Immune checkpoint inhibitors combined with chemotherapy as first-line treatment may improve clinical outcomes in advanced non-small cell lung cancer with bone metastases

Introduction

Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer, accounting for approximately 85% of all lung cancers (1,2). Most patients are diagnosed at locally advanced or metastatic stages, which explains why NSCLC is a leading cause of cancer-related mortality worldwide (3,4). In particular, bone metastases are highly prevalent in patients with NSCLC, present in 30–40% of patients at diagnosis (5,6). Bone metastases often lead to skeletal-related events (SREs), such as pathological fractures, spinal-cord compression, and severe bone pain, resulting in substantial declines in patients’ activities of daily living and quality of life (5,7). As a result, bone metastasis remains a poor prognostic factor and its optimal management is essential to improve the prognosis of advanced NSCLC.

Our previous studies revealed that immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway, which have brought about a paradigm shift in lung cancer treatment (8), yield favorable therapeutic effects on bone metastases and may improve the prognosis of patients with NSCLC with bone metastases (9-12). However, no studies have been published on the efficacy of ICI treatment in combination with chemotherapy (chemoimmunotherapy) in these patients.

ICI regimens with or without chemotherapy have become the first-line treatment for patients with advanced NSCLC without driver-gene mutations (13-17). Several clinical trials have demonstrated that chemoimmunotherapy provides better clinical outcomes than conventional chemotherapy with platinum-based anticancer drugs (18-31). However, few studies have been conducted to directly compare the effectiveness of ICI monotherapy and chemoimmunotherapy as first-line treatment (32,33), and none have specifically evaluated the comparative efficacy of these regimens for bone metastases of NSCLC. Therefore, the purpose of this study was to compare the clinical effectiveness of ICI monotherapy and chemoimmunotherapy as first-line treatment for patients with NSCLC and bone metastases, with a specific focus on therapeutic outcomes related to bone metastases, the pulmonary tumor response, overall prognosis, and treatment safety. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-476/rc).

Methods

Study design and patients

This was a retrospective study of clinical data from Kanazawa University Hospital. Patients diagnosed with NSCLC with bone metastases before ICI treatment from January 2016 to March 2024 were selected. Among them, only patients without known driver-gene mutations, such as epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations, who received ICIs with or without chemotherapy as first-line treatment were included in this study. Patients who received fewer than two cycles of ICI treatment or who were treated with a combination of two different ICIs were excluded. Patient characteristics, including age, sex, histological type, Eastern Cooperative Oncology Group performance status (ECOG PS), PD-L1 tumor proportion score (TPS), ICI treatment history, bone-modifying agent (BMA) use, and other distant metastases, were investigated. The ICIs used in this study were PD-1 inhibitors (nivolumab, pembrolizumab) and PD-L1 inhibitors (atezolizumab). Patients had received either ICI monotherapy or chemoimmunotherapy depending on their ECOG PS and PD-L1 TPS, according to the treatment guidelines. For patients with an unknown PD-L1 TPS, treatment had been selected based on disease progression and the potential for adverse effects due to the patient’s general condition.

This study was approved by the Ethics Committee of Kanazawa University Hospital (Approval No. 2019-323; approval date: June 17, 2020). Given the retrospective nature of the study, the requirement for individual informed consent was waived, and an opt-out approach was implemented. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Clinical outcomes

Participants were divided into an ICI monotherapy group (ICI group) and a chemoimmunotherapy group (ICI-chemo group) for evaluation of clinical outcomes. Response rates [complete response (CR) + partial response (PR)] and disease control rates (CR + PR + stable disease) for the bone metastases and lung disease were assessed using MD Anderson criteria (34) and the Response Evaluation Criteria in Solid Tumors version 1.1 (35), respectively. These radiological evaluations were based on changes in characteristics upon computed tomography or positron emission tomography performed before the initiation of ICI treatment and at the last follow-up, and not on the determination of best efficacy. In addition, overall survival (OS), progression-free survival (PFS), and the incidences of SREs and immune-related adverse events (irAEs) after initiation of ICIs were evaluated. SREs assessed in this study were pathological fractures and paralysis due to spinal-cord compression requiring surgery, severe bone pain uncontrolled by oral medications and severe osteolytic lesions requiring radiotherapy (RT), and hypercalcemia. The irAEs assessed in this study were events with a grade equal to or greater than 3 according to the Common Terminology Criteria for Adverse Events version 5.0.

