An observational study of concomitant immunotherapies and denosumab in patients with advanced melanoma or lung cancer

After a case report of profound clinical response in a melanoma patient following treatment with an immune checkpoint inhibitor (ICI) and RANK-ligand inhibitor denosumab, we identified similar patients from electronic health records (EHR) and described patient characteristics and outcomes. This 2017 observational study used Flatiron Health's EHR database from similar to 255 US cancer clinics. Included were advanced melanoma or non-small-cell lung cancer (NSCLC) patients who received denosumab within 30 days of CTLA-4 (ipilimumab) or PD1 (pembrolizumab, nivolumab) inhibitors start with a minimum of 6 months of follow up. Real-world tumor response (rwTR) was analyzed for scans available up to 30 days after concomitant therapy. Preclinical experiments evaluated sequencing of ICI, denosumab vs monotherapy or control. Melanoma (n = 66) patients received concomitant denosumab/ICI for a mean 4.0 months, 3.1 months for NSCLC (n = 241). Two-thirds of patients had best rwTR evaluable (complete [CR], partial response [PR], stable disease [SD], or disease progression [PD]). Longer mean duration of concomitant exposure was associated with overall response rate (ORR; CR+PR) in melanoma (p = 0.0172), NSCLC (p < .0001), and combined cohorts (p < .0001). The disease control rate (ORR plus SD) was 56% amongst melanoma patients and 58% amongst NSCLC patients. Longer concomitant therapy was associated with increased overall survival, primarily in NSCLC (p < .0001). Preclinical data suggest that ICI initiated before or at same time as denosumab was optimal. Results provide proof-of-concept that rwTR is associated with concomitant denosumab/ICI. Crude survival analyses supported the association of concomitant therapy and improved outcomes outside of clinical trials and warrant comparative study.