Transcript Document

Bone and Lung Cancer
Dr Peter Harper
Leaders in Oncology Care
London
WHAT UNITES TORINO AND
LIVERPOOL?
WHAT UNITES TORINO AND
LIVERPOOL?
Prof Giorgio Vittorio Scagliotti
&
Prof Pieter Edsge Postmus
WHAT UNITES TORINO AND
MANCHESTER?
TORINO
4th MAY 1949
The Superga air disaster occurred on 4
May 1949 when the Fiat G.212 of Avio Linee
Italiane (Italian Airlines),carrying the Entire
Torino football team crashed into the
retaining wall at the back of the Basilica of
Superga, which stands on the hill of Turin.
31 people died in the crash.
After refuelling at Barcelona, the plane carrying the team
flew into a thunderstorm on the approach to Turin and
encountered conditions of low cloud and poor visibility.
They were forced to descend to be able to fly visually..
The emotional impact of the crash on Italian sports fans
was profound, as it claimed the lives of the players of a
team which had won five successive Serie A titles, tying
the all-time record, and seriously weakened the Italian
national team, which had included up to 10 Torino players.
Torino itself would not claim another title until
1976.
Manchester United
February 6th 1958
On that day in 1958, the darkest day in United's history, 23
people - including eight players and three members of the
club's staff - suffered fatal injuries in the Munich air crash.
Flying back from a European Cup tie against Red Star Belgrade, the team
plane stopped in Germany to refuel. The first two attempts to take off from
Munich airport were aborted; following a third attempt, the plane crashed.
Twenty-one of the people on board died instantly. Aeroplane captain
Kenneth Rayment died a few weeks later from the injuries he sustained
while Duncan Edwards - one of the eight victims from the team - passed
away 15 days after the crash. The tragedy is an indelible part of United's
history, as is Sir Matt Busby overcoming his injuries to build another
great team which won the European Cup 10 years later.
Bone Metastases Have Debilitating Consequences
‘Skeletal Related Events’ (SREs)
Disease
Skeletal-related
events
Loss of
autonomy
Fracture
Radiation
to bone
Bone
mets
Consequences
Spinal cord
compression
Hypercalcemia
Surgery to bone
Kinnane N. Eur J Oncol Nurs. 2007;11(suppl):S28-S31.
Significant
morbidity
Bone pain
Increased healthcare
costs and resources
Bone Metastases Have Debilitating
Consequences
Disease
Skeletal-related
events
Loss of
autonomy
Fracture
Radiation
to bone
Bone
metastases
Consequences
Ultimate
consequence
Spinal cord
compression
Hypercalcemia
Surgery to bone
Kinnane N. Eur J Oncol Nurs. 2007;11(suppl):S28-S31.
Significant
morbidity
Bone pain
Increased healthcare
costs and resources
Decreased
survival
Bone Remodeling
Osteoclast
Osteoblasts
Phases of Bone “Metastasis”
A) Tumour cell colonisation of bone
Tumour cells
home to the
HSC niche
Environmental signals
maintain tumour cell
quiescence
B) Tumour cell proliferation and bone
metastasis progression
Escape from
quiescence
Tumour cell
proliferation
Re-circulation to
other metastatic
sites
HSC
Stimulation of
bone resorption
HSC niche
Tumour cell
Osteoblast
Hematopoietic
stem cell (HSC)
Osteoclast
Development of
bone lesions
Phases of Bone “Metastasis”
A) Tumour cell colonisation of bone
Tumour cells
home to the
HSC niche
Environmental signals
maintain tumour cell
quiescence
B) Tumour cell proliferation and bone
metastasis progression
Escape from
quiescence
Tumour cell
proliferation
Onward
Dissemination
HSC
Stimulation of
bone resorption
HSC niche
Tumour cell
Osteoblast
Hematopoietic
stem cell (HSC)
Osteoclast
Development of
bone lesions
Molecular Mechanisms Associated With the
Formation of OSTEOLYTIC Lesions
LPA
Bone marrow
Tumor
cell
DKK-1
Noggin
SMAD
COX2
Ca2+
IGF
PTHrP, IL-6, IL-8, IL-11,
PGE2, CTGF, MG-CSF
TGF
RANK
RANKL
Osteolytic lesion
Osteoblast
Osteoclast
Bone
Clézardin P. Rev Rhum. 2008;75(4):327-331.
