investigación clínica ¿cómo se construye la evidencia ...€¦ · 14/2/2014 · lipton a,...
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Investigación Clínica
¿Cómo se construye la evidencia?
El ejemplo de Denosumab
Miquel Balcells AMGEN Iberia
Premisas a cumplir cuando queremos
generar evidencia en salud
Identificar y cuantificar la relevancia del problema
Comprender las causas del problema (fisiopatología)
Seleccionar el candidato adecuado
Diseño adecuado
– Brazo control
– Enmascaramiento
– Objetivos y variables
– Seguridad
Plan de desarrollo clínico post-autorización
XGEVA® (denosumab)2
Dose 120 mg SC
Regimen Every 4 weeks
Indication(s)
Prevention of skeletal related events (pathological fracture,
radiation to bone, spinal cord compression or surgery to bone) in
adults with bone metastases from solid tumours
Denosumab (XGEVA®) – Therapeutic
indication approved by EMA
EMA: European Medicines Agency; SC, subcutaneous.
1. McClung MR et al. New Engl J Med 2006;354:821–31.
2. XGEVA® (Denosumab) Summary of product characteristics, Amgen. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002173/human_med_001463.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d124 Accessed 14 May 2012.
Denosumab is a fully human monoclonal antibody that binds human RANK Ligand with high affinity and specificity1
Metástasis óseas y eventos relacionados con
el esqueleto (EREs/SREs):
la magnitud del problema
Bone metastases may result in clinically significant and serious consequences of skeletal-related events (SREs)
SREs are defined as1,2:
1. Saad F, et al. J Natl Cancer Inst 2004;96:87982;
2. Ibrahim A, et al. Clin Cancer Res 2003;9:23949.
Pathological
fracture
Radiation to
bone
Surgery to
bone
Spinal cord
compression
SREs are both common and frequent in patients with advanced cancer untreated for bone metastases
Perc
enta
ge o
f patients
Breast1
(24 months)
Lung and
other solid
tumours3
(21 months)
Prostate2
(24 months)
Percentage of patients
developing SREs Mean number of SREs
per patient per year
Mean n
um
be
r of
SR
Es/p
atient/year
SRE: skeletal related event; IV: intravenous.
1. Lipton A, et al. Cancer 2000;88:108290;
2. Saad F, et al. J Natl Cancer Inst 2004;96:87982;
3. Rosen LS, et al. Cancer 2004;100:261321.
Breast1
Lung and
other solid
tumours3
Prostate2
Data are from the placebo arms of 3 major trials of
placebo vs. IV bisphosphonate in different tumour types
Patients have increased chances of developing SREs as survival times improve
Prostate3,4
Breast1,2
Lung5,6
12.3
21.7
25.2
5.2
10.7
7.0
0 5 10 15 20 25 30
Months
SRE: skeletal related event.
1. Lipton A, et al. Cancer 2000;88:108290; 2. Miller K, et al. N Engl J Med 2007;357:266676;
3. Saad F, et al. J Natl Cancer Inst 2002;94:145868; 4. Kantoff PW, et al. N Engl J Med 2010;363;41122;
5. Rosen LS, et al. Cancer 2004;100:261321; 6. Sandler A, et al. N Engl J Med 2006;355:254250.
Median time to first SRE
Median overall survival
Median time to first SRE vs median overall survival
Los EREs llevan asociadas una serie de implicaciones que agravan
significativamente la carga económica de esta enfermedad sobre el
Sistema Sanitario español.1
Se ha estimado que en España el coste medio de cada ERE oscila entre
los 2.378€ y los 7.903€ (€2010).1
1. Hechmati G, et al. J Med Econ 2013;16(5):691-700.
COSTES DEL TRATAMIENTO DE LOS EREs
Fisiopatología de las metástasis óseas
Normal bone remodelling is tightly regulated
RANK Ligand binds to
RANK on osteoclast
precursor cells, which
then develop into
osteoclasts and become
active
Osteoblasts
RANK Ligand
Osteoblasts release
RANK Ligand
Osteoclast
Active osteoclasts
remove bone tissue
(resorption)
RANK Ligand is an important mediator of bone resorption
The resultant bone lost needs to
be replaced – by osteoblasts
(formation)
Boyle WJ et al. Nature 2003;423:337–42.
