Dissociated skeletal response to first-line immunotherapy in synchronous bone metastatic non-small cell lung cancer patients: Clinical profiles and survival benefit of denosumab adjunction
Abstract
Introduction Patients with bone metastases (BM) from non-small cell lung cancer (NSCLC) derive less clinical benefit from immune checkpoint inhibitors (ICIs) than those without skeletal involvement. We aimed to characterize bone-specific disease control profiles under first-line ICI therapy and explore the association of denosumab with clinical outcomes. Methods We conducted a multicenter retrospective study in BM-NSCLC patients, naïve to systemic therapy, treated with first-line ICI monotherapy, with or without denosumab. Radiological response in soft tissue and bone compartments was assessed at 6 months using iRECIST. Disease control (DCR: iCR, iPR, or iSD) and dissociated response (discordant DCR between compartments) were predefined. Denosumab impact was evaluated using logistic regression and Cox models. Results Sixty-one patients were included (16 women [26%]; mean age 65.8 ± 9.6 years). Soft tissue DCR was 64% and bone DCR was 62% at M6. Dissociated response occurred in 21% (n = 13), associated with female sex, KRAS mutations, and elevated C-reactive protein (all p < 0.05). Denosumab did not alter bone DCR (73% vs. 60%; adjusted OR 0.64; 95% CI: 0.12–2.99; p = 0.582) but was associated with improved progression-free survival (log-rank p = 0.06) and reduced hazard of progression or death (adjusted HR 0.28; 95% CI: 0.06–1.33; p = 0.110). Conclusion ICI-driven immune activation does not translate uniformly across compartments. Female sex, KRAS mutation, and systemic inflammation are potential determinants of bone-specific resistance. While denosumab did not significantly modify bone DCR, its trend toward association with improved progression-free survival and reduced risk of progression or death generates the hypothesis of an immunomodulatory effect warranting prospective evaluation.
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BibTeX
@article{massy2026dissociated,
title = {{Dissociated skeletal response to first-line immunotherapy in synchronous bone metastatic non-small cell lung cancer patients: Clinical profiles and survival benefit of denosumab adjunction}},
author = {Emmanuel Massy and Nicolas Stacoffe and Fauvernier, M. and Michaël Duruisseaux and E. Grolleau and M. Lamkhioued and M. Pérol and Charlotte Domblides and Mathieu Roche and A. Stuani and Philippe Clezardin and E. Bonnelye and Jean-Baptiste Pialat and N. Girard and C. Confavreux},
journal = {Journal of Bone Oncology},
year = {2026},
month = sep,
doi = {10.1016/j.jbo.2026.100797},
url = {https://hal.science/hal-05761691v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Dissociated skeletal response to first-line immunotherapy in synchronous bone metastatic non-small cell lung cancer patients: Clinical profiles and survival benefit of denosumab adjunction
AU - Emmanuel Massy
AU - Nicolas Stacoffe
AU - Fauvernier, M.
AU - Michaël Duruisseaux
AU - E. Grolleau
AU - M. Lamkhioued
AU - M. Pérol
AU - Charlotte Domblides
AU - Mathieu Roche
AU - A. Stuani
AU - Philippe Clezardin
AU - E. Bonnelye
AU - Jean-Baptiste Pialat
AU - N. Girard
AU - C. Confavreux
PY - 2026
DA - 2026/09/23
JO - Journal of Bone Oncology
DO - 10.1016/j.jbo.2026.100797
UR - https://hal.science/hal-05761691v1
AB - Introduction Patients with bone metastases (BM) from non-small cell lung cancer (NSCLC) derive less clinical benefit from immune checkpoint inhibitors (ICIs) than those without skeletal involvement. We aimed to characterize bone-specific disease control profiles under first-line ICI therapy and explore the association of denosumab with clinical outcomes. Methods We conducted a multicenter retrospective study in BM-NSCLC patients, naïve to systemic therapy, treated with first-line ICI monotherapy, with or without denosumab. Radiological response in soft tissue and bone compartments was assessed at 6 months using iRECIST. Disease control (DCR: iCR, iPR, or iSD) and dissociated response (discordant DCR between compartments) were predefined. Denosumab impact was evaluated using logistic regression and Cox models. Results Sixty-one patients were included (16 women [26%]; mean age 65.8 ± 9.6 years). Soft tissue DCR was 64% and bone DCR was 62% at M6. Dissociated response occurred in 21% (n = 13), associated with female sex, KRAS mutations, and elevated C-reactive protein (all p < 0.05). Denosumab did not alter bone DCR (73% vs. 60%; adjusted OR 0.64; 95% CI: 0.12–2.99; p = 0.582) but was associated with improved progression-free survival (log-rank p = 0.06) and reduced hazard of progression or death (adjusted HR 0.28; 95% CI: 0.06–1.33; p = 0.110). Conclusion ICI-driven immune activation does not translate uniformly across compartments. Female sex, KRAS mutation, and systemic inflammation are potential determinants of bone-specific resistance. While denosumab did not significantly modify bone DCR, its trend toward association with improved progression-free survival and reduced risk of progression or death generates the hypothesis of an immunomodulatory effect warranting prospective evaluation.
SN - 2212-1374
ER -