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Clinical Trial Results:
A Randomized, Double-blind, Multi-center Phase 2 Trial of Denosumab in Combination With Chemotherapy as First-line Treatment of Metastatic Non-small Cell Lung Cancer

Summary
EudraCT number	2013-001662-42
Trial protocol	DE NL IT GB GR CZ
Global end of trial date	28 Nov 2017

Results information
Results version number	v1(current)
This version publication date	07 Dec 2018
First version publication date	07 Dec 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

20120249

ISRCTN number

US NCT number

NCT01951586

WHO universal trial number (UTN)

Sponsor organisation name

Amgen Inc.

Sponsor organisation address

One Amgen Center Drive, Thousand Oaks, CA, United States, 91320

Public contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Scientific contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

28 Nov 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

28 Nov 2017

Was the trial ended prematurely?

Main objective of the trial

The primary objective was to estimate the treatment effect of the combination of denosumab and standard of care (SOC) versus SOC alone on overall survival.

Protection of trial subjects

This study was conducted in accordance with the current version of the Declaration of Helsinki, and the Food and Drug Administration and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.

Background therapy

Evidence for comparator

Actual start date of recruitment

31 Dec 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 32

Country: Number of subjects enrolled

Netherlands: 21

Country: Number of subjects enrolled

Italy: 18

Country: Number of subjects enrolled

France: 16

Country: Number of subjects enrolled

Germany: 6

Country: Number of subjects enrolled

Czech Republic: 9

Country: Number of subjects enrolled

United States: 40

Country: Number of subjects enrolled

Australia: 26

Country: Number of subjects enrolled

Canada: 27

Country: Number of subjects enrolled

Greece: 31

Worldwide total number of subjects

226

EEA total number of subjects

133

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

113

From 65 to 84 years

112

85 years and over

Subject disposition

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Recruitment details

This study was conducted at 57 centers in 10 countries including the United Kingdom, Netherlands, France, Italy, Germany, Czech Republic, United States, Canada, Australia and Greece. Participants were enrolled from 31 December 2013 to 21 May 2015.

Screening details

Participants were randomized in a 2:1 ratio to receive denosumab or placebo. Randomization was stratified based on the presence of bone metastasis (yes or no), histology (squamous versus non-squamous), and geographic region (North America, Western Europe/Australia, and rest of world [ROW]).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants randomized to receive placebo matching to denosumab by subcutaneous injection once every 4 weeks (Q4W) plus one loading dose on study day 8 in addition to platinum-based standard chemotherapy. Participants may have received placebo as often as once every 3 weeks (Q3W) while receiving Q3W chemotherapy. Participants with bone metastases also received 4 mg zoledronic acid administered as an IV infusion Q4W or Q3W.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Administered by subcutaneous injection once every 4 weeks (Q4W) plus one loading dose on study day 8; could be administered as often as every 3 weeks (Q3W) to participants receiving Q3W chemotherapy.

Denosumab

Arm description

Participants randomized to receive 120 mg denosumab by subcutaneous injection once every 4 weeks plus one loading dose on study day 8 in addition to platinum-based standard chemotherapy. Participants may have received denosumab as often as Q3W while receiving Q3W chemotherapy. Participants with bone metastases also received placebo to zoledronic acid administered as an IV infusion Q4W or Q3W.

Arm type

Experimental

Investigational medicinal product name

Denosumab

Investigational medicinal product code

AMG 162

Other name

XGEVA

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Administered by subcutaneous injection once every 4 weeks (Q4W) plus one loading dose on study day 8; could be administered as often as every 3 weeks (Q3W) to participants receiving Q3W chemotherapy.

Number of subjects in period 1	Placebo	Denosumab
Started	78	148
Received Study Drug	76	145
Completed	0	0
Not completed	78	148
Consent withdrawn by subject	8	17
Death	61	120
Lost to follow-up	-	1
Decision by sponsor	9	10

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

Denosumab

Reporting group description

Reporting group values	Placebo	Denosumab	Total
Number of subjects	78	148	226
Age categorical
Units: Subjects
< 70 years	54	102	156
≥ 70 years	24	46	70
Age Continuous
Units: years
arithmetic mean (standard deviation)	64.0 ± 10.1	63.8 ± 9.7	-
Sex: Female, Male
Units: Subjects
Female	20	54	74
Male	58	94	152
Race/Ethnicity, Customized
Units: Subjects
Black or African American	2	7	9
White or Caucasian	73	133	206
Others	3	8	11
Presence of Bone Metastasis
Data are based on randomized strata.
Units: Subjects
Yes	35	65	100
No	43	83	126
Histology
Data are based on randomized strata.
Units: Subjects
Squamous	18	35	53
Non-squamous	60	113	173
Geographic region
Units: Subjects
North America/Australia	30	63	93
Western Europe	35	67	102
Rest of World	13	18	31
Eastern Cooperative Oncology Group (ECOG) Performance Status
Eastern Cooperative Oncology Group (ECOG) Performance Status is used by doctors and researchers to assess how a participants disease is progressing, assess how the disease affects the daily living activities of the participant and determine appropriate treatment and prognosis. 0 = Fully Active; 1 = Restricted activity but ambulatory; 2 = Ambulatory but unable to carry out work activities; 3 = Limited Self- Care; 4 = Completely Disabled, no self-care, confined to bed or chair; 5 = Dead.
Units: Subjects
0 (Fully active)	33	69	102
1 (Restrictive but ambulatory)	45	79	124
Time from Initial Diagnosis of NSCLC to Randomization
Units: months
arithmetic mean (standard deviation)	2.46 ± 5.28	6.32 ± 16.96	-

End points

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Reporting group title

Placebo

Reporting group description

Reporting group title

Denosumab

Reporting group description

Primary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

Overall survival was calculated as the time from the date of randomization to the date of death from any cause. Participants last known to be alive were censored at the last contact date. The analysis includes all randomized participants.

