Bone metastases are common in Non-Small Cell Lung Cancer (NSCLC), affecting 30-65% of the
      patients, depending on the series. They most often occur during disease progression (59.7% in
      the French Lung Cancer Group trial). The frequency of skeletal-related events (SREs)
      (pathological fractures, medullary compression, analgesic radiotherapy, preventive and/or
      analgesic surgery and hypercalcemia) is high. It is thought that more than half of the
      patients with bone metastases will have at least 1 SRE, with rates ranging from 55% to 62%.

      Expert and medical Society guidelines, notably European Society for Medical Oncology in 2014,
      then in 2016, recommended using anti-resorptive agents (bisphosphonates or denosumab) to
      prevent SREs, attenuate pain and improve the quality of life, and decrease the
      medical-economic impact of this major metastatic site.

      Denosumab is a humanized monoclonal antibody. It mimics the action of osteoprotegerin (OPG),
      thereby inhibiting osteoclastogenesis by blocking the binding of the receptor activator of
      nuclear factor-kappaB (RANK) to its ligand (RANKL), and thus interrupts the vicious circle
      between tumor cells and bone. RANK is a transmembrane protein expressed on osteoclasts, and
      its ligand, RANKL, is soluble and secreted by osteoblasts. Denosumab was accorded marketing
      authorization in France in 2011 as an anti-resorptive agent for bone metastases to delay the
      occurrence of SREs in lung-cancer patients. The results of 3 phase III studies evaluating the
      place of denosumab versus zoledronic acid have been published. Lung cancers were included in
      the trial examining solid tumors (other than breast and prostate) and multiple myeloma, and
      represented 40% of the population. In a non-inferiority analysis, the primary objective was
      reached with denosumab prolonging by approximately 4 months the time to the first SRE (20.6
      versus 16.3 months, hazard ratio 0.84 [95% confidence interval 0.71-0.98] p=0.0007). In the
      lung-cancer subgroup, this difference did not reach significance (hazard ratio 0.85 [95%
      confidence interval 0.65-1.12]). In contrast, the exploratory analysis of that subgroup
      showed overall survival prolonged by 1.2 months for the denosumab arm versus zoledronic acid
      (8.9 versus 7.7 months, hazard ratio 0.8 [95% confidence interval 0.67-0.95] p=0.01).

      Immunotherapy, notably immune-checkpoint inhibitors (ICPIs), like nivolumab (anti-programed
      death-1 (PD-1)), has recently become an integral part of the therapeutic arsenal against
      NSCLCs. Nivolumab was accorded marketing authorization based on the phase III CHECKMATE 017
      (squamous cell NSCLCs) and CHECKMATE 057 (non-squamous cell NSCLCs) trials versus docetaxel,
      after the phase II CHECKMATE 063 trial. The search for a biomarker predictive of the response
      to immunotherapy is becoming more-and-more crucial, so as not to expose patients who risk
      early cancer hyper-progression. Immunohistochemical labeling of PD-1 ligand (PD-L1) on tumor
      cells (± infiltrating the stroma) is the most studied and reliable biomarker. Knowing its
      status has become indispensable in immunotherapy trials because an elevated PD-L1 has been
      correlated to a better response. Prescribing second-line nivolumab is not conditioned by the
      PD-L1 status because those trials had not foreseen stratification according to this
      criterion's status. However, post-hoc analysis of PD-L1 in the CHECKMATE 057 trial on
      non-squamous cell NSCLCs showed prolonged overall survival for patients with PD-L1-positive
      tumors, whether the positivity threshold was 1%, 5% or 10%. Thus, knowing the PD-L1 status is
      necessary to interpret the results of immunotherapy trials.

      The RANK-RANKL system was studied in preclinical osteoimmunology models. It is expressed by
      certain cells, notably antigen-presenting cells, such as dendritic cells or lymphocytes,
      essential for the adaptive immunity function solicited by immunotherapy. It is part of the
      tumor necrosis factor receptor (TNF-R) family and is implicated in the interactions between
      dendritic cells and lymphocytes. The RANK-RANKL role in the development and function of
      regulatory T cells (Tregs) remains poorly elucidated. Information on the interaction of the
      RANK-RANKL system and adaptive immunity obtained with the preclinical models is discordant
      and rare. A case report on a patient with melanoma bone metastases treated with denosumab and
      ipilimumab (ICPI of the anti-cytotoxic T-lymphocyte antigen 4 type) obtained a promising
      carcinological outcome, without any sign of deleterious interaction.

      The aim of this trial is to evaluate the combination of denosumab and nivolumab in second
      line of NSCLC with bone metastases.