actualización en la primera línea de tratamiento en el ...732 25.5 vs. 13.1 8.4 vs. 4.9 18.3 vs....
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Actualización en la primera línea detratamiento en el Cáncer RenalAvanzado: agentes aprobados y
estudios en marcha
Hospital Universitario Central de AsturiasServicio de Oncología MédicaEmilio Esteban González
TRATAMIENTO CARCINOMA DE RIÑÓN
Choueiri TK et al. N Engl J Med 2017
EFICACIA TERAPÉUTICA EN 1ª LÍNEA
Pivotal trial N Response rate(%)
Median PFS(months)
Median OS(months)
Sunitinib vs. IFN-α1,2 750 47 vs. 12 11 vs. 5 26.4 vs. 21.8
Bevacizumab + IFN-α vs. IFN-α3–6649 31 vs. 12 10.4 vs. 5.5 23.3 vs. 21.3732 25.5 vs. 13.1 8.4 vs. 4.9 18.3 vs. 17.4
Pazopanib vs. placebo7,8 233 30 vs. 3 11.1 vs. 2.8 22.9 vs. 20.5Pazopanib vs. placebo7,8 233 30 vs. 3 11.1 vs. 2.8 22.9 vs. 20.5
Pazopanib vs. sunitinib9 1,110 31 vs. 25 8.4 vs. 9.5 28.4 vs. 29.3
Temsirolimus vs. IFN-α (poor risk)10 626 8.6 vs. 4.8 5.5 vs. 3.1* 10.9 vs. 7.3
1. Motzer RJ et al. N Engl J Med 2007;356:115–124; 2. Motzer RJ et al. J Clin Oncol 2009;27:3584–3590; 3. Escudier B, et al.Lancet. 2007;370:2103–11; 4. Escudier J Clin Oncol 2010 28:2144-50; 5. Rini B, et al. J Clin Oncol. 2008;26:5422-8; 6. Rini B,et al. J Clin Oncol. 2010 ;28:2137-43; 7. Sternberg C, et al. J Clin Oncol. 2010 20;28:1061-8; 8. Sternberg C, Eur J Cancer.2013 Apr;49(6):1287-96; 9. Motzer RJ, et al. N Engl J Med. 2013;369:722–31; 10. Hudes G, et al. N Engl J Med.2007;356(22):2271-81;
GUÍAS TERAPÉUTICA
• Objective: To compare first-line sunitinib and pazopanib in a population-based setting
• Data from 3,606 patients were compared
– Sunitinib (n=3,226)
– Pazopanib (n=380)
– Median follow-up: 43.5 months
• Objective: To compare first-line sunitinib and pazopanib in a population-based setting
• Data from 3,606 patients were compared
– Sunitinib (n=3,226)
– Pazopanib (n=380)
– Median follow-up: 43.5 months
Risk group, n (%) Sunitinib(n=3,226)
Pazopanib (n=380)
Favorable 440 (17.3) 72 (25)Intermediate 1414 (55.6) 153 (53)Poor 689 (27.1) 62 (22)
IMDC Risk Groups
IMDC = International Metastatic Renal Cell Carcinoma Database Consortium
Nº pacientes
89182545
Real life experience SUNITINIB.Patients outside EECC
Gore. BJC (2015) 1-8 DOI:10.1038/BJC.2015.196
4543 Patients
Individualised sunitinib treatmentAllocation of patients to dose and schedule during first and subsequent treatment cycles in
afirst-line Phase II study with sunitinib
≤Grade 1 toxicity:continue Rx
Toxicity evaluation after 4 weeks on first cycle
Grade 2 toxicityat 4 weeks:
stop Rx for 7 daysa
≤Grade 1 toxicityat 4 weeks:
stop Rx for 7 daysa
≥Grade 2 toxicitybefore 4 weeks:
stop Rx for 7 daysa
Toxicity evaluation after 2 weeks on first cycle (50 mg QD, intent to treat for 4 weeks)
≥Grade 2 toxicity:stop Rx for 7 daysa
Firs
t tre
atm
ent c
ycle
Bjarnason GA et al. Ann Oncol 2014;25(suppl 4):iv292.
