Bone Metastases, Skeletal-Related Events, and Survival in Patients With Metastatic Non–Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors

Abstract

Background: Bone metastases and skeletal-related events (SREs) are a frequent cause of morbidity in patients with metastatic non–small cell lung cancer (mNSCLC). Data are limited on bone metastases and SREs in patients with mNSCLC treated using immune checkpoint inhibitors (ICIs), and on the efficacy of bone-modifying agents (BMAs) in this setting. Here we report the incidence, impact on survival, risk factors for bone metastases and SREs, and impact of BMAs in patients with mNSCLC treated with ICIs in a multi-institutional cohort. Patients and Methods: We conducted a retrospective study of patients with mNSCLC treated with ICIs at 2 tertiary care centers from 2014 through 2017. Overall survival (OS) was compared between patients with and without baseline bone metastases using a log-rank test. A Cox regression model was used to evaluate the association between OS and the presence of bone metastases at ICI initiation, controlling for other confounding factors. Results: We identified a cohort of 330 patients who had received ICIs for metastatic disease. Median patient age was 63 years, most patients were treated in the second line or beyond (n=259; 78%), and nivolumab was the most common ICI (n=211; 64%). Median OS was 10 months (95% CI, 8.4–12.0). In our cohort, 124 patients (38%) had baseline bone metastases, and 43 (13%) developed SREs during or after ICI treatment. Patients with bone metastases had a higher hazard of death after controlling for performance status, histology, line of therapy, and disease burden (hazard ratio, 1.57; 95% CI, 1.19–2.08; P=.001). Use of BMAs was not associated with OS or a decreased risk of SREs. Conclusions: Presence of bone metastases at baseline was associated with a worse prognosis for patients with mNSCLC treated with ICI after controlling for multiple clinical characteristics. Use of BMAs was not associated with reduced SREs or a difference in survival.

Overall Survival Improvement in Patients with Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer and Bone Metastasis Treated with Denosumab

“…Subsequently, denosumab has become the most commonly used BMA in Taiwan. Despite this, not all NSCLC physicians prescribe BMAs to manage bone diseases or SREs [ 21 , 22 , 23 , 24 , 25 ]. In addition, physicians and/or patients often decide to initiate bone treatment upon the occurrence of SREs or later in clinical practice.…”

“…Another hypothesis is that the therapeutic effect of denosumab involves SREs reduction, which may prevent an exacerbation of the performance status and prolong survival. However, two recent analyses failed to show the advantage of denosumab in NSCLC patients receiving chemotherapies and immunotherapies [ 4 , 22 ]. This evidence prompted us to examine whether denosumab has beneficial effects in certain NSCLC subgroups.…”

“…Although bone-modifying therapies have been approved for NSCLC patients with bone metastasis, only around half of NSCLC patients with bone metastasis received BMAs to manage bone diseases or SREs [ 21 , 22 ]. In Taiwan, a recent national-based survey investigated 44,800 lung cancer patients with bone metastasis and reported that BMAs had been prescribed in only 28.4% patients [ 25 ].…”

Bone Metastasis and Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer (NSCLC): Microenvironment and Possible Clinical Implications

“…It was found that the tumor and bone microenvironment play an important role. Several studies [ 6 , 13 , 14 , 15 ] suggest that bone involvement may be a negative prognostic factor and the presence of BoM could be predictive of a poor response to ICIs.…”

Bone-specific Response According to MDA Criteria Predicts Immunotherapy Efficacy Among Advanced Non-small Cell Lung Cancer (NSCLC) Patients.

“…Bone involvement has been associated with poor survival either with platinum-based chemotherapy or immunotherapy in NSCLC patients (Qin et al 2021;Tournoy et al 2018;Landi et al 2019).…”