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Abstract

Background:

This study systematically assesses the efficacy of immunotherapy as a first-line treatment for patients with non-small-cell lung cancer (NSCLC) and bone metastases who lack driver gene mutations. This analysis draws on data from randomized controlled trials to support individualized treatment strategies.

Methods:

Randomized controlled trials published up to October 1, 2024, were retrieved from PubMed, EMBASE, the Cochrane Library, and the Web of Science. Statistical analyses were conducted using RevMan 5.4 and STATA 17.0, with the results presented in forest plots. Progression-free survival (PFS) and overall survival (OS) were analyzed using hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). This study was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42024604768).

Results:

Meta-analysis demonstrated a significant improvement in OS and PFS for patients with bone metastases receiving immunotherapy (OS: HR: 0.81, 95% CI: 0.71-0.92; PFS: HR: 0.78, 95% CI: 0.62-0.98). Although the survival benefit of immunotherapy was lower in patients with bone metastases than in those without, it was superior to chemotherapy.

Conclusions:

Among patients with driver gene-negative NSCLC and bone metastases, immunotherapy significantly improved OS and PFS, thus supporting its role as an effective first-line treatment. Further large-scale trials are recommended to enhance treatment precision and validate these findings.

Keywords

Non-small-cell lung cancer immune checkpoint inhibitor chemotherapy bone metastasis first-line therapy

Introduction

Lung cancer accounts for a significant proportion of the global cancer burden and is one of the leading causes of cancer-related deaths worldwide due to its high invasiveness and prevalence.¹ Non-small-cell lung cancer (NSCLC), which comprises approximately 82% of all lung cancers, generally progresses more slowly than other types. However, approximately 40% of patients with NSCLC are diagnosed at advanced stages, often with metastases, significantly reducing survival rates.² Advancements in tumor immunology have revolutionized NSCLC treatment, particularly through the introduction of immune checkpoint inhibitors (ICIs) for patients without driver gene mutations. For instance, the KEYNOTE-024 study found that patients with NSCLC and programmed death-ligand 1 (PD-L1) expression ⩾ 50% who received pembrolizumab had significantly longer progression-free survival (PFS) and overall survival (OS) than those receiving chemotherapy, with fewer adverse events.³

This finding led the US Food and Drug Administration (FDA) to approve pembrolizumab as a first-line monotherapy for patients with NSCLC and high PD-L1 expression.⁴ Despite its promising efficacy, PD-1/PD-L1 monotherapy is less effective in patients with low or negative PD-L1 expression, thus increasing interest in combination therapies.

The KEYNOTE-189 study⁵ demonstrated that combining pembrolizumab with chemotherapy (carboplatin and pemetrexed) significantly improved PFS and OS across various PD-L1 expression levels. For instance, in the pembrolizumab-combination group, 12-month OS (22.0 vs 10.6 months) and PFS (8.8 vs 4.9 months) were notably higher than in the chemotherapy-only group. This prompted the FDA to approve non-squamous NSCLC in May 2017 and squamous NSCLC in October 2018. Furthermore, in 2020, the FDA approved a combination of nivolumab and ipilimumab with 2 cycles of platinum-based chemotherapy as a first-line treatment for metastatic NSCLC based on findings from the CheckMate-9LA study.^6,7 These advances have firmly positioned ICIs as the cornerstone of advanced NSCLC treatment and fundamentally shifted the therapeutic approach for patients without driver gene mutations.^8,9

Despite advancements in immunotherapy for advanced NSCLC, OS remains relatively low, with a 5-year survival rate of only 19%.¹⁰ Research suggests that metastases significantly affect survival outcomes in NSCLC, with bone metastases among the most prevalent and affecting 20% to 40% of patients.^11
-13 Bone metastases cause severe pain and pathological fractures and lead to skeletal-related events (SREs), including spinal cord compression and hypercalcemia, which significantly reduce patients’ quality of life and survival rates.^14,15 Current treatments for bone metastases primarily include palliative radiotherapy, bisphosphonates, and bone-targeting therapies such as denosumab.¹⁶ However, their effectiveness in improving survival rates is limited.

Radiotherapy outcomes depend on factors such as dose, treatment site, and individual patient differences, with repeated sessions posing risks of bone marrow suppression and tissue damage. Bone-targeting therapies primarily reduce SREs and improve quality of life. However, as many patients with bone metastases are in advanced stages and have limited time for bone remodeling, the survival benefit of these therapies remains minimal.^12,17,18

Evidence suggests that bone marrow actively regulates immune function and immune cell trafficking. The immunosuppressive microenvironment of bone tissue fosters an immune-inhibitory state within the tumor microenvironment, which is mediated by suppressive immune cells and signaling molecules.¹⁹ Immune checkpoint inhibitors can counteract these effects by restoring T-cell activity to enhance antitumor immune responses, reduce tumor burden, and limit cancer spread within bone tissue.

