MANEJO EFICAZ DE LAS METÁSTASIS ÓSEAS EN EL PACIENTE CON CÁNCER: ACTUALIZACIÓN DE LA EVIDENCIA DE DENOSUMAB

Álvaro Rodríguez-LescureHospital General Universitario de ElcheHospital Vega Baja de Orihuela

BIOTECNOLOGÍA APLICADA AL TRATAMIENTO DEL CÁNCER

Henry DH, et al. J Clin Oncol 2011.

Henry et al

Primary Endpoint: TT1st SRE

Fizazi et al, Lancet 2011

Secondary Endpoint: TT 1st and subseq.SREs

Fizazi et al, Lancet 2011

Secondary Endpoints: DFS and OS

Fizazi et al, Lancet 2011

Estudio de extensión x 24 meses

Fizazi K, Brown JE, Carducci M. et al. ESMO 2012# 937P

•Cáncer de mama

•1 ó más mts óseas

•ECOG ≤2 A

•Cl Cr > 30 ml/min

1. TT 1st ERE (no inferioridad)

• TT 1st ERE (superioridad)

• TT 1st y subsiguientes EREs

• OS, PFS, Tasa de morbilidad ósea

• Marcadores de remodelado

• Seguridad y Tolerabilidad

N= 2049

Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Advanced Breast Cancer: A Randomized, Double-Blind Study Stopeck AT, et al. J Clin Oncol 2010

Denosumab 120 mg sc + placebo iv cada 4 semanas

Zoledronato 4 mg iv + placebo sc cada 4 semanas

CharacteristicZoledronic

acid (n = 1020)

Denosumab (n = 1026)

Women, n (%) 1011 (99) 1018 (99)

Post-menopausal, n (%) 831 (82) 839 (82)

Median (Q1, Q3) age, years 56 (49, 65) 57.0 (49, 65)

≥ 65 years, n (%) 266 (26) 275 (27)

ECOG status, n (%)

0 488 (48) 504 (49)

1 444 (44) 451 (44)

Prior SRE, n (%) 373 (37) 378 (37)Prior chemotherapy, n (%) 825 (81) 831 (81)

Prior hormonal therapy, n (%) 728 (71) 755 (74)

Hormone receptor positive, n (%) 726 (71) 740 (72)

Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Advanced Breast Cancer: A Randomized, Double-Blind Study Stopeck AT, et al. J Clin Oncol 2010

P = 0.004

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Zoledronic acid Denosumab

SREs

per

pati

ent p

er y

ear*

P = 0.004

22%

0.58

0.45

Tasa de morbilidad ósea

Beneficio de Denosumab

Kohno N et al. J Clin Oncol 2005;23:3314–21.

SREs

per

pati

ent p

er y

ear

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Placebo Zoledronic acid

1.10

0.63

Incidence of SREs

43%

SREs, Skeletal-Related Events.

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Zoledronic acid Denosumab

0.58

0.45

Incidence of SREs

22%

• Primary endpoint: time to first on-study SRE (non-inferiority)• Secondary endpoints: time to first on-study SRE (superiority);

time to first and subsequent on-study SRE; safety and tolerability

Supplemental calcium and vitamin D

†Per protocol and Zometa® label, IV product doseadjusted for baseline creatinine clearance and subsequent

dose intervals determined by serum creatinine.

Denosumab 120 mg SC Q4W+

Placebo IV Q4W†

Zoledronic acid 4 mg IV Q4W†

+ Placebo SC Q4W

Breast cancer1

Prostate cancer2

Other solid tumours*/MM3

A

Pre-

plan

ned

inte

grat

ed a

naly

sis4

(N =

572

3)

Baseline characteristic, n (%) or median Zoledronic acid(n = 2861)

Denosumab(n = 2862)

Women 1349 (47.2) 1316 (46.0)

Age, years 63.0 63.0

ECOG status of 0 or 1 2546 (89.0) 2585 (90.3)

Tumour type*

Breast 1020 (35.7) 1026 (35.8)

Prostate 951 (33.2) 950 (33.2)

Non-small cell lung 352 (12.3) 350 (12.2)

Multiple myeloma 93 (3.3) 87 (3.0)

Renal 85 (3.0) 70 (2.4)

Small cell lung 48 (1.7) 61 (2.1)

Other 312 (10.9) 318 (11.1)

Time from first bone metastasis to randomisation, months 2.30 2.17

Previous SRE† 1157 (40.4) 1112 (38.9)

HR = 0.83 (95% CI, 0.76–0.90)

P < 0.001 (superiority)

Time (months)

Patie

nts

with

out S

RE (%

)

0

40

60

80

100

0 6 12 18 24 30

27.66months

19.45months

90

70

50

30

20

10

Time to first on-study SRE

DenosumabZoledronic acid

(N = 5723)

Patient incidence, n (%) Zoledronic acid(n = 2836)

Denosumab(n = 2841)

Infectious AEs 1218 (42.9) 1233 (43.4)

Infectious serious AEs 309 (10.9) 329 (11.6)

Acute phase reactions (first 3 days) 572 (20.2) 246 (8.7)

Cumulative rate of ONJ 37 (1.3) 52 (1.8)

Year 1 15 (0.5) 22 (0.8)

Year 2 28 (1.0) 51 (1.8)

Hypocalcaemia 141 (5.0) 273 (9.6)

New primary malignancy 18 (0.6) 28 (1.0)

AEs leading to study discontinuation 280 (9.9) 270 (9.5)

Seguridad

Visión práctica de la eficacia

First on-study SRE, n Recurrent SREs, n

Tumour type

Zoledronic acid Denosumab NNT Zoledronic

acid Denosumab NNT

Breast cancer1 372 315 16 853 660 7

Prostate cancer2 386 341 10 943 780 5

Other solid tumours3 277 234 7.8 535 461 6.5

1. Martin M, et al. Clin Cancer Res 2012;18:4841−9;2. Miller K, et al. AUA 2011:abstract 648 (and oral presentation);3. Richardson G, et al. J Clin Oncol 2011;29(Suppl):abstract 9115

S u pe

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vi

n

nc

i

a

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i

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v

eDenosumab: ¿Algo más que EREs y masa ósea?

c

i

a

s

Libre de Metástasis

BMFS TT SYMPT BM

Smith et al. Lancet 2012

D-CARE

Para terminar…

• Denosumab es el nuevo estándar en la prevención de EREs.

• Disminuye significativamente el nº de eventos, la morbilidad ósea y aumenta la SLEREs

• Es más cómodo para el paciente• No precisa ajustes por insuficiencia renal• Bueno, bonito y …• …Probablemente barato.

GRACIAS