1ª línea tratamiento: avanzando desde la experiencia Sunitinib

1ªlíneatratamiento:avanzandodesde
laexperiencia
Sunitinib
HospitalCentraldeAsturias
ServiciodeOncologíaMédica
EmilioEstebanGonzález
2006-2012:
CambioeneltratamientodelCarcinomadeRiñón
Avanzado(CRA)
ApprovedagentsinRCC
Sorafenib(US2005,EU2006)3,4
SuniQnib(US&EU2006)3,4
High-doseIL-2approvedintheUS(1995).High
treatment-relatedtoxicity;smallnumberof
durableresponses2
Temsirolimusand
BevacizumabplusIFN
(US&EU2007)3,4
AxiQnib(US&EU2009)
Early1940s:
experimentswith
cytotoxicchemotherapy1
Early1980s:IFN-αandhigh-doseIL-2usedforRCC
treatment
Everolimus
(US&EU2009)3,4
CabozanQnib
Nivolumab
2015
Pazopanib
(US2009,EU2010)3,4
1.AbeloffMD,etal.ClinicalOncology4thed.Philadelphia,PA.2.CoppinC,etal.CochraneDatabaseSystRev2005;1:CD0014253.U.S.FoodandDrugAdministraQon
(www.accessdata.fda.gov).4.EuropeanMedicinesAgency(hVp://www.ema.europa.eu/)
TratamientoanQangiogénico
Resultados1ªLíneaCRA
Histología y grupo pronóstico
Nº Pts
ORR (%)
Mediana SLP
(meses)
Mediana SG
(meses)
Célula clara y favorableintermedio pronóstico
Sunitinib vs IFN-α (3)
750
47 vs 12
11 vs 5
26,4 vs 21,8
Bevacizumab+ IFN-α vs IFN-α (4)
649
31 vs 12
10 vs 5.5
23., vs 21,3
Bevacizumab+ IFN-α vs IFN-α(5)
732
25.5 vs 13
8,4 vs 4,5
18. vs 17
Pazopanib vs Placebo (6)
233
32 vs 4
11 vs 2,8
22,9 vs 20,5
Pazopanib vs Sunitinib (7)
1110
33 vs 29
8,4 vs 9,5
28,4 vs 29,3
626
8,6 vs 4,8
5,5 vs 3,1
10,9 vs 7,3
Guías y Recomendaciones
SEOM (1)
Categoría y
Evidencia
ESMO (2)
Nivel y grado
Evidencia
1A
Sunitinib
I,A
Sunitinib
1A
Bevacizumab
+ IFN
I,A
Bevacizumab+
IFN
1B
Pazopanib
I,A
Pazopanib
1A
Temsirolimus
II,A
Temsirolimus
Predominante célula no clara y
Mal pronóstico
Temsirolimus vs IFN-α (8)
(1)J.Bellmuntetal..SEOM.ClinTranslOncolDOI10.1007/s12094-014-1219-1.(2)Escudieretal,ESMO.AnnOncol2014;25(suppl3):49-56.
(3).Motzeretal.NEnglJMed2007;356(2):115–124.(4).EscudierBetal,Lancet2007;370:2103-2111.(6)SternbergCNetal.JClinOncol.2010;28(6):1061-1068.(7)Motzer
RJetal.NEnglJMed.2013;369(8):722-731.(8)HudesGetal.NEnglJMed2007;356(22):2271–2281.
¿Quéhemosaprendidoconlaexperienciade10años?
Ø MejorSecuenciadetratamiento
Ø Poblaciónnoseleccionadaehistologíanocélulaclara
Ø OpQmizacióndeltratamiento
Ø Perfildetoxicidad
Ø Esquemadetratamiento
Ø Largossupervivientes
EstudioRECORD-3
Study endpoints
Sunitinib
50 mg/day**
Primary
• PFS 1st-line
Cross-over upon
progression
1:1
Secondary
• Combined PFS
• ORR 1st-line
• OS
• Safety
Sunitinib
50 mg/day**
N=471
First-line
Second-line
Median follow-up 22.7 months
*Stratified by MSKCC prognostic factors; **4 weeks on, 2 weeks off.
