Potential efficacy of anti-angiogenic therapy combined with immunotherapy for advanced SMARCA4-deficient thoracic tumor: a retrospective study

Introduction

Background

SMARCA4, located on chromosome 19q13, is a component of a complex that encodes the BRG1 protein, namely the SWItch/Sucrose Non Fermentable complex (SWI/SNF). This complex is an adenosine triphosphate (ATP)-dependent chromatin remodelling unit comprising at least 15 protein subunits encoded by approximately 22 genes that regulate transcriptional processes that promote cellular differentiation and play a crucial role in DNA damage repair (1). Its abnormal expression is related to the occurrence of various tumors, involving multiple organs (2,3). In thoracic tumors, loss of SMARCA4 expression occurs in approximately 5–10% of non-small cell lung cancer (NSCLC) (4,5). Another thoracic tumor harboring genetic alterations and aberrant protein expression of SMARCA4 is SMARCA4-deficient undifferentiated tumor (SMARCA4-deficient UT), which is added in World Health Organization (WHO) 2021 classification of thoracic tumors (6). The clinicopathological features between SMARCA4-deficient NSCLC and SMARCA4-deficient UT exhibit notable disparities (7,8). Most patients with chest SMARCA4-deficient NSCLC are male, with a higher proportion of smokers and a poor prognosis (3,8). SMARCA4-deficient UT differs from SMARCA4-deficient NSCLC with a larger primary tumor size, younger patients, significantly worse prognosis and overall survival (OS) (9). Besides, this kind of tumor is often accompanied by genetic mutations in TP53, LRP1B, STK11, KEAP1, and KRAS (10).

Rationale and knowledge gap

The treatment options and survival of patients with SMARCA4 deletion are far less than those of wild-type patients (10,11). In addition, for advanced (stage III and stage IV) patients, immune checkpoint inhibitors (ICIs) combined with chemotherapy may provide longer survival period for patients. A study also confirmed that ICIs combined with chemotherapy prolonged progression-free survival (PFS) in patients with NSCLC and with UT (7). There was no significant difference in the prognosis between the SMARCA4-deficient UT and the SMARCA4-deficient NSCLC (7,12). Although platinum-based chemotherapy combined with ICIs is currently the most commonly used method in clinical practice, its efficacy is not conclusive. First-line treatment for such patients is not limited to chemotherapy combined with immunotherapy; for example, there are some patients who receive ICIs + anlotinib as a first-line treatment in our institution. We noted that immunotherapy combined with anlotinib achieved good outcomes in the treatment of pulmonary sarcomatoid carcinoma (PSC), negative NSCLC and small cell lung cancer (SCLC) (13-15), and perhaps such patients may benefit from this combination modality.

Objective

We conducted a comprehensive retrospective study to further investigate the effectiveness of different first-line treatments in SMARCA4-deficient thoracic tumors, especially ICIs-based treatment. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-556/rc).

Methods

Patient population and data collection

As shown in Figure S1, we retrospectively collected the statistics of 135 patients carrying loss of SMARCA4 who were treated at Shanghai Chest Hospital between January 1^st, 2017 and October 1^st, 2023. Patients were staged according to the American Joint Committee on Cancer Staging Manual (8th Edition) of NSCLC (16). Eligible criteria included: (I) diagnosed with histologically confirmed SMARCA4-deficient NSCLC or UT; (II) stage III or IV disease or post-operative recurrence; (III) patients who had not been lost to follow-up.

Moreover, clinicopathologic characteristics, including gender, age, smoking history, programmed cell death ligand 1 (PD-L1) expression, histologic type, and treatment details were recorded. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Shanghai Chest Hospital (No. IS23093) and individual consent for this retrospective analysis was waived.

PD-L1 tumor proportion scores and gene detection

Tissue samples were collected at the time of disease diagnosis. PD-L1 expression was detected using the PD-L1 IHC22C3 pharmDx assay (Agilent Technologies China, Beijing, China) prior to treatment. Gene detection was performed by next-generation sequencing (NGS) or single-gene testing (LungCureCDx, Burning Rock, Suzhou, China).