Molecular Mechanisms Associated With the
Formation of OSTEOBLASTIC Lesions
Osteoblastic lesion
LPA
Bone `marrow
Tumor
Cell
ET-1
PTHrP ET-1, VEGF,
BMP-6, Wnt, …
PSA
Osteoclast
PTHrP(1-23)
OPG
RANKL
Ca2+
IGF
BMP
OPG
RANKL
Osteoblast
Bone
Clézardin P. Rev Rhum. 2008;75(4):327-331.
Clinical Priorities Across the Spectrum of Bone
Disease
Prevention of
Treatment
Induced Bone Loss
Metastasis
Prevention
Prevention of
Skeletal Morbidity
Clinical Priorities Across the Spectrum of Bone
Disease
Prevention of
Treatment
Induced Bone Loss
Metastasis
Prevention
(ie ‘do something’)
Prevention of
Skeletal Morbidity
(ie ‘do something’)
Approved bone-targeted agents in the
oncology setting
Bisphosphonates14
Zoledronic acid
Clodronate
Pamidronate
Ibandronate
RANK Ligand
inhibitor5
Denosumab
1. Zometa SmPC, Novartis; 2. Bonefos SmPC, Bayer; 3. Aredia SmPC, Novartis;
4. Bondronat SmPC, Roche; 5. XGEVA SmPC, Amgen; 6. Xofigo PI, Bayer and Algeta;
7. Metastron PI, GE Healthcare; 8. Quadramet SmPC, CIS Bio International;
9. Quadramet PI, EUSA Pharma.
†Positive
Radiopharmaceuticals69
Radium-223†
Strontium-89‡
Samarium-153
CHMP opinion for CRPC with symptomatic bone metastases;
‡Not approved in EU.
Bisphosphonates
• High affinity for bone1
• Rapidly absorbed onto
bone surface1
• Induce apoptosis of
activated osteoclasts1
• Long half-life in bone
(110 years)2
• Excreted unchanged by
the kidneys2
1. Green JR. Oncologist 2004;9(Suppl 4):3–13; 2. Lin JH. Bone 1996;18:7585.
RANK Ligand
• Member of the tumour
necrosis factor (TNF) cytokine
family1
• Binds to receptor RANK1
• Key factor for
osteoclast differentiation and
activation1
• Physiological roles
also observed beyond
the bone211
1. Lacey DL, et al. Nat Rev Drug Discov 2012;11:40119; 2. Kong YY, et al. Nature 1999;397:31523;
3. Dougall WC, et al. Genes Dev 1999;13:241224; 4. Rossi SW, et al. J Exp Med 2007;204:126772;
5. Hanada R, et al. Nature 2009;462:5059; 6. Fata JE, et al. Nature 2000;103:4150;
7. Ock S, et al. Cardiovasc Res 2012;94:10514; 8. Schramek D, et al. Nature 2010;468:98102;
9. Gonzáles-Suárez E, et al. Nature 2010;468:1037; 10. Chen G, et al. Cancer 2006;107:28998;
11. Brown JM, et al. Urology 2001;57:611–6.
RANK, receptor activator of nuclear factor kappa-B.
Metastatic Bone Disease Is Common
5-year world
prevalence,
thousands1
Renal
Melanoma
Bladder
Thyroid
Lung
Breast
Prostate
586
643
1,100
475
1,362
4,406
2,369
Incidence of
Proportion
bone metastases Median survival,
developing
metastases in advanced cancers2
months2-3
60%
20%
40%
10%
90%
40%
35%
20 - 25
14 - 45
40
60
30 - 40
65 - 75
65 - 75
1. Ferlay J et al. GLOBOCAN 2002: 2. Coleman RE. Cancer Treat Rev. 2001;27:165-176
3. Coleman RE. Cancer. 1997;80:1588-1594
12
6
15
48
6-7
19 - 25
12 - 53
Frequency of Skeletal Morbidity (SREs) in Advanced Cancer with Bone metastases
Percentage of patients
Mean number of SREs/patient/year
Data are from the placebo arms of 3 major trials of placebo vs. IV bisphosphonate
in different tumour types
Mean number of SREs
Percentage of patients
per patient per year
developing SREs
Breast1
(24 months
fup)
Prostate2
(24 months
fup)