During bone metastasis, increased osteoclast activity accelerates bone degradation, whereas suppressed osteoblast activity contributes to bone destruction. Immunotherapy helps restore this balance by activating T cells, which regulate interactions between osteoclasts and osteoblasts, ultimately reducing bone tissue degradation.²⁰ Given the key mechanisms under which immunotherapy affects bone metastases, recent studies have investigated the use of ICIs to improve patients with NSCLC, bone metastases, and no driver gene mutations.

In a retrospective study, Li et al²¹ reported that bone metastases negatively affect the efficacy of ICI monotherapy in patients with NSCLC, thus significantly reducing both PFS and OS. Bone metastases are a prognostic factor associated with poor clinical outcomes in patients with lung cancer treated with ICIs. However, the JAVELIN Lung100 study²² found that ICI treatment significantly improves PFS and OS in patients with advanced, driver gene-negative NSCLC and bone metastases.

Similarly, the CheckMate 227 Part 1 study²³ showed that immunotherapy significantly prolonged the OS of patients with bone metastases. Overall, multiple studies suggest that ICIs may improve OS and PFS in driver gene-negative advanced NSCLC, particularly in cases with extensive metastases. However, the efficacy and safety of ICIs in patients with bone metastases remain poorly understood, with the incidence and severity of immune-related adverse events requiring careful evaluation. Therefore, a comprehensive meta-analysis is essential to systematically assess the efficacy and safety of immunotherapy as a first-line treatment for driver gene-negative NSCLC in patients with bone metastases.

This meta-analysis employed rigorous literature search and data selection criteria to ensure scientifically valid and reliable results. By systematically evaluating the OS and PFS, we provide empirical evidence to support clinical decision-making. Furthermore, this study explored the therapeutic potential and limitations of combining immunotherapy with chemotherapy and offers a foundation for personalized treatment strategies for patients with NSCLC and bone metastases lacking driver gene mutations.

Materials and methods

Search strategy

Following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines,²⁴ we conducted a systematic literature search using a prespecified protocol. As of October 1, 2024, we searched 4 major databases (PubMed, EMBASE, Cochrane Library, and Web of Science) for randomized controlled trials (RCTs) on immunotherapy in advanced NSCLC, thus limiting the results to English-language publications. We also reviewed references of relevant articles and abstracts from major conferences, including the American Society of Clinical Oncology (ASCO), World Conference on Lung Cancer (WCLC), European Society for Medical Oncology (ESMO), and American Association for Cancer Research (were). The search incorporated free text and MeSH terms combined with Boolean operators (AND/OR).

The key search terms included “pembrolizumab,” “nivolumab,” “atezolizumab,” “durvalumab,” “avelumab,” “sugemalimab,” “toripalimab,” “immune checkpoint inhibitors,” “NSCLC,” “non-small cell lung cancer,” “metastasis,” and “advanced.” The detailed search strategies for each database are presented in Supplementary Material 1. Duplicate records were removed before analysis of the remaining articles. Two researchers independently screened the studies, beginning with titles and abstracts, followed by a full-text review. A third researcher mediated disagreements until consensus was reached. The reference lists of the eligible studies were screened for additional relevant articles. The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42024604768.

Inclusion and exclusion criteria

Inclusion criteria

Studies were selected based on the population, intervention, comparison, outcomes and study (PICOS) framework. Population (P): patients diagnosed with NSCLC with bone metastases. Intervention (I): studies comparing an experimental and a control group. The experimental group received immunotherapy-based treatment, with or without additional drugs, whereas the control group received chemotherapy or a placebo. Outcomes (O): Studies reporting PFS and OS data stratified by bone metastasis status (presence or absence), with associated hazard ratios (HRs). Progression-free survival was defined as the time from randomization to the first progression (local or distant) or death, and OS was defined as the time from randomization to death from any cause. Study design (S): Only RCTs were included in this meta-analysis.

Exclusion criteria

Studies were excluded based on the following criteria: (1) absence of OS and PFS data based on bone metastasis status; (2) study type limitations, including reviews, abstracts, case reports, letters, animal studies, and retrospective studies; (3) incomplete or unclear survival data affecting result interpretation; and (4) incorrect statistical methods or missing HRs and 95% CIs that could not be calculated or converted. For duplicate clinical trials, the most recent or most complete dataset was used. Two authors independently reviewed the final results, and specific study disagreements were resolved through consensus discussions among all researchers.

Data extraction

The following information was extracted from each study: title, author(s), publication year, study phase, intervention and control measures, sample sizes for both groups, and HRs for PFS or OS with corresponding 95% CIs for patients with and without bone metastases. For studies reporting multiple datasets, the most recent or most complete dataset was used.

