• Skeletal-related events (SREs) [ Time Frame: 1, 3, 6, and 12 months post-treatment ]
  Skeletal-related events (SREs) defined as the adverse events associated with bone metastases. SREs would include pathologic fractures, the requirement for surgery or radiotherapy, spinal cord compression.
• Progression Free Survival (PFS) [ Time Frame: at 1 year ]
  Progression Free Survival (PFS) would be defined as progression of disease or death from any cause from time of randomization until the end of study.
• Objective Response Rate (ORR) [ Time Frame: at 1 year ]
  Objective Response Rate (ORR) defined as proportion of patients with reduction in bony metastases as evaluated by using both the MD Anderson (MDA) criteria for patients who receive CT or bone scans and Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) for patients who undergo FDG PET/CT. These criteria allow for categorization of disease response from complete response to progressive disease.
• Percentage reduction in the bone turnover markers including urine N-telopeptide (NTX) and serum C-terminal telopeptide (CTX) [ Time Frame: From Baseline at 1, 6, and 12 months post-treatment ]
  Percentage reduction in the bone turnover markers including urine N-telopeptide (NTX) and serum C-terminal telopeptide (CTX) from baseline at 1, 6 and 12 months.
• Percentage normalization of blood total alkaline phosphatase [ Time Frame: From baseline at 1, 3, 6, and 12 months ]
  Percentage normalization of blood total alkaline phosphatase from baseline at 1, 3, 6, and 12 months. Normal level of blood total alkaline phosphatase would be defined as equal or less than 147 IU/L.

• Skeletal-related events (SREs) [ Time Frame: 1, 3, 6, and 12 months post-treatment ]
  Skeletal-related events (SREs) defined as the adverse events associated with bone metastases. SREs would include pathologic fractures, the requirement for surgery or radiotherapy, spinal cord compression.
• Progression Free Survival (PFS) [ Time Frame: at 1 year ]
  Progression Free Survival (PFS) would be defined as progression of disease or death from any cause from time of randomization until the end of study.
• Objective Response Rate (ORR) [ Time Frame: at 1 year ]
  Objective Response Rate (ORR) defined as proportion of patients with reduction in bony metastases as evaluated by using both the MD Anderson (MDA) criteria for patients who receive CT or bone scans and Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) for patients who undergo FDG PET/CT. These criteria allow for categorization of disease response from complete response to progressive disease.
• Percentage normalization in the bone turnover marker urine N-telopeptide (NTX) [ Time Frame: From Baseline at 1, 6, and 12 months post-treatment ]
  Percentage normalization in the bone turnover marker urine N-telopeptide (NTX) from baseline at 1, 6 and 12 months.
• Percentage normalization of blood total alkaline phosphatase [ Time Frame: From baseline at 1, 3, 6, and 12 months ]
  Percentage normalization of blood total alkaline phosphatase from baseline at 1, 3, 6, and 12 months. Normal level of blood total alkaline phosphatase would be defined as equal or less than 147 IU/L.

This is an observational study involving two arms of NSCLC with metastatic bony disease at the time of enrollment in the study. One group will have an actionable driver oncogene and initiate treatment in any line with a TKI as standard of care and concurrent to participation to this study; expected to have an objective response rate in ≥40% who have not previously seen anti-bone resorptive therapy. The other group will not have actionable mutations and initiate treatment with chemotherapy/immunotherapy along with new onset therapy with IV zoledronic acid 4mg Q4 weeks or subcutaneous denosumab 120 mg Q12 weeks for bone disease, which is standard of care and would be concurrent to participation in this study.

Baseline and on-treatment imaging and serum total alkaline phosphatase will be performed per SOC.

Additional non-SOC bone turnover markers including , urine N-telopeptide (NTX) and serum C-terminal telopeptide (CTX), will be checked at baseline and then at 1, 3, 6, and 12 months.

• Biological: Tyrosine Kinase Inhibitor
  Targeted therapy given as standard of care.
• Drug: Zoledronic Acid 4 MG/100 ML Intravenous Solution [ZOMETA]
  Given Q4 weeks as standard of care
• Drug: Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA]
  Given Q12 weeks for bone disease as standard of care

• Actionable driver oncogene
  One group will have an actionable driver oncogene and initiate treatment in any line with a TKI as standard of care and concurrent to participation to this study; expected to have an objective response rate in ≥40% who have not previously seen anti-bone resorptive therapy.
  Intervention: Biological: Tyrosine Kinase Inhibitor
• No Actionable Mutations
  The other group will not have actionable mutations and initiate treatment with chemotherapy/immunotherapy along with new onset therapy with IV zoledronic acid 4mg Q4 weeks or subcutaneous denosumab 120 mg Q12 weeks for bone disease, which is standard of care and would be concurrent to participation in this study.
  Interventions:

  • Drug: Zoledronic Acid 4 MG/100 ML Intravenous Solution [ZOMETA]
  • Drug: Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA]

Inclusion Criteria:

1. Provision to sign and date the consent form
2. Stated willingness to comply with all study procedures and be available for the duration of the study
3. Be a male or female aged 18-100 years
4. Pathologically confirmed Non-Small Cell Lung Cancer with bone metastasis and with or without driver actionable oncogene
5. ECOG PS 0-2
6. Decision to be on a particular standard of care TKI or chemotherapy/immunotherapy (clinical decision that would occur prior to study enrollment)

Exclusion Criteria:

1. Actionable driver mutation NSCLC patient who has been on anti-bone resorptive therapy
2. Have any condition or illness that, in the opinion of the investigator, would compromise participant safety or interfere with evaluation while on standard of care treatments for the NSCLC
3. Patients with actionable driver mutation who received TKI in past or currently on TKI prior to screening