Statistical analysis

Fisher’s exact test was used to compare categorical variables, including clinical characteristics and response rates for bone metastases and lung lesions, between the ICI and ICI-chemo groups. Clinical characteristics were used as variables, and their relationships with these clinical outcomes were evaluated using univariate and multivariable logistic regression analyses. OS and PFS after initiation of ICI treatment were estimated using the Kaplan-Meier method, and differences between treatment groups were assessed using the log-rank test. Cox proportional hazards regression models were used for univariate and multivariable analyses to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) and to identify prognostic factors for survival outcomes. The proportional hazards assumption was tested using Schoenfeld residuals, and all models in the present study met this assumption. All statistical analyses were performed using EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan), and a P value less than 0.05 was considered statistically significant.

Results

Patient characteristics

A total of 97 patients with NSCLC with bone metastases were included in this study, 76 males and 21 females, with a median follow-up of 15.5 (range, 2.5–77.2) months after initiation of ICIs. The histological type was adenocarcinoma in 78.4% of patients, and the PD-L1 TPS was assessed in 77 patients (<50%: 53.6%, ≥50%: 25.8%, unknown: 20.6%). In total, 79.4% of patients had distant metastases other than the bone metastases, and 72.2% received concomitant BMAs. The ICI group comprised 44 patients and the ICI-chemo group comprised 53 patients; their clinical characteristics are summarized in Table 1. None of the clinical characteristics differed significantly between the treatment groups, although more patients in the ICI-chemo group seemed to have an ECOG PS of 0 or 1 (92.5% vs. 86.4%, P=0.51) and used concomitant BMAs (77.4% vs. 65.9%, P=0.26). In the ICI group, pembrolizumab was the most commonly used ICI (52.3%), followed by nivolumab (25.0%) and atezolizumab (22.7%). In the ICI-chemo group, pembrolizumab-containing regimens were more common than atezolizumab-containing regimens (Table 1). The most common pembrolizumab- and atezolizumab-containing regimens were pembrolizumab + carboplatin + pemetrexed and atezolizumab + carboplatin + paclitaxel + bevacizumab.

Clinical outcomes

The overall bone metastasis response and disease control rates were 32.0% and 71.1%, respectively, and the response and disease control rates were significantly higher in the ICI-chemo group than those in the ICI group (response rate: 43.4% vs. 20.5%, P=0.01; disease control rate: 81.1% vs. 56.8%, P=0.02; Table 2). The overall lung-lesion response and disease control rates were 29.6% and 62.9%, respectively. Neither outcome differed between the treatment groups (response rate: 26.4% vs. 11.4%, P=0.07; disease control rate: 69.8% vs. 54.5%, P=0.14), although the outcome seemed better in the ICI-chemo group (Table 2).

The median OS (95% CI) and 1-year OS rate in the ICI-chemo group were 20.7 (14.2–51.5) months and 66.2% (51.3–77.5%), respectively, better than those in the ICI group [16.0 (8.8–19.5) months and 61.0% (44.9–73.7%), P=0.01; Figure 1A]. The median PFS in the ICI-chemo group was 10.4 (4.9–20.1) months, better than that in the ICI group [5.5 (3.2–8.8) months, P=0.01; Figure 1B].

Figure 1 OS (A) and PFS (B) of ICI monotherapy (ICI group) and in combination with chemotherapy (ICI-chemo group). CI, confidence interval; ICI, immune checkpoint inhibitor; OS, overall survival; PFS, progression-free survival.