aOr until toxicity has resolvedbIt is recommended that mRCC patients receiving sunitinib areinitiated on 50 mg/dayon a 4/2 schedule
Escalate dose/modify schedule
DL+1: 62.5 mg 14/7daysDL+2: 75.0 mg 14/7days
Reduce off-Rx timeto7 daysa
DL+: 50.0 mg28/7 days
Grade 2 toxicityat 4 weeks:
stop Rx for 7 daysa
≤Grade 1 toxicityat 4 weeks:
stop Rx for 7 daysa
≥Grade 2 toxicitybefore 4 weeks:
stop Rx for 7 daysa
Modify dose/scheduleb
DL−1: pa ents that cannot take 50 mg for 28 days50 mg individualised # of days/ 7 days offDL−2: pa ents that cannot take 50 mg for ≥7 days37.5 mg individualised # of days / 7 days offDL−3: pa ents that cannot take 37.5 mg for ≥7 days25 mg individualised # of days / 7 days off
Individually maximise days on Rx during continued therapy based on toxicity
Firs
t tre
atm
ent c
ycle
Subs
eque
nt c
ycle
Schedule 4/2 Schedule 2/1
FFS at 6 mo, % 44 63
Eligibility:-Treatment naïve patients ≥18 yearsof age with mRCC
Schedule 4/2
Schedule 2/1
1:1 Randomization basedon MSKCC score
n=38
n=38
Schedule 4/2 Schedule 2/1
Neutropenia(grade 3/4), %
61 37
ESTUDIO RESTORE: ESQUEMA 2/1 SUNITINIBRRE study:Randomized phase II trial of sunitinib four-week on and two-week off versus two-week onand one-week off in metastatic clear cell type renal cell carcinoma:
FFS at 6 mo, % 44 63
Median treatmentduration, mo (95% CI)
5.7 (5.0–6.5) 7.7 (3.0–12.3)
HR=0.54, 95% CI: 0.32–0.91,p=0.021
ORR, % 33 47
Median time-to-progression, mo
10.1 15.1
HR=0.69, 95% CI: 0.39–1.20
FFS=failure-free survival; ORR=objective response rate.
Lee JL, et al. American Society of Clinical Oncology Genitourinary Cancers Symposium. February 26–28, 2015.. Abstract 427
Neutropenia(grade 3/4), %
61 37
p=0.0368
Fatigue(all grade), %
83 58
p=0.0167
Mucositis(all grade), %
86 71
p=0.116
Hand-foot-syndrome (grade3/4), %
33 18
p=0.143
Rash (all grade), % 56 34
p=0.0648
Schedule(N=598)
Sunitinibindividualised(N=355)
Sunitinibstandard(N=151)
Pazopanibstandard(N=92)
Median age(range), years 64 (38–83) 63 (43–82) 66 (43–87)
KPS <80% 55/319 (17%) 26/145 (18%) 21/89 (24%)
Diagnosis totreatment <1 yr 181/355 (51%) 93/150 (62%) 44/92 (48%)
High neutrophils 21/310 (7%) 10/136 (7%) 10/81 (12%) 0.00
0.25
0.50
0.75
1.00
Overall survival Sunitinib individualisedSunitinib standardPazopanib standard
Surv
ivin
g p
ropo
rtio
n
Median OS*37.9 months22.3 months19.6 months
*p<0.001 for SI vsSS, SI vs PS
High neutrophils 21/310 (7%) 10/136 (7%) 10/81 (12%)
High platelets 20/314 (7%) 17/139 (14%) 8/82 (11%)
Low Hb 140/305 (46%) 68/129 (53%) 40/81 (49%)
High calcium 41/242 (12%) 22/110 (20%) 10/65 (15%)
IDMC criteria:Favourab
leIntermedi
atePoor
25%57%17%
17%62%20%
25%54%21%
Nephrectomy 315/355 (89%) 126/151 (83%) 78/92 (85%)
1. Basappa N, et al. J Clin Oncol 2017;35(suppl 6S; abstract 468)
0Time to death (months)
0.00 20 40 60
Surv
ivin
g p
ropo
rtio
n
0
Time to failure (months)
0.00
0.25
