denosumab vs bisfosfonato en metástasis óseas
TRANSCRIPT
Bifosfonatos Vs. Denosumab para el manejo de enfermedad metastásica
ósea
Mauricio Lema Medina MD
Clínica de Oncología Astorga / Clínica SOMA - Medellín, Colombia
Barranquilla, 29.10.2016
Bifosfonatos Vs. Denosumab para el manejo de enfermedad metastásica
ósea Mauricio Lema Medina
@onconerd
Conflict of interest: I own a (smaller than I would like) part of an infusional center. Therefore, non-IV
agents put me out-of-business
Mauricio Lema Medina
The Majority of Patients With Advanced Breast and Prostate Cancer Are Likely to Get Bone Metastases
SREs Are Clinically Significant and Serious Consequences of Bone Metastases
SREs Are Both a Common and Frequent Problem for Patients With Advanced Cancer Untreated for
Bone Metastases
1. Lipton A, et al. Cancer. 2000;88:1082-1090. 2. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882. 3. Rosen LS, et al. Cancer. 2004;100:2613-2621. 4. Saad F, et al. Clin Prostate Cancer. 2005;4:31-37
With Improvements in Survival, Patients Are More Likely to Experience an SRE
1. Lipton A, et al. Cancer 2000;88:1082-1090. 2. Miller K, et al. N Engl J Med. 2007;357:2666-2676. 3. Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468. 4. Kantoff PW, et al. N Engl J Med. 2010;363;411-422. 5. Rosen LS, et al. Cancer. 2004;100:2613-2621. 6. Sandler A, et al. N Engl J Med. 2006;355:2542-2550.
RANK Ligand Is an Essential Mediator of the Vicious Cycle of Bone Destruction
Roodman, GD. N Engl J Med. 2004;350:1655-1664.
Denosumab: From Bench to Bedside
OPG = osteoprotegerin.1. ClinicalTrials.gov. Available at: http://clinicaltrials.gov. Accessed Nov 20, 2010. 2. Anderson DM, et al. Nature. 1997;390:175-179. 3. Simonet WS, et al. Cell. 1997;89:309-319. 4. Lacey DL, et al. Cell. 1998;93:165-176. 5. Yasuda H, et al. Proc Natl Acad Sci U S A. 1998;95:3597-3602. 6. Bekker, PJ, et al. J Bone Miner Res. 2004;19:1059-1066.
Denosumab
Denosumab: Targets and Inhibits RANK Ligand to Break the Vicious Cycle of Bone Destruction and
Prevents SREs
Roodman, GD. N Engl J Med. 2004;350:1655-1664.
Is denosumab MORE effective than bisphosphonates in
(relevant outcomes of bone metastases) in solid tumors?
Is denosumab SAFER than bisphosphonates metastatic
bone disease in solid tumors?
Is denosumab COST-EFFECTIVE when compared to (active)
bisphosphonates in solid tumors?
Three Identically Designed Head-to-Head Studies Comparing Denosumab vs Zoledronic Acid Enables
a Prespecified Intregated Analysis
*Daily supplementation of calcium 500 mg and vitamin D 400 IU recommended. 1. XGEVATM (denosumab) prescribing information, Amgen. 2. Data on file, Amgen. 3. Lipton A, et al. Ann Oncol. 2010;21(suppl 8):382. Abstract 1249 and poster.
J Clin Oncol 28:5132-5139. © 2010J Clin Oncol 29:1125-1132. © 2011
Lancet 2011; 377: 813–22
Three Identically Designed Head-to-Head Studies Comparing Denosumab vs Zoledronic Acid Enables
a Prespecified Intregated Analysis
SREs in this study were defined as either pathologic fracture, surgery to bone, radiation to bone, or spinal cord compression. 1. XGEVATM (denosumab) prescribing information, Amgen. 2. Data on file, Amgen. 3. Lipton A, et al. Ann Oncol. 2010;21(suppl 8):382. Abstract 1249 and poster.
J Clin Oncol 28:5132-5139. © 2010
J Clin Oncol 29:1125-1132. © 2011
Lancet 2011; 377: 813–22
J Clin Oncol 28:5132-5139. © 2010
SRE Rate: Denosumab vs ZA in Breast Cancer Patients With Bone Metastases
Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.
Denosumab0
1.2SR
Es p
er P
atie
nt p
er Y
r
0.4
0.6
0.8
0.2
1.0
ZA
0.580.45
-22% (P = .004)
Time to First On-Study SRE: Extended Analysis
Zoledronic acid 1020 831 675 584 498 429 356 265 186 111 38 4Denosumab 1026 834 692 597 510 444 384 280 193 101 38 9
Patients at Risk, n
KM Estimate ofMedian Mos
DenosumabZoledronic acid
32.727.4
HR: 0.82 (95% CI: 0.71-0.95; P = .0096, superiority)
Study Mo
0
1.0
Subj
ects
With
out S
RE
(%)
0.2
0.4
0.6
0 3 6 9 12 15 18 21 24 27 3330
0.8
Stopeck A, et al. SABCS 2010. Abstract P6-14-01.