RANK, receptor activator of nuclear factor κ B
A vicious cycle of bone destruction may
develop in the presence of tumour cells
Overexpression of RANK
Ligand drives increased
formation, function and
survival of osteoclasts,
leading to excessive
bone resorption
Osteoblasts
Tumour cells produce
factors that stimulate
osteoblasts to secrete
RANK Ligand
RANK Ligand
Tumour
Osteoblasts and
other bone cells
increase expression
of RANK Ligand
Osteoclast
Bone resorption releases growth
factors from the bone matrix that
may perpetuate tumour activity
Roodman GD. N Engl J Med 2004;350:1655–64;
Mundy GR. Nat Rev Cancer 2002;2:58493.
RANK, receptor activator of nuclear factor κ B
Denosumab targets RANK Ligand to break the
vicious cycle
By binding to RANK
Ligand denosumab
inhibits osteoclast
formation, function, and
survival
Osteoblasts
Osteoclast
Denosumab precisely
binds to RANK Ligand,
preventing activation of
the RANK receptor on
osteoclasts
Denosumab prevents the
maturation of osteoclasts,
decreasing bone resorption and
breaking the vicious cycle of
bone destruction
Tumour
RANK
Ligand
Denosumab
Roodman GD. N Engl J Med 2004;350:1655–64;
Mundy GR. Nat Rev Cancer 2002;2:58493.
RANK, receptor activator of nuclear factor κ B
Selección del diseño adecuado :
estudios fase III en prevención de SREs
• 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 1. Stopeck AT, et al. J Clin Oncol 2010;28:5132–9; 2. Fizazi K, et al. Lancet 2011;377:813–22;
3. Henry DH, et al. J Clin Oncol 2011;29:112532; 4. Lipton A, et al. Eur J Cancer 2012;48:3082–92. *Excluding breast and prostate.
Three pivotal Phase III trials of denosumab
vs zoledronic acid in patients with bone metastases
from advanced cancer
Supplemental calcium and vitamin D
†Per protocol and Zometa® label, IV product dose
adjusted 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
R
A
N
D
O
M
I
S
A
T
I
O
N
Pre
-pla
nn
ed
in
teg
rate
d a
naly
sis
4
(N =
5723)
Inclusion Criteria: Overview
Unspecific Inclusion Criteria 136 244 103
Current or prior radiographic (ie x-ray, CT, MR) evidence of 1 bone met X X X
ECOG PS 0-2 X X X
Adequate organ function X X X
Written informed consent X X X
15
IV: intravenous, BP: bisphosphonate, ONJ: osteonecrosis of the jaw, BC: breast cancer, Cis: carcinoma in situ, BCC: basal cell carcinoma, HIV: human
immunodeficiency virus, HBV: hepatitis B virus, HCV:hepatitis C virus, ZA: zoledronic acid, Dmab: denosumab, Ca2+ : calcium, Vit D: vitamin D
Specific Inclusion Criteria
136 244 103
Adult (incl men) with
histologically or cytologically
confirmed breast
adenocarcinoma
Adult with histologically or
cytologically confirmed
advanced cancers including
solid tumors, multiple myeloma
and lymphoma
Men with histologically confirmed prostate
cancer
+
Documented failure of at least one hormonal
therapy as evidenced by a rising PSA
+
Serum testosteron level of <50 ng/dl due
either chemical or surgical castration
Protocol denosumab study 20050136, 20050244, 2005103
SRE definition
Pathologic fracture (vertebral or non-vertebral)
– Fracture that occurs spontaneously or results from trivial trauma