0.50
0.75
1.00
20 40 60
Time-to-treatment failure
Surv
ivin
g p
ropo
rtio
n
Median TTF*12.9 months5.6 months7.0 months
*p<0.001 for SI vsSS, SI vs PS
Sunitinib individualisedSunitinib standardPazopanib standard
PAPEL DE SUNITINIBHISTOLOGÍA NO CÉLULA CLARA
Metaanalysis
Fernández-Pello S, et al. Eur Urol 2017
PRIMERA LÍNEA: ESTUDIO CABOSUN
Alternative hypothesis HR 0.67favoring cabozantinib123 events Power 85%
CARÁCTERÍSTICAS DE LOS PACIENTES
SUPERVIVENCIA LIBRE DE PROGRESIÓN (PFS)
ModulaciónInmunológica
ActivaImmunoterapia
Induction, enhancement orsuppression of the immune system
Relies on the immune systemto function
PasivaImmunoterapia
Immunologically active agent that isexternally derived and does not relyon the recipient’s immune system
to function
• Non-specific• Cytokines• Immune-modulating Abs• Tumour cell/lysate
immunotherapy• Antigen-specific
INMUNOTERAPIA
Cytokines
Immunomodulatorantibodies
Vaccines
AdjuvantsAdoptiveimmunotherapyMonoclonal antibodiesAdoptive T cell transfer
• Non-specific• Cytokines• Immune-modulating Abs• Tumour cell/lysate
immunotherapy• Antigen-specific
Estudios en CRa con VacunasEligibility criteria: Metastatic and/or locally
advanced ccRCC Favourable/intermediate
risk HLA-A*02-positive No prior systemic
therapy
IMA901 + GM-CSF +sunitinib
RANDOMISED
IMPRINT randomisedPhase III trial
N=330
SunitinibSunitinib
Study completion: July 2015
IMPRINT STUDY
ADAPT study trial highlights. Available at: http://adaptkidneycancer.com. Accessed September 19, 2014;www.clinicaltrials.gov (NCT01582672); www.clinicaltrials.gov (NCT01265901)
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
Sunitinib + AGS-003Sunitinib + AGS-003
SunitinibSunitinib
Diagnosis of advancedkidney cancer
Diagnosis of advancedkidney cancer
SurgeryTumour sample taken
SurgeryTumour sample taken
ADAPT randomisedPhase III trial
N=450
RANDOMISED
Study completion: April 2016
ADAPT STUDY
IMPRINT:Sunitinib +/- IMA-901 vaccine in mRCC
PFS OS
Prog
ress
ion-
free
sur
viva
l (%
)
50
75
100
Prog
ress
ion-
free
sur
viva
l (%
)
50
75
100mPFS according to blinded,independent central review:•Sunitinib plus IMA90115.22 months•Sunitinib alone15.12 months
OS:•Sunitinib plus IMA90133.17 months•Sunitinib = not reached
IMA-901 vaccination failed to improve outcomes in mRCC(even worse, there was a trend for harm)
0
Prog
ress
ion-
free
sur
viva
l (%
)
0
25
6 12 18 24 30No. at Risk
(no. censored)Sunitinib
Sunitinib plusIMA901
135 (0)204 (0)
100 (10)138 (26)
68 (15)87 (45)
25 (46)33 (81)
1 (105)
SunitinibSunitinib plus IMA901
HR 1.05 (95% CI 0.77–1.43)
0
Prog
ress
ion-
free
sur
viva
l (%
)
0
25
6 12 18 24 30No. at Risk
(no. censored)Sunitinib
Sunitinib plusIMA901
135 (0)204 (0)
122 (1)185 (4)
111 (1)155 (4)
102 (2)139 (6)
SunitinibSunitinib plus IMA901
HR 1.34 (95% CI 0.96–1.86); p=0.087
36 42 48
92 (3)121 (6)
67 (21)78 (36)
14 (67)23 (82)
2 (79)3 (100)
