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Research Paper

Efficacy and safety of tanezumab in the treatment of


pain from bone metastases
Maciej Sopataa, Nathaniel Katzb,c, William Careyd,*, Michael D. Smithd, David Kellerd, Kenneth M. Verburgd,
Christine R. Westd, Gernot Wolframd, Mark T. Brownd

Abstract
Patients with metastatic bone cancer report life-altering pain. Nerve growth factor is involved in pain signaling. Tanezumab, a nerve
growth factor monoclonal antibody, has demonstrated efficacy in chronic pain. Placebo-controlled parent (NCT00545129; study
1003) and noncontrolled open-label extension (NCT00830180; study 1029) studies evaluated efficacy and safety of tanezumab in
patients with painful bone metastases taking daily opioids. Patients in study 1003 received a single intravenous injection of 10 mg
tanezumab or placebo and were followed up to 16 weeks. Efficacy analyses included change from baseline in daily average and
worst pain at week 6 on an 11-point numeric rating scale. At week 8, patients could enroll in study 1029 and receive 4 infusions of
10 mg tanezumab at 8-week intervals with follow-up to 40 weeks. Safety assessments included adverse events and physical and
neurologic examinations. Overall, 59 patients were randomized and treated (placebo, n 5 30; tanezumab, n 5 29). At the primary
endpoint of study 1003, least squares mean (SE) difference in change from baseline in daily average pain vs placebo was 20.26
(0.45; P 5 0.569). Post hoc analyses suggested that tanezumab had greater efficacy in patients with lower baseline opioid use
and/or higher baseline pain. Mean (SE) pain scores in study 1029 were reduced through week 40 compared with study 1029 or 1003
baselines (20.21 [0.76] and 21.27 [0.68], respectively). Adverse event incidence of study 1003 was similar between groups.
Although the primary endpoint was not achieved, tanezumab may provide additional sustained analgesia in patients with metastatic
bone pain taking daily opioids. Additional larger studies are warranted.
Keywords: Bone metastases, Cancer pain, Efficacy, Nerve growth factor, Safety, Tanezumab

1. Introduction
An estimated 30% to 50% of patients with cancer experience
moderate to severe cancer-related pain, and in advanced or
metastatic cancer, 75% to 95% report life-altering cancerinduced pain.31 Although pain arises from numerous causes,
bone metastasis is the most common cause of cancer pain,
occurring in 60% to 84% of patients.25,27 Therapeutics such as
opioids, which are commonly used in these patients, are not fully
effective in many patients and often have significant side
effects.26 Thus, a significant unmet need remains for development of novel agents for cancer pain treatment.
The neurotrophin nerve growth factor (NGF) plays an important
role in pain signaling. In animal studies, elevated NGF levels are
observed with increased pain behavior.2,17,20,32,42 In human
clinical trials, NGF administration has resulted in hyperalgesia,
pressure allodynia, and generalized muscle pain.3,13 A number of

Sponsorships or competing interests that may be relevant to content are disclosed


at the end of this article.
a

Department of Palliative Medicine, Poznan University of Medical Sciences,


Poznan, Poland, b Analgesic Solutions, Natick, MA, USA, c Department of
Anesthesiology, Tufts University School of Medicine, Boston, MA, USA, d Pfizer Inc,
Groton, CT, USA
*Corresponding author. Address: Clinical Sciences, Global Innovative Pharmaceuticals Business, Pfizer Limited (F5-2), Walton Oaks, Dorking Rd, Tadworth,
Surrey, KT20 7NS, United Kingdom. Tel.: 144 (0) 1304 640 777; fax: 144 (0) 1737
332 214. E-mail address: william.carey@pfizer.com (W. Carey).
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2015 International Association for the Study of Pain
http://dx.doi.org/10.1097/j.pain.0000000000000211

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cancers express or are stimulated by NGF.4,10,11,18,28,38,41,43


Anti-NGF therapy reduces pain-related behavior in a mouse
model of bone cancer pain and was more effective or equivalent
to acute morphine therapy in reducing prostate/bone cancer
pain-related behavior in mice.19,37
Nerve growth factor stimulates sensory neurons by binding to 2
receptors (tropomyosin receptor kinase A [TrkA] and p75 [lowaffinity receptor]).1 Tanezumab, a humanized monoclonal antibody with high selectivity and specificity for NGF, inhibits NGF
binding to both TrkA and p75.1 In clinical studies, tanezumab
administered once every 8 weeks significantly reduced pain and
improved physical function and global status in patients with
osteoarthritis and chronic low back pain.58,14,15,2224,29,30,35,36
To assess tanezumab as a potential treatment for cancer pain,
a phase 2 randomized, placebo-controlled, initial proof-of-concept
parent study (NCT00545129; study 1003) was conducted. The
primary objective was to evaluate analgesic efficacy of a single
dose of intravenous (i.v.) tanezumab 10 mg in patients with cancer
and chronic pain due to bone metastases treated with opioids. A
phase 2 open-label safety extension study (NCT00830180; study
1029) was conducted to evaluate the long-term safety and
effectiveness of tanezumab 10 mg i.v. every 8 weeks.

