Denosumab in Combination With Chemotherapy as First-line Treatment of Metastatic Non-small Cell Lung Cancer

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01951586
• Collaborator: (none)
• Enrollment: 226
• Locations: 74
• Arms: 2
• Actual Duration (Months): 46.9
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This randomized phase 2 trial is studying the effect of adding denosumab to standard chemotherapy in the treatment of advanced lung cancer.

Condition or Disease	Intervention/Treatment	Phase
Non-Small Cell Lung Cancer	Drug: Denosumab; Drug: Zoledronic acid; Drug: Placebo to Denosumab; Drug: Standard Chemotherapy; Drug: Placebo to Zoledronic Acid	Phase 2

Detailed Description

This is a global randomized double-blind placebo-controlled study in patients with Stage IV untreated non-small cell lung cancer (NSCLC) with or without bone metastasis. Eligible participants are to receive 4 to 6 cycles of a standard of care platinum-doublet chemotherapy regimen. Participants will be randomized in a 2:1 ratio to receive denosumab or matching placebo with the first investigational product dose coinciding with participant's first cycle of chemotherapy and continuing until the primary analysis, unacceptable toxicity, withdrawal of consent, death, or lost to follow-up. Participants who discontinued the investigational product early (ie, before primary analysis) were followed for disease status and survival. The primary analysis took place when 149 events of death had been reported. All participants were followed for 2 years after the last dose of blinded investigational product.

Study Design

• Study Type: Interventional
• Actual Enrollment: 226 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Dec 31, 2013
• Actual Primary Completion Date: Jul 29, 2016
• Actual Study Completion Date: Nov 28, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received placebo matching to denosumab by subcutaneous injection once every 4 weeks plus one loading dose on study day 8 in addition to platinum-based standard chemotherapy. Participants with bone metastases also received 4 mg zoledronic acid administered as an IV infusion Q4W or Q3W.	Drug: Zoledronic acid; Administered by intravenous infusion in participants with bone metastasis upon investigative site request for IV bone-targeted therapy.; Other Names: Zometa ; Drug: Placebo to Denosumab; 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.; Drug: Standard Chemotherapy; Standard of care chemotherapy consisting of pemetrexed or gemcitabine in combination with cisplatin or carboplatin administered according to local practice.
Experimental: Denosumab 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 with bone metastases also received placebo to zoledronic acid administered as an IV infusion Q4W or Q3W.	Drug: Denosumab; 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.; Other Names: XGEVA ; Drug: Standard Chemotherapy; Standard of care chemotherapy consisting of pemetrexed or gemcitabine in combination with cisplatin or carboplatin administered according to local practice.; Drug: Placebo to Zoledronic Acid; Administered by intravenous infusion in participants with bone metastasis upon investigative site request for IV bone-targeted therapy.

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) [From randomization until the end of study; median time on study was 9.64 months.]

   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.

Secondary Outcome Measures

1. Correlation of Tumor Tissue RANK Expression With Overall Survival [From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.]

   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.

2. Correlation of Tumor Tissue RANK Ligand Expression With Overall Survival [From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.]

   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.

3. Objective Response Rate [From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.]

   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.

4. Correlation of Tumor Tissue RANK Expression With Objective Response Rate [From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.]

   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.

5. Correlation of Tumor Tissue RANKL Expression With Objective Response Rate [From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.]

   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.

6. Clinical Benefit Rate [From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.]

   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.

7. Progression-free Survival (PFS) [From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.]

   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.

8. Serum Denosumab Trough Levels in Participants Who Received Q3W Dosing [Prior to dosing at day 8 and weeks 3, 6, 9, 12, 15, 18, 21 and 24.]

   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.

9. Serum Denosumab Trough Levels in Participants Who Received Q4W Dosing [Prior to dosing at day 8 and weeks 4, 8, 12, 16, 20 and 24]

   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.

10. Number of Participants With Treatment-emergent 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.]

    An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant. The event does not necessarily have a causal relationship with study treatment. A serious adverse event is defined as an AE that meets at least 1 of the following criteria fatal life threatening requires in-patient hospitalization or prolongation of existing hospitalization results in persistent or significant disability/incapacity congenital anomaly/birth defect other medically important serious event Treatment-related AEs include only TEAEs for which the investigator indicated there was a reasonable possibility they may have been caused by study drug. Fatal adverse events include only deaths reported on the Adverse Event Case Report Form.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically confirmed stage IV non-small cell lung carcinoma (NSCLC), according to 7th Tumor/Node/Metastasis (TNM) classification (cytological specimens obtained by bronchial washing or brushing, or fine-needle aspiration are acceptable)

• Subject has available and has provided consent to release to the sponsor (or designee) a tumor block with confirmed tumor content (or approximately 20 unstained charged slides [a minimum of 7 slides is mandatory]) and the corresponding pathology report

