Características de los
pacientes*
• 4564 pacientes incluidos de la práctica clínica habitual
• Se incluyeron pacientes que tradicionalmente no son incluidos en los estudios de
Fase III
Uso expandido sunitinib: Supervivencia Libre de Progresión
Gore M, et al. Lancet Oncol. 2009; 10:757–763. Gore et al , Lancet Oncol 2009
Tolerabilidad Sunitinib, EA’s Grado 3/4
Gore Lancet Oncol 2009
Motzer JCO 2009
Gore et al , Lancet Oncol
2009
Al iniciar el tratamiento, el paciente debe de ser consciente
de los factores que influyen en el resultado
Dosis
Duración Tratamiento
Eficacia Óptima
Manejo Efectos Secundarios
KM estimate of PFS by the presence
or absence of any-grade asthenia/fatigue1
0 5 10 15 20 25 30 35 40 45 50 Time (months)
Pro
bab
ilit
y o
f P
FS
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Present (n=583)
Median, 10.9 months (95% CI: 0.6, 12.0)
Absent (n=187)
Median, 6.4 months (95% CI: 4.7, 8.0)
Pro
bab
ilit
y o
f O
S
0 5 10 15 20 25 30 35 40 45 50 55 60 Time (months)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Grade ≥2 (n=164)
Median, 25.2 months (95% CI: 21.3, 32.6)
Grade <2 (n=252)
Median, 15.7 months (95% CI: 13.0,18.6)
p<0.001
KM estimate of OS by neutropenia severity grade2
OS
pro
bab
ilit
y
With HFS (n=179)
Median: 38.2 months
Without HFS (n=591)
Median: 18.9 months
p<0.001
KM estimate of OS by HFS status3
Time (months)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 0 6 12 18 24 30 36 42 48 54 60
Some adverse events are biomarkers of treatment efficacy
1. Davis MP, et al. ESMO 2011; Abstract 1139;
2. Donskov F, et al. ESMO 2011; Abstract 1141; 3. Puzanov I, et al. ESMO 2011; Abstract 1444.
With hypertension (n=442)
Median OS, 30.9 months
(95% CI: 27.9 to 33.7)
Without hypertension (n=92)
Median OS, 7.2 months
(95% CI: 5.6 to 10.7)
0 5 10 15 20 25 30 35 40 45
50 Time (months)
p<0.0001
Why the management of sunitinib therapy
is important
Houk BE, et al. Cancer Chemother Pharmacol. 2010;66:357–371;
Yang JC, et al. N Engl J Med. 2003.
p=0.014
Relative risk 0.49
p=0.001
Relative risk 0.52
Days
Fra
ctio
n o
f p
atie
nts
no
t p
rogre
sse
d
0 100 200 300 400 500
0.0
0.2
0.4
0.6
0.8
1.0
Days
Fra
ctio
n o
f p
atie
nts
su
rviv
ing
0 100 200 300 400 500
0.0
0.2
0.4
0.6
0.8
1.0
600
AUC >Median (N=120)
AUC <Median (N=117)
AUC >Median (N=120)
AUC <Median (N=117)
*
Historical
placebo median
*
Historical
placebo median
Time to tumor progression OS
Concentración de Pazopanib eficacia y toxicidad
Una mayor duración de tratamiento con Sunitinib
proporciona una mayor respuesta al tratamiento
Sunitinib (n=374) IFN-α (n=373)
Análisis Duración, ms (rango) ORR, % (95%CI)
Duración, ms (rango) ORR, % (95%CI) p
Interino 6 (1–15) 31 (26–36) 4 (1–13) 6 (4–9) <0.001
Final 11 (<1–41) 39 (34–44) 4 (<1–40) 8 (6–12) <0.001
Motzer RJ, et al. N Engl J Med 2007;
Motzer RJ, et al. J Clin Oncol 2009.
• Las tasas de respuesta del fase III se incrementaron con una mayor
duración del tratamiento :
Los pacientes se deben mantener en tratamiento mientras se observe un beneficio
Respuestas completas con sunitinib
Albiges L, et al. J Clin Oncol. 2012;30:482–487.