2. Methods
Study 1003 was a randomized, double-blind, placebo-controlled,
parallel-group, phase 2 study in patients with cancer with chronic
pain due to bone metastases who were being treated with opioids
(Clinicaltrials.gov identifier: NCT00545129). Study 1029 was
a phase 2 open-label extension study (Clinicaltrials.gov identifier:
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M. Sopata et al. 156 (2015) 17031713

NCT00830180). Both studies were conducted in compliance with


the Declaration of Helsinki and the International Conference on
Harmonisation Good Clinical Practice guidelines. The study
protocols and informed consent documentation were reviewed
and approved by an institutional review board at all sites. Written
informed consent was obtained from patients before initiation of
any protocol-specified procedures.

2.1. Study 1003


2.1.1. Study population
The key inclusion criteria were patients with prostate cancer,
breast cancer, renal cell carcinoma, or multiple myeloma
diagnosed as having metastasized to bone, with moderate to
severe bone metastasis pain (average pain intensity over the last
24 hours scores from days 1-3 of the baseline assessment
period $4 on an 11-point numeric rating scale [NRS]);
radiographic or bone scan confirmation of bone metastasis
within 30 days before the screening visit; and Karnofsky
Performance Status score $50% at the screening visit.21
Patients requiring regimens of oral codeine, hydrocodone,
oxycodone, morphine, hydromorphone, oxymorphone, levorphanol, or transdermal fentanyl were eligible. Patients requiring
regimens of methadone, tramadol, propoxyphene, meperidine,
or a mixed opioid agonist/antagonist compound were excluded.
Consistent with standard clinical practice, opioid regimens were
to consist of single fixed-dose opioid (around-the-clock) and
single immediate-release (IR) opioid for breakthrough pain. The
regimen was tailored for each patient during an opioid adjustment
period before randomization by following accepted clinical
guidelines.40 In most cases, the regimen consisted of a fixed as
well as a rescue component. Patients on stable regimens of IR
opioids only (taken #3 times daily) were also eligible, as were
patients whose stable opioid regimen consisted of only a fixed
component, provided they had access to an IR opioid for
breakthrough pain. Between study visits, change in total daily
opioid dose was not to exceed baseline total daily dose by more
than 10%.
Patients were excluded if their pain was related to an oncologic
emergency such as bowel obstruction/perforation; brain metastases, epidural metastases, leptomeningeal metastases; fracture
or impending fracture of weight-bearing bone; infection-related;
primarily classified as neuropathic or nature unknown; a result of
previous cancer therapy; or not related to bone metastasis.
Because of reports of joint destruction in tanezumab osteoarthritis studies and a subsequent clinical hold placed on all studies
of tanezumab in chronic pain (excluding cancer pain), protocol
amendments excluded patients with comorbid osteoarthritis,
osteonecrosis, or recent joint trauma.

(1) Total daily dose (fixed component plus rescue doses) of the opioid
regimen had not changed by more than 120% from day 1 to day
2 and from day 1 to day 3 of the baseline assessment period.
(2) There had been #3 IR rescue episodes per day from day 1 to
day 3 of the baseline assessment period for breakthrough pain.
(3) The mean value of the average pain intensity over the last 24
hours scores from day 1 to day 3 of the baseline assessment
period must have been $4 on an 11-point NRS (scores range
from 0 to 10).
(4) There were no intolerable side effects in the judgment of the
patient from day 1 to day 3 of the baseline assessment period.
The treatment phase lasted up to 113 days. Patients were
randomized to receive a single dose of 10 mg tanezumab or
matching placebo (tanezumab vehicle) in a 1:1 ratio (Fig. 1). After
week 8 but no later than week 16, patients had the option of
enrolling in the extension study; patients who did not were
followed through week 16 in study 1003.
2.1.3. Efficacy
The primary efficacy endpoint was change from baseline to week 6
in daily average pain as measured by an 11-point NRS recorded
daily through an e-diary (0 5 no pain, 10 5 pain as bad as you can
imagine). Secondary endpoints included change from baseline to
weeks 1, 2, 4, 6, 8, 12, and 16 in daily worst pain score; change
from baseline to the same time points (excluding week 6) in daily
average pain; and percentage of patients with a response (defined
by $30%, $50%, $70%, or $90% reduction from baseline in
daily average pain NRS). Additional secondary assessments
included the Brief Pain Inventory Short Form (BPI-sf), consisting
of questions designed to measure pain intensity and interference of
pain with daily activities; responses were provided on an 11-point
NRS ranging from 0 to 10.9 Although the landmark analysis was
prespecified as week 6 after dosing, week 8 was deemed a highinterest time point because of intended 8-week dosing intervals for
tanezumab in the treatment of chronic pain conditions.
2.2. Study 1029
2.2.1. Study population
Inclusion criteria required patients to have been treated in study
1003 with enrollment in study 1029 after 8 weeks but no later

