BIOTECNOLOGÍA APLICADA AL TRATAMIENTO DEL CÁNCER MANEJO EFICAZ DE LAS METÁSTASIS ÓSEAS EN EL PACIENTE CON CÁNCER: ACTUALIZACIÓN DE LA EVIDENCIA DE DENOSUMAB Álvaro Rodríguez-Lescure Hospital General Universitario de Elche Hospital Vega Baja de Orihuela

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

Denosumab 120 mg sc + placebo iv cada 4 semanas 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 Cáncer de mama 1 ó más mts óseas ECOG ≤2 A Cl Cr > 30 ml/min Denosumab 120 mg sc + placebo iv cada 4 semanas N= 2049 Zoledronato 4 mg iv + placebo sc cada 4 semanas 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

Stopeck AT, et al. J Clin Oncol 2010 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 Characteristic Zoledronic 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 (%) 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)

Tasa de morbilidad ósea P = 0.004 0.1 0.2 0.3 0.4 0.5 0.6 0.7 Zoledronic acid Denosumab SREs per patient per year* 22% 0.58 0.45

Beneficio de Denosumab DMO-IHQ-AMG-551-2011 05/2011 Beneficio de Denosumab Incidence of SREs 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% 1.2 1.10 1.0 43% 0.8 0.63 SREs per patient per year 0.6 . 0.4 0.2 0.0 Placebo Zoledronic acid SREs, Skeletal-Related Events. Kohno N et al. J Clin Oncol 2005;23:3314–21.

Pre-planned integrated analysis4 (N = 5723) Other solid tumours*/MM3 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 A Breast cancer1 Denosumab 120 mg SC Q4W + Placebo IV Q4W† Prostate cancer2 Pre-planned integrated analysis4 (N = 5723) Supplemental calcium and vitamin D Zoledronic acid 4 mg IV Q4W† + Placebo SC Q4W Other solid tumours*/MM3 †Per protocol and Zometa® label, IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine.

Baseline characteristic, n (%) or median Zoledronic acid (n = 2861) Denosumab (n = 2862) Women 1349 (47.2) 1316 (46.0) Age, years 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)

Patients without SRE (%) HR = 0.83 (95% CI, 0.76–0.90) P < 0.001 (superiority) Time (months) Patients without SRE (%) 40 60 80 100 6 12 18 24 30 27.66 months 19.45 months 90 70 50 20 10 Time to first on-study SRE Denosumab Zoledronic acid (N = 5723)

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

Visión práctica de la eficacia First on-study SRE, n Recurrent SREs, n Tumour type 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

d i e n c p S u a e Libre de Metástasis e v v E i n a r i s c i v Denosumab: ¿Algo más que EREs y masa ósea? d i e n c p S u a e Libre de Metástasis e v v E i n a r i s c i v

Smith et al. Lancet 2012 BMFS TT SYMPT BM

D-CARE

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

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