Radiation therapy to bone (including radioisotopes)
– Pain control
– Treat or prevent pathologic fractures or spinal cord compression
Surgery to bone
– Prodedures to set or stabilize a fracture or to prevent an
imminent fracture or spinal cord compression
Spinal cord compression 16 Protocol denosumab study 20050136, 20050244, 2005103
Risk reduction in time to first SRE consistently
favoured denosumab across tumour types
1. Stopeck AT et al. J Clin Oncol 2010;28:5132–9;
2. Fizazi K et al. Lancet 2011;377:813–22;
3. Henry DH et al. J Clin Oncol 2011;29:112532. †Excluding breast and prostate. All data from primary analyses
Pa
tie
nts
with
ou
t S
RE
(%
)
Denosumab
Study month
0 0 3 6 9 12 15 18 21 24 27
Breast
cancer
study1
(n = 2046)
HR = 0.82 (95% CI: 0.71–0.95)
P = 0.01 (superiority)
Prostate
cancer
study2
(n = 1901)
HR = 0.82 (95% CI: 0.71–0.95)
P = 0.008 (superiority)
0 3 6 9 12 15 18 21 24 27
Other solid
tumour/multiple
myeloma study3†
(n = 1776)
HR = 0.84 (95% CI: 0.71–0.98)
P = 0.0007 (non-inferiority)
P = 0.06 (NS for superiority)
0 3 6 9 12 15 18 21 24
100
90
80
70
60
50
40 26.4 months
Not yet reached
20.6 months
17.1 months 16.3 months
Zoledronic acid
18% Risk
Reduction
20.7 months
18% Risk
Reduction
16% Risk
Reduction
30
20
10
Time to first SRE
SRE, skeletal related event.
Significantly fewer SREs with denosumab across
different tumour types
Cu
mu
lati
ve
me
an
nu
mb
er
of
SR
Es
per
pati
en
t
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0 0 3 6 9 12 15 18 21 24 27
RR = 0.77 (95% CI, 0.66–0.89)
P = 0.001 (superiority)
Total SREs:
Zoledronic acid: 608
Denosumab: 474
0 3 6 9 12 15 18 21 24 27 30 33
RR = 0.82 (95% CI, 0.71–0.94)
P = 0.008 (superiority)
Total SREs:
Zoledronic acid: 584
Denosumab: 494
0 3 6 9 12 15 18 21 24 27
RR= 0.90 (95% CI, 0.77–1.04)
P = 0.14 (NS for superiority)
Total SREs:
Zoledronic acid: 436
Denosumab: 392
Breast
cancer1
(n = 2046)
Prostate
cancer2
(n = 1901)
Other solid tumour/
multiple myeloma3
(n = 1776)
23% Risk
Reduction
18% Risk
Reduction
10% Risk
Reduction
1. Stopeck AT et al. J Clin Oncol 2010;28:5132–9; 2. Fizazi K et al. Lancet
2011;377:813–22; 3. Henry DH et al. J Clin Oncol 2011;29:112532.
All data from primary analyses;
RR, rate ratio
Time to first and subsequent SREs
Study month SREs, skeletal related events.
Integrated analysis: power from identical study
designs
Zoledronic acid 4 mg IV Q4W*
+
Placebo
SC Q4W
(n = 2862)
Denosumab 120 mg SC Q4W
+
Placebo
IV Q4W*
(n = 2861)
Breast Cancer
N = 2046
R
A
N
D
O
M
I
S
A
T
I
O
N
Lipton A, Fizazi K, Stopeck A, et al. Eur J Cancer 2012;48:3082-3092.
IV, intravenous; Q4W, every 4 weeks; SC, subcutaneous
Daily supplementation with calcium (≥ 500 mg) and vitamin D (≥ 400 IU)
*Per protocol and Zometa® label, IV product dose adjusted for baseline
creatinine clearance and subsequent dose intervals determined by serum creatinine
N = 5723
Prostate Cancer
N = 1901
Solid Tumors + Multiple Myeloma
N = 1776
Key inclusion criteria: Patients with ≥ 1 bone metastasis/lesion
Lipton A, Fizazi K, Stopeck A, et al. Eur J Cancer 2012;48:3082-3092.
