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