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

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.

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.