• Planned to receive 4 to 6 cycles of pemetrexed or gemcitabine in combination with cisplatin or carboplatin

• For subjects to receive pemetrexed, planned to receive vitamin B12 and folate per pemetrexed approved labeling

• Radiographically evaluable (measurable or non-measurable) disease (according to modified Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria

• Other inclusion criteria may apply

Exclusion Criteria:

• Known presence of documented sensitizing epidermal growth factor receptor (EGFR) activating mutation or echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) translocation (screening following local standards, but strongly encouraged in non-squamous histology)

• Known brain metastases (systematic screening of patients not mandatory)

• Any prior systemic therapy (before randomization) for the treatment of NSCLC (including chemoradiation), except if for non-metastatic disease and was completed at least 6 months prior to randomization

• Planned to receive bevacizumab

• Significant dental/oral disease, including prior history or current evidence of osteonecrosis/ osteomyelitis of the jaw, or with the following:

• Active dental or jaw condition which requires oral surgery

• Non-healed dental/oral surgery

• Planned invasive dental procedures for the course of the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Goodyear	Arizona	United States	85338
2	Research Site	Anaheim	California	United States	92801
3	Research Site	Long Beach	California	United States	90813
4	Research Site	Los Angeles	California	United States	90024
5	Research Site	Los Angeles	California	United States	90048
6	Research Site	Farmington	Connecticut	United States	06030-1628
7	Research Site	Alexandria	Louisiana	United States	71301
8	Research Site	Brewer	Maine	United States	04412
9	Research Site	Westminster	Maryland	United States	21157
10	Research Site	Fairhaven	Massachusetts	United States	02719
11	Research Site	Detroit	Michigan	United States	48202
12	Research Site	East Setauket	New York	United States	11733
13	Research Site	Durham	North Carolina	United States	27710
14	Research Site	Hickory	North Carolina	United States	28602
15	Research Site	Winston-Salem	North Carolina	United States	27157
16	Research Site	Bismarck	North Dakota	United States	58501
17	Research Site	Cincinnati	Ohio	United States	45267
18	Research Site	Nashville	Tennessee	United States	37203
19	Research Site	Kogarah	New South Wales	Australia	2217
20	Research Site	Wahroonga	New South Wales	Australia	2076
21	Research Site	Adelaide	South Australia	Australia	5000
22	Research Site	Footscray	Victoria	Australia	3011
23	Research Site	Parkville	Victoria	Australia	3050
24	Research Site	Wodonga	Victoria	Australia	3690
25	Research Site	Edmonton	Alberta	Canada	T6G 1Z2
26	Research Site	Saint John	New Brunswick	Canada	E2L 4L2
27	Research Site	Kitchener	Ontario	Canada	N2G 1G3
28	Research Site	Sudbury	Ontario	Canada	P3E 5J1
29	Research Site	Toronto	Ontario	Canada	M5G 2M9
30	Research Site	Toronto	Ontario	Canada	M9N 1N8
31	Research Site	Montreal	Quebec	Canada	H2W 1S6
32	Research Site	Chomutov		Czechia	430 12
33	Research Site	Ostrava-Poruba		Czechia	708 52
34	Research Site	Pardubice		Czechia	532 03
35	Research Site	Praha 8		Czechia	180 81
36	Research Site	Usti nad Labem		Czechia	401 13
37	Research Site	Caen Cedex 5		France	14076
38	Research Site	Dijon cedex		France	21079
39	Research Site	Nantes Cedex 2		France	44202
40	Research Site	Paris Cedex 10		France	75475
41	Research Site	Paris Cedex 14		France	75674
42	Research Site	Paris Cedex 20		France	75020
43	Research Site	Pessac Cedex		France	33604
44	Research Site	Reims Cedex		France	51056
45	Research Site	Saint Quentin		France	02321
46	Research Site	Tours Cedex 9		France	37044
47	Research Site	Berlin		Germany	14165
48	Research Site	Grosshansdorf		Germany	22927
49	Research Site	Köln-Merheim		Germany	51109
50	Research Site	Ulm		Germany	89081
51	Research Site	Athens		Greece	11522
52	Research Site	Athens		Greece	12462
53	Research Site	Heraklion		Greece	71110
54	Research Site	Patra		Greece	26504
55	Research Site	Thessaloniki		Greece	54622
56	Research Site	Thessaloniki		Greece	57010
57	Research Site	Monza (MB)		Italy	20900
58	Research Site	Orbassano (TO)		Italy	10043
59	Research Site	Pavia		Italy	27100
60	Research Site	Roma		Italy	00128
61	Research Site	Saronno VA		Italy	21047
62	Research Site	's Hertogenbosch		Netherlands	5223 GZ
63	Research Site	Arnhem		Netherlands	6815 AD
64	Research Site	Harderwijk		Netherlands	3844 DG
65	Research Site	Tilburg		Netherlands	5022 GC
66	Research Site	Zutphen		Netherlands	7207 AE
67	Research Site	Bristol		United Kingdom	BS2 8ED
68	Research Site	Exeter		United Kingdom	EX2 5DW
69	Research Site	Glasgow		United Kingdom	G42 9LF
70	Research Site	Guildford		United Kingdom	GU2 7XX
71	Research Site	London		United Kingdom	SE1 9RT
72	Research Site	London		United Kingdom	W6 8RF
73	Research Site	Plymouth		United Kingdom	PL6 8DH
74	Research Site	Preston		United Kingdom	PR2 9HT