1. Lipton A, et al. Cancer 2000;88:108290;
2. Saad F, et al. J Natl Cancer Inst 2004;96:87982;
3. Rosen LS, et al. Cancer 2004;100:261321.
Lung and
other solid
tumours3
(21 months
fup)
Breast1
Prostate2
Lung and
other solid
tumours3
ZOL in Patients With Bone Metastases From
NSCLC and Other Solid Tumors
R
A
N
D
O
M
I
Z
E
D
n = 257
Zoledronic acid 4 mg q 3 weeks
+ Daily oral vitamin D 400 IU and calcium 500 mg
n = 266
8-mg dose reduced to 4 mg for renal safety
n = 250
Placebo q 3 weeks
+ Daily oral vitamin D 400 IU and calcium 500 mg
0
9 months
Core analysis
21 months
Final analysis
• Stratification based on non-small cell lung cancer
(NSCLC) versus other solid tumors
Rosen LS, et al. Cancer. 2004;100(12):2613-2621.
Tumour Types Enrolled:
Randomized, Placebo-Controlled Trial of ZOL in
Patients With Solid Tumours
Tumor type
NSCLC
Small-cell lung cancer (SCLC)
Renal cell carcinoma
Colon/rectum/intestinal
Cancer unknown primary
Bladder
Esophagus/gastroesophageal
Head and neck
Melanoma
Thyroid
Other tumor types (n = 11)
n
244
36
46
37
35
26
12
10
10
6
39
Rosen LS, et al. Cancer. 2004;100(12):2613-2621.
%
49
7
9
7
7
5
2
2
2
1
8
Disease Progression and Survival in the
Overall Trial Population
Median time to, [days]
Bone lesion progression
ZOL 4 mg
(n = 257)
Placebo
(n = 250)
145days
109
P = .415
Overall disease progression
89days
84
P = .089
Death
203days
P = .929
Rosen LS, et al. Cancer. 2004;100(12):2613-2621.
183
Bone Metastases
are all bone metastases the
same????
Bone Resorption Rates Prior to Bisphosphonate Treatment as
reflected in NTX excretion (nmol/mmol creatinine)
%
40%
50
45
30%
40
30%
35
Prostate (n=611)
Breast (n=744)
Myeloma (n=318)
NSCLC (n=263)
Others (n=247)
30
25
20
15
10
5
0
0-50
50-100
>100
NTX excretion (nmol/mmol creatinine)
Coleman et al – J Clin Oncol 2005
Elevated NTX Levels (high levels of bone turnover)Are Associated
With an Increased Risk of ‘BAD’ Clinical Outcomes
[from the control arm of the trial]
NSCLC/OST (NTX ≥ 100 versus NTX < 100 nmol/mmol creatinine)
P value
1.79
.010
SREs
1.91
.011
Disease
progression
2.67
<.001
Death
0
NTX < 100
1
2
Relative risk
3
NTX ≥ 100
NTX= n-telopeptide
4
Zoledronic Acid Normalized NTX Levels in a
Majority of Patients With Elevated Baseline NTX
90
Normalized 3-month NTX (E-N)
80
Remain Elevated 3-month NTX
(E-E)
Patients, %
70
60
50
40
30
20
10
(n =)
0
70
11
NSCLC/OST
38
8
NSCLC
Abbreviations: NSCLC, non-small cell lung cancer; NTX, N-telopeptide of type l collagen; OST, other solid tumors.
Hirsh V. Presented at: 12th World Conference on Lung Cancer; September 2-6, 2007; Seoul, Korea. Abstract D5-07.
Normalization of NTX Levels With ZOL Improved
Survival
NSCLC/OST (n = 87)
Bone progression-free
survival
Risk reduction, %
P value
61
.023
57
.012
52
.174
46
.142
0.39
0.43
Death
NSCLC (n = 49)
Bone progression-free
survival
0.48
0.54
Death
0
0.5
1.0
1.5
2.0
Relative risk
Reduced risk for E to N
Reduced risk for E to E
Abbreviations: NSCLC, non-small cell lung cancer; NTX, N-telopeptide of type I collagen; OST, other solid tumors; ZOL, zoledronic acid.