2.1.2. Study design


This study included a pretreatment phase (3-30 days) consisting
of screening; an opioid dose adjustment phase for determining
the stabilized opioid regimen per clinical guidelines40; and a 3-day
baseline assessment period for assessment of pain intensity,
opioid use, and adverse event occurrence. The purpose of the
opioid dose adjustment phase (days 230 to 24) was to
determine optimal total daily opioid dose using a stable aroundthe-clock regimen of opioids and IR opioids as needed for
breakthrough pain. Strict criteria needed to be met during the
3-day baseline assessment period to be eligible for randomization. These criteria included:

Figure 1. Study design. BL, baseline; IV, intravenous. a Opioid adjustment


period (day 230 to 23) and baseline assessment period (day 23 to 21).
b
Transition between studies #8 weeks.

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than 16 weeks after the dose of study medication in study 1003.


Patients who discontinued study 1003 before week 8 because
of lack of efficacy were eligible to enter the open-label study after
8 weeks had elapsed since the study drug infusion in study
1003. Patients were excluded if they withdrew from study 1003
for an adverse event; discontinued before week 8 because of
lack of compliance, protocol violation, not meeting entrance
criteria, consent withdrawal, disease progression; or were lost
to follow-up. Because of the protocol amendment described,
patients with osteoarthritis, rheumatoid arthritis, primary osteonecrosis, or recent joint trauma were subsequently excluded
from the study.
2.2.2. Study design
Study 1029 was a 40-week open-label safety extension of the
double-blind randomized study 1003. Patients received 4
infusions of 10 mg tanezumab at 8-week intervals under openlabel conditions, with final visit at week 40. For compassionate
reasons, 1 patient was granted extended treatment of 619 days
(8 infusions).
2.2.3. Effectiveness
Effectiveness in study 1029 was assessed as change from study
1003 baseline to weeks 4, 8, 16, 24, and 40 in the BPI-sf
endpoints of study 1029 for daily average pain and daily worst
pain. The BPI-sf was assessed at each study visit before dosing.
2.2.4. Safety (both studies)
Safety was evaluated throughout both studies, and assessments
included adverse event documentation (including severity and
investigators opinion of relationship to study drug), vital signs,
physical and neurologic examinations, 12-lead electrocardiograms (ECGs), and laboratory tests.
Study investigators performed neurologic examinations at
each clinic visit using the Neuropathy Impairment Score,
a standardized testing instrument for both healthy patients and
for patients with neuropathy, and for evaluation of patients with
signs of peripheral neuropathy.3,12 If a neurologic adverse event
was reported or a clinically significant change was noted on
neurologic examination, the patient was referred to a neurologist
for further evaluation. Adverse events in study 1029 were defined
as any that began in study 1029, or in study 1003 and worsened
during study 1029.

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total daily opioid use (morphine equivalent dose [MED] #60.5 or


.60.5 mg/d). In a further analysis of change from baseline to
weeks 6 and 8 for average pain, the study site was used as a fixed
term in the ANCOVA model. All statistical tests in study 1003 used
2-sided 5% significance. Because study 1029 was noncomparative, no statistical testing was performed. Efficacy results are
presented through extension study week 40; safety was
evaluated over the entire study.
A minimum of 58 patients were to be randomized equally to
tanezumab or placebo in study 1003 based on a sample size
calculated for the primary endpoint with 80% power to detect
a treatment difference, assuming within-group SD of 2.0, with
a target mean difference of 1.5 and using 2-sided significance
level of 5%.24 There was no required number of patients for any
analyses in study 1029.

3. Results
Studies 1003 and 1029 were conducted in 32 and 27 centers,
respectively, in Europe, North America, South America, Latin
America, and Asia. Demographics and baseline characteristics of
study 1003 were comparable across treatments (Table 1). In
study 1003, 7 of 29 (24.1%) patients randomized to the
tanezumab 10-mg treatment group received concomitant
chemotherapy and 5 of 30 (16.7%) patients randomized to
placebo received concomitant chemotherapy. In this study, 7 of
29 (24.1%) patients randomized to the tanezumab 10-mg
treatment group and 3 of 30 (10%) patients randomized to
placebo received a concomitant bisphosphonate.
Excluding the single renal cell carcinoma patient, the mean
duration of cancer was generally 3 to 6 years, and the duration
since bone metastasis diagnosis was generally 0.5 to 1.9 years
(Table 2). All patients were on an opioid regimen upon
study 1003 entry. The average daily total opioids dosage at
baseline was similar between groups; small reductions in the
average daily total dosage occurred through week 8 for both
groups, but differences were not statistically significant (P 5
0.744; Table 1). The mean tanezumab treatment duration in
the parent and extension studies combined was 225 days;
most patients received at least 4 doses of tanezumab
(Table 3).
3.1. Study 1003
Overall, 101 patients were screened; 59 were randomized and
treated (placebo, n 5 30; tanezumab 10 mg, n 5 29; Fig. 2).

