Effect of bone metastases on immunotherapy efficacy in pretreated advanced non small cell lung cancer (NSCLC).

Background: Bone is a common site of metastatic spread in advanced NSCLC, with 35-40% of patients developing bone metastases (BoM) during the course of the disease. Beyond its supportive role, bone is a critical hematopoietic organ with active functions in regulating immune system and trafficking of immune cells, such as myeloid-derived suppressor cells and mesenchymal stem cells. To date, no trial evaluated the role of BoM in modulating response to immunotherapy. Aim of the present study was to investigate whether presence of BoM impact on immunotherapy efficacy. Methods: Two different cohorts of pretreated NSCLC patients (cohort A: Non-squamous; cohort B: Squamous) were evaluated for nivolumab efficacy in terms of objective response rate (ORR), progression free survival (PFS), and overall survival (OS) according to presence or absence of BoM. All patients received nivolumab at standard dose of 3 mg/kg every 2 weeks within the Italian Expanded Access Program. Results: Cohort A accounted for 1588 patients with nonsquamous NSCLC: 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 371 patients with squamous histology: 120 BoM+ (32%) and 251 BoM- (68%). In Cohort A, BoM+ had a significantly lower ORR (12% versus 34%; p < 0.0001), shorter PFS (3.0 versus 4.0 months, p < 0.0001) and shorter OS (7.4 versus 15.3 months, p <0.0001). In cohort B, BoM+ had significantly lower ORR (13% versus 22%; p < 0.04), shorter PFS (2.7 versus 5.2 months, p <0.0001) and shorter OS (5.0 versus 10.9 months, p <0.0001). Presence of BoM negatively affected outcome irrespective of performance status (PS; OS cohort A: PS-0 BoM+ 12.0 versus 20.9 months in PS-0 BoM-, p<0.0001; OS cohort B: PS-0 BoM+ 5.8 versus 16.4 months in PS-0 BoM-, p<0.0001). In multivariate analysis, PS, presence of liver metastases and BoM independently associated with higher risk of death. In cohort A and B, BoM+ patients had HR for survival of 1.50 and 1.78, respectively. Conclusion: Our results, the first assessing BoM in patients treated with immunotherapy, suggest that presence of BoM is a negative prognostic factor and could predict lower efficacy of immunotherapy in pretreated NSCLCs irrespective of histology. Baseline bone assessment should be performed in all clinical trials with immunotherapy