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Peters S, Danson S, Ejedepang D, Dafni U, Hasan B, Radcliffe HS, Bustin F, Crequit J, Coate L, Guillot M, Surmont V, Rauch D, Rudzki J, O'Mahony D, Barneto Aranda I, Scherz A, Tsourti Z, Roschitzki-Voser H, Pochesci A, Demonty G, Stahel RA, O'Brien M. Combined, patient-level, analysis of two randomised trials evaluating the addition of denosumab to standard first-line chemotherapy in advanced NSCLC - The ETOP/EORTC SPLENDOUR and AMGEN-249 trials. Lung Cancer. 2021 Nov;161:76-85. doi: 10.1016/j.lungcan.2021.09.002. Epub 2021 Sep 9.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01951586
• Other Study ID Numbers: 20120249; 2013-001662-42
• First Posted: Sep 26, 2013
• Last Update Posted: Oct 25, 2021
• Last Verified: Oct 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Zoledronic Acid; Denosumab

Study Results

Participant Flow

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.
Pre-assignment Detail	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]).

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants were 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.	Participants were 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.
Period Title: Overall Study
STARTED	78	148
Received Study Drug	76	145
COMPLETED	0	0
NOT COMPLETED	78	148

Baseline Characteristics

Arm/Group Title	Placebo	Denosumab	Total
Arm/Group Description	Participants were 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.	Participants were 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.	Total of all reporting groups
Overall Participants	78	148	226
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.0 (10.1)	63.8 (9.7)	63.8 (9.8)
Sex: Female, Male (Count of Participants)
Female	20 25.6%	54 36.5%	74 32.7%
Male	58 74.4%	94 63.5%	152 67.3%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	2 2.6%	7 4.7%	9 4%
White or Caucasian	73 93.6%	133 89.9%	206 91.2%
Others	3 3.8%	8 5.4%	11 4.9%
Presence of Bone Metastasis (Count of Participants)
Yes	35 44.9%	65 43.9%	100 44.2%
No	43 55.1%	83 56.1%	126 55.8%
Histology (Count of Participants)
Squamous	18 23.1%	35 23.6%	53 23.5%
Non-squamous	60 76.9%	113 76.4%	173 76.5%
Geographic region (Count of Participants)
North America/Australia	30 38.5%	63 42.6%	93 41.2%
Western Europe	35 44.9%	67 45.3%	102 45.1%
Rest of World	13 16.7%	18 12.2%	31 13.7%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
0 (Fully active)	33 42.3%	69 46.6%	102 45.1%
1 (Restrictive but ambulatory)	45 57.7%	79 53.4%	124 54.9%
Time from Initial Diagnosis of NSCLC to Randomization (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	2.46 (5.28)	6.32 (16.96)	4.99 (14.17)

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
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.
Time Frame	From randomization until the end of study; median time on study was 9.64 months.

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants were 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.	Participants were 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.
Measure Participants	78	148
Median (95% Confidence Interval) [months]	10.9	10.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5157
	Comments
	Method	Log Rank
	Comments	Log rank test stratified by the randomization stratification factors.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.53
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a Cox proportional hazards model stratified by the randomized stratification factors. Hazard ratio < 1 favors denosumab.

2. Secondary Outcome

Title	Correlation of Tumor Tissue RANK Expression With Overall Survival
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.
Time Frame	From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.

Outcome Measure Data

Analysis Population Description

All randomized participants who had evaluable pre-treatment tumor RANK expression.

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants were 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.	Participants were 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.
Measure Participants	64	123
Cytoplasm all intensity	0.84	1.00
Membrane all intensity	0.72	0.92
Total all intensity	0.80	1.00
Cytoplasm H-score	0.83	1.00
Membrane H-score	0.72	0.93
Total H-score	0.80	1.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3759
	Comments
	Method	Cox propotional hazard model
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3666
	Comments
	Method	Cox propotional hazard model
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1917
	Comments
	Method	Cox propotional hazard model
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3353
	Comments
	Method	Cox propotional hazard model
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3179
	Comments
	Method	Cox propotional hazard model
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1583
	Comments
	Method	Cox propotional hazard model
	Comments

3. Secondary Outcome

Title	Correlation of Tumor Tissue RANK Ligand Expression With Overall Survival
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.
Time Frame	From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.