2.2.5. Statistical analysis (both studies)

3.1.1. Efficacy

Efficacy and safety were assessed in the intent-to-treat (ITT)


population in study 1003 (because all randomized patients
received study medication, ITT is equivalent to all randomized
patients). For study 1029, the ITT population was defined as all
patients who received at least 1 dose of study medication. The
primary analysis was an analysis of covariance (ANCOVA) with
terms for cancer type, baseline average pain score, and study
site, with missing data imputed using baseline observation
carried forward. Additional analyses explored sensitivity of the
effect of missing data using last-observation-carried-forward
imputation and a mixed model for repeated measurements.
Additional post hoc exploratory analyses of ANCOVA for daily
average pain at weeks 6 and 8 in study 1003 evaluated
a combination of 2 patient subgroups dichotomized at the
median for baseline daily average pain (#5 or .5) and average

In the primary analysis, least squares (LS) mean (SE; 95%


confidence interval [CI]) changes from baseline to week 6 for daily
average pain were 20.76 (0.64; 22.06 to 0.54) for tanezumab
treatment and 20.50 (0.55; 21.62 to 0.61) for placebo, resulting
in LS mean differences vs placebo of 20.26 (0.45; 21.18 to 0.66)
(P 5 0.569).
In secondary analyses, LS mean (SE; 95% CI) changes from
baseline to week 8 for daily average pain were 21.02 (0.60; 22.24
to 0.20) for tanezumab treatment and 20.56 (0.52; 21.61 to
0.49) for placebo treatment, resulting in LS mean difference vs
placebo of 20.46 (0.43; 21.34 to 0.42) (P 5 0.292; baseline
observation carried forward; Fig. 3). For daily worst pain, LS
mean (SE; 95% CI) changes from baseline to week 6 were
20.65 (0.64; 21.96 to 0.67) with tanezumab treatment
and 20.63 (0.55; 21.76 to 0.5) for placebo, resulting in LS

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Table 1

Patient baseline and demographic characteristics.


Study 1003
Sex, n (%)
Female
Age, y
Mean 6 SD
Range
Race, n (%)
White
Asian
Other
Baseline daily average pain score*
Mean 6 SD
Baseline daily worst pain score*
Mean 6 SD
Total daily opioid use (at baseline, mg/d MED)
Mean 6 SD
Total daily opioid use (through wk 8, mg/d MED)
Mean (SE)
Cancer type, n (%)
Prostate
Breast
Multiple myeloma
Renal cell carcinoma
Screening Karnofsky score, n (%)
100
90
80
70
60
50
Mean 6 SD

Study 1029

Placebo, n 5 30

Tanezumab 10 mg, n 5 29

Tanezumab 10 mg, n 5 41

16 (53.3)

16 (55.2)

21 (51.2)

55.8 6 11.9
32-77

62.1 6 11.9
40-90

58.7 6 12.4
32-91

21 (70.0)
9 (30.0)
0 (0.0)

23 (79.3)
4 (13.8)
2 (6.9)

32 (78.0)
9 (22.0)
0 (0.0)

5.3 6 0.98

5.4 6 1.02

4.21 6 2.21

6.4 6 1.06

6.3 6 1.30

5.34 6 2.63

102.0 6 112.78

111.8 6 134.59

101.59 (6.05)

103.20 (7.02)

12 (40.0)
15 (50.0)
2 (6.7)
1 (3.3)

13 (44.8)
16 (55.2)
0 (0.0)
0 (0.0)

18 (43.9)
20 (48.8)
2 (4.9)
1 (2.4)

1 (3.3)
6 (20.0)
13 (43.3)
5 (16.7)
5 (16.7)
0 (0.0)
78.0 6 10.9

0 (0.0)
6 (20.7)
9 (31.0)
9 (31.0)
5 (17.2)
0 (0.0)
75.5 6 10.2

1 (2.4)
10 (24.4)
14 (34.1)
7 (17.1)
7 (17.1)
2 (4.9)
76.3 6 12.4

* Daily average and daily worst pain scores rated on an 11-point numeric rating scale (0-10), ranging from 0 5 no pain to 10 5 pain as bad as you can imagine.
Baseline of study 1029 (includes tanezumab- and placebo-treated patients from study 1003).
Least squares means were estimated from the corresponding ANCOVA model.
ANCOVA, analysis of covariance; MED, morphine equivalent dose.