End point type

Primary

End point timeframe

From randomization until the end of study; median time on study was 9.64 months.

End point values	Placebo	Denosumab
Number of subjects analysed	78	148
Units: months
median (confidence interval 95%)	10.9 (9.26 to 15.54)	10.7 (8.54 to 12.35)

Final Analysis of Overall Survival

Statistical analysis description

Overall survival was analyzed using a Cox proportional hazard model with treatment groups as the independent variable and stratified by the randomization stratification factors. A hazard ratio < 1 favors denosumab.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5157 ^[1]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

1.53

Notes
[1] - Log rank test stratified by the randomization stratification factors (presence of bone metastasis [yes or no], histology [squamous versus non-squamous], geographic region [North America, Western Europe/Australia, rest of world]).

Secondary: Correlation of Tumor Tissue RANK Expression with Overall Survival

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End point title

Correlation of Tumor Tissue RANK Expression with Overall Survival

End point description

To assess whether the treatment effect on overall survival was correlated with receptor activator of nuclear factor (NF)-κB (RANK) protein expression in tumor cells, RANK expression in archival tumor samples was measured using immunohistochemistry. The intensity of stain in the cytoplasm, membrane, and total was categorized as 0 (negative), 1+ (weak), 2+ (moderate) or 3+ (strong); All intensity is the sum of levels +1, +2 and +3. In addition, an H-score was calculated using the following formula: H-score=(percentage of cells of weak×1)+(percentage of cells of moderate×2)+(percentage of cells of strong×3). The maximum H-score was 300, corresponding to 100% of cells with strong intensity. The correlation between RANK expression level and OS was evaluated using a Cox proportional hazard models that included RANK expression level stratified by the randomization stratification factors in the corresponding treatment group.

End point type

Secondary

End point timeframe

From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.

End point values	Placebo	Denosumab
Number of subjects analysed	64 ^[2]	123 ^[3]
Units: hazard ratio
number (confidence interval 95%)
Cytoplasm all intensity	0.84 (0.65 to 1.09)	1.00 (0.85 to 1.17)
Membrane all intensity	0.72 (0.51 to 1.01)	0.92 (0.74 to 1.14)
Total all intensity	0.80 (0.62 to 1.03)	1.00 (0.85 to 1.17)
Cytoplasm H-score	0.83 (0.65 to 1.07)	1.00 (0.86 to 1.16)
Membrane H-score	0.72 (0.52 to 1.00)	0.93 (0.77 to 1.13)
Total H-score	0.80 (0.62 to 1.02)	1.00 (0.86 to 1.16)

Notes
[2] - All randomized participants who had evaluable pre-treatment tumor RANK expression
[3] - All randomized participants who had evaluable pre-treatment tumor RANK expression

Treatment-by-biomarker Interaction

Statistical analysis description

The interaction of RANK expression level measured in the cytoplasm (all intensity) and treatment effect was evaluated using a Cox proportional hazard model that included treatment group, RANK expression level and treatment-by-RANK expression level interaction stratified by the randomization stratification factors.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

187

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3759

Method

Cox propotional hazard model

Confidence interval

Treatment-by-biomarker Interaction

Statistical analysis description

The interaction of RANK expression level measured in membranes (all intensity) and treatment effect was evaluated using a Cox proportional hazard model that included treatment group, RANK expression level and treatment-by-RANK expression level interaction stratified by the randomization stratification factors.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

187

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3666

Method

Cox propotional hazard model

Confidence interval

Treatment-by-biomarker Interaction

Statistical analysis description

The interaction of RANK expression level total (cytoplasm + membranes; all intensity) and treatment effect was evaluated using a Cox proportional hazard model that included treatment group, RANK expression level and treatment-by-RANK expression level interaction stratified by the randomization stratification factors.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

187

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1917

Method

Cox propotional hazard model

Confidence interval

Treatment-by-biomarker Interaction

Statistical analysis description

The interaction of RANK expression level measured in the cytoplasm (H-score) and treatment effect was evaluated using a Cox proportional hazard model that included treatment group, RANK expression level and treatment-by-RANK expression level interaction stratified by the randomization stratification factors.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

187

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3353

Method

Cox propotional hazard model

Confidence interval

Treatment-by-biomarker Interaction

Statistical analysis description

The interaction of RANK expression level measured in membranes (H-score) and treatment effect was evaluated using a Cox proportional hazard model that included treatment group, RANK expression level and treatment-by-RANK expression level interaction stratified by the randomization stratification factors.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

187

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3179

Method

Cox propotional hazard model

Confidence interval

Treatment-by-biomarker Interaction

Statistical analysis description

The interaction of RANK expression level total (cytoplasm + membranes; H-score) and treatment effect was evaluated using a Cox proportional hazard model that included treatment group, RANK expression level and treatment-by-RANK expression level interaction stratified by the randomization stratification factors.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

187

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1583

Method

Cox propotional hazard model

Confidence interval

Secondary: Correlation of Tumor Tissue RANK Ligand Expression with Overall Survival

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End point title

Correlation of Tumor Tissue RANK Ligand Expression with Overall Survival

End point description

To assess whether the treatment effect on overall survival was correlated with RANK ligand (RANKL) protein expression in tumor cells, RANKL expression in archival tumor samples was measured using immunohistochemistry. The intensity of stain in the cytoplasm was categorized as 0 (negative), 1+ (weak), 2+ (moderate) or 3+ (strong); All intensity is the sum of levels +1, +2 and +3. In addition, an H-score was calculated using the following formula: H-score=(percentage of cells of weak×1)+(percentage of cells of moderate×2)+(percentage of cells of strong×3). The maximum H-score was 300, corresponding to 100% of cells with strong intensity. The correlation between RANKL expression level and OS was evaluated using a Cox proportional hazard models that included RANKL expression level stratified by the randomization stratification factors in the corresponding treatment group.