Quality and bias assessment

The quality of RCTs was assessed using the Cochrane risk of bias 2 (RoB 2) tool,²⁵ which evaluates 5 key domains: (1) bias from the randomization process, (2) bias due to deviations from intended interventions, (3) missing outcome data, (4) bias in outcome measurement, and (5) bias in selecting reported results.

Statistical analysis

Statistical analyses were conducted using RevMan 5.4 and STATA 17.0, with results presented in forest plots. Progression-free survival and OS were analyzed using HRs with corresponding 95% CIs. Heterogeneity was assessed using the I² test: an I² ⩽ 50% indicated low heterogeneity, warranting the use of a fixed-effects model, whereas an I² > 50% indicated significant heterogeneity, prompting the use of a random-effects model. Funnel plots were constructed based on the number of studies in the PFS and OS analyses. Publication bias was evaluated using Begg and Egger tests. Sensitivity analyses were performed to assess the robustness of the results, with P < .05 considered statistically significant.

Results

Literature search

The initial search yielded 17 439 articles. After removing 2672 duplicates, 6874 studies were excluded for not being RCTs. Screening titles and abstracts led to the exclusion of 5326 studies that were not relevant. Full-text reviews were conducted on the remaining 2576 potentially eligible articles. Following the inclusion and exclusion criteria, 8 RCTs,^22,23,26
-31 were included in the final analysis. Figure 1 illustrates the literature selection process.

Figure 1.

The flow chart of search and study collection.

Study characteristics

All included studies were phase III RCTs, with patient diagnoses based on the tumor-node-metastasis (TNM) staging criteria for NSCLC, thus focusing on advanced or metastatic stages. The intervention group received ICI-based antitumor therapy, whereas the control group was treated with non-ICI chemotherapy regimens, with ICIs administered as the first-line treatment. Seven RCTs^{22,23,26,27,29
-31} included patients with NSCLC regardless of histological subtype, whereas 1 study²⁸ specifically focused on patients with non-squamous cell carcinoma. Each study reported an association between bone metastasis and OS or PFS, with some provided OS or PFS data for patients without bone metastases. Table 1 presents the study characteristics.

Table 1.

Baseline characteristics of the included studies.

Study	Year	Author	Phase	Bone metastasis no.(I/C)	Non-bone metastasis no.(I/C)	Histology	PD-L1	TMB	Intervention	Control treatment	OS HR (95% CI)	PFS HR (95% CI)
JAVELIN Lung 100a	2023	Martin Reck	Ⅲ	28/49	122/165	Sq or no-sq	PD-L1 ⩾ 80%	NA	Avelumab(Q2 W)	CT(gem + ddp or cbp/ptx + cbp/pem + cbp or ddp)	0.81 (0.49-1.33)	0.65 (0.37-1.15)
JAVELIN Lung 100b	2023	Martin Reck	Ⅲ	40/30	90/98	Sq or no-sq	PD-L1 ⩾ 80%	NA	Avelumab(QW)	CT(gem + ddp or cbp/ptx + cbp/pem + cbp or ddp)	0.56 (0.32-0.99)	0.64 (0.35-1.19)
ONO-4538-52/TASUKI-52	2023	Hye Ryun Kim	Ⅲ	56/83	219/192	no-sq	PD-L1 < 1%, 1%-49%, or ⩾ 50%	NA	Nivolumab + Bevacizumab + CT	Bev + CT (ptx + cbp)	1.03 (0.66-1.59)	0.87 (0.56-1.37)
CheckMate 227 Part 1	2022	LuisG. Paz-Ares	Ⅲ	163/153	420/430	Sq or no-sq	PD-L1 < 1% or ⩾ 1%	TMB < 10 or ⩾ 10	Nivolumab + Ipilimumab	CT(cbp + ddp)	0.68 (0.53-0.87)	-
CheckMate 9LA	2024	Martin Reck	Ⅲ	97/111	264/247	Sq or no-sq	PD-L1 < 1%, ⩾ 1%, 1%-49%, or ⩾ 50%	NA	Nivolumab + Ipilimumab + CT	CT(pem/gem + cbp or ddp	0.74 (0.560.99)	-
CHOICE-01	2022	Zhijie Wang	Ⅲ	92/46	217/110	Sq or no-sq	PD-L1 < 1% or ⩾ 1%	TMB < 10, ⩾ 10 or NA	Toripalimab + CT	CT(nab-p + cbp/pem + ddp or cbp)	0.84 (0.52-1.37)	0.69 (0.45-1.06)
CheckMate 227 Part 2	2023	H. Borghaei	Ⅲ	108/120 82/86	269/258 188/187	Sq or no-sq no-sq	PD-L1 < 1%, ⩾ 1%, or ⩾ 50%	TMB < 10 or ⩾ 10	Nivolumab + CT	CT(ptx + cbp/pem + cbp or ddp)	0.97 (0.72-1.31) 0.99 (0.69-1.40)	- -
BFAST cohort C	2022	Solange Peters	Ⅲ	34/30	111/116	Sq or no-sq	NA	TMB ⩾ 16	Atezolizumab + CT	CT(pem/gem + cbp or ddp)	1.40 (0.77-2.53)	1.15 (0.66-2.00)