mean difference vs placebo of 20.01 (0.45; 20.93 to 0.91) (P 5


0.978). At week 8, LS mean changes from baseline in daily worst
pain were 20.98 (0.63; 22.27 to 0.31) for tanezumab-treated
patients and 20.79 (0.55; 21.91 to 0.32) for placebo-treated
patients, resulting in LS mean difference vs placebo of 20.18 (0.45;
21.10 to 0.73) (P 5 0.689). The mean observed change
(improvement) from baseline in daily average pain and daily worst
pain scores over the course of the study declined slightly more in
the tanezumab group than in the placebo-treated group, although

differences between treatments did not reach statistical significance (Fig. 4). Changes from baseline suggested modestly
greater efficacy with tanezumab-treated vs placebo-treated
patients toward the end of the 8-week postdose period. The
observed treatment differences were below that assumed in the
sample size estimation.
Post hoc dichotomization of baseline pain yielded consistently
greater improvements in daily average pain scores in patients with
baseline pain scores .5 in the tanezumab group vs placebo. At

Table 2

Study 1003 patient duration of disease characteristics.


Prostate cancer, n
Duration since histopathological diagnosis, mean (range), y
Duration since diagnosis of bone metastases, mean (range), y
Breast cancer, n
Duration since histopathologic diagnosis, mean (range), y
Duration since diagnosis of bone metastases, mean (range), y
Multiple myeloma, n
Duration since histopathologic diagnosis, mean (range), y
Duration since diagnosis of bone metastases, mean, y*
Renal cell carcinoma, n
Duration since histopathologic diagnosis, mean, y
Duration since diagnosis of bone metastases, mean, y

Placebo, n 5 30

Tanezumab 10 mg, n 5 29

12
4.02 (0.50-11.91)
1.92 (0.03-6.12)
15
3.82 (0.52-8.58)
1.59 (0.06-6.22)
2
6.64 (2.69-10.60)
0.59
1
0.37
0.37

13
3.44 (1.54-8.01)
1.69 (0.08-4.87)
16
6.8 (0.09-16.01)
1.74 (0.09-5.92)
0
0
0
0
0
0

* n 5 1.

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Table 3

Number of doses of study drug administered and duration in the study.


Studies 1003 and 1029 combined,* N 5 41

Study 1003
No. i.v. doses, n (%)
1
2
3
4
5
6
7
8
Patients remaining in study
At wk 6
At wk 8
Duration in study, d
Mean
Range

Placebo, n 5 30

Tanezumab 10 mg, n 5 29

30

29

9 (22.0)
7 (17.1)
3 (7.3)
10 (24.4)
11 (26.8)
0 (0.0)
0 (0.0)
1 (2.4)

27
25

25
25

68.9
15-125

83.1
20-127

225
15-619

* Tanezumab-treated only.

week 6, change from baseline vs placebo was 21.11 (95% CI, 22.81
to 0.59) and at week 8 was estimated at 21.67 (95% CI, 23.41 to
0.08) and approached significance (P 5 0.061).
In post hoc analyses of patients with high baseline pain
scores (.5) and low baseline opioid use (#60.5 mg/d MED),
the LS mean (SE) change from baseline at week 8 was 23.55
(1.36) with tanezumab treatment (n 5 6) and 20.83 (1.18) with

placebo (P 5 0.027, n 5 7), although in this subgroup, the


difference at week 6 was not statistically significant (tanezumab, 23.39 [1.23], n 5 6; placebo, 21.72 [1.06], n 5 7; P 5
0.121; Table 4).
At week 6, 41.4% of tanezumab-treated and 33.3% of
placebo-treated patients reported a $30% reduction in daily
average pain (P 5 0.596; Fig. 5A). By week 8, 48.3% of

Figure 2. Patient disposition. a Does not include death of a single patient during extended-use period or 4 patients who died after extended-use period.

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Figure 3. Least squares (LS) mean change (SE) from baseline at weeks 6 and 8
in (A) daily average pain and (B) daily worst pain scores in study 1003.

tanezumab-treated patients but only 20% of placebo-treated


patients reported $30% reduction (P 5 0.029; Fig. 5B). No
significant differences between treatments in responses at
$50%, $70%, or $90% for reduction in daily average pain were
noted.
3.2. Study 1029
A total of 42 patients were screened for study 1029, and 41
patients were treated with tanezumab 10 mg i.v. study
medication. Overall, 15 patients completed the study (ITT analysis
set; Fig. 2).

Figure 4. (A) Daily average pain scores or (B) daily worst pain scores in study
1003 (intent to treat, observed data). BL, baseline.

3.2.2. Safety (both studies)


3.2.1. Effectiveness
Repeated doses of tanezumab in study 1029 resulted in
consistent improvements from study 1003 baseline in daily
average pain and daily worst pain scores. For the overall
analysis, the observed mean (SE) change remained below
baseline for study 1003 through week 40 of study 1029,
indicating improvements of 21.27 (0.68) and 21.40 (0.65) for
daily average pain and daily worst pain, respectively (Fig. 6).
Percentages of patients reporting clinically meaningful improvements were generally similar throughout study 1029, with 13 of
30 (43.3%) and 11 of 30 (36.7%) patients reporting $30% and
$50% improvement in daily average pain, respectively, at week
8 of study 1029.