Sunitinib-treated patients: n=59; sorafenib-treated patients: n=5
• Long lasting CRs can occur after TKI treatment alone or when
combined with local treatment
• Relapsing patients responded well to further therapy
• Median time to CR was 12.6 months in patients receiving TKIs alone,
highlighting the importance of maintaining therapy
RAINBOW Study: Sunitinib management by
using individualised schemes
Retrospective observational study of mRCC patients administered
sunitinib on a 2/1 schedule*
Grade ≥3 toxicities† Fatigue† Hypertension‡
*Patients moved to 2/1 schedule due to treatment-related toxicities during initial therapy using 4/2 schedule; †p<0.001; ‡p=0.007. Off-label data presented. Bracarda et al. ASCO GU 2014
Rat
e (%
)
RAINBOW Study: Eficacia en pacientes
que pasaron de sunitinib 50 MG 4:2 a 2:1
Group A (n=208) [4/2 2/1]
Group B (n=41)
[2/1]
Median treatment
duration, months 28.2
[4.3 19.7] 7.8
Median PFS, months
(95% CI) 38.6
(24.0-58.6)
9.6 (6.3-14.2)
Potential improvement of PFS with an alternative 2/1 schedule Results observed in the group B should be analyzed taking into account
poorer patient characteristics
. Bracarda et al. ASCO GU 2014
Ajustes de dosis sunitinib no condicionan la eficacia de
sunitinib
Análisis retrospectivos de estudios de fase II y fase III sunitinib in mRCC1
Pacientes con reducciones de dosis en esquemas de 4/2 y con reducciones
de dosis alcanzan una mayor PFS que aquellos que no tuvieron un ajuste de
dosis
1. Khosravan R, et al. ASCO-Genitourinary Cancers Symposium Annual Meeting 2012: Abstract 363
Fase III trial Fase II trial
Con reducción
de dosis
Sin reducción
de dosis
Con reducción
de dosis
Sin reducción
de dosis
n 194 181 51 95
Eventos, n (%) 107 (55.2) 104 (57.5) 28 (54.9) 58 (61.1)
Mediana PFS, meses
(95% CI)
14.0
(13.1‒16.2)
8.1
(6.3‒10.6)
13.4
(9.8‒19.8)
5.8
(3.9‒8.5)
Sunitinib
50 mg/day**
RECORD-3 trial
S
C
R
E
E
N
R
A
N
D
O
M
I
Z
E
*
Everolimus
10 mg/day
Sunitinib
50 mg/day**
Everolimus
10 mg/day
Study endpoints
Primary
•PFS 1st-line
Secondary
•Combined PFS
•ORR 1st-line
•OS
•Safety
1:1 Cross-over upon
progression
N=471 First-line Second-line
*Stratified by MSKCC prognostic factors; **4 weeks on, 2 weeks off.
Motzer RJ et al. ASCO 2013; Abstract 4504.
Median follow-up 22.7 months
RECORD-3 Trial Confirms first-line TKI
is better than mTOR inhibitor
The ESPN Trial
Nizar M. Tannir et al
SWITCH Phase 3 open-label study design
365 patients •mRCC unsuitable for
cytokines and no prior
systemic therapy
•Age >18 and ≤85 years
•ECOG PS 0/1
•≥1 measurable lesion
Sorafenib 400 mg
Twice daily
Sorafenib 400 mg
Twice daily
Sunitinib 50 mg
Once daily*
Sunitinib 50 mg
Once daily*
Primary
endpoint •Total PFS**
Progression
or
intolerable
toxicity
Randomization
1:1
Patients enrolled in Germany, Austria and The Netherlands
Stratified by MSKCC prognostic group (favourable or intermediate)
Efficacy assessed every 12 weeks (RECIST v1.0) and at treatment end***
Michel MS, Oral Presentation at ASCO GU 2014
SWITCH Study
Sunitinib base para la planificación de una secuencia
óptima en cáncer renal avanzado
Heng DYC. ASCO 2010
T size
1st Line 2nd Line
3rd Line
time
Sunitinib TKI / mTOR mTOR / TKI
OS P-value
Patients on >8 months
first-line treatment
14.3 months
p<0.0001, HR 1.53
(95%CI 1.09−2.13) Patients on <8 months
first-line treatment
9.9 months
Duration of first-line TTP predicts overall survival from second-line in an analysis of 1.084 pts
Experiencia Basada en estudios Comparativos
Sunitinib
1st-line 2nd-line (mSLP)
Axitinib (AXIS)
Everolimus (RECORD-1)
Sorafenib (AXIS/INTORSECT)
Temsirolimus (INTORSECT)
4.8 m
4.6 m
3.4 /3.9 m
4.3 m
3rd-line
Everolimus Dovitinib Sorafenib
4 m
SG: 30 m.
SG: 14-16 m. SG: 11 m.
Conclusiones: Sunitinib en 1ª línea de tratamiento
1. Representa el tratamiento con mayor grado de evidencia y
experiencia en pacientes con buen e intermedio pronóstico
2. Su efectividad se reproduce en la práctica clínica y en diferentes
grupos de pacientes
3. Prevención y manejo apropiado de los efectos adversos para
maximizar la duración del tratamiento y optimizar resultados
4. Sunitinib representa la piedra angular para el tratamiento integral
y el resultado global en pacientes con CCRm
Recommended