End point type

Secondary

End point timeframe

From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.

End point values	Placebo	Denosumab
Number of subjects analysed	65 ^[4]	121 ^[5]
Units: hazard ratio
number (confidence interval 95%)
Cytoplasm all intensity	0.77 (0.63 to 0.95)	0.93 (0.82 to 1.05)
Cytoplasm H-score	0.79 (0.66 to 0.95)	0.93 (0.84 to 1.04)

Notes
[4] - All randomized participants who had evaluable pre-treatment tumor RANKL expression
[5] - All randomized participants who had evaluable pre-treatment tumor RANKL expression

Treatment-by-biomarker Interaction

Statistical analysis description

The interaction of RANKL expression level measured in the cytoplasm (H-score) and treatment effect was evaluated using a Cox proportional hazard model that included treatment group, RANKL expression level and treatment-by-RANKL expression level interaction stratified by the randomization stratification factors.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

186

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3735

Method

Cox propotional hazard model

Confidence interval

Treatment-by-biomarker Interaction

Statistical analysis description

The interaction of RANKL expression level measured in the cytoplasm (all intensity) and treatment effect was evaluated using a Cox proportional hazard model that included treatment group, RANKL expression level and treatment-by-RANKL expression level interaction stratified by the randomization stratification factors.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

186

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3946

Method

Cox propotional hazard model

Confidence interval

Secondary: Objective Response Rate

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End point title

Objective Response Rate

End point description

Objective response rate was defined as the percentage of participants with a complete response (CR) or partial response (PR) based on modified RECIST 1.1 achieved over the study duration. CR: Disappearance of all target and non target lesions, normalization of tumor marker levels and no new lesions. PR: At least a 30% decrease in the size of target lesions with no progression of non-target lesions and no new lesions, or, disappearance of target lesions with persistence of one or more non-target lesions and/or maintenance of tumor marker levels above normal limits and no new lesions. Participants who underwent surgical resection while on study were not evaluated for response after the surgery. Participants who did not meet the criteria for an objective response by the analysis cutoff date were considered non-responders. Response rate was analyzed in randomized participants with at least one baseline measurable lesion per modified RECIST 1.1.

End point type

Secondary

End point timeframe

From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.

End point values	Placebo	Denosumab
Number of subjects analysed	76	144
Units: percentage of participants
number (not applicable)	43.4	36.8

Analysis of Objective Response Rate

Statistical analysis description

Odds ration was based on a logistic regression model adjusted for the randomization stratification factors; an odds ratio ≥ 1 favors denosumab.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

220

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3491 ^[6]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.76

Confidence interval

level

95%

sides

2-sided

lower limit

0.43

upper limit

1.35

Notes
[6] - Logistic regression model adjusted for the randomization stratification factors (presence of bone metastasis [yes or no], histology [squamous versus non-squamous], geographic region [North America, Western Europe/Australia, rest of world]).

Secondary: Correlation of Tumor Tissue RANK Expression with Objective Response Rate

Top of page

End point title

Correlation of Tumor Tissue RANK Expression with Objective Response Rate

End point description

To assess whether the treatment effect on objective response rate (ORR) based on RECIST 1.1 was correlated with RANK protein expression in tumor cells, RANK expression in archival tumor samples was measured using immunohistochemistry. The intensity of stain in the cytoplasm, membrane, and total was categorized as 0 (negative), 1+ (weak), 2+ (moderate) or 3+ (strong); All intensity is the sum of levels +1, +2 and +3. In addition, an H-score was calculated using the following formula: H-score=(percentage of cells of weak×1)+(percentage of cells of moderate×2)+(percentage of cells of strong×3). The maximum H-score was 300, corresponding to 100% of cells with strong intensity. The correlation between RANK expression level and ORR was evaluated within each treatment group using a logistical regression model that included RANK expression value as an independent variable and stratified by the randomization stratification factors. The odds ratio and 95% confidence interval are reported.

End point type

Secondary

End point timeframe

From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.

End point values	Placebo	Denosumab
Number of subjects analysed	63 ^[7]	119 ^[8]
Units: odds ratio
number (confidence interval 95%)
Cytoplasm all intensity	1.00 (0.67 to 1.50)	0.88 (0.68 to 1.13)
Membrane all intensity	1.18 (0.74 to 1.89)	0.82 (0.57 to 1.17)
Total all intensity	1.16 (0.78 to 1.71)	0.88 (0.68 to 1.13)
Cytoplasm H-score	1.00 (0.69 to 1.47)	0.87 (0.68 to 1.11)
Membrane H-score	1.14 (0.74 to 1.76)	0.82 (0.59 to 1.14)
Total H-score	1.14 (0.79 to 1.65)	0.87 (0.69 to 1.11)

Notes
[7] - Participants with ≥ 1 baseline measurable lesion and evaluable pre-treatment tumor RANK expression
[8] - Participants with ≥ 1 baseline measurable lesion and evaluable pre-treatment tumor RANK expression

Treatment-by-RANK Interaction

Statistical analysis description

The interaction of RANK expression level measured in the cytoplasm (all intensity) and treatment effect was evaluated using a logistic regression model that included treatment group, RANK expression level and treatment-by-RANK expression level interaction stratified by the randomization stratification factors.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

182

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.476

Method

Regression, Logistic

Confidence interval

Treatment-by-RANK Interaction

Statistical analysis description

The interaction of RANK expression level measured in the membranes (all intensity) and treatment effect was evaluated using a logistic regression model that included treatment group, RANK expression level and treatment-by-RANK expression level interaction stratified by the randomization stratification factors.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

182

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2582

Method

Regression, Logistic

Confidence interval

Treatment-by-RANK Interaction

Statistical analysis description

The interaction of RANK expression level total (cytoplasm + membrane; all intensity) and treatment effect was evaluated using a logistic regression model that included treatment group, RANK expression level and treatment-by-RANK expression level interaction stratified by the randomization stratification factors.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