In study 1003, adverse event incidence was similar between


treatments (tanezumab, 62.1%; placebo, 60.0%; Table 5). The
types of adverse events in study 1029 were comparable to those
observed during study 1003 for tanezumab-treated patients.
Nausea was the most common adverse event in both studies.
Treatment-emergent serious adverse events were reported by 5
(17.2%) patients in the tanezumab group and by 2 (6.7%)
patients in the placebo group during study 1003. Serious
adverse events in the 5 tanezumab-treated patients consisted
of embolic stroke caused by atrial fibrillation and lung disorder
caused by hospitalization (2 events reported in the same
patient), femur fracture due to bone metastasis, malaise due
to dehydration, urinary tract infection, and hemorrhagic

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Table 4

Subgroup analyses for daily average pain score, change from baseline to weeks 6 and 8 in study 1003 (intent-to-treat population;
baseline observation carried forward).
Week 6
Low baseline pain* and low opioid use
N
Change from baseline, LS mean (SE)
Change from baseline vs placebo, LS mean
(95% CI)
P
Low baseline pain* and high opioid use
N
Change from baseline, LS mean (SE)
Change from baseline vs placebo, LS mean
(95% CI)
P
High baseline pain{ and low opioid use
N
Change from baseline, LS mean (SE)
Change from baseline vs placebo, LS mean
(95% CI)
P
High baseline pain{ and high opioid use
N
Change from baseline, LS mean (SE)
Change from baseline vs placebo, LS mean
(95% CI)
P

Week 8

Placebo, n 5 30

Tanezumab 10 mg, n 5 29

Placebo, n 5 30

Tanezumab 10 mg, n 5 29

9
22.77 (0.93)

7
23.15 (0.96)
20.38 (22.09 to 1.33)

9
22.24 (1.03)

7
22.99 (1.06)
20.75 (22.65 to 1.15)

0.647
7
0.45 (0.78)

8
0.75 (1.09)
0.31 (21.80 to 2.41)

0.420
7
20.01 (0.87)

0.765
7
21.72 (1.06)

6
23.39 (1.23)
21.67 (23.82 to 0.48)

0.921
7
20.83 (1.18)

0.121
7
21.56 (1.46)

8
21.70 (1.22)
20.14 (22.47 to 2.18)
0.899

8
0.11 (1.21)
0.11 (22.23 to 2.46)

6
23.55 (1.36)
22.72 (25.11 to 20.33)
0.027

7
21.36 (1.62)

8
21.57 (1.35)
20.21 (22.79 to 2.38)
0.870

* Baseline daily average pain score #5.


#60.5 mg/d morphine equivalent dose.
Least squares means were estimated from the corresponding ANCOVA models.
P value is based on ANCOVA from pairwise comparisons.
.60.5 mg/d morphine equivalent dose.
{ Baseline daily average pain score .5.
ANCOVA, analysis of covariance; CI, confidence interval; LS mean, least squares mean.

prostatitis (single events reported in 4 other patients). Serious


adverse events in the 2 placebo-treated patients consisted of
a urinary tract infection and metastatic disease progression
(1 patient each). In study 1029, 23 (56.1%) patients reported
serious adverse events, including anemia in 4 (9.8%) patients,
disease progression and prostate cancer in 3 (7.3%) patients
each, and metastatic neoplasm, pathologic fracture, and
metastatic prostate cancer in 2 (4.9%) each. No serious adverse
event in either study was considered to be related to tanezumab
by study investigators. Incidence of discontinuations due to
adverse events was greater in study 1029 (14.6%) than in study
1003 (tanezumab, 3.4%; placebo, 3.3%).
Three patients died while participating in study 1003 (1,
placebo; 2, tanezumab). Four additional deaths (placebo, n 5 3;
tanezumab, n 5 1) occurred after patients permanently
discontinued study participation for other reasons; no death
was attributed to treatment. Sixteen deaths occurred during
study 1029. Twelve of these were reported as adverse events
leading to a fatal outcome, with the adverse event being the
patients cancer at study entry or progression of the same;
therefore, none of the deaths were deemed by the investigators to
be related to tanezumab but were instead related to the
underlying cancer or cancer-related treatment such as
chemotherapy.
In study 1003, 2 events of abnormal peripheral sensation
were reported (moderate hyperesthesia and mild peripheral
neuropathy), both in the same patient (tanezumab). The
investigator determined these events were related to tanezumab treatment. In study 1029, 1 patient reported 2 adverse