Motzer RJ, et al. ASCO 2013; Abstract 4504.
EstudioSWITCH
SWITCH:Resultados
365 patients
• mRCC unsuitable for
cytokines and no prior
systemic therapy
• Age >18 and !85 years
• ECOG PS 0/1
• "1 measurable lesion
Sorafenib
Sunitinib
400 mg
Twice daily
50 mg
Once daily*
Randomization
1:1
Sunitinib
50 mg
Once daily*
Progression
or
intolerable
toxicity
Primary
endpoint
• Total PFS**
Sorafenib
400 mg
Twice daily
! 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***
CómoinfluyeelfármacouQlizadoenprimeralíneaenla
SLPdelostratamientossubsiguientes
EstudioMETEOR.Powles,ASCO2016.Abstract4557
Experienciaenlavidareal.
PacientesfueradelosEECC
Gore.BJC(2015)1-8DOI:10.1038/BJC.2015.196
4543
Pacientes
¿Podemosmejoraraúnmás?
(vsIFN-α)1,2
(COMPARZ)3†
(RECORD3)4
(EAP)5
(EAP: CEE)6
(EAP:
Spanish data)7
(EAP:
Italiandata)8
Vidareal
Finalanalysesandinves_gatorreviewunlessotherwisestated;†independentreview
CEE,CentralandEasternEuropeancountries;EAP,expanded-accessprogramme;IFN-α,interferonalpha
1.MotzerRJetal.NEnglJMed2007;356:115–124;2.MotzerRJetal.JClinOncol2009;27:3584–3590;3.MotzerRJetal.NEnglJMed2013;369:722–731;4.MotzerRJetal.JClinOncol
2014;32:2765–2772;5.GoreMEetal.BrJCancer2015;113:12–19;6.VrdoljakEetal.
PatholOncolRes2015;21:775–782;7.CastellanoDetal.ESMO2013;Abstract2772;8.SternbergCNetal.Oncology2015;88:273–280
Suni_nibenHistologíaNoCélulaClara
ASCO 2015 - Armstrong et al, Abstract 4507
Resultados finales de un estudio aleatorizado fase II internacional de
everolimus vs. sunitinib en pacientes con CCRm no células claras (ASPEN)
(IIR)
•  Métodos
•  Objetivos
‒  ASPEN es el mayor estudio aleatorizado hasta la fecha en CCR no células claras con
intención de informar sobre la práctica clínica y desarrollar biomarcadores
predictivos.
http://abstracts.asco.org/156/AbstView_156_149050.html
TresFactoresatenerencuentaen
losresultados
Dosis
Eficacia
Óptima
Manejo Efectos
Secundarios
Duración
Tratamiento
SUNITINIBYEXPOSICIONALADROGARELACIÓNCONRESULTADOS
Timetotumourprogression
Overallsurvival
HighAUCSS(n=67)
LowAUCSS(n=79)
1.0
1.0
0.8
OSprobability
TTPprobability
0.8
HighAUCSS(n=67)
LowAUCSS(n=79)
0.6
0.4
0.6
0.4
0.2
0.2
0
0
0
100
200 300
Time(days)
400
500
0 100 200 300 400 500 600
Time(days)
EFECTOS ADVERSOS TODOS LOS GRADOS*
Efectos adversos que decrecen
• 
• 
• 
• 
• 
• 
Fatiga
HTA
Diarrea
Anorexia
Dispepsia
Estomatitis
Efectos adversos que decrecen en
el 2º año un poco pero
permanecen estables a partir de
los 2-3 años:
• 
• 
• 
• 
Síndrome mano-pie
Mucositis
Disgeusia
Náuseas
Efecto adverso que crece en frecuencia:
Hipotiroidismo
(desde el 14% al 36%)
* Que aparecen en al menos el 15% de los pacientes
Portaetal.LongTermSafetyofSuni_nibinmetasta_cRCC.EuropeanUrology.(2015)sept.Doi:org.10.1016/j.eururo.2015.07.006
PerfildeToxicidadcomopredictorde
Ac_vidad
181 consecutive mRCC patients treated with sunitinib1
41 mRCC patients treated with sunitinib2
*
**
**
**
(n=60)
(n=121)
Hypertension
Grade ≥2
*p=0.042; **p<0.0001
(n=88)
(n=92)
Neutropenia
Grade ≥2
(n=135)
(n=45)
Thrombocytopenia
Grade ≥1
(n=7)
(n=34)
Hypothyroidism
Grade ≥2
Esquemaytoxicidad
•  EsquemaalternaQvo37,5mg/díasindescanso.