Assessment and treatment

Patients’ clinical stage was assessed by the International Association for the Study of Lung Cancer (IASLC) 8th edition tumor-node-metastasis (TNM) classification (17). In accordance with Response Evaluation Criteria in Solid Tumors 1.1 (RECIST1.1) guidelines (18), tumor response was evaluated every 6–8 weeks after treatment initiation by use of high-resolution chest computed tomography (HRCT) and abdominal ultrasound. Radiologic images were reviewed by both experienced physicians and independent radiologists. Clinicians make comprehensive treatment decisions for this patient population by integrating multiple factors: the patient’s individual condition, clinical treatment guidelines, and cutting-edge advances from clinical trials.

The definition of PFS is the time from the start of treatment until the date of disease progression or death from any cause. OS is defined as the time from treatment initiation to the date of death from any cause. If the patient died, the date of death was taken as the last follow-up time.

Statistical analysis

Data analysis was performed using SPSS 24.0 (authorized version by Shanghai Jiao Tong University), and the results were plotted in R version 3.2.0 and GraphPad Prism 8.0. All patients were dichotomized into two groups: first-line with immunotherapy and first-line without immunotherapy. The demographic and clinical characteristics were compared between the two groups using with chi-squared test. Numbers and percentages were tabulated. Median PFS and OS were estimated by use of the Kaplan-Meier method, and the difference in survival between groups was compared using the log-rank test. Univariate and multivariate analyses for PFS and OS were performed using Cox proportional hazards models [with 95% confidence intervals (CIs)]. The multivariate analysis included factors with a P value of less than 0.2. Statistical significance was considered when the P value was less than 0.05.

Follow up

The last follow-up was performed on October 1^st, 2024 and the median follow-up time was 30.47 months. Patient follow-up data were obtained from regular clinical records. Patients receiving chemotherapy or immunotherapy were admitted monthly, while other outpatients were required to follow up at least every two months. To verify information and to contact patients who were not regularly followed up, telephone interviews were also conducted.

Results

Baseline characteristics

This study identified 55 patients with advanced SMARCA4-deficient thoracic tumors using immunohistochemistry during routine clinical practice. Among these patients, 26 patients (47.2%) received immunotherapy in the first line, complete baseline clinicopathologic characteristics of both groups are shown in Table 1. As outlined in Table 1, a significant majority (n=53, 96.3%) of the patients were male, with an average age of 66 years (range, 46–81 years). All 32 patients with documented smoking history were current or former smokers. Stage IV disease was predominant (n=45, 81.8%), with extrathoracic metastasis at baseline (n=30, 54.5%). Histologically, 40 patients (72.7%) were diagnosed with SMARCA4-deficient NSCLCs, and the remaining 15 patients (27.2%) had SMARCA4-deficient UTs. Only a small proportion (n=3, 5.4%) showed high PD-L1 expression, whereas the majority (n=20, 36.3%) of tested patients were PD-L1 negative. The majority of patients had Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0–1 (n=46, 83.6%), while fewer patients were PS =2 (n=9, 16.3%). There were 33 patients with advanced lung cancer at the time of initial diagnosis, and the remainder were patients with postoperative recurrence.

For the genetic characteristics of patients, pathological specimens from all patients were tested for gene mutations by single-gene test or NGS. We evaluated the genetic characteristics of 38 cases, excluding 17 cases, owing to lack of NGS results (n=8) and without concomitant mutation genes (n=9). As shown in Figure 1, the most common concomitant mutation genes were TP53 (86.8%), STK11 (23.6%) and KRAS (18.4%).

Figure 1 Molecular features of the 38 patients with gene mutations. ICI, immune checkpoint inhibitor.

Treatment characteristics

Out of the 55 patients, the majority received either first-line chemotherapy alone (n=20, 36.3%) or a combination of chemotherapy and ICIs for their treatment (n=21, 38.1%). The remaining patients received a combination of anti-angiogenesis drugs with chemotherapy (n=9, 16.3%) or anti-angiogenesis drugs with ICIs (n=5, 9.0%).