events of abnormal peripheral sensation (hypoesthesia, which


the investigator determined was related to the disease under
study, and oral hypoesthesia, determined as being related to
mental nerve mononeuropathy, or result of metastatic cancer
progression); 1 patient reported hypoesthesia and 1 patient
reported peripheral neuropathy, both of which the investigator
determined to be related to tanezumab treatment.
Similar numbers of patients in both groups in study 1003
had a new or worsened abnormality on final neurologic
assessment (Table 6). Two patients in study 1003 from the
tanezumab group underwent neurologic consultation. One
patient had neurologic symptoms or signs not suggestive of
neuropathy (diagnosed as myelopathy), deemed by the
investigator to be cancer related. The other patient was
diagnosed with a new or worsened peripheral neuropathy with
clinically significant signs but without a confirmatory diagnostic test. Two patients in study 1029 were referred for
neurologic consultation. One had lip and chin numbness
categorized as neurologic symptoms or signs suggestive of
a preexisting neuropathy. The other had lumbar sacral region
pain categorized as neurologic symptoms or signs not
suggestive of a neuropathy.
In study 1003, 1 clinically significant ECG (moderate, nonserious tachycardia, placebo group) was captured as an adverse
event and attributed to the disease under study. In study 1029, no
clinically relevant changes in ECGs were observed. In both
studies, there was no clear evidence of a tanezumab effect on
vital signs or laboratory safety data and no reported events of
osteonecrosis or total joint replacements.

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1710

M. Sopata et al. 156 (2015) 17031713

PAIN

Figure 5. Percentage of patients rated as responders in daily average pain


reduction at (A) week 6 and (B) week 8 of study 1003 (intent to treat, baseline
observation carried forward). *P 5 0.029 vs placebo.

4. Discussion
Two studies examined tanezumab 10 mg i.v. in the treatment of
patients with cancer-taking background opioids for chronic pain
caused by bone metastases. Study 1003 was an initial proof-ofconcept study, designed without previous clinical data on the
use of an anti-NGF agent in this patient population. Although no
statistically significant changes were noted, numeric improvement in analgesic efficacy after a single tanezumab 10-mg dose
compared with placebo was demonstrated based on the
prespecified primary comparison of change in daily average
pain from baseline to week 6 and on additional comparison at
week 8; also, the data suggest that tanezumab treatment
resulted in sustained analgesic improvements throughout both
studies.
Subgroup analysis indicated statistically significant improvement with tanezumab 10 mg at week 8 in patients with higher
baseline daily average pain scores (.5) and lower total opioid
usage (,60.5 mg/d MED). Those results suggest demonstrating
overall tanezumab efficacy was challenging, because having
patients on a stabilized background analgesic regimen with the
option of IR opioids as rescue medication leads to lower baseline
values for daily average pain (;5). Baseline pain scores in study
1003 were lower than those typically reported in tanezumab
osteoarthritis studies,5,6,8,24,29,35,36,39 making it difficult to
achieve substantial improvements because there was less room
for improvement.16
Clinically meaningful pain relief is often described as a reduction
in pain intensity of $30% from baseline.33,34 Among secondary

Figure 6. Change from study 1003 baseline in Brief Pain Inventory short form
score for (A) daily average pain and (B) daily worst pain for patients who rolled
over to study 1029 by parent and extension study treatment (intent to treat,
observed data). BL, baseline. a Transition between studies #8 weeks.

endpoints, evidence of statistically significant efficacy at week 8


was observed in patients who had at least 30% reduction in daily
average pain because 48.3% of tanezumab-treated patients
experienced $30% reduction in daily average pain vs only 20.0%
of placebo-treated patients (P 5 0.029).
In study 1003, reported adverse events with 10 mg tanezumab
were comparable to those in the placebo group, indicating that
tanezumab addition to a stable opioid regimen was not
associated with an appreciable increase in adverse events in
patients with cancer pain caused by metastatic bone disease;
more serious adverse events were noted in the tanezumab group,
but no serious event was deemed caused by tanezumab, and the
small numbers of subjects in each group prevented statistical

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September 2015

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Number 9

www.painjournalonline.com

1711

Table 5

Incidence of adverse events, n (%).


Study 1003

Study 1029

Studies 1003 and 1029 combined

Placebo, n 5 30 Tanezumab 10 mg, n 5 29 Tanezumab 10 mg, n 5 41 Tanezumab and/or placebo, n 5 41


Patients with adverse events*
Patients with serious adverse events
Patients discontinued because of adverse
events
Adverse events occurring in $3 patients in any
group
Nausea
Anemia
Asthenia
Dyspnea
Peripheral edema
Pyrexia
Prostate cancer
Vomiting
Arthralgia
Constipation
Cough
Decreased appetite
Disease progression
Weight decreased
Fatigue

18 (60.0)
4 (13.3)
1 (3.3)

18 (62.1)
7 (24.1)
1 (3.4)

35 (85.4)
23 (56.1)
8 (19.5)

36 (87.8)
23 (56.1)
8 (19.5)