Comparison is throughout the study for patients with elevated baseline NTX that normalized within 3 months of zoledronic acid (E-N group) versus patients
whose NTX levels remained elevated at 3 months (E-E group).
Hirsh V. Presented at: 12th World Conference on Lung Cancer; September 2-6, 2007; Seoul, Korea. Abstract D5-07.
Survival in Patients With NSCLC and Normal
Baseline NTX
Normal NTX
100
Zoledronic acid (81 at risk, 68 died)
Proportion alive, %
Placebo (37 at risk, 26 died)
80
RR = 1.33
CI = (0.84, 2.09) P = 0.223
60
40
20
0
0
3
6
9
12
15
18
21
Time since randomization, months
Abbreviations: CI, confidence interval; NSCLC, non-small cell lung cancer; NTX = N-telopeptide of type I collagen; RR = Relative risk.
Adapted from Hirsh V, et al. J Thorac Oncol. 2008;3(3):228-236.
Survival in Patients With NSCLC and High Baseline NTX
(> 64 nmol/mmol Cr) Who Received ZOL or Placebo
Elevated NTX (> 64 nmol/mmol Cr)
Proportion alive, %
100
Zoledronic acid (102 at risk, 91 died)
Placebo (42 at risk, 41 died)
80
RR = 0.65
CI = 0.45 - 0.95
P = .025
60
40
20
0
0
3
6
9
12
15
18
21
Time since randomization, months
Abbreviations: CI, confidence interval; Cr, creatinine; NSCLC, non-small cell lung cancer; NTX, N-telopeptide of type I collagen; RR, relative risk.
Adapted from Hirsh V, et al. J Thorac Oncol. 2008;3(3):228-236.
Kaplan-Meier Estimates of Survival by
3-Month NTX Status
Proportion deceased, % patients
NSCLC and OST
100
80
E-E
E-N
60
40
P = .0116
20
0
3
6
9
12
15
18
21
Time on study, months (starting at month 3)
Abbreviations: E-E = Patients whose NTX levels remained elevated at 3 months; E-N = Patients whose NTX levels normalized at 3 months
from elevated baseline levels; NSCLC = Non-small cell lung cancer; NTX = N-telopeptide of type I collagen; OST = Other solid tumors.
Hirsh V. Presented at: 12th World Conference on Lung Cancer; September 2-6, 2007; Seoul, Korea. Abstract D5-07.
ZOL Significantly  Survival in NSCLC Patients With
High Baseline NTX in a Multivariate Analysis
P value
0.565
ZOL vs placebo
.0047
43%  risk of death
Other significant variables
0.569
No narcotics use
.016
0.515
. 019
Excellent/good ECOG
0.977
Lymphocytes (per % )
.011
0.2
0.4
0.6
0.8
1.0
1.2
Risk ratio
Reduced risk of death for variable
Increased risk of death
Abbreviations: ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer; ZOL, zoledronic acid.
Hirsh V, et al. J Thoracic Oncol. 2008:3(3):228-236.
Potential Survival Benefits With Zoledronic Acid in
Metastatic Bone Disease; META-ANALYSIS
Coleman et al. J Bone Oncology 2013 : 2, 70-76.
QUESTION was;
‘Is survival improved by bisphosphonates in patients with
a high rate of bone turnover?’
Potential Survival Benefits With Zoledronic Acid in
Metastatic Bone Disease; META-ANALYSIS
Coleman et al. J Bone Oncology 2013 : 2, 70-76.
QUESTION was;
‘Is survival improved by bisphosphonates in patients with
a high rate of bone turnover?’
Independent individual patient level meta-analysis of
placebo controlled trials of zoledronic acid
1642 patients
– Prostate cancer – 643 patients
– Breast cancer – 227 patients
– Lung and other solid tumours – 772 patients
– Overall survival RR, 0.939; 95% CI, 0.828 to 1.064,
Survival Benefits With Zoledronic Acid Seen in
Patients With Increased Bone Resorption
(n = 703 - 62%)
(n = 423 - 38%)
Coleman et al. J Bone Oncology 2013:2, 70-76.