Immunotherapy for all patients enrolled in this study was anti-pd1 antibody: tislelizumab for 11 of the 26 patients (42.3%), 11 patients (42.3%) received pembrolizumab, 3 patients (11.5%) received camrelizumab and the remaining 1 patient (3.8%) received sintilimab. Figure 2 shows that a total of 26 patients received ICIs-based therapy for first-line during their clinical course. Five patients were treated in the first line with ICIs in combination with anlotinib, a multi-targeted tyrosine kinase inhibitor that targets tumor angiogenesis. It is worth noting that three patients (2 patients with UT and 1 patient with NSCLC) achieved long-term disease control for more than one year, with two patients’ disease control period even exceeding 36 months. This indicates the potentially excellent efficacy of this treatment combination.

Figure 2 Swimming plot of treatments and clinical information of 26 patients with immunotherapy. 1st, first line; 2nd, second line; 3rd, third line. AC, pemetrexed + carboplatin; beva, bevacizumab; camrel, camrelizumab; D, docetaxel; DC, docetaxel + carboplatin; E, etoposide; ICI, immune checkpoint inhibitor; NE, not examined; PD-L1, programmed cell death ligand 1; pembro, pembrolizumab; sintil, sintilimab; TC, paclitaxel + carboplatin; tegafur, gimeracil and oteracil potassium, S-1; tisle, tislelizumab; TP, paclitaxel + cisplatin.

Clinical outcomes

Comparison of survival time of the first-line treatment in patients with advanced SMARCA4-deficient thoracic tumors

Figure 3A shows that patients who received ICIs in combination with anti-angiogenesis therapy had a longer PFS [20.43 vs. 12.70 months (chemotherapy plus immunotherapy) vs. 6.63 months (chemotherapy plus anti-angiogenesis therapy) vs. 3.10 months (chemotherapy), P<0.001]. As for benefits in OS, the patients receiving ICIs in combination with anti-angiogenesis therapy in the first line had longer OS than other treatments [not reached vs. 21.67 months (chemotherapy plus immunotherapy) vs. 8.80 months (chemotherapy plus anti-angiogenesis therapy) vs. 7.83 months (chemotherapy), P=0.02, Figure 3B]. Furthermore, Figure 3C demonstrated significantly longer PFS in NSCLC patients receiving ICIs combined with anti-angiogenesis therapy (15.93 months) compared to other treatment groups: chemotherapy plus immunotherapy (13.93 months), chemotherapy plus anti-angiogenesis therapy (7.77 months), and chemotherapy alone (3.20 months; P<0.001). Similarly, Figure 3D shows that the combination of ICIs with chemotherapy resulted in the longest OS (21.67 months), followed by anti-angiogenesis therapy plus immunotherapy (20.43 months), chemotherapy plus anti-angiogenesis therapy (17.92 months), and chemotherapy alone (5.23 months; P<0.001). Direct comparison between treatment regimens revealed that immunotherapy combined with chemotherapy significantly improved PFS compared to immunotherapy plus anti-angiogenic therapy (20.43 vs. 11.97 months, P=0.01; Figure S2A). However, while immunotherapy plus anti-angiogenic therapy showed a numerically longer OS than chemotherapy-based immunotherapy (not reached vs. 21.67 months), this difference was not statistically significant (P=0.46; Figure S2B).

Figure 3 Comparison of survival time of the first-line treatment in patients with advanced SMARCA4-deficient thoracic tumors. PFS (A) and OS (B) in all enrolled patients treated with different therapies for first-line treatment. PFS (C) and OS (D) in NSCLC patients treated with different therapies for first-line treatment. ICI, immune checkpoint inhibitor; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival.