•  Reduccionesdedosisentramosde12.5mg
(37.5mg25mg)
•  EsquemaalternaQvodedescanso2semanas
ac_vas/1semanadedescansocon50mg/día.
EstudioEFFECT:
37,5mgcon_nuovs4/2
22
21
Time to Deterioration
Composite endpoint: death, progression or FKSI-DRS decrease ≥3 points (MID)
1.0
Schedule 4/2 (N=146)
Median, 4.0 months
(95% CI, 2.8–5.4)
Eligibility Criteria
(N=146)
Sunitinib 50 mg/d
on Schedule 4/2
2-year
survival
Between January
2007 and June 2008, follow-up
292 patients were
randomized*
(N=146)
1:1 randomization
stratified by risk factors
based on published
MSKCC data
[Motzer, 2002]
Sunitinib 37.5 mg/d
on CDD Schedule
0.8
CDD Schedule (N=146)
Median, 2.9 months
(95% CI, 2.3–4.0)
0.6
Proportion of patients
R
A
•  Clear-cell locally
N
recurrent or
D
metastatic RCC
O
•  Measurable disease
(N=292) M
(RECIST)
I
•  No prior systemic
Z
therapy for
A
advanced RCC
T
I
•  Karnofsky
O
performance status
N
≥70%
0.4
HR, 0.77
(95% CI, 0.60–0.98)
P=0.034 (unstratified log-rank test)
0.2
0.0
0
10
20
Time to composite endpoint (months)
30
40
Esquema50mg2/1vs4/2
Actividad Antitumoral
Authors, year
Schedule(s)
Perfil de toxicidad con respecto al esquema 4/2
Efficacy
N
ORR (%)
mPFS (months)
AE (%)
All grades
mOS (months)
Grade ≥3
Gyergyay et al. 20091
4/2 → 2/1
14
–
–
–
Neri et al. 20132
4/2 → 2/1
or 2/1
31
42
16.4
18.1
32 →
Atkinson et al. 20143
4/2 vs 4/2 → 2/1 or 2/1 187
Bjarnason et al. 20144
4/2 vs 4/2 →2/1→ 1/1
172 15.8 vs 18.0 vs 21.0
vs CDD
–
4.3 vs 14.5
NA
5.3 vs 10.9 vs 11.9
180
–
4 vs 10 vs 9
Kondo et al. 20146
4/2 vs 2/1
48
50 vs 32
9.1 vs 18.4
–
Najjar et al. 20147
4/2 → 2/1
30
–
–
–
Togo et al. 20148
2/1
24
8
–
–
4/2 → 2/1
45
–
–
–
2/1
37
–
–
75.1
4/2 → 2/1 vs 2/1 vs 4/2 249
–
30.2 vs 10.4 vs 9.7
Bracarda et al. 201511
Bracada
(RAINBOW)
4/2 → 2/1
(n=208)3
Miyake
4/2 → 2/1
(n=45)4
40 → 37
41.8 → 37.5
60 → 50
20 →
3.9 →
2.2 →
3
0
0
15.4 vs 23.4 vs 24.5
4/2 vs 2/1 vs CDD
Schmidinger et al. 201510
6
Najjar
4/2 → 2/1
(n=30)2
17.7 vs 33.0 Diarrhoea
Cheng et al. 20145
Miyake et al. 20159
Atkinson
4/2 → 2/1
(n=63)1
9 vs 23 vs 13 Fatigue
64 →
29
NA
10 →
5
70 → 53
74.5 → 63.7
51.1 → 28.9
37 →
10.1 →
17.8 → 8.9
7
0
27 → 27
45.7 → 26.0
55.6 → 35.6
20 →
7
9.1 → 2.4
11.1 → 2.2
50 → 17
55.8 → 41.4
55.6 → 33.3
27 →
10.1 → 3.4
11.1 → 2.2
Hypertension
Hand–foot
NR vs 23.2 vs 27.8syndrome
NA
38 →
NA
10
0
