The Clinical Outcome and Risk Factors Analysis of Immune Checkpoint Inhibitor-Based Treatment in Lung Adenocarcinoma Patients With Brain Metastases

Juan Zhou; Yinfei Wu; Mengqing Xie; Yujia Fang; Jing Zhao; Sung Yong Lee; Yunjoo Im; Lingyun Ye; Chunxia Su


Transl Lung Cancer Res. 2022;11(4):656-669. 

In This Article

Abstract and Introduction


Background: The data about efficacy of immunotherapy for non-small cell lung cancer with brain metastases (BMs) from real-word settings are controversial. This real-word study is aimed to evaluate the clinical outcome of immune checkpoint inhibitor (ICI)-based treatment in lung adenocarcinoma patients with brain metastases (BMs) and explore potential risk factors, with a focus on the spatial distribution of BMs as previous studies suggested spatial heterogeneity on the brain immune microenvironment.

Methods: Advanced lung adenocarcinoma patients with non-oncogene-addicted, who received ICI monotherapy or plus chemotherapy, were enrolled. Efficacy was assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Intergroup comparisons were performed using Pearson's χ 2 or Fisher's exact tests for categorical variables. The progression-free survival (PFS) was estimated using Kaplan-Meier method and compared using log-rank test. Cox proportional hazards model was used for multivariate analyses. Peripheral blood was collected from 15 patients with BMs. Tumor-derived exosomes in plasma were isolated by size exclusion chromatography and the cDNA library preparations for miRNA were sequenced on an Illumina Hiseq platform. Differentially expressed genes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed.

Results: A total of 198 patients were enrolled and brain metastasis occurred in 20.7% patients (N=41). Compared with patients without BMs, those with BMs had a comparable objective response rate (ORR; 29.3% vs. 43.9%; P=0.089), a lower disease control rate (DCR; 58.5% vs. 78.3%; P=0.01), and a shorter PFS (3.6 vs. 8.6 months; P=0.069). For patients with BMs, factors, including the presence of neurological symptoms, the treatment of intracranial radiotherapy, and the combination of ICI with chemotherapy, had no impact on PFS, whereas cerebellum metastasis was significantly associated with shorter PFS (2.8 vs. 13.8 months, P=0.007). Six upregulated miRNAs were identified in patients with cerebellum metastases (N=8) compared with those without (N=7). The enrichment of differentially expression genes in the KEGG pathways indicated upregulated sulfur metabolism pathway in patients with cerebellum metastases.

Conclusions: For lung adenocarcinoma patients, those with BMs have inferior response to ICI-based treatment, but not significantly, and cerebellum metastasis is an independent risk factor with poor outcome for such patients, might attributing to the upregulated sulfur metabolism.


The brain is one of the most common sites of distant metastasis for non-small cell lung cancer (NSCLC).[1] With improvements in systemic therapy, the longer survival of patients also translates to increased incidence of brain metastasis (BM). A large study, involving 457,481 patients with NSCLC, reported that BM was detected in 26% of patients with stage IV disease at presentation, and adenocarcinoma histology was significantly associated with the presence of BM compared with squamous cell lung cancer (26.8% vs. 15.9%, odds ratio 2.93).[2] BM is traditionally considered a negative factor for treatment efficacy and survival prognosis, but unprecedented achievements in the use of immune checkpoint inhibitor (ICI) in lung cancer patients have propelled this issue into a new clinical practice setting.

ICI was believed to be ineffective for intracranial lesions since brain was thought as an immune-privileged site due to the blood-brain barrier. In addition, the large molecular size of the antibody reduced intracerebral drug availability.[3] However, retrospective analysis of clinical trials [KeyNote 024[4] and KeyNote 189[5]] suggested that NSCLC patients with brain metastases (BMs) could derive survival benefits from ICI-based treatment compared with chemotherapy. A pooled analysis[6] of KeyNote-001, -010, -024, and -042 studies also indicated that for patients with high programmed cell death ligand-1 (PD-L1) expression, the advantages of overall survival (OS) gained from pembrolizumab over chemotherapy were comparable between patients with and without BMs [hazard ratio (HR) 0.83 versus 0.78]. Nevertheless, the population from clinical trials has been selected by rigorous criteria, much differing from that in real-word practice. Clinically, the presence of neurological symptoms, the use of glucocorticoid and the treatment of intracranial radiotherapy are important for the prognosis of patients with BMs. Some studies have proved that the treatment of glucocorticoid or intracranial radiotherapy had influences on activity of ICI.[7,8] But, in fact, only 6.2–17.5% of the patients enrolled in the pivotal NSCLC ICI trials had asymptomatic or previously treated or stable BMs, and none of them allowed patients with symptomatic or untreated BMs.[9] Recently, a prospective phase II study[10] examined the efficacy of ICI in advanced NSCLC patients with untreated BMs and showed an intracranial response of 29.7%, but it still required patients be no neurologic symptomatic. The data from real-word practice about efficacy of ICI on patients with BMs remain limited and controversial. For example, a subgroup analysis from Qiao et al.'s study[11] indicated that NSCLC patients with BMs had significantly shorter progression-free survival (PFS) and OS than those without, whereas another real-word study by Sun et al. suggested a comparable objective response rate (ORR), PFS, and OS between patients with and without BMs.[12] Therefore, further studies are needed to better clarify the efficacy of ICI for NSCLC patients with BMs and to identify the relevant risk factors in a clinical practice setting.

In addition, the reported risk factors affecting the prognosis of NSCLC patients with BMs include age, Karnofsky Performance Status, extracranial metastases, the number of BMs, molecular subtype, the method of intracranial radiotherapy, carcinoembryonic antigen levels, and so on,[13–17] however, there is no study on the correlation between the location of BMs and prognosis. We notice that the tumor microenvironment in BMs is organ-specific as there are some specialized resident immune cells, like astrocytes and microglia that are proved to be crucial in promoting tumor progression and immune evasion in NSCLC BMs.[18,19] Previous studies suggested that these cells were much heterogeneous in their morphological and functional properties based on their different spatiotemporal distribution,[20,21] existing influences on tumor microenvironment and malignant progression.[22] Thus, we speculated that regional heterogeneity of the brain microenvironment might lead to different responses of metastatic tumors to immunotherapy.

Collectively, this real-word study is aimed to evaluate the efficacy and clinical outcome of ICI-based treatment in lung adenocarcinoma patients with BMs and to explore the potential risk factors that affect those patients' outcome, with a special focus on the spatial distribution of BMs. We present the following article in accordance with the STROBE reporting checklist (available at