Significantly longer time (8.2 months) without
an SRE with denosumab vs zoledronic acid
17% Risk
Reduction
HR = 0.83
(95% CI: 0.76–0.90)
P 0.0001 (superiority)
Zoledronic acid 2861 1596 991 522 178 26
Denosumab 2862 1666 1077 570 197 22
Study month
Patients
without
SR
E (
%)
0
40
60
80
100
0 6 12 18 24 30
27.6 months
19.4 months
90
70
50
30
No. at risk
Time to first SRE
(n = 5723)
Denosumab Zoledronic acid
20
10
HR, hazard ratio SRE, skeletal related event.
Lipton A, Fizazi K, Stopeck A, et al. Eur J Cancer 2012;48:3082-3092.
Significantly fewer SREs with denosumab
vs zoledronic acid
18% Risk
Reduction
Time to first and subsequent SREs
(n = 5723) RR = 0.82
(95% CI, 0.75–0.89) P < 0.001 (superiority)
0 3 6 9 12 15 18 21 24 27 30 33 36
Cum
ula
tive m
ean n
um
be
r of
SR
Es p
er
patient
Study month
0.0
1.0
1.6
1.4
1.2
0.8
0.6
0.4
0.2
Total SREs:
Zoledronic acid: 1628
Denosumab: 1360
Events occurring at least 21 days apart (multiple event analysis)
RR, rate ratio SREs, skeletal related events.
von Moos R, et al. Support Care Cancer 2013;21:3497507. †BPISF worst pain score. Patients with MM were not included in this analysis.
Denosumab delayed pain worsening
by almost 2 months vs zoledronic acid M
edia
n tim
e f
rom
no o
r m
ild p
ain
to
modera
te o
r severe
pain
(m
onth
s)
+ 1.8
mths
HR = 0.83
(95% CI, 0.760.92)
P < 0.001
Time to moderate or severe pain (> 4 points)
among patients with no or mild pain (0–4 points) at baseline (n = 2683)†
• Depending on the tumour type:
− Treatment of 7.8−16 patients for 1 year with denosumab would be
needed to prevent 1 additional first SRE
− Treatment of 5−7 patients for 1 year with denosumab would be needed
to prevent 1 additional recurrent SRE
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 (and poster) NNT, number needed to treat.
Denosumab had a favourable NNT vs zoledronic
acid for prevention of first and recurrent SREs
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
Análisis de seguridad
ONJ, osteonecrosis of the jaw.
Safety results of interest
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)
572 (20.2) 246 (8.7)
141 (5.0) 273 (9.6)
37 (1.3) 52 (1.8)
Lipton A, et al. Eur J Cancer 2012;48:308292.
Cumulative incidence of ONJ
0.5
1.0 0.8
1.8
1.3
1.8
0
2
4
012 024 036*
Pro
port
ion o
f patients
(%
)
Denosumab (n = 2814)
Zoledronic acid (n = 2836)
Saad F, et al. Ann Oncol 2012;23:1341–7.
Proportions are % of all patients treated with zoledronic acid or denosumab.
No significant difference in ONJ rate between
treatment arms
*P = 0.13
Denosumab
(n = 52)
1.8%
Zoledronic acid
(n = 37)
1.3%
Positively adjudicated
for ONJ
(n = 89)
Potential ONJ
(n = 276)
All patients
(N = 5723)
Study month
*Treatment and outcomes as per 1 October 2010. †Resolved = complete mucosal coverage of exposed bone.
‡Among patients with ONJ resolution.
Resolution of ONJ occurred in 40% of patients
who experienced ONJ on denosumab
Outcomes* Zoledronic acid
(n = 37)
Denosumab
(n = 52)
All
(n = 89)
Resolved,† n (%) 11 (30) 21 (40) 32 (36)
Median time to resolution,‡
months (range) 8.7 (3.718.3) 8.0 (0.225.6) 8.2 (0.225.6)
Ongoing, present at time of death
or unknown, n (%) 26 (70) 31 (60) 57 (64)
Saad F, et al. Ann Oncol 2012;23:1341–7.