Abbreviations: Bev, bevacizumab; cbp, carboplatin; CI, confidence interval; CT, chemotherapy; ddp, cisplatin; no-sq, non-squamous; GEM, gemcitabine; HR, hazard ratio; NA, not available; nab-p, nab-paclitaxel; OS, overall survival; PD-L1, programmed death-ligand 1; pem, pemetrexed; PFS, progression-free survival; ptx, paclitaxel; Sq, squamous; TMB, tumor mutational burden.

Quality assessment of included studies

The RoB in the included RCTs was assessed using the RoB 2 tool across the 5 domains. Three studies were classified as having a low RoB. Several studies had an unclear RoB due to insufficient reporting of specific methodological details, whereas none were classified as high risk. Overall, the included studies demonstrated a low RoB (Figure 2).

Figure 2.

Quality assessment of the included studies. (A) The details of bias assessment. (B) The summary of bias assessment.

Meta-analysis results

A meta-analysis was conducted to assess the efficacy of immunotherapy in the bone metastasis subgroup across all included studies. Forest plots from the meta-analysis indicated that immunotherapy significantly improved OS and PFS than chemotherapy-based non-ICI strategies. For OS, heterogeneity analysis showed low heterogeneity (P = .20, I² = 29%), thus confirming the use of a fixed-effects model. The combined analysis demonstrated that immunotherapy significantly improved OS in patients with NSCLC and bone metastases who lacked driver gene mutations (HR: 0.81, 95% CI: 0.71-0.92), with a statistically significant difference (Figure 3A).

Figure 3.

Forest plot comparing OS and PFS. (A) OS in patients with bone metastases. (B) PFS in patients with bone metastases. (C) OS in patients without bone metastases. (D) PFS in patients without bone metastases.

Five studies provided data on PFS, with no observed heterogeneity; therefore, a fixed-effects model was used. As shown in the forest plot (Figure 3B), immunotherapy-based treatments significantly outperformed chemotherapy-based regimens regarding PFS (HR: 0.78; 95% CI: 0.62-0.98). These results suggest a survival advantage of immunotherapy in patients with bone metastases. In addition, 6 studies reported OS outcomes for patients with NSCLC without bone metastases (Figure 3C). The findings indicated that immunotherapy was significantly more effective than chemotherapy in improving OS (HR: 0.77, 95% CI: 0.70-0.84). Progression-free survival outcomes were reported in 3 studies, where immunotherapy also showed a survival advantage over chemotherapy (HR: 0.71, 95% CI: 0.59-0.85), with a statistically significant difference (Figure 3D).

Among patients with driver gene-negative NSCLC, those without bone metastases experienced significant improvements in OS and PFS with immunotherapy than those with bone metastases. These findings suggest that patients without bone metastases may derive significant benefits from immunotherapy. This highlights the need for optimizing subgroup-specific immunotherapy regimens in future clinical practice. Although the survival benefits are less pronounced in patients with bone metastases, immunotherapy remains an effective treatment option.

Sensitivity analysis

Sensitivity analyses were conducted for PFS and OS by sequentially excluding each study to evaluate its impact on the overall results. The findings showed that removing any single study did not significantly affect the pooled effect estimates (Supplementary Figure 1), thus confirming the robustness of the results and the absence of undue influence from any individual study.

Publication bias

Publication bias for the PFS and OS outcomes related to bone metastases was assessed. Funnel plots of PFS and OS (Figure 4) showed a visually symmetrical distribution, which indicated a low risk of publication bias. Given the limited number of studies, Begg and Egger tests were conducted at a significance level of P < .05. Neither test showed a significant publication bias. Detailed results of the Egger and Begg tests are presented in Supplementary Table 1.

Figure 4.

Funnel plot for the meta-analysis of bone metastasis on OS (A) and PFS (B) in patients with NSCLC.

Discussion

The bone is one of the most common metastatic sites in NSCLC, and its presence is typically associated with significantly reduced survival.³² Despite advancements in treatment, including bone-targeted therapies and immunotherapy, patient outcomes remain suboptimal. Therefore, it is essential to evaluate the efficacy of immunotherapy in patients with NSCLC and bone metastases without driver gene mutations and identify factors influencing treatment outcomes.