1. Rini BI, et al. Lancet Oncol 2016;17(11):1599–611.
ADAPT: Press release 22nd February 2017
https://globenewswire.com/news-release/2017/02/22/926327/0/en/Independent-Data-Monitoring-Committee-Recommends-Discontinuation-of-the-ADAPT-Phase-3-Clinical-Trial-of-Rocapuldencel-T-in-Metastatic-Renal-Cell-Carcinoma-for-Futility-Following-It.html [Accessed March 2017]
Phase II IMmotion 150 (RAPID):Study design
PFS per RECIST v.1.1 viaindependent review in ITTpatients and patients with PD-L1 expression on ≥1%a ofimmune cellsb
PFS per investigatorassessment perimmune-related criteriaORR; DoR, OSDOR, ORR and PFS in patientsprogressing on sunitinib- andatezolizumab-alone arms whosubsequently cross over tocombinationSafetyPK of atezolizumab alone and incombination with bevacizumab
Atezolizumab1200 mg IV Q3W +
bevacizumab15 mg/kg IV Q3W
RANDOMISATION
Locally advanced ormetastatic RCCwith clear-celland/or sarcomatoidcomponentNo prior systemictherapyKarnofsky PS ≥70
Objective: To evaluate the efficacy and safety of atezolizumab as monotherapy or incombination with bevacizumab vs sunitinib in patients with previously untreatedlocally advanced or metastatic RCC
PFS per RECIST v.1.1 viaindependent review in ITTpatients and patients with PD-L1 expression on ≥1%a ofimmune cellsb
PFS per investigatorassessment perimmune-related criteriaORR; DoR, OSDOR, ORR and PFS in patientsprogressing on sunitinib- andatezolizumab-alone arms whosubsequently cross over tocombinationSafetyPK of atezolizumab alone and incombination with bevacizumab
Atezolizumab1200 mg IV Q3W +
bevacizumab15 mg/kg IV Q3W
Sunitinib50 mg/day
4/2 schedule
Atezolizumab1200 mg IV Q3W
RANDOMISATION
N=305
Locally advanced ormetastatic RCCwith clear-celland/or sarcomatoidcomponentNo prior systemictherapyKarnofsky PS ≥70
aAmended from ≥5% to ≥1% of immune cells based on Phase Ia data; bSecond co-primary endpoint added after interim analysis.Following disease progression, patients in either of the monotherapy groups will be given the option to receive combination treatment.DoR, duration of response; IRC, independent review committee; ITT, intent to treat; ORR, objective response rate; OS, overall survival;PD-L1, programmed death-ligand 1; PFS, progression-free survival; PK, pharmacokinetic; PS, performance status; Q3W, every 3 weeks;RECIST, Response Evaluable Criteria In Solid Tumours. See slide notes for stratification information.www.clinicaltrials.gov (NCT01984242) (last accessed January 2017); McDermott DF, et al. Presented at ASCO GU 2017.
RESULTADOS DEL RAPID
14,7 (3-13)5,5 (3-13)7,8 (3-11)
RESULTADOS DEL RAPIDCARACTERIZACIÓN MOLECULAR
RESULTADOS DEL RAPID
Estudios de Inmunoterapia en marcha(4143 pacientes)
Checkmate214 – NCT02231749:Combination PD-1 + CTLA-4
inhibition1
IMmotion151 – NCT02420821:Combination PD-L1 + VEGF
inhibition4
Javelin Renal 101 – NCT02684006:Combination PD-L1 + VEGFR TK
inhibition2
Powered for intermediate and poor risk
RANDOMISATION RANDOMISATIONRANDOMISATION
Nivolumab+
ipilimumabSunitinib SunitinibAvelumab +
axitinibAtezolizumab
+bevacizumab
Sunitinib
1. www.clinicaltrials.gov (NCT02231749);2. www.clinicaltrials.gov (NCT02684006);3. www.clinicaltrials.gov (NCT02853331); 4. www.clinicaltrials.gov (NCT02420821);
5. www.clinicaltrials.gov (NCT02811861) [All accessed April 2017].
Keynote426 – NCT02853331:Combination PD-1 + VEGFR TK
inhibition3
Nivolumab+
ipilimumabSunitinib SunitinibAvelumab +
axitinibAtezolizumab
+bevacizumab
Sunitinib
SunitinibPembrolizumab+ axitinib
CLEAR – NCT02811861:Combination VEGFR TK +mTOR / PD-1 inhibition5
RANDOMISATION
SunitinibLenvatinib +pembrolizumab
Lenvatinib+
everolimus
Actualización en la primera línea de tratamiento en elCáncer Renal Avanzado
Conclusiones
• El tratamiento anti-angiogénico debe seguir siendo de elección
• SUNITINIB es considerado como agente de referencia comparadory continúa mejorando los resultados terapéuticos optimizando suesquema de administración
• La caracterización molecular e identificación de biomarcadorespredictivos es esencial para planificar el tratamiento masadecuado y mejor secuencia o combinación con la inmunoterapia
• El tratamiento anti-angiogénico debe seguir siendo de elección
• SUNITINIB es considerado como agente de referencia comparadory continúa mejorando los resultados terapéuticos optimizando suesquema de administración
• La caracterización molecular e identificación de biomarcadorespredictivos es esencial para planificar el tratamiento masadecuado y mejor secuencia o combinación con la inmunoterapia