RANK Ligand
• Member of the tumour
necrosis factor (TNF) cytokine
family1
• Binds to receptor RANK1
• Key factor for
osteoclast differentiation and
activation1
• Physiological roles
also observed beyond
the bone211
1. Lacey DL, et al. Nat Rev Drug Discov 2012;11:40119; 2. Kong YY, et al. Nature 1999;397:31523;
3. Dougall WC, et al. Genes Dev 1999;13:241224; 4. Rossi SW, et al. J Exp Med 2007;204:126772;
5. Hanada R, et al. Nature 2009;462:5059; 6. Fata JE, et al. Nature 2000;103:4150;
7. Ock S, et al. Cardiovasc Res 2012;94:10514; 8. Schramek D, et al. Nature 2010;468:98102;
9. Gonzáles-Suárez E, et al. Nature 2010;468:1037; 10. Chen G, et al. Cancer 2006;107:28998;
11. Brown JM, et al. Urology 2001;57:611–6.
RANK, receptor activator of nuclear factor kappa-B.
Three Identical Randomized Trials ;
Zoledronic Acid vs Denosumab ;
(each ‘arm’ Placebo
 Adults with breast, prostate,
or other solid tumors and
bone metastases, or multiple
myeloma
 No current or previous IV
bisphosphonate
administration for treatment
of bone metastases
(N = 5723)
Controlled)
Denosumab 120 mg SC + Placebo IV* q4w
(n = 2862)
Supplemental calcium and
vitamin D recommended
Zoledronic Acid 4 mg IV* + Placebo SC q4w
(n = 2861)
1° Endpoint
 Time to first on-study SRE (noninferiority)
2° Endpoints
 Time to first on-study SRE (superiority)
 Time to first and subsequent on-study SRE (superiority)
*Per protocol and zoledronic acid label, IV product dose adjusted for baseline creatinine.
Lipton A, et al. ESMO 2010. Abstract 1249P.
Proportion without SRE
Primary Endpoint: Time to First On-Study SRE
n=5,723pts
1.0
HR 0.83 (95% CI: 0.76, 0.90)
P<0.001 (Superiority)
17%
Risk Reduction
0.8
0.6
KM Estimate of
Median Months
0.4
0.2
Denosumab
27.66
Zoledronic Acid
19.45
0
0
6
12
18
24
30
570
522
197
178
22
26
Month
Patients at Risk:
Denosumab
2862
Zoledronic Acid 2861
1666
1596
1077
991
Lipton A, Fizazi K, Stopeck A, et al. Eur J Cancer 2012; http://dx.doi.org/10.1016/j.ejca.2012.08.002.
Risk of First On-study SRE by Solid Tumor Type
HR (95% CI)
Integrated Analysis
Risk
P Value
Reduction, % (Superiority)
0.82 (0.75-0.89)
18
< .0001
Breast
0.82 (0.71-0.95)
18
.0101
Prostate
0.82 (0.71-0.95)
18
.0085
Lung and other
Solid tumors
0.81 (0.68-0.96)
19%
.0168
Tumor Type
0
0.6
1.0
1.4
2.0
HR
Favors
Favors
Denosumab Zoledronic Acid
Richardson G, et al. Clinical Oncological Society of Australia Annual Meeting 2011. Abstract 296.
Denosumab Trial Results: Effects on First
and Subsequent SREs
Time to first and subsequent SREs
(n = 5723)
Cumulative mean number
of SREs per patient
1.6
RR = 0.82
(95% CI, 0.75–0.89)
P < 0.001 (superiority)
1.4
1.2
18% Risk
Reduction
1.0
0.8
0.6
0.4
Total SREs:
Denosumab: 1360
0.2
Zoledronic acid: 1628
0.0
0
3
6
9
12
15 18 21 24 27 30 33 36
Study month
Lipton A et al. Poster presented at ESMO 35; Milan, Italy;
8–12 October, 2010 [Abstract 1249P].