182

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.223

Method

Regression, Logistic

Confidence interval

Treatment-by-RANK Interaction

Statistical analysis description

The interaction of RANK expression level measured in the cytoplasm (H-score) and treatment effect was evaluated using a logistic regression model that included treatment group, RANK expression level and treatment-by-RANK expression level interaction stratified by the randomization stratification factors.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

182

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.4329

Method

Regression, Logistic

Confidence interval

Treatment-by-RANK Interaction

Statistical analysis description

The interaction of RANK expression level measured in the membranes (H-score) and treatment effect was evaluated using a logistic regression model that included treatment group, RANK expression level and treatment-by-RANK expression level interaction stratified by the randomization stratification factors.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

182

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.262

Method

Regression, Logistic

Confidence interval

Treatment-by-RANK Interaction

Statistical analysis description

The interaction of RANK expression level total (cytoplasm + membrane; H-score) and treatment effect was evaluated using a logistic regression model that included treatment group, RANK expression level and treatment-by-RANK expression level interaction stratified by the randomization stratification factors.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

182

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2081

Method

Regression, Logistic

Confidence interval

Secondary: Correlation of Tumor Tissue RANKL Expression with Objective Response Rate

Top of page

End point title

Correlation of Tumor Tissue RANKL Expression with Objective Response Rate

End point description

To assess whether the treatment effect on objective response rate (ORR) based on RECIST 1.1 was correlated with RANKL protein expression in tumor cells, RANKL expression in archival tumor samples was measured using immunohistochemistry. The intensity of stain in the cytoplasm was categorized as 0 (negative), 1+ (weak), 2+ (moderate) or 3+ (strong); All intensity is the sum of levels +1, +2 and +3. In addition, an H-score was calculated using the following formula: H-score=(percentage of cells of weak×1)+(percentage of cells of moderate×2)+(percentage of cells of strong×3). The maximum H-score was 300, corresponding to 100% of cells with strong intensity. The correlation between RANKL expression level and ORR was evaluated within each treatment group using a logistical regression model that included RANKL expression value as an independent variable and stratified by the randomization stratification factors. The odds ratio and 95% confidence interval are reported.

End point type

Secondary

End point timeframe

From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.

End point values	Placebo	Denosumab
Number of subjects analysed	64 ^[9]	117 ^[10]
Units: odds ratio
number (confidence interval 95%)
Cytoplasm all intensity	1.27 (0.88 to 1.83)	1.10 (0.90 to 1.35)
Cytoplasm H-score	1.25 (0.91 to 1.72)	1.09 (0.91 to 1.30)

Notes
[9] - Participants with ≥ 1 baseline measurable lesion and evaluable pre-treatment tumor RANKL expression
[10] - Participants with ≥ 1 baseline measurable lesion and evaluable pre-treatment tumor RANKL expression

Treatment-by-RANKL Interaction

Statistical analysis description

The interaction of RANKL expression level measured in the cytoplasm (H-score) and treatment effect was evaluated using a logistic regression model that included treatment group, RANKL expression level and treatment-by-RANKL expression level interaction stratified by the randomization stratification factors.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.4236

Method

Regression, Logistic

Confidence interval

Treatment-by-RANKL Interaction

Statistical analysis description

The interaction of RANKL expression level measured in the cytoplasm (all intensity) and treatment effect was evaluated using a logistic regression model that included treatment group, RANKL expression level and treatment-by-RANKL expression level interaction stratified by the randomization stratification factors.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.4671

Method

Regression, Logistic

Confidence interval

Secondary: Clinical Benefit Rate

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End point title

Clinical Benefit Rate

End point description

Clinical benefit rate was defined as the percentage of participants with an objective response (CR or PR) or stable disease (SD) or better for at least 16 weeks achieved over the study duration. If a participant underwent surgical resection while on study, the participant was not evaluated for response after the surgery. Participants who did not meet the criteria for clinical benefit by the analysis cutoff date were considered as non-responders. Clinical benefit rate was analyzed in randomized participants with at least one baseline measurable lesion per modified RECIST 1.1.

End point type

Secondary

End point timeframe

From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.

End point values	Placebo	Denosumab
Number of subjects analysed	76	144
Units: percentage of participants
number (not applicable)	53.9	47.9

Analysis of Clinical Benefit Rate

Statistical analysis description

The odds ratio is based on a logistic regression model adjusted for the randomization stratification factors; an odds ratio ≥ 1 favors denosumab.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

220

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4654 ^[11]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

0.46

upper limit

1.43

Notes
[11] - Logistic regression model adjusted for the randomization stratification factors (presence of bone metastasis [yes or no], histology [squamous versus non-squamous], geographic region [North America, Western Europe/Australia, rest of world]).

Secondary: Progression-free Survival (PFS)

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End point title

Progression-free Survival (PFS)

End point description

Progression-free survival was defined as the time from randomization to the first observed disease progression per modified RECIST 1.1 criteria or death from any cause. Participants last known to be alive who did not experience disease progression were censored at their last imaging assessment date, last contact date if they were in the survival follow up phase, end of the study date, or the primary analysis cut-off date, whichever was first. If a participant underwent surgical resection while on study, the participant was censored at the last evaluable imaging assessment prior to the surgery. The analysis includes all randomized participants.

End point type

Secondary

End point timeframe

From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.

End point values	Placebo	Denosumab
Number of subjects analysed	78	148
Units: months
median (confidence interval 95%)	5.7 (4.37 to 7.16)	5.2 (4.24 to 5.78)

Analysis of Progression-free Survival

Statistical analysis description

The hazard ratio is based on a Cox proportional hazards model stratified by the randomization stratification factors. A hazard ratio < 1 favors denosumab.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7363 ^[12]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.78

upper limit

1.43

Notes
[12] - Log rank test stratified by the randomization stratification factors (presence of bone metastasis [yes or no], histology [squamous versus non-squamous], geographic region [North America, Western Europe/Australia, rest of world]).