1. Gyergyay et al. J Clin Oncol 2009; 2. Neri et al. Int J Urol 2013; 3. Atkinson et al. J Urol 2014; 4. Bjarnason et al. Urol Oncol 2014; 5. Cheng et al. J Clin
Oncol 2014; 6. Kondo et al. Jpn J Clin Oncol 2014; 7. Najjar et al. Eur J Cancer 2014; 8. Togo et al. Hinyokika Kiyo 2014; 9. Miyake et al. Med Oncol 2015;
10. Schmidinger et al. J Clin Oncol 2015; 11. Bracarda et al. Ann Oncol 2015
1. Atkinson et al. J Urol 2014; 2. Najjar et al. Eur J Cancer 2014; 3. Bracarda et al. Annals Oncol 2015; 4. Miyake et al. Med Oncol 2015
Esimportantemanteneralospacientesentratamientoconsuni9nib
mientrashayabeneficioclínico
LosrespondedorestardíosaSuniQnibcuatriplicanelQempodesupervivencialibredeprogresión
(PFS)respectoalosnorespondedores
38% Respuesta Objetiva =
Respuesta Completa +
Respuesta Parcial
Semana 6
26%
Semana 12
61%
Semana 18
79%
Semana 24
86%
Semana >24
100%
61%
39%
1059 Pacientes
tratados con Sunitinib
En EECC
Respondedores
precoces
Respondedores
tardíos
62% Enfermedad Estable +
Progresión de la Enfermedad
Supervivencia libre de progresión:
13.8 meses
Supervivencia libre de progresión :
20.2 meses
USO INTERNO
EXCLUSIVO
Molina A.M et al. Sunitinib objetive response in metastasic
renal cell carcinoma:
Analysis of 1059 patients treated on clinical trials,
Eur J Cancer (2013) http://dx.doi.org/10.1016/j.ejca.2013.08.021
Umbral Terapéutico CRA 1ª Línea
Umbral Terapéutico CRa
Sunitinib como base de inicio en 1ª Línea
32 months
Median OS (Months)
30
19–26
25
*
*
2014
SWITCH
Sequencing
2013
RECORD-3
Sequencing
@-#1(&'4"#))<'#'4"#)-+)-#&14%"#)3";$'.'A,"#)
1st-line
2nd-line (mSLP)
0B%A+%<)C0DE2F)
3rd-line
4.8 m
N);)
20
15
:,-."(%;1#)C@:/5@GHIF)
13
10
21+%A+%<)
M-;#%."(%;1#)CELM5@2:/MF)
4.6 m
4.3 m
5
:,-."(%;1#)
)G",%A+%<)
2".'J-+%<)
0
Interferon era
TKIs period
Escudier B, et al. Lancet 2007; Motzer RJ, et al. J Clin Oncol 2009; Motzer ASCO 2013
2".'J-+%<)C0DE2KELM5@2:/MF)
3.4 /3.9 m
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$$$$$$$$!"#$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$&&$'(
SuniQnib,comparadorgoldestándarenlosensayos
clínicosrecientes
Agent
Phase
Intervention
III
Nivolumab + ipilimumab vs sunitinib (CheckMate 214)
(NCT02231749)
II
Atezolizumab ± bevacizumab vs sunitinib (RAPID) (NCT01984242)
III
Atezolizumab + bevacizumab vs sunitinib (IMmotion) (NCT02420821)
III
Avelumab+axiQnibvssuniQnib(JAVELINRenal101)(NCT02684006)
III
AGS-003 + sunitinib vs sunitinib (ADAPT) (NCT01582672)
Cabozantinib
II