Outcome Measure Data

Analysis Population Description

All randomized participants who had evaluable pre-treatment tumor RANKL expression.

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants were 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.	Participants were 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.
Measure Participants	65	121
Cytoplasm all intensity	0.77	0.93
Cytoplasm H-score	0.79	0.93

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3946
	Comments
	Method	Cox propotional hazard model
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3735
	Comments
	Method	Cox propotional hazard model
	Comments

4. Secondary Outcome

Title	Objective Response Rate
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.
Time Frame	From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.

Outcome Measure Data

Analysis Population Description

Randomized participants with at least one baseline measurable lesion per modified RECIST 1.1.

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants were 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.	Participants were 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.
Measure Participants	76	144
Number [percentage of participants]	43.4 55.6%	36.8 24.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3491
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression model adjusted for the randomization stratification factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.43 to 1.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a logistic regression model adjusted for the randomization stratification factors; an odds ratio ≥ 1 favors denosumab.

5. Secondary Outcome

Title	Correlation of Tumor Tissue RANK Expression With Objective Response Rate
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.
Time Frame	From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.

Outcome Measure Data

Analysis Population Description

All randomized participants with at least one baseline measurable lesion per modified RECIST 1.1 who had evaluable pre-treatment tumor RANK expression.

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants were 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.	Participants were 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.
Measure Participants	63	119
Cytoplasm all intensity	1.00	0.88
Membrane all intensity	1.18	0.82
Total all intensity	1.16	0.88
Cytoplasm H-score	1.00	0.87
Membrane H-score	1.14	0.82
Total H-score	1.14	0.87

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.4760
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2582
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2230
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.4329
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2620
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2081
	Comments
	Method	Regression, Logistic
	Comments

6. Secondary Outcome

Title	Correlation of Tumor Tissue RANKL Expression With Objective Response Rate
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.
Time Frame	From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.

Outcome Measure Data

Analysis Population Description

All randomized participants with at least one baseline measurable lesion per modified RECIST 1.1 who had evaluable pre-treatment tumor RANKL expression.

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants were 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.	Participants were 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.
Measure Participants	64	117
Cytoplasm all intensity	1.27	1.10
Cytoplasm H-score	1.25	1.09

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.4671
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.4236
	Comments
	Method	Regression, Logistic
	Comments

7. Secondary Outcome

Title	Clinical Benefit Rate
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.
Time Frame	From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.

Outcome Measure Data

Analysis Population Description

Randomized participants with at least one baseline measurable lesion per modified RECIST 1.1.

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants were 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.	Participants were 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.
Measure Participants	76	144
Number [percentage of participants]	53.9 69.1%	47.9 32.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.4654
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression model adjusted for the randomization stratification factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.46 to 1.43
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a logistic regression model adjusted for the randomization stratification factors; an odds ratio ≥ 1 favors denosumab.

8. Secondary Outcome

Title	Progression-free Survival (PFS)
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.
Time Frame	From randomization until the data cut-off date of 29 July 2016; median time on study was 9.64 months.

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants were 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.	Participants were 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.
Measure Participants	78	148
Median (95% Confidence Interval) [months]	5.7	5.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7363
	Comments
	Method	Log Rank
	Comments	Log rank test stratified by the randomized stratification factors.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 95%; 0.78 to 1.43
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a Cox proportional hazards model stratified by the randomized stratification factors. Hazard ratio < 1 favors denosumab.

9. Secondary Outcome

Title	Serum Denosumab Trough Levels in Participants Who Received Q3W Dosing
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.
Time Frame	Prior to dosing at day 8 and weeks 3, 6, 9, 12, 15, 18, 21 and 24.

Outcome Measure Data

Analysis Population Description

Randomized participants who received denosumab every 3 weeks with at least one valid denosumab concentration measurement.

Arm/Group Title	Denosumab
Arm/Group Description	Participants were 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.
Measure Participants	104
Dose 2 - Day 8	8590 (4080)
Dose 3 - Week 3	12200 (5710)
Dose 4 - Week 6	19700 (7350)
Dose 5 - Week 9	19600 (8270)
Dose 6 - Week 12	22800 (10400)
Dose 7 - Week 15	24300 (11500)
Dose 8 - Week 18	22700 (10600)
Dose 9 - Week 21	22100 (11200)
Dose 10 - Week 24	23300 (12700)

10. Secondary Outcome

Title	Serum Denosumab Trough Levels in Participants Who Received Q4W Dosing
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.
Time Frame	Prior to dosing at day 8 and weeks 4, 8, 12, 16, 20 and 24

Outcome Measure Data

Analysis Population Description

Randomized participants who received denosumab every 4 weeks with at least one valid denosumab concentration measurement.