Desarrollo clínico post-autorización
Estudios orientados a responder las preguntas que han
quedado abiertas en la fase de previa a la autorización
1.- Cummings SR, et al. N Engl J Med. 2009;361:756-765. 2.- Bone HG, et al. J Clin Endocrinol Metab. 2008;93:2149-2157. 3.- Brown JP, et al. J Bone Miner Res. 2009;24:153-161. 4.- Kendler DL, et al. J Bone Miner Res.
2010;25:72–81. 5.- Smith MR, et al. N Engl J Med. 2009;361:745-755. 6.- Ellis GK, et al. J Clin Oncol. 2008;25:4875-4882. 7.- www.clinicaltrials.gov Accessed 14 Feb 2014. 8.- Smith MR, et al. Lancet 2012;379:39-46. 9.-
Fizazi K et al. The Lancet 2011;377;813-822. 10.- Stopeck AT et al. J Clin Oncol 2010;28:5132-5139 11.- Henry DH et al. J Clin Oncol 2011;29(9):1125-32.
PMO Treatment (FREEDOM)1 (n = 7.868)
Prostate cancer5 (n = 1.468)
Prostate cancer8 (n = 1.432)
Prostate cancer9 (n = 1.904)
PMO Prevention (DEFEND)2 (n = 332)
Breast cancer6 (n = 252)
Breast cancer - D-CARE7 (n ~ 4500)
*Active, not enrolling
Breast cancer10 (n = 2046)
Denosumab vs. alendronate (DECIDE)3 (n = 1.189)
ABCSG-18 breast7 (n ~ 2.800)
*Active, not enrolling
Solid tumor and MM11** (n = 1.776)
Alendronate to denosumab Transition (STAND)4
(n = 504)
MM7** (n ~1.520)
*Enrolling
Postmenopausal osteoporosis
~ 10.000 patients
Cancer Treatment-Induced Bone Loss
~ 4.500 patients
Prevention or Delay of Bone Metastasis*
~ 6.000 patients
SREs = Skeletal Related Events; PMO = postmenopausal osteoporosis; FREEDOM = Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months; DEFEND = DEnosumab Evaluation For PrEserving BoNe
Density; DECIDE = Determining Efficacy: Comparison of Initiating Denosumab vs. AlEndronate; STAND = Study of Transitioning from AleNdronate to Denosumab; ABCSG = Austrian Breast and Colorectal Cancer Study Group;
D-CARE= Denosumab as adjuvant Treatment for Women with early-stage breast CAncer at high risk of Recurrence; MM = multiple myeloma .
*Denosumab is currently not approved in EU for the prevention or delay of the development of bone metastases. Denosumab is investigational in that setting.
**Denosumab is not indicated for use in patients with multiple myeloma (MM). Denosumab is investigational in that setting.