To our knowledge, this meta-analysis consolidates the largest number of phase III RCTs evaluating immunotherapy for patients with NSCLC and bone metastases without driver gene mutations. Our rigorously conducted analysis demonstrates that immunotherapy improves PFS and OS in patients, regardless of bone metastasis status. Moreover, patients without bone metastases derive significant survival benefits from immunotherapy than those with bone metastases.

Several studies have identified bone metastasis as an independent predictor of a poor prognosis following immunotherapy. Landi et al³³ conducted a retrospective cohort study to assess the effect of bone metastasis on the efficacy of immunotherapy in patients with advanced NSCLC by focusing on the ICI nivolumab. Their findings revealed that regardless of the histological subtype (squamous or non-squamous cell carcinoma), patients with bone metastasis had significantly lower PFS and OS than those without the condition.

Multivariate analysis further demonstrated a significant association between the bone metastasis and increased mortality risk. Similarly, Li et al²¹ found that, within the ICI monotherapy group, patients with bone metastases experienced shorter PFS (4.2 vs 6.7 months, P = .048) and OS (12.5 vs 23.9 months, P = .004) than those without bone metastases. In contrast, the presence of bone metastases did not significantly affect the PFS or OS in patients receiving combination therapy. These findings suggest that bone metastasis may reduce the efficacy of ICI monotherapy in patients with advanced NSCLC; however, combination therapy may help mitigate this adverse effect. A retrospective study by Qiang et al³⁴ examined the efficacy of pembrolizumab, administered either as a monotherapy or in combination, in patients with advanced NSCLC with bone metastases. This study analyzed 110 patients with advanced NSCLC and found that pembrolizumab was effective in this population, with notably improved outcomes in patients receiving concurrent bone-targeted therapies. In addition, patients with solitary bone metastases demonstrated significantly longer survival than those with multiple bone metastases. Baseline levels of lactate dehydrogenase and the neutrophil-to-lymphocyte ratio were identified as potential biomarkers for predicting the prognosis of patients with bone metastases.

The previous sections have briefly discussed the mechanisms underlying the role of bone metastasis as a prognostic factor in immunotherapy, including the immunosuppressive characteristics of the bone microenvironment. The bone marrow harbors a significant population of immunosuppressive cells, including regulatory T cells and myeloid-derived suppressor cells, which inhibit the immune clearance of tumor cells. In addition, osteoclasts contribute to an immunosuppressive “cold” tumor microenvironment by releasing molecules such as indoleamine 2,3-dioxygenase-1 (IDO1), interleukin 10 (IL-10), and transforming growth factor-β (TGF-β), thereby suppressing T-cell antitumor activity. The “vicious cycle” mechanism involves tumor cell-derived factors, such as parathyroid hormone–related peptide (PTHrP) and prostaglandin E2 (PGE2), which promote osteoclast formation, leading to bone resorption and a tumor-supportive microenvironment.^33,35,36

The limited efficacy of immunotherapy observed in the studies discussed may be partly due to small sample sizes and potential study biases. Furthermore, combination immunotherapy may help improve bone metastatic tumors and enhance the effectiveness of immunotherapy. Based on these insights, a comprehensive treatment strategy targeting bone metastases may optimize immunotherapy outcomes for patients with NSCLC with bone metastases in future clinical applications.

Recently, several meta-analyses examined the relationship between bone metastasis in NSCLC and the efficacy of ICIs. A systematic review and meta-analysis published in 2023³⁷ found a significant association between bone metastases and poor OS (HR: 1.55, 95% CI: 1.24-1.94), indicating reduced survival in patients with bone metastases. However, in the PFS analysis, bone metastases did not demonstrate a significant impact (HR: 1.31, 95% CI: 0.85-2.01), suggesting no strong association between bone metastasis and tumor progression rate. In another meta-analysis by Huang et al,³⁸ patients with bone metastases receiving PD-1 inhibitors showed significantly reduced OS with an increased risk of death (HR: 1.67, 95% CI: 1.30-2.16).

Similar to previous studies, bone metastasis did not significantly affect PFS (P > .05), indicating that there was no strong association between bone metastasis and the rate of tumor progression. These findings suggest that bone metastasis is associated with poor OS in patients with advanced NSCLC receiving PD-1 inhibitor therapy, highlighting its role as a critical adverse prognostic factor. However, most studies included in these meta-analyses were retrospective, potentially introducing a selection bias that may have affected the results. While previous meta-analyses have demonstrated that bone metastasis is associated with reduced efficacy of immunotherapy compared to non-bone metastasis subgroups,^37,38 our study provides critical evidence that immunotherapy remains superior to chemotherapy in patients with bone metastasis, albeit with an attenuated benefit. These findings underscore the necessity of distinguishing between prognostic factor analysis and therapeutic efficacy comparison; as bone metastasis is associated with attenuated immunotherapy benefit (prognostic effect), it does not diminish the superiority of immunotherapy over chemotherapy in this subgroup.