Secondary: Serum Denosumab Trough Levels in Participants who Received Q3W Dosing

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End point title

Serum Denosumab Trough Levels in Participants who Received Q3W Dosing ^[13]

End point description

Serum samples were analyzed for denosumab using enzyme-linked immunosorbent assay (ELISA) following a validated procedure. The lower limit of quantification for the assay was 20 ng/mL. The analysis includes randomized participants who received denosumab every 3 weeks with at least one valid denosumab concentration measurement.

End point type

Secondary

End point timeframe

Prior to dosing at day 8 and weeks 3, 6, 9, 12, 15, 18, 21 and 24.

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Trough serum denosumab was analyzed separately for participants who received Q4W and Q3W dosing.

End point values	Denosumab
Number of subjects analysed	104
Units: ng/mL
arithmetic mean (standard deviation)
Dose 2 - Day 8 (n = 63)	8590 ± 4080
Dose 3 - Week 3 (n = 17)	12200 ± 5710
Dose 4 - Week 6 (n = 46)	19700 ± 7350
Dose 5 - Week 9 (n = 56)	19600 ± 8270
Dose 6 - Week 12 (n = 51)	22800 ± 10400
Dose 7 - Week 15 (n = 46)	24300 ± 11500
Dose 8 - Week 18 (n = 40)	22700 ± 10600
Dose 9 - Week 21 (n = 31)	22100 ± 11200
Dose 10 - Week 24 (n = 28)	23300 ± 12700

No statistical analyses for this end point

Secondary: Serum Denosumab Trough Levels in Participants who Received Q4W Dosing

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End point title

Serum Denosumab Trough Levels in Participants who Received Q4W Dosing ^[14]

End point description

Serum samples were analyzed for denosumab using enzyme-linked immunosorbent assay (ELISA) following a validated procedure. The lower limit of quantification for the assay was 20 ng/mL. The analysis includes randomized participants who received denosumab every 4 weeks with at least one valid denosumab concentration measurement.

End point type

Secondary

End point timeframe

Prior to dosing at day 8 and weeks 4, 8, 12, 16, 20 and 24

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Trough serum denosumab was analyzed separately for participants who received Q4W and Q3W dosing.

End point values	Denosumab
Number of subjects analysed	8
Units: ng/mL
arithmetic mean (standard deviation)
Dose 2 - Day 8 (n = 4)	8990 ± 2470
Dose 3 - Week 4 (n = 4)	10900 ± 3170
Dose 4 - Week 8 (n = 3)	15700 ± 6710
Dose 5 - Week 12 (n = 6)	14500 ± 4940
Dose 6 - Week 16 (n = 5)	13000 ± 4380
Dose 7 - Week 20 (n = 6)	15400 ± 5620
Dose 8 - Week 24 (n = 4)	15900 ± 7810

No statistical analyses for this end point

Secondary: Number of Participants with Treatment-emergent Adverse Events

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End point title

Number of Participants with Treatment-emergent Adverse Events

End point description

The analysis includes all randomized participants who received at least one dose of study drug. Participants were analyzed according to the actual treatment received; participants who received at least one dose of denosumab were analyzed in the “Denosumab” treatment group regardless of the randomized treatment assigned.

End point type

Secondary

End point timeframe

From first dose of study drug to the end of study date; the median (min, max) duration was 10.0 (0.2, 41.4) and 9.4 (0.2, 42.9) months for Placebo and Denosumab respectively.

End point values	Placebo	Denosumab
Number of subjects analysed	76	145
Units: participants
All adverse events (AEs)	76	144
Serious adverse events	68	129
AEs leading to discontinuation of study drug	6	20
Fatal adverse events	53	113
Treatment-related adverse events (TRAEs)	24	51
Treatment-related serious adverse events	0	6
TRAEs leading to discontinuation of study drug	0	7
Treatment-related fatal adverse events	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug to the end of study date; the median (min, max) duration was 10.0 (0.2, 41.4) and 9.4 (0.2, 42.9) months for Placebo and Denosumab respectively.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

Denosumab

Reporting group description

Participants received 120 mg denosumab by subcutaneous injection once every 4 weeks plus one loading dose on study day 8 in addition to platinum-based standard chemotherapy. Participants may have received denosumab as often as Q3W while receiving Q3W chemotherapy. Participants with bone metastases also received placebo to zoledronic acid administered as an IV infusion Q4W or Q3W.

Reporting group title

Placebo

Reporting group description

Participants received placebo matching to denosumab by subcutaneous injection once every 4 weeks (Q4W) plus one loading dose on study day 8 in addition to platinum-based standard chemotherapy. Participants may have received placebo as often as once every 3 weeks (Q3W) while receiving Q3W chemotherapy. Participants with bone metastases also received 4 mg zoledronic acid administered as an IV infusion Q4W or Q3W.