Time to First and Subsequent On-Study SRE* (Multiple Event Analysis)
0 3 6 9 12 15 18 21 24 27 300
0.5
1.0
1.5
Cum
ulat
ive
Mea
n N
umbe
r of S
RE
Mos
Total No. of Events
DenosumabZoledronic acid
474608
Rate ratio: 0.77 (95% CI: 0.66-0.89;P = .001†)
*Events that occurred at least 21 days apart. †Adjusted for multiplicity.Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.
n = number of patients randomizedLipton A, et al. ASCO 2010. Abstract 9015.
Pooled Analysis: Time to First On-Study SRE by Previous SRE History
HR: 0.82 (95% CI: 0.70-0.96;P = .015)
HR: 0.83 (95% CI: 0.72-0.97;P = .021)
HR: 0.83 (95% CI: 0.74-0.92; P < .001)Pr
opor
tion
of P
atie
nts
With
out O
n-St
udy
SRE
0 6 12 18 24 30
1.0
0.8
0.6
0.4
0.2
0
With Previous SREZoledronic acid (n = 819)Denosumab (n = 818)
0 6 12 18 24 30
Without Previous SREZoledronic acid (n = 1091)Denosumab (n = 1094)
0 6 12 18 24 30
OverallZoledronic acid (n = 1910)Denosumab (n = 1912)
Study MoRisk Set, n
ZADmab
819818
01
425411
266266
145144
3648
19101912
44
10521084
692716
382402
114127
10911094
43
627673
426450
237258
7879
Skeletal Complication Risk: Incremental Benefits in Breast Cancer
No bisphosphonate 64% risk at 2 yrs Pamidronate
~ 20% risk reduction
64% 51% 34%
Zoledronic acid Additional ~ 20%
risk reduction
27%
Denosumab Additional 18% risk reduction
Lipton A, et al. Cancer. 2000;88:3033-3037. Rosen LS, et al. Cancer. 2003;100:36-43. Stopeck A, et al. ECCO/ESMO 2009. Abstract 2LBA. Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.
Between-Group Differences in AEs With Unadjusted P < .05
Favors denosumab Favors zoledronic acid
HypocalcemiaToothache
Renal failure acuteBlood urea increased
BronchospasmHyperthermia
Skin hyperpigmentationMetastases to spine
HypercalcemiaEdema
Alanine aminotransferase increasedLumbar vertebral fracture
DyspepsiaRenal failure
PainChills
AnemiaArthralgiaBone pain
Pyrexia
Risk Difference -10 10-5 50
Zoledronic Acid,n (%) (n = 1013)
Denosumab, n (%) (n = 1020)
247 (24.4)170 (16.7)238 (23.5)186 (18.2)291 (28.7)250 (24.5)232 (22.9)192 (18.8)
58 (5.7)29 (2.8)97 (9.6)72 (7.1)25 (2.5)2 (0.2)74 (7.3)52 (5.1)56 (5.5)35 (3.4)47 (4.6)28 (2.7)40 (3.9)22 (2.2)35 (3.5)17 (1.7)21 (2.1)9 (0.9)19 (1.9)7 (0.7)15 (1.5)4 (0.4)10 (1.0)2 (0.2)
8 (0.8)0 (0.0)7 (0.7)1 (0.1)
37 (3.7)57 (5.6)34 (3.4)56 (5.5)
Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.
*P = .2861 †No cases of hypocalcemia were grade 5 (fatal). ‡In the first 3 days after initial treatment.
Stopeck A, et al. SABCS 2010. Abstract P6-14-01.
Adverse Events: From Extended Analysis
Event, n (%) Zoledronic Acid(n = 1013)
Denosumab(n = 1020)
All adverse events 987 (97.4) 961 (96.2)Serious adverse events 509 (50.2) 489 (47.9)Adverse events related to renal toxicity 95 (9.4) 55 (5.4)Osteonecrosis of the jaw* 18 (1.8) 26 (2.5)Hypocalcemia (any) 37 (3.7) 62 (6.1) Hypocalcemia of grade 3 or 4† 12 (1.2) 18 (1.8)
Acute-phase reactions‡ 286 (28.2) 109 (10.7)
ONJ Associated With Bone-Targeted Therapy in Patients With Bone Metastases
Saad F, et al. Ann Oncol. 2012;23:1341-1347.
