Pembrolizumab Monotherapy or Combination Therapy for Bone Metastases in Advanced Non-Small Cell Lung Cancer

A Real-World Retrospective Study

Huiping Qiang; Yuqiong Lei; Yinchen Shen; Jiaqi Li; Hua Zhong; Runbo Zhong; Xueyan Zhang; Qing Chang; Jiahuan Lu; Hui Feng; Yan Zhu; Alfredo Addeo; Giuseppe L. Banna; In-Jae Oh; Jialin Qian; Tianqing Chu


Transl Lung Cancer Res. 2022;11(1):87-99. 

In This Article

Abstract and Introduction


Background: The incidence of bone metastases in non-small cell lung cancer (NSCLC) patients is about 30–40% and bone-related events can seriously affect quality of life. Immune checkpoint inhibitor (ICI) therapy has become the standard treatment for advanced NSCLC patients. However, the specific efficacy of ICIs in NSCLC patients with bone metastases remains unclear. The aim of the present study was to explore the prognosis of immunotherapy in this population and to find potential biomarkers.

Methods: In this retrospective study, a total of 110 advanced NSCLC patients with bone metastases who received pembrolizumab therapy were enrolled. Patient characteristics; palliative bone radiotherapy or bone-targeted therapy; serum levels of lactate dehydrogenase (LDH), and the neutrophil-to-lymphocyte ratio (NLR) at baseline were assessed. The correlation of these factors with progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) was analyzed.

Results: The ORR of the total population was 29.1%, and PFS and OS were 7.0 and 14.8 months, respectively. Fifty-eight patients (52.7%) received pembrolizumab treatment as first-line therapy, and 52 patients (47.3%) as second-line therapy or beyond [ORR: 41.4% vs. 15.4%, P=0.011; PFS: 9.0 vs. 4.0 months, P=0.004; OS: not reached (NR) vs. 11.5 months, P<0.0001]. Bone therapy, including palliative bone radiotherapy and bone-targeted therapy, increased the ORR (34.9% vs. 11.1%, P<0.0001) and prolonged PFS (8.5 vs. 2.0 months, P=0.002). Eastern Cooperative Oncology Group performance status score of 0–1 [OS: hazard ratio (HR) =0.117, P<0.0001] and first-line pembrolizumab therapy (OS: HR =0.372, P=0.004) were independent predictors of OS. Patients whose baseline serum LDH level was ≤240.5 IU/L (NR vs. 10.0 months, P<0.0001) or NLR ≤5.55 (NR vs. 18.0 months, P=0.039) showed longer OS.

Conclusions: The efficacy of Pembrolizumab therapy is confirmed in advanced NSCLC patients with bone metastases, particularly when palliative bone radiotherapy or bone-targeted therapy is delivered. Baseline serum LDH level ≤240.5 IU/L and NLR ≤5.55 might predict the prognosis of patients with bone metastases from advanced NSCLC treated with immunotherapy.


Lung cancer is the leading cause of cancer-related deaths globally. In 2020, approximately 1.8 million patients died of lung cancer worldwide (18% of all cancer-related deaths).[1] Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers. In recent years, immune checkpoint inhibitor (ICI) therapy has become one of the main treatment strategies for advanced or metastatic NSCLC without driver gene mutations. The most used ICIs target the programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1) pathway, including nivolumab, pembrolizumab, and atezolizumab. Pembrolizumab is a highly selective humanized monoclonal antibody responsible for inhibiting the PD-1 receptor on T cells while preserving the antitumor function of host immune cells. Several preclinical and clinical studies have shown that its addition to tumor management led to a regression of tumor size in NSCLC patients. Pembrolizumab monotherapy for PD-L1 positive NSCLC or combined with chemotherapy has become the first-line treatment for advanced NSCLC.[2,3]

Most lung cancer patients are diagnosed with locally advanced or metastatic lung cancer.[4] The bone is one of the most common metastatic sites of lung cancer.[5] About 30–40% of advanced NSCLC patients will develop bone metastases, which can cause severe pain and fractures, leading to hospitalizations, loss of autonomy and poor quality of life.[6] Treatment strategies for bone metastases include systemic treatment of the primary tumor, combined with palliative radiotherapy and bone-targeted therapy.[7,8] Combination of denosumab and ICIs, including pembrolizumab, has been clarified to be effective for bone metastases in lung cancer.[9] However, real-world data on the impact of metastatic lesions and treatment regimens on immunotherapy is lacking. As reported, numerous routine blood parameters have been investigated as inflammatory biomarkers in patients with cancer, such as absolute neutrophil count, absolute platelet count and serum levels of lactate dehydrogenase (LDH), which are also associated with poor outcomes.[10] The neutrophil-to-lymphocyte ratio (NLR) is a novel predictor of inflammatory status in NSCLC and may represents the frequency and activity of myeloid-derived suppressor cells (MDSCs).[11] The two indicators are simple and easy to access from blood routine examination. Therefore, we conducted this retrospective clinical study to evaluate the efficacy of immunotherapy in these patients and explored potential biomarkers. We present the following article in accordance with the STROBE reporting checklist (available at