ICI-based therapy was more effective than other traditional therapies in advanced SMARCA4-deficient NSCLC and SMARCA4-deficient UT

First-line ICI-based therapy demonstrated superior clinical outcomes compared to non-ICI regimens. Patients receiving ICIs as first-line treatment had significantly longer PFS (13.93 vs. 3.20 months, P<0.001; Figure 4A) and OS (21.67 vs. 8.80 months, P=0.003; Figure 4B) than those treated without ICIs. Timing of immunotherapy initiation influenced outcomes. Among all patients receiving ICIs, first-line immunotherapy was associated with numerically longer PFS than second- or later-line use (13.93 vs. 6.95 months, P=0.27; Figure 4C), though this difference did not reached statistical significance. Similarly, a trend toward prolonged OS was observed with first-line immunotherapy compared to delayed initiation (21.67 vs. 15.50 months, P=0.14; Figure 4D).

Figure 4 ICI-based therapy was significantly more effective than other therapies in patients with advanced SMARCA4-deficient thoracic tumors. PFS (A) and OS (B) in patients treated with immunotherapy versus those without immunotherapy for first-line. Graphs show PFS (C) and OS (D) in patients who received first-line immunotherapy versus those who received second-line or later-line immunotherapy. PFS (E) and OS (F) in patients with NSCLC versus UT. ICI, immune checkpoint inhibitor; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; UT, undifferentiated tumor.

We conducted separate analyses for the two pathological types, revealing that all eligible patients (regardless of NSCLC or UT diagnosis) should be prioritized for combination immunotherapy regimens. Among NSCLC patients, first-line immunotherapy demonstrated statistically significant improvements in both PFS (14.00 vs. 4.17 months, P=0.003; Figure S3A) and OS (21.67 vs. 7.77 months, P=0.003; Figure S3B). Similarly, UT patients receiving first-line immunotherapy showed significantly prolonged PFS (7.53 vs. 2.67 months, P=0.008; Figure S3C), while the observed OS benefit did not reached statistical significance (not reached vs. 12.25 months, P=0.37; Figure S3D). Notably, survival outcomes did not differ significantly between SMARCA4-deficient NSCLC and UT cases. Comparative analyses demonstrated comparable PFS (6.80 vs. 3.03 months, P=0.63; Figure 4E) and OS (13.70 vs. 15.70 months, P=0.42; Figure 4F) between the two pathological subtypes.

Subgroup analyses revealed distinct patterns of treatment benefit. For PFS, first-line immunotherapy demonstrated preferential efficacy in male patients, non-smokers, those with ECOG PS 0–1, individuals aged <65 years, stage IV, UT histology, patients with extrathoracic or intrathoracic metastases, and those with PD-L1 expression <1% (Figure 5A). Similarly, OS benefits were most pronounced in male patients, younger individuals (<65 years), non-smokers, stage IV NSCLC cases, and patients with good performance status (ECOG PS 0–1) (Figure 5B).

Figure 5 Subgroups analysis of PFS (A) and OS (B) with immunotherapy for first-line and without immunotherapy for first-line groups. CI, confidence interval; E/P, events/patients; HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survival; PD-L1, programmed cell death ligand 1; PFS, progression-free survival; PS, performance status; TNM, tumor-node-metastasis; UT, undifferentiated tumor.

We included factors affecting PFS and OS. Cox proportional-hazards models were used to analyze factors that may affect PFS and OS. In univariate analysis, P<0.2 was considered significant. We found that age and smoking history were significant factors affecting PFS to improve sensitivity in univariate analysis. Further multivariate analysis showed that smoking history was the independent risk factor for PFS (Table 2). Regarding OS, univariate analysis showed that age and smoking history were significant factors for OS. When these variables were incorporated into the multivariate analysis, it was found that age was the independent risk factor for OS (Table 3).

Discussion

It is worth noting that many studies have revealed a strong association between thoracic tumors and gene mutations or protein aberrant expression of SMARCA4 (3,19). This finding underscores the importance of continued research into the potential mechanism and effective treatments of SMARCA4-deficient thoracic tumors.