Serious adverse events	Denosumab	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	129 / 145 (88.97%)	68 / 76 (89.47%)
number of deaths (all causes)	118	59
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma
subjects affected / exposed	4 / 145 (2.76%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 4	0 / 2
Bronchial carcinoma
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cancer pain
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	2 / 145 (1.38%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 2	0 / 2
Lung adenocarcinoma stage IV
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Lung cancer metastatic
subjects affected / exposed	9 / 145 (6.21%)	3 / 76 (3.95%)
occurrences causally related to treatment / all	0 / 10	0 / 3
deaths causally related to treatment / all	0 / 9	0 / 3
Lung neoplasm malignant
subjects affected / exposed	10 / 145 (6.90%)	5 / 76 (6.58%)
occurrences causally related to treatment / all	0 / 10	0 / 5
deaths causally related to treatment / all	0 / 10	0 / 4
Lung squamous cell carcinoma metastatic
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Lymphangiosis carcinomatosa
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	2 / 145 (1.38%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 2
Malignant pleural effusion
subjects affected / exposed	1 / 145 (0.69%)	3 / 76 (3.95%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	0 / 145 (0.00%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to bone marrow
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	6 / 145 (4.14%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 10	0 / 2
deaths causally related to treatment / all	0 / 4	0 / 1
Metastases to lung
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Metastases to meninges
subjects affected / exposed	2 / 145 (1.38%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metastatic neoplasm
subjects affected / exposed	0 / 145 (0.00%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2
Non-small cell lung cancer
subjects affected / exposed	19 / 145 (13.10%)	9 / 76 (11.84%)
occurrences causally related to treatment / all	0 / 19	0 / 10
deaths causally related to treatment / all	0 / 18	0 / 9
Non-small cell lung cancer metastatic
subjects affected / exposed	14 / 145 (9.66%)	7 / 76 (9.21%)
occurrences causally related to treatment / all	0 / 14	0 / 7
deaths causally related to treatment / all	0 / 14	0 / 7
Non-small cell lung cancer stage IV
subjects affected / exposed	12 / 145 (8.28%)	5 / 76 (6.58%)
occurrences causally related to treatment / all	0 / 14	0 / 7
deaths causally related to treatment / all	0 / 11	0 / 5
Vascular disorders
Aortic thrombosis
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 145 (0.69%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Embolism
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Embolism venous
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Hypotension
subjects affected / exposed	4 / 145 (2.76%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Jugular vein thrombosis
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Superior vena cava syndrome
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chest pain
subjects affected / exposed	4 / 145 (2.76%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chills
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Disease progression
subjects affected / exposed	5 / 145 (3.45%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 4	0 / 1
Condition aggravated
subjects affected / exposed	1 / 145 (0.69%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fatigue
subjects affected / exposed	2 / 145 (1.38%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	7 / 145 (4.83%)	4 / 76 (5.26%)
occurrences causally related to treatment / all	0 / 9	0 / 5
deaths causally related to treatment / all	0 / 2	0 / 2
Infusion site extravasation
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 145 (0.00%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	12 / 145 (8.28%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 18	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	5 / 145 (3.45%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	16 / 145 (11.03%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 20	0 / 2
deaths causally related to treatment / all	0 / 5	0 / 0
Epistaxis
subjects affected / exposed	1 / 145 (0.69%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	2 / 145 (1.38%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Haemothorax
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	2 / 145 (1.38%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Laryngeal mass
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Laryngeal obstruction
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	6 / 145 (4.14%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	3 / 145 (2.07%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	6 / 145 (4.14%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	3 / 145 (2.07%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Respiratory failure
subjects affected / exposed	4 / 145 (2.76%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 3	0 / 2
Psychiatric disorders
Confusional state
subjects affected / exposed	3 / 145 (2.07%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Delirium
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Device issue
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
C-reactive protein increased
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General physical condition abnormal
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Glomerular filtration rate decreased
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nutritional condition abnormal
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	1 / 145 (0.69%)	3 / 76 (3.95%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femoral neck fracture
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fracture
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Radiation oesophagitis
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Hereditary angioedema
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 145 (0.69%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	3 / 145 (2.07%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac tamponade
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	4 / 145 (2.76%)	3 / 76 (3.95%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 4	0 / 3
Myocardial infarction
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Coronary artery insufficiency
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Tachycardia
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Palpitations
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Altered state of consciousness
subjects affected / exposed	2 / 145 (1.38%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Brain oedema
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	2 / 145 (1.38%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1
Consciousness fluctuating
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Depressed level of consciousness
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Headache
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lethargy
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Seizure
subjects affected / exposed	2 / 145 (1.38%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stroke in evolution
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 145 (3.45%)	5 / 76 (6.58%)
occurrences causally related to treatment / all	0 / 7	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	6 / 145 (4.14%)	5 / 76 (6.58%)
occurrences causally related to treatment / all	0 / 6	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	3 / 145 (2.07%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	2 / 145 (1.38%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	4 / 145 (2.76%)	5 / 76 (6.58%)
occurrences causally related to treatment / all	0 / 4	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal wall haematoma
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	1 / 145 (0.69%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Melaena
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	6 / 145 (4.14%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 8	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	2 / 145 (1.38%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal perforation
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Vomiting
subjects affected / exposed	4 / 145 (2.76%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic failure
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	1 / 145 (0.69%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal haemorrhage