Arm/Group Title	Denosumab
Arm/Group Description	Participants were 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.
Measure Participants	8
Dose 2 - Day 8	8990 (2470)
Dose 3 - Week 4	10900 (3170)
Dose 4 - Week 8	15700 (6710)
Dose 5 - Week 12	14500 (4940)
Dose 6 - Week 16	13000 (4380)
Dose 7 - Week 20	15400 (5620)
Dose 8 - Week 24	15900 (7810)

11. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events
Description	An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant. The event does not necessarily have a causal relationship with study treatment. A serious adverse event is defined as an AE that meets at least 1 of the following criteria fatal life threatening requires in-patient hospitalization or prolongation of existing hospitalization results in persistent or significant disability/incapacity congenital anomaly/birth defect other medically important serious event Treatment-related AEs include only TEAEs for which the investigator indicated there was a reasonable possibility they may have been caused by study drug. Fatal adverse events include only deaths reported on the Adverse Event Case Report Form.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug (denosumab or placebo)

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants were 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.	Participants were 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.
Measure Participants	76	145
All adverse events (AEs)	76 97.4%	144 97.3%
Serious adverse events	68 87.2%	129 87.2%
AEs leading to discontinuation of study drug	6 7.7%	20 13.5%
Fatal adverse events	53 67.9%	113 76.4%
Treatment-related adverse events (TRAEs)	24 30.8%	51 34.5%
Treatment-related serious adverse events	0 0%	6 4.1%
TRAEs leading to discontinuation of study drug	0 0%	7 4.7%
Treatment-related fatal adverse events	0 0%	0 0%

