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