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	2 / 145 (1.38%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	2 / 145 (1.38%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 145 (0.69%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Osteonecrosis of jaw
subjects affected / exposed	4 / 145 (2.76%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	7 / 7	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vertebral lesion
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	2 / 145 (1.38%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fungal infection
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	1 / 145 (0.69%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gangrene
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis shigella
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 145 (0.69%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lung abscess
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Oral herpes
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural infection
subjects affected / exposed	1 / 145 (0.69%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	14 / 145 (9.66%)	7 / 76 (9.21%)
occurrences causally related to treatment / all	0 / 19	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	3 / 145 (2.07%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 145 (1.38%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	3 / 145 (2.07%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 145 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	1 / 145 (0.69%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1
Dehydration
subjects affected / exposed	6 / 145 (4.14%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	2 / 145 (1.38%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 145 (0.69%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Denosumab	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	139 / 145 (95.86%)	71 / 76 (93.42%)
Vascular disorders
Hypotension
subjects affected / exposed	4 / 145 (2.76%)	5 / 76 (6.58%)
occurrences all number	4	6
General disorders and administration site conditions
Asthenia
subjects affected / exposed	24 / 145 (16.55%)	8 / 76 (10.53%)
occurrences all number	30	18
Fatigue
subjects affected / exposed	67 / 145 (46.21%)	33 / 76 (43.42%)
occurrences all number	112	55
Mucosal inflammation
subjects affected / exposed	8 / 145 (5.52%)	4 / 76 (5.26%)
occurrences all number	13	5
Oedema peripheral
subjects affected / exposed	26 / 145 (17.93%)	17 / 76 (22.37%)
occurrences all number	33	19
Pyrexia
subjects affected / exposed	23 / 145 (15.86%)	9 / 76 (11.84%)
occurrences all number	33	12
Pain
subjects affected / exposed	10 / 145 (6.90%)	7 / 76 (9.21%)
occurrences all number	11	13
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	26 / 145 (17.93%)	16 / 76 (21.05%)
occurrences all number	35	17
Dyspnoea
subjects affected / exposed	35 / 145 (24.14%)	18 / 76 (23.68%)
occurrences all number	46	21
Epistaxis
subjects affected / exposed	8 / 145 (5.52%)	5 / 76 (6.58%)
occurrences all number	9	5
Haemoptysis
subjects affected / exposed	10 / 145 (6.90%)	6 / 76 (7.89%)
occurrences all number	11	8
Hiccups
subjects affected / exposed	7 / 145 (4.83%)	4 / 76 (5.26%)
occurrences all number	7	4
Productive cough
subjects affected / exposed	9 / 145 (6.21%)	2 / 76 (2.63%)
occurrences all number	11	2
Psychiatric disorders
Anxiety
subjects affected / exposed	14 / 145 (9.66%)	5 / 76 (6.58%)
occurrences all number	17	5
Depression
subjects affected / exposed	2 / 145 (1.38%)	6 / 76 (7.89%)
occurrences all number	2	6
Insomnia
subjects affected / exposed	12 / 145 (8.28%)	7 / 76 (9.21%)
occurrences all number	13	7
Investigations
Blood creatinine increased
subjects affected / exposed	12 / 145 (8.28%)	3 / 76 (3.95%)
occurrences all number	26	5
Aspartate aminotransferase increased
subjects affected / exposed	3 / 145 (2.07%)	4 / 76 (5.26%)
occurrences all number	3	6
Platelet count decreased
subjects affected / exposed	14 / 145 (9.66%)	8 / 76 (10.53%)
occurrences all number	25	11
Weight decreased
subjects affected / exposed	8 / 145 (5.52%)	10 / 76 (13.16%)
occurrences all number	9	13
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	2 / 145 (1.38%)	5 / 76 (6.58%)
occurrences all number	2	6
Nervous system disorders
Dizziness
subjects affected / exposed	20 / 145 (13.79%)	7 / 76 (9.21%)
occurrences all number	21	9
Dysgeusia
subjects affected / exposed	8 / 145 (5.52%)	11 / 76 (14.47%)
occurrences all number	8	12
Headache
subjects affected / exposed	24 / 145 (16.55%)	8 / 76 (10.53%)
occurrences all number	30	8
Neuropathy peripheral
subjects affected / exposed	5 / 145 (3.45%)	9 / 76 (11.84%)
occurrences all number	5	11
Paraesthesia
subjects affected / exposed	8 / 145 (5.52%)	2 / 76 (2.63%)
occurrences all number	12	2
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	60 / 145 (41.38%)	38 / 76 (50.00%)
occurrences all number	156	101
Neutropenia
subjects affected / exposed	32 / 145 (22.07%)	15 / 76 (19.74%)
occurrences all number	77	32
Thrombocytopenia
subjects affected / exposed	16 / 145 (11.03%)	16 / 76 (21.05%)
occurrences all number	37	27
Leukopenia
subjects affected / exposed	6 / 145 (4.14%)	4 / 76 (5.26%)
occurrences all number	14	7
Eye disorders
Dry eye
subjects affected / exposed	2 / 145 (1.38%)	4 / 76 (5.26%)
occurrences all number	2	5
Lacrimation increased
subjects affected / exposed	9 / 145 (6.21%)	3 / 76 (3.95%)
occurrences all number	10	5
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	1 / 145 (0.69%)	4 / 76 (5.26%)
occurrences all number	1	4
Abdominal pain
subjects affected / exposed	13 / 145 (8.97%)	4 / 76 (5.26%)
occurrences all number	13	5
Constipation
subjects affected / exposed	50 / 145 (34.48%)	27 / 76 (35.53%)
occurrences all number	70	35
Diarrhoea
subjects affected / exposed	26 / 145 (17.93%)	14 / 76 (18.42%)
occurrences all number	29	16
Dyspepsia
subjects affected / exposed	8 / 145 (5.52%)	5 / 76 (6.58%)
occurrences all number	10	5
Dysphagia
subjects affected / exposed	5 / 145 (3.45%)	6 / 76 (7.89%)
occurrences all number	7	7
Gastrooesophageal reflux disease
subjects affected / exposed	6 / 145 (4.14%)	4 / 76 (5.26%)
occurrences all number	6	4
Nausea
subjects affected / exposed	64 / 145 (44.14%)	34 / 76 (44.74%)
occurrences all number	105	53
Vomiting
subjects affected / exposed	35 / 145 (24.14%)	14 / 76 (18.42%)
occurrences all number	57	19
Stomatitis
subjects affected / exposed	7 / 145 (4.83%)	6 / 76 (7.89%)
occurrences all number	11	9
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	9 / 145 (6.21%)	6 / 76 (7.89%)
occurrences all number	9	6
Dry skin
subjects affected / exposed	6 / 145 (4.14%)	4 / 76 (5.26%)
occurrences all number	6	4
Rash
subjects affected / exposed	18 / 145 (12.41%)	8 / 76 (10.53%)
occurrences all number	21	11
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	11 / 145 (7.59%)	7 / 76 (9.21%)
occurrences all number	15	8
Back pain
subjects affected / exposed	20 / 145 (13.79%)	15 / 76 (19.74%)
occurrences all number	23	24
Muscle spasms
subjects affected / exposed	4 / 145 (2.76%)	4 / 76 (5.26%)
occurrences all number	4	4
Musculoskeletal chest pain
subjects affected / exposed	9 / 145 (6.21%)	5 / 76 (6.58%)
occurrences all number	9	10
Pain in extremity
subjects affected / exposed	14 / 145 (9.66%)	7 / 76 (9.21%)
occurrences all number	22	10
Musculoskeletal pain
subjects affected / exposed	10 / 145 (6.90%)	5 / 76 (6.58%)
occurrences all number	14	6
Infections and infestations
Herpes zoster
subjects affected / exposed	0 / 145 (0.00%)	4 / 76 (5.26%)
occurrences all number	0	5
Oral candidiasis
subjects affected / exposed	5 / 145 (3.45%)	5 / 76 (6.58%)
occurrences all number	6	6
Nasopharyngitis
subjects affected / exposed	3 / 145 (2.07%)	5 / 76 (6.58%)
occurrences all number	3	6
Urinary tract infection
subjects affected / exposed	11 / 145 (7.59%)	4 / 76 (5.26%)
occurrences all number	12	4
Pneumonia
subjects affected / exposed	10 / 145 (6.90%)	2 / 76 (2.63%)
occurrences all number	11	2
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	34 / 145 (23.45%)	23 / 76 (30.26%)
occurrences all number	39	30
Hypercalcaemia
subjects affected / exposed	5 / 145 (3.45%)	4 / 76 (5.26%)
occurrences all number	5	4
Hyperglycaemia
subjects affected / exposed	6 / 145 (4.14%)	4 / 76 (5.26%)
occurrences all number	8	4
Hypokalaemia
subjects affected / exposed	8 / 145 (5.52%)	4 / 76 (5.26%)
occurrences all number	9	4
Hypocalcaemia
subjects affected / exposed	24 / 145 (16.55%)	4 / 76 (5.26%)
occurrences all number	39	6
Hypomagnesaemia
subjects affected / exposed	17 / 145 (11.72%)	12 / 76 (15.79%)
occurrences all number	28	19
Hyponatraemia
subjects affected / exposed	3 / 145 (2.07%)	4 / 76 (5.26%)
occurrences all number	4	4
Hypophosphataemia
subjects affected / exposed	11 / 145 (7.59%)	5 / 76 (6.58%)
occurrences all number	15	6