Adverse Events

Time Frame	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.
Adverse Event Reporting Description	Data are included for all participants who received at least one dose of study drug. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Placebo		Denosumab
Arm/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.		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.
All Cause Mortality
	Placebo		Denosumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Denosumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	68/76 (89.5%)		129/145 (89%)
Blood and lymphatic system disorders
Anaemia	5/76 (6.6%)		5/145 (3.4%)
Febrile neutropenia	5/76 (6.6%)		6/145 (4.1%)
Neutropenia	2/76 (2.6%)		3/145 (2.1%)
Pancytopenia	0/76 (0%)		2/145 (1.4%)
Thrombocytopenia	5/76 (6.6%)		4/145 (2.8%)
Cardiac disorders
Acute myocardial infarction	1/76 (1.3%)		0/145 (0%)
Atrial fibrillation	2/76 (2.6%)		1/145 (0.7%)
Cardiac failure	2/76 (2.6%)		3/145 (2.1%)
Cardiac failure congestive	0/76 (0%)		1/145 (0.7%)
Cardiac tamponade	0/76 (0%)		1/145 (0.7%)
Cardio-respiratory arrest	3/76 (3.9%)		4/145 (2.8%)
Coronary artery insufficiency	1/76 (1.3%)		0/145 (0%)
Myocardial infarction	0/76 (0%)		1/145 (0.7%)
Palpitations	0/76 (0%)		1/145 (0.7%)
Tachycardia	0/76 (0%)		1/145 (0.7%)
Congenital, familial and genetic disorders
Hereditary angioedema	0/76 (0%)		1/145 (0.7%)
Endocrine disorders
Inappropriate antidiuretic hormone secretion	0/76 (0%)		2/145 (1.4%)
Gastrointestinal disorders
Abdominal pain	0/76 (0%)		1/145 (0.7%)
Abdominal wall haematoma	1/76 (1.3%)		0/145 (0%)
Constipation	1/76 (1.3%)		0/145 (0%)
Diarrhoea	0/76 (0%)		1/145 (0.7%)
Intestinal obstruction	2/76 (2.6%)		1/145 (0.7%)
Melaena	1/76 (1.3%)		0/145 (0%)
Nausea	1/76 (1.3%)		6/145 (4.1%)
Small intestinal obstruction	0/76 (0%)		2/145 (1.4%)
Small intestinal perforation	0/76 (0%)		1/145 (0.7%)
Upper gastrointestinal haemorrhage	0/76 (0%)		1/145 (0.7%)
Vomiting	2/76 (2.6%)		4/145 (2.8%)
General disorders
Asthenia	0/76 (0%)		1/145 (0.7%)
Chest pain	1/76 (1.3%)		4/145 (2.8%)
Chills	0/76 (0%)		1/145 (0.7%)
Condition aggravated	1/76 (1.3%)		1/145 (0.7%)
Disease progression	2/76 (2.6%)		5/145 (3.4%)
Fatigue	0/76 (0%)		2/145 (1.4%)
General physical health deterioration	4/76 (5.3%)		7/145 (4.8%)
Infusion site extravasation	1/76 (1.3%)		0/145 (0%)
Malaise	1/76 (1.3%)		0/145 (0%)
Oedema peripheral	1/76 (1.3%)		0/145 (0%)
Pain	2/76 (2.6%)		0/145 (0%)
Pyrexia	2/76 (2.6%)		12/145 (8.3%)
Hepatobiliary disorders
Hepatic failure	0/76 (0%)		1/145 (0.7%)
Hyperbilirubinaemia	1/76 (1.3%)		0/145 (0%)
Immune system disorders
Anaphylactic reaction	0/76 (0%)		1/145 (0.7%)
Infections and infestations
Bronchitis	0/76 (0%)		1/145 (0.7%)
Cellulitis	1/76 (1.3%)		2/145 (1.4%)
Device related infection	1/76 (1.3%)		1/145 (0.7%)
Fungal infection	1/76 (1.3%)		0/145 (0%)
Gangrene	0/76 (0%)		1/145 (0.7%)
Gastroenteritis shigella	0/76 (0%)		1/145 (0.7%)
Lower respiratory tract infection	2/76 (2.6%)		1/145 (0.7%)
Lung abscess	0/76 (0%)		1/145 (0.7%)
Lung infection	0/76 (0%)		1/145 (0.7%)
Oral herpes	0/76 (0%)		1/145 (0.7%)
Pleural infection	1/76 (1.3%)		1/145 (0.7%)
Pneumonia	7/76 (9.2%)		14/145 (9.7%)
Respiratory tract infection	0/76 (0%)		3/145 (2.1%)
Sepsis	1/76 (1.3%)		2/145 (1.4%)
Septic shock	0/76 (0%)		3/145 (2.1%)
Staphylococcal bacteraemia	1/76 (1.3%)		0/145 (0%)
Injury, poisoning and procedural complications
Femoral neck fracture	0/76 (0%)		1/145 (0.7%)
Fracture	0/76 (0%)		1/145 (0.7%)
Radiation oesophagitis	1/76 (1.3%)		0/145 (0%)
Radius fracture	1/76 (1.3%)		0/145 (0%)
Investigations
C-reactive protein increased	1/76 (1.3%)		0/145 (0%)
General physical condition abnormal	0/76 (0%)		1/145 (0.7%)
