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