Denosumab(n = 52)
1.8%
Zoledronic acid(n = 37)
1.3%
Positively adjudicatedfor ONJ(n = 89)
Potential ONJ(n = 276)
All patients (N = 5723)
Integrated analysis of pivotal denosumab SRE prevention trials
No significant difference between groups (P = .13)
Denosumab vs Zoledronic Acid Pivotal Phase III SRE Prevention Trials
1. Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139. 2. Fizazi K, et al. Lancet. 2011;377:813-822. 3. Henry DH, et al. J Clin Oncol. 2011;29:1125-1132.
Supplemental calcium and vitamin D
Denosumab 120 mg SC q4w+
Placebo IV q4w†
Zoledronic Acid 4 mg IV q4w†
+ Placebo SC q4w
Study 136[1]
Breast cancer(N = 2049)
Study 103[2]
Prostate cancer(N = 1904)
Study 244[3]
Other solid tumors/MM(N = 1779)
RANDOMIZATION
In total, > 5700 patients with bone metastases
Prespecified Integrated Analysis: Baseline Demographics
ECOG = Eastern Cooperative Oncology Group.1. Data on file, Amgen. 2. Lipton A, et al. Ann Oncol. 2010;21(suppl 8):382. Abstract 1249 and poster.
Denosumab Was Superior to Zoledronic Acid: 17% Risk Reduction in First SRE
P value for superiority.1. Data on file, Amgen. 2. Lipton A, et al. Ann Oncol. 2010;21(suppl 8):382. Abstract 1249 and poster.
Denosumab 120 mg Q4W (n= 2862)Zoledronic acid 4 mg Q4W (n= 2861)
Superior Efficacy Across Multiple Solid Tumor Types: Reduction in Risk of First SRE
*P value for superiority. †Excluding breast and prostate.1. XGEVATM (denosumab) prescribing information, Amgen. 2. Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139. 3. Fizazi K, et al. Lancet. 2011;377:813-822. 4. Henry D, et al. J Clin Oncol. [Epub ahead of print] doi: 10.1200/JCO.2010.31.3304.
Denosumab 120 mg Q4W (n= 2862)Zoledronic acid 4 mg Q4W (n= 2861)
Proven Efficacy in Multiple Solid Tumor Types: Reduction in Risk in the Subanalysis of Other Solid Tumors
Henry D, et al. Presentation at: ASCO Annual Meeting. June 4-8, 2010; Chicago, IL
Denosumab
Zoledronic Acid
Excluding Multiple Myeloma (10% of the patients)
Increased Time to First SRE
1. Denosumab prescribing information, Amgen. 2. Lipton A, et al. Cancer 2000;88:1082-1090. 3. Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.
Denosumab Zoledronic None Denosumab Zoledronic None
Increased Time to First SRE
1. Henry D, et al. Presentation at: ASCO Annual Meeting. June 4 8, 2010; Chicago, ILL. 2 Rosen LS, et al. Cancer. 2004;100:2613-‐2621.
Denosumab Zoledronic None
Denosumab Was Superior to Zoledronic Acid: 18% Risk Reduction in First and Subsequent SREs
1. Henry D, et al. Presentation at: ASCO Annual Meeting. June 4 8, 2010; Chicago, ILL. 2 Rosen LS, et al. Cancer. 2004;100:2613-‐2621.
DenosumabZoledronic Acid
Denosumab Was Superior to Zoledronic Acid: 18% Risk Reduction in First and Subsequent SREs
*P value for superiority. †Excluding breast and prostate. Study Month1. Denosumab prescribing information, Amgen. 2. Stopeck A, et al. Presentation at: ECCO/ESMO Multidisciplinary Congress. Sept 20-24, 2009; Berlin, Germany. 3. Stopeck AT, et al. J Clin Oncol. 2010;28:5132- 5139. 4. Fizazi K, et al. Lancet. 2011;377:813-822. 5. Henry D, et al. J Clin Oncol. [Epub ahead of print] doi: 10.1200/JCO.2010.31.3304.
DenosumabZoledronic Acid
Overal Survival
*Excluding breast and prostate.1. Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139. 2. Fizazi K, et al. Lancet. 2011;377:813-822. 3. Henry D, et al. J Clin Oncol. [Epub ahead of print] doi: 10.1200/JCO.2010.31.3304. 4. XGEVATM (denosumab) prescribing information, Amgen.
DenosumabZoledronic Acid
Denosumab: Superior Efficacy
*Excluding breast and prostate.1. Data on file, Amgen. 2. XGEVATM (denosumab) prescribing information, Amgen. 3. Henry D, et al. Presentation at: ASCO Annual Meeting. June 4-8, 2010; Chicago, ILL. 4. Stopeck A, et al. Presentation at: ECCO/ESMO. Sept 20-24, 2009; Berlin, Germany. Abstract 2LBA. 5. Fizazi K, et al. Lancet. 2011;377:813-822. 6. Henry D, et al. J Clin Oncol. [Epub ahead of print] doi: 10.1200/JCO.2010.31.3304. 7. Lipton A, et al. Ann Oncol. 2010;21(suppl 8):382. Abstract 1249 and poster.