Glomerular filtration rate decreased	0/76 (0%)		1/145 (0.7%)
Nutritional condition abnormal	1/76 (1.3%)		0/145 (0%)
Platelet count decreased	3/76 (3.9%)		1/145 (0.7%)
Metabolism and nutrition disorders
Cachexia	1/76 (1.3%)		1/145 (0.7%)
Dehydration	2/76 (2.6%)		6/145 (4.1%)
Hyperglycaemia	1/76 (1.3%)		2/145 (1.4%)
Hypocalcaemia	0/76 (0%)		1/145 (0.7%)
Hypoglycaemia	0/76 (0%)		1/145 (0.7%)
Hypokalaemia	0/76 (0%)		1/145 (0.7%)
Musculoskeletal and connective tissue disorders
Back pain	1/76 (1.3%)		2/145 (1.4%)
Musculoskeletal chest pain	1/76 (1.3%)		0/145 (0%)
Musculoskeletal pain	2/76 (2.6%)		1/145 (0.7%)
Osteonecrosis of jaw	0/76 (0%)		4/145 (2.8%)
Spinal pain	0/76 (0%)		1/145 (0.7%)
Vertebral lesion	0/76 (0%)		1/145 (0.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma	2/76 (2.6%)		4/145 (2.8%)
Bronchial carcinoma	1/76 (1.3%)		0/145 (0%)
Cancer pain	0/76 (0%)		1/145 (0.7%)
Lung adenocarcinoma	2/76 (2.6%)		2/145 (1.4%)
Lung adenocarcinoma stage IV	0/76 (0%)		1/145 (0.7%)
Lung cancer metastatic	3/76 (3.9%)		9/145 (6.2%)
Lung neoplasm malignant	5/76 (6.6%)		10/145 (6.9%)
Lung squamous cell carcinoma metastatic	1/76 (1.3%)		0/145 (0%)
Lymphangiosis carcinomatosa	0/76 (0%)		1/145 (0.7%)
Malignant neoplasm progression	2/76 (2.6%)		2/145 (1.4%)
Malignant pleural effusion	3/76 (3.9%)		1/145 (0.7%)
Metastases to bone	2/76 (2.6%)		0/145 (0%)
Metastases to bone marrow	0/76 (0%)		1/145 (0.7%)
Metastases to central nervous system	1/76 (1.3%)		6/145 (4.1%)
Metastases to lung	1/76 (1.3%)		0/145 (0%)
Metastases to meninges	1/76 (1.3%)		2/145 (1.4%)
Metastatic neoplasm	2/76 (2.6%)		0/145 (0%)
Non-small cell lung cancer	9/76 (11.8%)		19/145 (13.1%)
Non-small cell lung cancer metastatic	7/76 (9.2%)		14/145 (9.7%)
Non-small cell lung cancer stage IV	5/76 (6.6%)		12/145 (8.3%)
Nervous system disorders
Altered state of consciousness	0/76 (0%)		2/145 (1.4%)
Brain oedema	0/76 (0%)		1/145 (0.7%)
Cerebrovascular accident	1/76 (1.3%)		2/145 (1.4%)
Consciousness fluctuating	0/76 (0%)		1/145 (0.7%)
Depressed level of consciousness	0/76 (0%)		1/145 (0.7%)
Epilepsy	1/76 (1.3%)		0/145 (0%)
Haemorrhage intracranial	0/76 (0%)		1/145 (0.7%)
Headache	0/76 (0%)		1/145 (0.7%)
Ischaemic stroke	0/76 (0%)		1/145 (0.7%)
Lethargy	1/76 (1.3%)		0/145 (0%)
Loss of consciousness	1/76 (1.3%)		0/145 (0%)
Seizure	0/76 (0%)		2/145 (1.4%)
Stroke in evolution	0/76 (0%)		1/145 (0.7%)
Transient ischaemic attack	0/76 (0%)		1/145 (0.7%)
Generalised tonic-clonic seizure	1/76 (1.3%)		0/145 (0%)
Product Issues
Device issue	1/76 (1.3%)		0/145 (0%)
Psychiatric disorders
Confusional state	0/76 (0%)		3/145 (2.1%)
Delirium	0/76 (0%)		1/145 (0.7%)
Mental status changes	0/76 (0%)		1/145 (0.7%)
Suicide attempt	0/76 (0%)		1/145 (0.7%)
Renal and urinary disorders
Acute kidney injury	0/76 (0%)		1/145 (0.7%)
Haematuria	1/76 (1.3%)		1/145 (0.7%)
Renal haemorrhage	0/76 (0%)		1/145 (0.7%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/76 (0%)		1/145 (0.7%)
Acute respiratory failure	1/76 (1.3%)		0/145 (0%)
Chronic obstructive pulmonary disease	1/76 (1.3%)		5/145 (3.4%)
Dyspnoea	2/76 (2.6%)		16/145 (11%)
Epistaxis	1/76 (1.3%)		1/145 (0.7%)
Haemoptysis	1/76 (1.3%)		2/145 (1.4%)
Haemothorax	0/76 (0%)		1/145 (0.7%)
Hypoxia	0/76 (0%)		2/145 (1.4%)
Laryngeal mass	0/76 (0%)		1/145 (0.7%)
Laryngeal obstruction	0/76 (0%)		1/145 (0.7%)
Lung disorder	1/76 (1.3%)		0/145 (0%)
Pleural effusion	2/76 (2.6%)		6/145 (4.1%)
Pleuritic pain	0/76 (0%)		1/145 (0.7%)
Pneumonitis	0/76 (0%)		1/145 (0.7%)
Pneumothorax	1/76 (1.3%)		3/145 (2.1%)
Pulmonary embolism	1/76 (1.3%)		6/145 (4.1%)
Pulmonary haemorrhage	0/76 (0%)		1/145 (0.7%)
Pulmonary hypertension	0/76 (0%)		1/145 (0.7%)
Respiratory distress	0/76 (0%)		3/145 (2.1%)