The overall incidence of SREs was 12.4%: eight events occurred in the ICI group (two cases of surgery for L1 compression fracture and six of RT to the femoral head, pelvis, and spine), and four occurred in the ICI-chemo group (one case each of RT to T1, T9, L2, and L4). The incidence rate did not differ between the treatment groups (ICI group: 18.2% vs. ICI-chemo group: 7.5%, P=0.13), and no cases required surgery (Table 2). The overall incidence of irAEs (grade ≥3) was 19.6%, with rates of 18.2% and 20.8% in the ICI and ICI-chemo groups, respectively. The incidence of irAEs was slightly higher in the ICI-chemo group, but the difference was not significant (P=0.81; Table 2).

Therapeutic predictors of response and survival

Univariate analysis revealed the concomitant use of BMAs [odds ratio (OR) (95% CI): 4.44 (1.15–17.2), P=0.04] and the combined use of ICIs and chemotherapy [OR (95% CI): 0.30 (0.09–0.96), P=0.04] as predictors of the therapeutic response of bone metastases. Multivariable analysis of these factors confirmed combination therapy as an independent predictor [OR (95% CI): 0.34 (0.11–0.91), P=0.04; Table 3].

Univariate analysis revealed the presence of other distant metastases [HR (95% CI): 2.35 (1.07–5.14), P=0.03] and the combined use of ICIs and chemotherapy [HR (95% CI): 0.49 (0.27–0.90), P=0.02] as predictors of OS. Multivariable analysis confirmed combination therapy as an independent predictor of OS [HR (95% CI): 0.53 (0.29–0.97), P=0.03; Table 4].

For PFS, univariate analysis revealed the concomitant use of BMAs [HR (95% CI): 3.38 (1.28–8.93), P=0.01] and the combined use of ICIs and chemotherapy [HR (95% CI): 0.46 (0.25–0.84), P=0.01] as predictors. Multivariable analysis confirmed both as independent predictors of PFS [BMA—HR (95% CI): 5.03 (1.81–14.01), P<0.01; combination therapy—HR (95% CI): 0.38 (0.20–0.72), P<0.01; Table 4].

Discussion

In this study, we evaluated the therapeutic effectiveness and safety of ICI monotherapy versus chemoimmunotherapy as first-line treatment of patients with NSCLC with bone metastases. Our results suggest that the combined use of ICIs and chemotherapy may improve the bone metastasis response and prognosis compared with those of ICIs alone, with a similar incidence of irAEs (grade ≥3).

ICIs, which have brought about a paradigm shift in lung cancer treatment (8), were first studied as second-line treatment, yielding significant improvements in the median OS compared with conventional anticancer therapy (36,37). In addition, ICI therapy reportedly provides a similarly significant improvement in prognosis when used as first-line treatment (21-25,38-40). Such reports include a study in which the combined use of ICI and chemotherapy yielded a significantly better prognosis than chemotherapy alone, comparable to that of ICI monotherapy, in patients unselected for PD-L1 expression status (21-25). Based on those studies, ICIs have become first-line treatment options for patients with advanced NSCLC without driver-gene mutations (13-17,30). Although the PD-L1 TPS has been used as an important indicator in the selection of patients for ICI treatment, it is not an indicator for whether chemotherapy should be used in combination with ICIs. No randomized, head-to-head comparisons have been conducted to guide treatment selection between ICIs alone and chemoimmunotherapy in the first-line setting (32,33,41). Therefore, in practice, clinicians often select the treatment based on clinical scenarios (41).

This study focused on bone metastases, which are a common distant metastasis in patients with NSCLC and are often present at the time of initial diagnosis (5,6). Most bone metastases of lung cancer are osteolytic lesions, which have a high risk of early-stage SREs and are considered poor prognostic factors (5,42). Therefore, appropriate management of bone metastases during the early stage of lung cancer is essential, and primary treatment is very important. Thus, in this study, we analyzed the therapeutic efficacy of ICI alone and in combination with chemotherapy to determine which is more effective as primary treatment of patients with NSCLC with bone metastases.