In addition, unlike previous meta-analyses, our study specifically focused on patients without driver gene mutations, which allowed us to exclude the confounding effects of these mutations and gain a clearer understanding of the role of immunotherapy in this distinct patient subgroup. The potential mechanisms underlying these findings are as follows: (1) Higher tumor mutational burden (TMB): Patients with NSCLC without driver gene mutations generally exhibit a higher TMB, which causes an increased neoantigen production that activates antitumor immune responses. High TMB is closely associated with enhanced efficacy of ICIs, such as PD-1/PD-L1 inhibitors.³⁹ (2) More immunogenic tumor microenvironment: The tumor microenvironment in patients without driver genes tends to be more immunogenic, with higher T-cell infiltration and elevated PD-L1 expression. These characteristics enhance the action of ICIs and enable the immune system to more effectively recognize and eliminate tumor cells.⁴⁰ (3) Immune suppression in driver-positive patients: Certain driver-positive patients (eg, those with epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase mutations) experience immune suppression because of the activation of specific signaling pathways. For example, EGFR mutations can upregulate PD-L1 expression, inhibit the immune response, and reduce the effectiveness of immunotherapy. Conversely, patients without driver genes are less affected by these inhibitory mechanisms, thus resulting in better immunotherapy outcomes.⁴¹ (4) Pro-inflammatory pathway activation: Tumor cells in patients without driver genes may activate pro-inflammatory pathways that enhance the sensitivity of the tumor microenvironment to immunotherapy and increase its antitumor efficacy.⁴²

Our findings suggest that immunotherapy is a promising first-line treatment for patients with NSCLC with bone metastases who lack driver gene mutations. However, these results should be interpreted with caution to avoid overestimating the role of immunotherapy in this specific population. Future large-scale clinical trials are necessary to further investigate optimal first-line immunotherapy regimens for this patient subgroup.

Our study had several limitations. First, the analysis was based on data from published RCTs rather than individual patient data. While our meta-analysis represents the largest synthesis of RCT data to date in this population, the absolute number of bone metastasis-specific cases remains limited compared with broader NSCLC trials. This reflects the inherent challenge of recruiting homogeneous subgroups for global RCTs. Second, the included studies employed different immunotherapy agents, potentially introducing heterogeneity in treatment protocols and increasing result variability. Third, the lack of sufficient blinding in several studies may have led to a selection bias, lowering the quality of evidence. Fourth, due to the limited number of included studies, we were unable to conduct subgroup analyses based on histological type, specific immunotherapy protocols, differences between multiple and solitary bone metastases, or the presence of multiorgan metastasis alongside bone metastasis.

Conclusions

Overall, our analysis of RCTs suggests that patients with driver gene-negative NSCLC and bone metastases should not be excluded from ICI treatment, despite the potentially lower OS and PFS benefits compared with patients without bone metastases. These findings may help clinicians optimize treatment strategies for this patient group. However, given the limited number of studies, our results should be interpreted with caution and validated in future clinical trials. In addition, exploring additional combination treatment strategies in clinical practice is crucial for improving patient prognosis.

Supplemental Material

sj-docx-1-onc-10.1177_11795549251338144 – Supplemental material for Efficacy of Immunotherapy in Patients With Bone Metastases From Driver Gene-Negative Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Supplemental material, sj-docx-1-onc-10.1177_11795549251338144 for Efficacy of Immunotherapy in Patients With Bone Metastases From Driver Gene-Negative Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials by Weixing Zhao, Xiaoni Jin, Bo Li, Yujia Gu, Zirui Li, Wanjing Guo, Xinxin Lu and Jun Jiang in Clinical Medicine Insights: Oncology

Supplemental Material

sj-docx-2-onc-10.1177_11795549251338144 – Supplemental material for Efficacy of Immunotherapy in Patients With Bone Metastases From Driver Gene-Negative Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Supplemental material, sj-docx-2-onc-10.1177_11795549251338144 for Efficacy of Immunotherapy in Patients With Bone Metastases From Driver Gene-Negative Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials by Weixing Zhao, Xiaoni Jin, Bo Li, Yujia Gu, Zirui Li, Wanjing Guo, Xinxin Lu and Jun Jiang in Clinical Medicine Insights: Oncology

Footnotes

ORCID iD

Weixing Zhao

Author Contributions

Weixing Zhao and Xiaoni Jin: Writing the original draft and conceptualization. Bo Li: Methodology. Yujia Gu: Formal analysis. Zirui Li: Formal analysis. Wanjing Guo: Supervision. Xinxin Lu: Resources. Jun Jiang: Writing-review and editing, funding acquisition.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from the Science and Technology Agency of Qinghai Province (2022-ZJ-719).

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

Availability of data and materials All study data are included in the published article.