Respiratory failure	2/76 (2.6%)		4/145 (2.8%)
Vascular disorders
Aortic thrombosis	0/76 (0%)		1/145 (0.7%)
Circulatory collapse	0/76 (0%)		1/145 (0.7%)
Deep vein thrombosis	1/76 (1.3%)		1/145 (0.7%)
Embolism	0/76 (0%)		1/145 (0.7%)
Embolism venous	0/76 (0%)		1/145 (0.7%)
Hypotension	0/76 (0%)		4/145 (2.8%)
Jugular vein thrombosis	1/76 (1.3%)		0/145 (0%)
Superior vena cava syndrome	0/76 (0%)		1/145 (0.7%)
Thrombosis	0/76 (0%)		1/145 (0.7%)
Other (Not Including Serious) Adverse Events
	Placebo		Denosumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	71/76 (93.4%)		139/145 (95.9%)
Blood and lymphatic system disorders
Anaemia	38/76 (50%)		60/145 (41.4%)
Leukopenia	4/76 (5.3%)		6/145 (4.1%)
Neutropenia	15/76 (19.7%)		32/145 (22.1%)
Thrombocytopenia	16/76 (21.1%)		16/145 (11%)
Eye disorders
Dry eye	4/76 (5.3%)		2/145 (1.4%)
Lacrimation increased	3/76 (3.9%)		9/145 (6.2%)
Gastrointestinal disorders
Abdominal distension	4/76 (5.3%)		1/145 (0.7%)
Abdominal pain	4/76 (5.3%)		13/145 (9%)
Constipation	27/76 (35.5%)		50/145 (34.5%)
Diarrhoea	14/76 (18.4%)		26/145 (17.9%)
Dyspepsia	5/76 (6.6%)		8/145 (5.5%)
Dysphagia	6/76 (7.9%)		5/145 (3.4%)
Gastrooesophageal reflux disease	4/76 (5.3%)		6/145 (4.1%)
Nausea	34/76 (44.7%)		64/145 (44.1%)
Stomatitis	6/76 (7.9%)		7/145 (4.8%)
Vomiting	14/76 (18.4%)		35/145 (24.1%)
General disorders
Asthenia	8/76 (10.5%)		24/145 (16.6%)
Fatigue	33/76 (43.4%)		67/145 (46.2%)
Mucosal inflammation	4/76 (5.3%)		8/145 (5.5%)
Oedema peripheral	17/76 (22.4%)		26/145 (17.9%)
Pain	7/76 (9.2%)		10/145 (6.9%)
Pyrexia	9/76 (11.8%)		23/145 (15.9%)
Infections and infestations
Nasopharyngitis	5/76 (6.6%)		3/145 (2.1%)
Oral candidiasis	5/76 (6.6%)		5/145 (3.4%)
Pneumonia	2/76 (2.6%)		10/145 (6.9%)
Urinary tract infection	4/76 (5.3%)		11/145 (7.6%)
Herpes zoster	4/76 (5.3%)		0/145 (0%)
Injury, poisoning and procedural complications
Fall	5/76 (6.6%)		2/145 (1.4%)
Investigations
Aspartate aminotransferase increased	4/76 (5.3%)		3/145 (2.1%)
Blood creatinine increased	3/76 (3.9%)		12/145 (8.3%)
Platelet count decreased	8/76 (10.5%)		14/145 (9.7%)
Weight decreased	10/76 (13.2%)		8/145 (5.5%)
Metabolism and nutrition disorders
Decreased appetite	23/76 (30.3%)		34/145 (23.4%)
Hypercalcaemia	4/76 (5.3%)		5/145 (3.4%)
Hyperglycaemia	4/76 (5.3%)		6/145 (4.1%)
Hypocalcaemia	4/76 (5.3%)		24/145 (16.6%)
Hypokalaemia	4/76 (5.3%)		8/145 (5.5%)
Hypomagnesaemia	12/76 (15.8%)		17/145 (11.7%)
Hyponatraemia	4/76 (5.3%)		3/145 (2.1%)
Hypophosphataemia	5/76 (6.6%)		11/145 (7.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	7/76 (9.2%)		11/145 (7.6%)
Back pain	15/76 (19.7%)		20/145 (13.8%)
Muscle spasms	4/76 (5.3%)		4/145 (2.8%)
Musculoskeletal chest pain	5/76 (6.6%)		9/145 (6.2%)
Musculoskeletal pain	5/76 (6.6%)		10/145 (6.9%)
Pain in extremity	7/76 (9.2%)		14/145 (9.7%)
Nervous system disorders
Dizziness	7/76 (9.2%)		20/145 (13.8%)
Dysgeusia	11/76 (14.5%)		8/145 (5.5%)
Headache	8/76 (10.5%)		24/145 (16.6%)
Neuropathy peripheral	9/76 (11.8%)		5/145 (3.4%)
Paraesthesia	2/76 (2.6%)		8/145 (5.5%)
Psychiatric disorders
Anxiety	5/76 (6.6%)		14/145 (9.7%)
Depression	6/76 (7.9%)		2/145 (1.4%)
Insomnia	7/76 (9.2%)		12/145 (8.3%)
Respiratory, thoracic and mediastinal disorders
Cough	16/76 (21.1%)		26/145 (17.9%)
Dyspnoea	18/76 (23.7%)		35/145 (24.1%)
Epistaxis	5/76 (6.6%)		8/145 (5.5%)
Haemoptysis	6/76 (7.9%)		10/145 (6.9%)
Hiccups	4/76 (5.3%)		7/145 (4.8%)
Productive cough	2/76 (2.6%)		9/145 (6.2%)
Skin and subcutaneous tissue disorders
Alopecia	6/76 (7.9%)		9/145 (6.2%)
Dry skin	4/76 (5.3%)		6/145 (4.1%)
Rash	8/76 (10.5%)		18/145 (12.4%)
Vascular disorders
Hypotension	5/76 (6.6%)		4/145 (2.8%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.