This study showed for the first time that chemoimmunotherapy may improve the bone metastasis response compared with ICI monotherapy. Although our previous studies suggested a similar trend to that observed in the present study, they did not demonstrate a significant association (9-12). This may be owing to differences in patient background characteristics, particularly the line of ICI treatment, as the previous studies included patients who received ICIs in later-line settings. In addition, this study showed that chemoimmunotherapy may significantly prolong the OS and PFS of patients with NSCLC and bone metastases. Although the inclusion criteria differed from those of our study, several clinical trials revealed that chemoimmunotherapy yielded a better prognosis than ICI monotherapy (18-31), consistent with our results. Based on these results, chemoimmunotherapy may be a more effective treatment for NSCLC with bone metastases in the first-line setting than ICIs alone. However, although our analysis demonstrated a significant survival benefit with chemoimmunotherapy, several other clinical variables did not significantly differ between the groups, possibly owing to the limited sample size. Therefore, these results should be interpreted with caution and validated in larger, prospective cohorts.

The overall incidence of SREs in this study (12.4%) was similar to that in a previous study with the same design (13%) (43). In addition, the ICI-chemo group had a lower rate of SREs (7.5%) and no events requiring surgery. Therefore, combination therapy may provide better local control of bone metastases. The incidence of irAEs (grade ≥3) did not significantly differ between the ICI and ICI-chemo groups and was similar to that in previous reports (44-46). ICI monotherapy has the advantage of avoiding the toxicities inherent in chemotherapy, but based on this study, the benefits of combined chemotherapy may outweigh the disadvantages of side effects. This benefit may be an important factor in the choice of first-line treatment of patients with NSCLC with bone metastases.

This study had several limitations. First, it was a small, single-center, retrospective study. Second, although patient baseline characteristics did not significantly differ between the ICI and ICI-chemo groups, potential selection bias cannot be completely ruled out owing to the retrospective nature of the study. In particular, the PD-L1 TPS, a key factor in the selection of ICI-based treatment, was not assessed in all patients, which might have influenced clinical decision-making regarding treatment selection. Although adjustments using propensity score matching might have reduced such bias, the small sample size limited the feasibility and statistical reliability of this method. Therefore, larger-scale, prospective studies incorporating such adjustments are necessary to validate our results. Third, although our data suggested improvements in both bone and lung lesions with chemoimmunotherapy, the difference in lung-lesion response was not statistically significant (P=0.07). This may reflect the effects of biological heterogeneity on treatment sensitivity and differences in the tumor microenvironment between metastatic sites. To better understand these variations and optimize therapeutic strategies, further clinical studies are warranted, along with basic research on the synergistic effects of ICIs and chemotherapy within the distinct microenvironments of bone and lung lesions.

Conclusions

The combined use of ICIs with chemotherapy as first-line treatment for patients with NSCLC and bone metastases may be associated with an improved response of bone metastases and prolonged survival. Additionally, the incidence of grade 3 or higher irAEs was similar between the ICI and ICI-chemo groups, indicating that chemoimmunotherapy may have a comparable safety profile to ICI monotherapy. In the future, the presence of bone metastases may serve as a potential factor in the selection of ICI monotherapy versus chemoimmunotherapy, and the relationship between clinical outcomes and the PD-L1 TPS should be explored further.

Acknowledgments

We would like to thank Editage (https://www.editage.jp/) for English language editing.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-476/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-476/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-476/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-476/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the Ethics Committee of Kanazawa University Hospital (Approval No. 2019-323; approval date: June 17, 2020). Given the retrospective nature of the study, the requirement for individual informed consent was waived, and an opt-out approach was implemented. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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