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Were there any global substantial amendments to the protocol? Yes

15 Sep 2014

• to clarify that randomization must be before the first dose (cycle 1 day 1) of the planned chemotherapy described in the protocol • modify the duration after the last dose of investigational product for using contraception, becoming pregnant, and breast feeding from 7 months to 5 months • deleting ‘pegylated interferon-based treatment’ in the previous treatment for hepatitis C • deleting the trade name “Zometa®” to allow for the use of branded or generic ZA supplied for the study • permitting commercial, open-label IV bisphosphonates to be administered for hypercalcemia of malignancy, if necessary • clarifying that baseline tumor tissue can be submitted soon after randomization, and that samples should have ample tumor tissue • local laboratory tests (serum chemistry and complete blood count) can be from before each dosing visit, if per SOC • deaths that occur in survival follow-up will be reported to Amgen as serious adverse events • the criteria for authorship credit in a publication was updated per International Committee of Medical Journal Editor guidelines

22 Apr 2016

• expanding primary endpoint to OS • evaluating “Tumor tissue RANK expression in correlation with OS” as a secondary endpoint • adding the opportunity for study subjects on regular assessments to obtain/remain on open-label denosumab should a positive benefit:risk profile be determined

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical Trial Results:
A Randomized, Double-blind, Multi-center Phase 2 Trial of Denosumab in Combination With Chemotherapy as First-line Treatment of Metastatic Non-small Cell Lung Cancer

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Primary: Overall Survival (OS)

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Secondary: Objective Response Rate

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Clinical trials

Clinical Trial Results: A Randomized, Double-blind, Multi-center Phase 2 Trial of Denosumab in Combination With Chemotherapy as First-line Treatment of Metastatic Non-small Cell Lung Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overall Survival (OS)

Primary: Overall Survival (OS)

Secondary: Correlation of Tumor Tissue RANK Expression with Overall Survival

Secondary: Correlation of Tumor Tissue RANK Expression with Overall Survival

Secondary: Correlation of Tumor Tissue RANK Ligand Expression with Overall Survival

Secondary: Correlation of Tumor Tissue RANK Ligand Expression with Overall Survival

Secondary: Objective Response Rate

Secondary: Objective Response Rate

Secondary: Correlation of Tumor Tissue RANK Expression with Objective Response Rate

Secondary: Correlation of Tumor Tissue RANK Expression with Objective Response Rate

Secondary: Correlation of Tumor Tissue RANKL Expression with Objective Response Rate

Secondary: Correlation of Tumor Tissue RANKL Expression with Objective Response Rate

Secondary: Clinical Benefit Rate

Secondary: Clinical Benefit Rate

Secondary: Progression-free Survival (PFS)

Secondary: Progression-free Survival (PFS)

Secondary: Serum Denosumab Trough Levels in Participants who Received Q3W Dosing

Secondary: Serum Denosumab Trough Levels in Participants who Received Q3W Dosing

Secondary: Serum Denosumab Trough Levels in Participants who Received Q4W Dosing

Secondary: Serum Denosumab Trough Levels in Participants who Received Q4W Dosing

Secondary: Number of Participants with Treatment-emergent Adverse Events

Secondary: Number of Participants with Treatment-emergent Adverse Events

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Randomized, Double-blind, Multi-center Phase 2 Trial of Denosumab in Combination With Chemotherapy as First-line Treatment of Metastatic Non-small Cell Lung Cancer