Supplemental Material

Supplemental material for this article is available online.

References

Singh

Vignat

Lorenzoni

, et al. Global estimates of incidence and mortality of cervical cancer in 2020: a baseline analysis of the WHO Global Cervical Cancer Elimination Initiative. Lancet Glob Health. 2023;11:e197-e206. doi:10.1016/s2214-109x(22)00501

Miller

Nogueira

Devasia

, et al. Cancer treatment and survivorship statistics, 2022. CA Cancer J Clin. 2022;72:409-436. doi:10.3322/caac.21731

Reck

Rodríguez-Abreu

Robinson

, et al. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019;37:537-546. doi:10.1200/jco.18.00149

Pai-Scherf

Blumenthal

, et al. FDA approval summary: pembrolizumab for treatment of metastatic non-small cell lung cancer: first-line therapy and beyond. Oncologist. 2017;22:1392-1399. doi:10.1634/theoncologist.2017-0078

Gandhi

Rodríguez-Abreu

Gadgeel

, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378:2078-2092. doi:10.1056/NEJMoa1801005

Paz-Ares

Ciuleanu

Cobo

, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22:198-211. doi:10.1016/s1470-2045(20)30641

US Food & Drug Administration. FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC. Published 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-ipilimumab-and-chemotherapy-first-line-treatment-metastatic-nsclc

Doroshow

Sanmamed

Hastings

, et al. Immunotherapy in non-small cell lung cancer: facts and hopes. Clin Cancer Res. 2019;25:4592-4602. doi:10.1158/1078-0432.Ccr-18-1538

Pasello

Pavan

Attili

, et al. Real world data in the era of Immune Checkpoint Inhibitors (ICIs): increasing evidence and future applications in lung cancer. Cancer Treat Rev. 2020;87:102031. doi:10.1016/j.ctrv.2020.102031

10.

Schabath

Cote

ML.

Cancer progress and priorities: lung cancer. Cancer Epidemiol Biomarkers Prev. 2019;28:1563-1579. doi:10.1158/1055-9965.Epi-19-0221

11.

Simmons

Victor

, et al. Impact of new chemotherapeutic and targeted agents on survival in stage IV non-small cell lung cancer. Oncologist. 2011;16:1307-1315. doi:10.1634/theoncologist.2011-0079

12.

Knapp

Devarakonda

Govindan

Bone metastases in non-small cell lung cancer: a narrative review. J Thorac Dis. 2022;14:1696-1712. doi:10.21037/jtd-21-1502

13.

Tsuya

Kurata

Tamura

Fukuoka

Skeletal metastases in non-small cell lung cancer: a retrospective study. Lung Cancer. 2007;57:229-232. doi:10.1016/j.lungcan.2007.03.013

14.

Clézardin

Coleman

Puppo

, et al. Bone metastasis: mechanisms, therapies, and biomarkers. Physiol Rev. 2021;101:797-855. doi:10.1152/physrev.00012.2019

15.

Zajączkowska

Kocot-Kępska

Leppert

, et al. Bone pain in cancer patients: mechanisms and current treatment. Int J Mol Sci. 2019;20:6047. doi:10.3390/ijms20236047

16.

Reinstein

Pamarthy

Sagar

, et al. Overcoming immunosuppression in bone metastases. Crit Rev Oncol Hematol. 2017;117:114-127. doi:10.1016/j.critrevonc.2017.05.004

17.

Sun

Ahn

Lee

, et al. Predictors of skeletal-related events in non-small cell lung cancer patients with bone metastases. Lung Cancer. 2011;71:89-93. doi:10.1016/j.lungcan.2010.04.003

18.

Qin

Zhao

Miah

, et al. Bone metastases, skeletal-related events, and survival in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors. J Natl Compr Canc Netw. 2021;19:915-921. doi:10.6004/jnccn.2020.7668

19.

Gnoni

Brunetti

Longo

, et al. Immune system and bone microenvironment: rationale for targeted cancer therapies. Oncotarget. 2020;11:480-487. doi:10.18632/oncotarget.27439

20.

Zhao

Wang

, et al. Bone marrow and the control of immunity. Cell Mol Immunol. 2012;9:11-19. doi:10.1038/cmi.2011.47

21.

Wang

Chen

, et al. Adverse impact of bone metastases on clinical outcomes of patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors. Thorac Cancer. 2020;11:2812-2819. doi:10.1111/1759-7714.13597

22.

Reck

Barlesi

Yang

, et al. Avelumab versus platinum-based doublet chemotherapy as first-line treatment for patients with high-expression programmed death-ligand 1-positive metastatic NSCLC: primary analysis from the phase 3 JAVELIN lung 100 trial. J Thorac Oncol. 2024;19:297-313. doi:10.1016/j.jtho.2023.09.1445

23.