Events occurring at least 21 days apart (multiple event analysis)
RR, rate ratio
QoL: FACT-G Mean Change From Baseline
From Baseline Mean
Change in FACT-G
Score
1
0
-1
-2
-3
Denosumab
Zoledronic acid
1
3
6
9
Mos
12
15
18
Pts at risk, n
Denosumab
913
878
787
709
640
575
460
Zoledronic acid
890
845
768
700
640
592
467
Health-related QoL higher with denosumab than zoledronic acid throughout study
Fallowfield L, et al. ASCO 2010. Abstract 1025.
Denosumab Trials: Safety Results
Zoledronic acid
(n = 2836)
Denosumab
(n = 2841)
Infectious adverse events (AEs)
1218 (42.9)
1233 (43.4)
Infectious serious AEs
309 (10.9)
329 (11.6)
572
(20.2)
572
(20.2%)
246(8.7%)
(8.7)
246
Patient incidence, n (%)
Acute phase reactions (first 3 days)
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)
141(5.0)
(5.0)
141
273(9.6)
(9.6)
273
18 (0.6)
28 (1.0)
Hypocalcaemia
New primary malignancy
Lipton A et al. Poster presented at ESMO 35; Milan, Italy;
8–12 October, 2010 [Abstract 1249P].
Denosumab Phase III Bone Metastasis
Programme - ONJ Summary
6
Zoledronic acid (n = 2836)
Proportion of patients (%)
Denosumab (n = 2814)
4
P = 0.13*
1.8
1.8
2
0.5
0.8
1.0
1.3
0
Year 1
Breast
Other solid tumours & MM
Brown J et al. Presented at CIBD, 2010 [Abstract OC-15].
Year 2
Year 3*
Prostate
Proportions are % of all patients treated with zoledronic acid or denosumab
Phase III Denosumab SRE Prevention Trial in Solid
Tumours/MM: Exploratory Endpoint Overall Survival
Overall survival (proportion)
1.00
HR = 0.95 (95% CI, 0.83–1.08)
P = 0.43
0.75
0.50
0.25
Denosumab
Zoledronic acid
0.00
0
Subjects at risk:
Zoledronic acid 890
Denosumab 886
3
6
9
727
726
540
557
410
420
12
15
Study month
343
340
232
247
45 |
Henry DH, et al. J Clin Oncol 2011;29:1125−32.
18
21
24
27
176
181
118
127
64
66
26
15
Post-hoc Analysis in Lung Cancer
Subgroup of Study 244 Scagliotti GV, et al. J Thorac Oncol
2012;7:18239.
Key inclusion
Adults with lung cancer and bone
metastases
Key exclusion
Current or prior IV bisphosphonate
administration
Denosumab 120 mg SC Q4W
+
Placebo IV* Q4W
1:1
Calcium and Vitamin D Supplementation
Zoledronic acid 4 mg IV* Q4W
+
Placebo SC Q4W
Zoledronic acid
(n = 400)
Denosumab
(n = 411)
352 (88)
350 (85)
Adenocarcinoma
211 (60)
189 (54)
Squamous cell
75 (21)
88 (25)
Other
66 (19)
73 (21)
48 (12)
61 (15)
Lung cancer type, n (%)
NSCLC
SCLC
46 |
Post-hoc Analysis  Overall Survival:
Denosumab vs Zoledronic Acid in NSCLC
Proportion of patients surviving
1.0
KM estimate of
median, months
Denosumab
9.5
Zoledronic acid
8.0
0.8
0.6
0.4
0.2
HR = 0.78 (95% CI, 0.65–0.94)
P = 0.0104
0.0
0
Patients at risk:
Zoledronic acid 352
Denosumab
350
3
6
275
278
185
203
9
12
Study month
123
148
47 |
Scagliotti GV, et al. J Thorac Oncol 2012;7:18239.
91
110
15
18
21
40
66
23
39
12
24
What is the Mechanism of the Observed
Survival Benefit in the Denosumab Lung Cancer
Subgroup?
• Mechanism currently unknown
• Possible explanations:
 Direct or indirect anticancer effect of denosumab
 NFkB modulation through RANK in cancer cells
 Impact on micro-environment?