Cabozantinib vs sunitinib (CABOSUN) (NCT01835158)
Anlotinib
II
Anlotinib vs sunitinib (NCT02072031)
Anti-PD1
Nivolumab
Anti-PD-L1
Atezolizumab
Avelumab
Cancer vaccines
AGS-003
Other
Estudios en CRa con Vacunas
Eligibility criteria:
§ 
Metastatic and/or locally
advanced ccRCC
§ 
Favourable/intermediate
risk HLA-A*02-positive
§ 
N=330
No prior systemic
therapy
Diagnosis of advanced
kidney cancer
Surgery
Tumour sample taken
N=450
R
A
N
D
O
M
I
S
E
D
R
A
N
D
O
M
I
S
E
D
IMA901 + GM-CSF +
sunitinib
Sunitinib
IMPRINT randomised
Phase III trial
Study completion: July 2015
Sunitinib + AGS-003
ADAPT randomised
Phase III trial
Sunitinib
Study completion: April 2016
AGS-003, autonomous dendritic cell product; ccRCC, clear cell renal cell carcinoma;
GM-CSF, granulocyte macrophage colony-stimulating factor; IMA901, consists of
multiple tumour-associated peptides; SOC, standard of care
ADAPT study trial highlights. Available at: http://adaptkidneycancer.com. Accessed September 19, 2014;
www.clinicaltrials.gov (NCT01582672); www.clinicaltrials.gov (NCT01265901)
ESTUDIOIMPRINT
Overall Survival (0S)
!"#$%&'&$()'*+,-./*-+
R
A
Eligibility:
N
• Advanced/mRCC with
D
clear-cell histology
O
M
• No prior systemic
I
therapy
N=330
S
• Candidate for treatment
A
with sunitinib
T
• Favourable/
I
intermediate-risk
O
N
Favorable
IMA901 plus GM-CSF
added to sunitinib*
All patients
HR: 1.34; p = 0.08*
Con: 33.7 mo
Vac: n.r.
Sunitinib
KLM=).4.#<#$=.,J.*G&%N&%CH.%&()'>=);'$.-'##%&'N,&*.!%(O.PQL834.?$G*.RQE1BI.'*.'>SG-'&(.!%$$.C=.'??$%=>.J,).'.
?=)%,>.,J.T.;,&(O*.!O%$=.#,&N&G%&+.()='(;=&(.!%(O.*G&%N&%C.
• :)%;')<.=&>?,%&(*@.AB.
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)=*?,&*=H.*'J=(<.'&>.(,$=)'C%$%(<H.#=$$G$').%;;G&,;,&%(,)%&+.
!!!"#$%&%#'$()%'$*"+,-.
/012345678349.
HR: 0.82; p = 0.59**
Intermediate
Con: Median OS: n.r.
HR: 1.52; p < 0.05**
Vac: Median OS: 33.1 mo
Con: n.r.
Vac: 27.8 mo
n.r. = not reached
*log Rank stratified on risk group
**unstratified log Rank
0'('+!"#$%&#'((+1234#
1ªlíneaavanzadacarcinomaderiñón
desdelaexperienciadesuniQnib
•  SuniQnib sigue demostrando la evidencia más robusta de
beneficioterapéuQcoparapacientesconCRAconhistologíade
célula clara y no clara considerados de buen e intermedio
pronósQco
•  LaeficaciaterapéuQcasebasaenunaopQmauQlizacióndela
dosis/esquemayduracióndeltratamiento
•  El reto presente: La opQmización de la anQ-angiogénesis e
inmunoterapia