Paz-Ares

Ramalingam

Ciuleanu

, et al. First-line nivolumab plus ipilimumab in advanced NSCLC: 4-year outcomes from the randomized, open-label, phase 3 CheckMate 227 part 1 trial. J Thorac Oncol. 2022;17:289-308. doi:10.1016/j.jtho.2021.09.010

24.

Page

McKenzie

Bossuyt

, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj. 2021;372:n71. doi:10.1136/bmj.n71

25.

Sterne

JAC

Savović

Page

, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. Bmj. 2019;366:l4898. doi:10.1136/bmj.l4898

26.

Wang

, et al. Toripalimab plus chemotherapy for patients with treatment-naive advanced non-small-cell lung cancer: a multicenter randomized phase III trial (CHOICE-01). J Clin Oncol. 2023;41:651-663. doi:10.1200/jco.22.00727

27.

Borghaei

O’Byrne

Paz-Ares

, et al. Nivolumab plus chemotherapy in first-line metastatic non-small-cell lung cancer: results of the phase III CheckMate 227 part 2 trial. ESMO Open. 2023;8:102065. doi:10.1016/j.esmoop.2023.102065

28.

Kim

Sugawara

Lee

, et al. First-line nivolumab, paclitaxel, carboplatin, and bevacizumab for advanced non-squamous non-small cell lung cancer: updated survival analysis of the ONO-4538-52/TASUKI-52 randomized controlled trial. Cancer Med. 2023;12:17061-17067. doi:10.1002/cam4.6348

29.

Reck

Ciuleanu

Schenker

, et al. Five-year outcomes with first-line nivolumab plus ipilimumab with 2 cycles of chemotherapy versus 4 cycles of chemotherapy alone in patients with metastatic non-small cell lung cancer in the randomized CheckMate 9LA trial. Eur J Cancer. 2024;211:114296. doi:10.1016/j.ejca.2024.114296

30.

Peters

Dziadziuszko

Morabito

, et al. Atezolizumab versus chemotherapy in advanced or metastatic NSCLC with high blood-based tumor mutational burden: primary analysis of BFAST cohort C randomized phase 3 trial. Nat Med. 2022;28:1831-1839. doi:10.1038/s41591-022

31.

Brahmer

Lee

Ciuleanu

, et al. Five-year survival outcomes with nivolumab plus ipilimumab versus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer in CheckMate 227. J Clin Oncol. 2023;41:1200-1212. doi:10.1200/jco.22.01503

32.

Kuchuk

Sabri

Hutton

Clemons

Wheatley-Price

The incidence and clinical impact of bone metastases in non-small cell lung cancer. Lung Cancer. 2015;89:197-202. doi:10.1016/j.lungcan.2015.04.007

33.

Landi

D’Incà

Gelibter

, et al. Bone metastases and immunotherapy in patients with advanced non-small-cell lung cancer. J Immunother Cancer. 2019;7:316. doi:10.1186/s40425-019-0793-8

34.

Qiang

Lei

Shen

, et al. Pembrolizumab monotherapy or combination therapy for bone metastases in advanced non-small cell lung cancer: a real-world retrospective study. Transl Lung Cancer Res. 2022;11:87-99. doi:10.21037/tlcr-21-1033

35.

Wang

Liao

, et al. PD-1 blockade inhibits osteoclast formation and murine bone cancer pain. J Clin Invest. 2020;130:3603-3620. doi:10.1172/jci133334

36.

Del Conte

De Carlo

Bertoli

, et al. Bone metastasis and immune checkpoint inhibitors in non-small cell lung cancer (NSCLC): microenvironment and possible clinical implications. Int J Mol Sci. 2022;23:6832. doi:10.3390/ijms23126832

37.

Liu

Shi

Qiu

Impact of bone metastasis on the prognosis of non-small cell lung cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Clin Transl Oncol. 2024;26:747-755. doi:10.1007/s12094-023-03300-8

38.

Huang

Zhu

Guo

, et al. Metastatic sites as predictors in advanced NSCLC treated with PD-1 inhibitors: a systematic review and meta-analysis. Hum Vaccin Immunother. 2021;17:1278-1287. doi:10.1080/21645515.2020.1823779

39.

Rizvi

Hellmann

Snyder

, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124-128. doi:10.1126/science.aaa1348

40.

Hegde

Chen

DS.

Top 10 challenges in cancer immunotherapy. Immunity. 2020;52:17-35. doi:10.1016/j.immuni.2019.12.011

41.

Gainor

Shaw

Sequist

, et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin Cancer Res. 2016;22:4585-4593. doi:10.1158/1078-0432.Ccr-15-3101

42.

Xia

Herbst

RS.

Immune checkpoint therapy for non-small-cell lung cancer: an update. Immunotherapy. 2016;8:279-298. doi:10.2217/imt.15.123

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