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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nc
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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