 Secondary consequence of SRE reduction
 Spurious result
SPLENDOUR
A Randomised Phase III Trial Evaluating the Addition of
Denosumab to Standard First-line Anticancer Treatment in
Advanced NSCLC
• Sponsor: European Thoracic Oncology Platform (ETOP)
• Trial Coordinators:
European Organization for Research and Treatment of Cancer
(EORTC)
Central European Cooperative Oncology Group (CECOG)
• Pharma Partner: Amgen
• PI: Solange Peters
Survival imProvement in Lung cancEr iNduced by
DenOsUmab theRapy (SPLENDOUR)
SPLENDOUR Study Design
Screening, Eligibility and
Enrollment
First-line
Stage IV
NSCLC
Stratify:
- Bone Mets
- Region
- ECOG PS
- Histology
Sample size: 1000
R
A
N
D
O
M
I
S
E
Trial Treatment
A
46 Cycles Chemotherapy
q. 3 Weeks
+ BSC
B
46 Cycles Chemotherapy
q. 3 Weeks
+ Denosumab 120 mg
q. 3 (4) Weeks s.c.
Objectives and Endpoints
Primary Objective
Overall survival
Secondary Objectives
Progression free survival (PFS) (RECIST 1.1)
Toxicity profile of denosumab (CTCAE v 4)
Determination of biomarkers for translational research
Translational
Mandatory FFPE tissue (slides or block), serum and urine samples will be
collected at baseline (prior to the start of chemotherapy), on day 1 of
cycle 3 and at progression
Serum analyses by ELISA include:
Osteopontin (OPN); bone sialoprotein (BSP); RANK Ligand by ELISA
kit designed for the quantitative determination of total (free RANK
Ligand and RANK Ligand complexed to osteoprotegerin [OPG])
soluble RANK Ligand
in serum and OPG levels
Urine samples:
Will be analysed for NTX
• FFPE tumour samples:
• Will be accessed for correlative research whenever possible.
Evaluations will include: IHC for RANK Ligand and RANK; NFkB
pathway components, and potentially BSP and OPN levels in
primary tumour may correlate with tumour aggressiveness
Radium-223 Targets Bone Metastases
• Radium-223 acts as
a calcium mimic
• Naturally targets new
bone growth in and
around bone
metastases
Ca
Sr
Ba
Ra
Radium-223 Targets Bone Metastases
• Radium-223 acts as
a calcium mimic
• Naturally targets
new bone growth in
and around bone
metastases
Ca
Sr
Ba
Ra
ALSYMPCA (ALpharadin in SYMptomatic Prostate
CAncer) Phase III Study Design
PATIENTS
TREATMENT
STRATIFICATION
6 injections at
4-week intervals
• Confirmed
symptomati
c CRPC
• ≥ 2 bone
metastases
• No known
visceral
metastases
• Total ALP:
< 220 U/L vs ≥ 220 U/L
• Bisphosphonate use:
Yes vs No
• Prior docetaxel:
Yes vs No
• Postdocetaxel
or unfit for
docetaxel
Planned follow-up is 3 years
R
A
N
D
O
M
I
Z
E
D
2:1
N = 921
Radium-223 (50 kBq/kg)
+ Best standard of care
Placebo (saline)
+ Best standard of care
ALSYMPCA: Overall Survival
100
HR = 0.695; 95% CI, 0.581-0.832
P = 0.00007
90
% of Patients
80
70
60
50
Radium-223, n = 614
Median OS: 14.9 months
40
30
20
Placebo, n = 307
Median OS: 11.3 months
10
0
Month 0
3
6
9
12
15
18
21
24
27
30
33
36
39
Radium-223 614
578
504
369
274
178
105
60
41
18
7
1
0
0
Placebo 307
288
228
157
103
67
39
24
14
7
4
2
1
0
Parker C, et al NEJM 2013
Bone Metastases Have Debilitating
Consequences
Disease
Skeletal-related
events
Loss of
autonomy
Fracture
Radiation
to bone
Bone
metastases
Consequences
Ultimate
consequence
Spinal cord
compression
Hypercalcemia
Surgery to bone
Kinnane N. Eur J Oncol Nurs. 2007;11(suppl):S28-S31.
Significant
morbidity
Bone pain
Increased healthcare
costs and resources
Decreased
survival