Is denosumab SAFER than bisphosphonates metastatic
bone disease in solid tumors?
Denosumab does not require dose adjustments, regardless of renal function
1. Lewiecki EM. Biologics. 2008;2:645-653. 2. Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066. 3. Mould DR, Green B. BioDrugs. 2010;24:23-39. 4. Data on file, Amgen. 5. Zometa® Prescribing Information, Novartis.
Zoledronic Acid Denosumab
Most Common Adverse Reactions Ocurring in More than 25% of Patients
*Laboratory-derived and below the central laboratory lower limit of normal (2.2–2.8 mg/dL [0.71–0.9 mmol/L] for phosphorus).
Zoledronic AcidDenosumab
Hypocalcemia
1. Data on file, Amgen. 2. XGEVA (denosumab) prescribing information, Amgen.
Zoledronic Acid Denosumab
Adverse events of hypocalcemia were predominantly transient and generally not associated with clinical consequences.Most adverse events of hypocalcemia were single events that resolved with oral calcium or no action taken.
Osteonecrosis of the Jaw (ONJ)
Denosumab: 1.8%Zoledronic acid: 1.3% (NS)
Acute-Phase Reactions
Denosumab: 8.7%Zoledronic acid: 20.2%
Acute phase reaction events occurred within the first 3 days of
treatment, and the most common were pyrexia, fatigue, bone
pain, arthralgia, and chills.
Sun L, Am J Clin Oncol 2013;36:399–403
Sun L, Am J Clin Oncol 2013;36:399–403
Time to First SRE Time to Multiple SREs
Overall survival Disease progression
Sun L, Am J Clin Oncol 2013;36:399–403
This meta-analysis indicates that denosumab is more effective than ZA in reducing morbidity for patients with bone metastases. In addition, the risk of relative serious AEs was not significantly
increased in patients receiving denosumab compared with those given ZA
Is denosumab COST-EFFECTIVE when compared to (active)
bisphosphonates in solid tumors?
Carter JA, Botteman MF. Health-economic review of zoledronic acid for the management of skeletal-related events in bone-metastatic prostate cancer. Expert Rev Pharmacoecon Outcomes Res. 2012;12:425–437
Can we SELECT who will reap a greater benefit from
denosumab?
Lipton A. Eur Journal of Cancer 53 (2016) 75-83
Lipton A. Eur Journal of Cancer 53 (2016) 75-83
Lipton A. Eur Journal of Cancer 53 (2016) 75-83
Favors denosumab
Lipton A. Eur Journal of Cancer 53 (2016) 75-83
Favors denosumab
Lipton A. Eur Journal of Cancer 53 (2016) 75-83
Favors denosumab
Denosumab prior to bone events in solid tumors
Smith MR, Lancet 2012; 379: 39–46
High-Risk Non-metastatic castration-resistant prostate cancer (PSA greater or equal than 8 or PSA doubling time
less than 10 months)
R
Denosumab
Placebo
Composite endpoint determined by time to fi rst occurrenceof bone metastasis (symptomatic or asymptomatic) or death from any cause
n=716
n=716
120 mg q4wk
Smith MR, Lancet 2012; 379: 39–46
Smith MR, Lancet 2012; 379: 39–46
Bone-Metastasis-Free Survival
Smith MR, Lancet 2012; 379: 39–46
Time to bone metastases
Smith MR, Lancet 2012; 379: 39–46
Time to symptomatic bone metastases
Smith MR, Lancet 2012; 379: 39–46
Time to symptomatic bone metastases
Smith MR, Lancet 2012; 379: 39–46
Gnant M, Lancet Oncol 2015
Post-menopausal women with HR+ Early-Stage Breast
Cancer and receiving AIR
Denosumab
Placebo
Time from randomization to first fracture
n=1711
n=1709
60 mg Q6m
Gnant M, Lancet Oncol 2015
Gnant M, Lancet Oncol 2015
Is denosumab MORE effective than bisphosphonates in
(relevant outcomes of bone metastases) in solid tumors?
Yes
Is denosumab SAFER than bisphosphonates metastatic
bone disease in solid tumors?
Probably, at least in patients with renal
impairment
Is denosumab COST-EFFECTIVE when compared to (active)
bisphosphonates in solid tumors?
Maybe
Should YOU use it routinely in your patients with solid
tumors ?
…
@onconerd