2 (6.7)
0 (0.0)
2 (6.7)
1 (3.3)
2 (6.7)
0 (0.0)
0 (0.0)
2 (6.7)
1 (3.3)
2 (6.7)
1 (3.3)
2 (6.7)
2 (6.7)
1 (3.3)
3 (10.0)

5 (17.2)
2 (6.9)
0 (0.0)
0 (0.0)
2 (6.9)
2 (6.9)
0 (0.0)
2 (6.9)
0 (0.0)
3 (10.3)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (3.4)

8 (19.5)
6 (14.6)
6 (14.6)
6 (14.6)
5 (12.2)
5 (12.2)
4 (9.8)
4 (9.8)
3 (7.3)
3 (7.3)
3 (7.3)
3 (7.3)
3 (7.3)
3 (7.3)
1 (2.4)

9 (21.6)
7 (17.1)
6 (14.6)
6 (14.6)
5 (12.2)
7 (17.1)
4 (9.8)
5 (12.2)
3 (7.3)
5 (12.2)
3 (7.3)
3 (7.3)
3 (7.3)
3 (7.3)
1 (2.4)

* An adverse event in study 1029 was defined as one that started during study 1029 (even if a separate event of the same adverse event term occurred in study 1003) or started during study 1003 and worsened in study 1029.
An adverse event for studies 1003 and 1029 combined was defined as one that started or worsened while the patient was receiving tanezumab.
Includes 2 patients discontinued from study 1029 classified in other discontinuation categories (progressive disease and death) in Fig. 2.
Presentation order for adverse events based on incidence in study 1029.

comparisons. Some adverse events of abnormal peripheral


sensation were reported. Nausea was the most common adverse
event in both studies and is a well-known side effect of opiates
taken as background analgesia.31 The adverse event profiles
were comparable to other tanezumab studies, with the exception
that gastrointestinal-related events (such as nausea and constipation) were more commonly reported in these studies and are
attributed, at least in part, to concomitant opioid use. Gastrointestinal adverse events are uncommon in other tanezumab
studies lacking opioid comparators.5,6,8,14,15,2224,29,30,35,36 The
increased incidence of serious adverse events (including death)
and discontinuations due to adverse events in study 1029
compared with study 1003 most likely reflect the progression of
underlying cancer and longer duration of study 1029.
Incidence of adverse events of abnormal peripheral sensation
reported in both studies was lower than in previous noncancer
tanezumab studies. Only 2 adverse events of abnormal peripheral
sensation were reported in study 1003 and 4 (in 3 patients) in
study 1029. Two patients in each study underwent neurologic
consultations. Only 1 of these events was considered suggestive
of a new or worsened clinical neuropathy. Limitations of this study

include a small sample size and a patient population taking daily


analgesia for a progressive disease.
In conclusion, although tanezumab 10-mg treatment did not
result in statistically significant efficacy improvement compared
with placebo in study 1003, the observed difference after the
8-week period suggests that tanezumab had greater efficacy
than placebo. Across both studies, numeric improvements were
seen in daily average and daily worst pain scores from study
1003 baseline. Evidence suggests that a further study in
patients with cancer pain is warranted. No new safety issues
were identified.

Conflict of interest statement


N. Katz is a consultant for Bayer, Biogen, Collegium, Concert,
Covidien, Cubist, DePuy, GW Pharmaceuticals, Lilly, Pfizer,
Phosphagenics, Purdue Pharma LP, and Zogenix; is a consultant
for and has received research grants from Astellas, AstraZeneca,
Fidia, Forest, Grunenthal, Janssen, and Purdue Pharma; is
a consultant for and participant on scientific advisory boards
for Genentech, Mallinckrodt, and Novartis. W. Carey, D. Keller,

Table 6

Summary of final neurologic examinations.


Study 1003
Final neurologic examination assessments,
n (%)*
Patients assessed
New or worsened abnormality
Clinically significant
Not clinically significant
No new or worsened abnormality

Study 1029

Placebo, n 5 30

Tanezumab 10 mg, n 5 29

Tanezumab 10 mg, n 5 41

28
4 (14.3)
0 (0.0)
4 (14.3)
24 (85.7)

28
3 (10.7)
2 (7.1)
1 (3.6)
25 (89.3)

37
5 (13.5)
0 (0.0)
5 (13.5)
32 (86.5)

* Neurologic examinations were performed per protocol by study investigators.

Copyright 2015 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.

1712

M. Sopata et al. 156 (2015) 17031713

K. M. Verburg, C. R. West, G. Wolfram, and M. T. Brown are


employees of and hold stock and/or stock options in Pfizer. M. D.
Smith was an employee of and held stock options in Pfizer Inc at the
time of the study. M. Sopata was a principal investigator for Pfizer.
This study was supported by Pfizer.

Acknowledgements
Editorial support was provided by Joseph Oleynek of Engage
Scientific Solutions and was funded by Pfizer Inc.
Article history:
Received 7 January 2015
Received in revised form 8 April 2015
Accepted 17 April 2015
Available online 25 April 2015

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