Prevention or Delay of SREs
~ 7.000 patients
60 mg Q6M 120 mg Q4W
Discovery and development of denosumab and the RANK/RANK Ligand/OPG pathway
2008 2007 2006 2004 2001 1998 1997 1995 2009
OPG is
disclosed in
patent filings as
an important
regulator of
bone density
Identification and cloning of
RANK/RANK Ligand and OPG
published in Nature and Cell1,2
A molecule that binds to OPG
was identified and referred to
as OPGL; found to be identical
to RANK Ligand; OPG
recognised as a decoy
receptor3,4
Mid-2001
first-in-human dose
study for denosumab
First single-dose study
of denosumab in
PM women published in
J Bone Miner Res5
Phase 3 trials with denosumab in
oncology pts and
PM women initiated6
Phase 2 trial in PMO with low
BMD published in
N Engl J Med7
Phase 1 trial of denosumab in
breast cancer or MM patients
with bone metastases
published in Clin Can Res8
Phase 2 trial in breast cancer
patients with bone metastases
published in
J Clin Oncol9
Phase 3 CTIBL-BC
published in JCO10
Phase 3 PMO fracture (216) study
published in
N Engl J Med11
Phase 3 CTIBL-PC published in N
Engl J Med12
Denosumab
120 mg Q4W (XGEVA®) approved in
USA for prevention of SREs
in pts with bone metastases from
solid tumors
Denosumab 60 mg Q6M (Prolia®)
approved in USA and EU in PMO
and EU PMO and CTIBL13,14
Phase 3 oncology study(breast
cancer) in SREs published in JCO15
2010 2011-12
Denosumab 120 mg Q4W (XGEVA®)
approved in EU for prevention of
SREs in adults with bone metastases
from solid tumours14
Denosumab 60 mg Q6M (Prolia®)
approved in USA in CTIBL13
Denosumab 60 mg Q6M (Prolia®)
available in Spain
Phase 3 (ST-MM
and prostate
cancer) in SREs
published in
JCO16 and The
Lancet17
Phase 3 and bone
metastasis free
survival study
published in The
Lancet18
2013
Denosumab
120 mg Q4W
(XGEVA®)
available in
Spain.
1. Anderson DM, et al. Nature 1997;390:175–9; 2. Simonet WS, et al. Cell 1997;89:309–19;
3. Lacey DL, et al. Cell 1998;93:165–76; 4. Yasuda H, et al. Proc Natl Acad Sci USA
1998;95:3597–602; 5. Bekker PJ, et al. J Bone Miner Res 2004;19:1059–66;
6. www.amgen.com; 7. McClung MR, et al. New Engl J Med 2006;354:821–31;
8. Body JJ et al. Clin Cancer Res 2006;12:1221–8; 9. Lipton A et al. J Clin Oncol 2007;25:4431–7; 10. Ellis GK, et al.
J Clin Oncol 2008;26:4875–82; 11. Cummings SR, et al. N Engl J Med 2009;361:756–65; 12. Smith MR, et al. N
Engl J Med 2009;361:745–55; 13. www.fda.gov; 14. www.ema.europa.eu; 15. Stopeck AT, et al. J Clin Oncol
2010;28:5132–9; 16. Henry DH, et al. J Clin Oncol 2011; 29:1125-1132; 17. Fizazi K, et al. Lancet. 2011;377:813–
822; 18. Smith MR, et al. Lancet 2012;379:3946.
Denosumab is not indicated for use in patients with multiple myeloma (MM). Denosumab is investigational in that setting.
Denosumab is currently not approved in EU for the prevention or delay of the development of bone metastases. Denosumab is investigational in that setting.
BC, breast cancer; BMD, bone mineral density; CTIBL, cancer treatment
induced bone loss; SREs, skeletal related events; OPG, Osteoprotegerin; PM,
postmenopausal; MM, multiple myeloma; PMO, postmenopausal osteoporosis;
Q4W, every four weeks; Q6M, every six months; RANK, receptor activator of
nuclear factor κ B; ST; solid tumors; PC, prostate cancer.
Overview of guideline recommendations
for denosumab
ASCO NCCN ESMO EAU AUA
Breast cancer N/A N/A
CRPC N/A
NSCLC N/A N/A N/A
Renal cell carcinoma N/A N/A N/A
Bladder cancer N/A N/A N/A N/A
Cancer pain N/A N/A
Bone health N/A N/A N/A A/A
Denosumab use recommended
N/A No relevant guidelines exist
†Guideline published in 2012 states that denosumab use is still investigational in renal cell carcinoma.
ASCO, American Society of Clinical Oncology; AUA, American Urological Association;
CRPC, castration-resistant prostate cancer; EAU, European Association of Urology;
ESMO, European Society for Medical Oncology; NCCN, National Comprehensive Cancer Network;
NSCLC, non-small cell lung cancer.
†
Denosumab use not currently recommended
¡Muchas gracias!