An Observational Study of Concomitant Immunotherapies and Denosumab in Patients With Advanced Melanoma or Lung Cancer

Oncoimmunology. 2018 Sep 5;7(12):e1480301. doi: 10.1080/2162402X.2018.1480301. eCollection 2018.

Abstract

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 ~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.

Keywords: Immune checkpoint inhibitor; RANK-ligand inhibitor; denosumab; melanoma; non-small cell lung cancer; real-world; response; survival.

Grant support

The study was supported in part by Amgen Inc., Thousand Oaks, CA, USA. M.J. Smyth was supported by a National Health and Medical Research Council of Australia (NH&MRC) Senior Principal Research Fellowship (1078671) and NH&MRC Program Grant (1132519);Amgen [NA];National Health and Medical Research Council (NHMRC) [1132519];National Health and Medical Research Council (NHMRC) [1078671];