The results of our study demonstrate that immune-combination therapy is an effective treatment for SMARCA4-deficient lung tumors, which is consistent with the findings of previous studies (9,12,20). The combination of ICIs and chemotherapy is an important strategy to improve treatment efficacy, and chemotherapy improves the immune milieu and thus enhances the anti-tumor response of ICIs, even in immune-desert tumors (21). ICIs in combination with platinum-based chemotherapy is an important strategy in the treatment of NSCLC and has the potential to rapidly control disease within the first few weeks (22,23). This is even more important in advanced SMARCA4-deficient NSCLC and SMARCA4-deficient UT, where lung tumors are often large and symptomatic relief is urgently needed.

Another immune combination therapy, anti-angiogenic therapy combined with ICIs treatment, was also included in our study. ICIs in combination with anlotinib in the first-line treatment for patients with SMARCA4-deficient thoracic tumors showed potential strengths that had not been addressed in any previous study. It is noteworthy that the 3 patients who received anlotinib combination immunotherapy are still undergoing the treatment (SMARCA4-deficient UT, n=2; SMARCA4-deficient NSCLC, n=1). In recent studies, anlotinib has been found to be highly effective in treating PSC (24,25). It was believed that the combination of anti-angiogenic drugs and ICI had a synergistic effect. Anti-angiogenic drugs work by inhibiting tumor angiogenesis, which improves the tumor microenvironment (TME) (26,27). At the same time, anti-PD-1 immunotherapy activated immune cells and promoted vascular normalization. The two worked together in a positive feedback loop mechanism (28-31). Therefore, the combination of anti-angiogenic therapy with immunotherapy may have a greater impact on SMARCA4-deficient thoracic tumor cells. This finding provided physicians with more options for subsequent treatment strategies in this patient population. Notably, while NSCLC patients receiving ICIs combined with anti-angiogenic therapy demonstrated longer median PFS compared to those treated with chemotherapy plus ICIs, this regimen did not show superior median OS outcomes relative to the chemotherapy-immunotherapy combination. This may be attributed to the fact that the majority of these limited cases were undifferentiated tumors, previously characterized as SMARCA4-deficient thoracic sarcomas and sarcomatoid carcinomas. These tumors typically exhibit large tumor volume, poor differentiation, and high aggressiveness, leading to more rapid disease progression. Furthermore, SMARCA4-deficient tumors generally demonstrate an immunologically cold phenotype, with their TME contributing to primary drug resistance. Consequently, even significant improvements in PFS often fail to translate into meaningful OS benefits. However, the observation of a longer PFS with this regimen served to illustrate the regimen’s potential for superiority.

A study by Shinno et al. on ICIs of SMARCA4-deficient thoracic tumors showed that PFS time with first-line ICIs regimens was significantly longer than with second-line or advanced treatment (32). In our study, the survival time of first-line applied immunotherapy regimen was longer than that of second-line or posterior therapy, but probably because of the low number of patients receiving second-line or posterior immunotherapy, the difference was not statistically significant. This trend suggested that such patients should receive immune combination therapy early, thus potentially achieving longer survival.

With advances in clinicopathological studies, SMARCA4-deficient thoracic tumors have been subdivided into two major types: SMARCA4-deficient NSCLC and SMARCA4-deficient UT. As mentioned in the earlier studies, there was no significant difference in OS between the two types (7,12). According to our study, there was no significant difference in prognosis between patients with UTs and those with NSCLCs. However, some studies indicated that SMARCA4-deficient UT had a poorer prognosis (33,34). One possible reason for the differing results could be that the studies did not include patients with advanced tumors. For example, Luo et al. found that patients with resectable SMARCA4-deficient UT had significantly worse time to progression (TTP) (hazard ratio =4.35, 95% CI: 1.77–10.71, P=0.001) and OS (hazard ratio =4.27, 95% CI: 1.12–16.35, P=0.022) compared to those with resectable SMARCA4-deficient NSCLC (9). In addition, the studies’ limited sample size is a significant factor contributing to the divergent results. In our study, 55 patients with advanced SMARCA4-deficient NSCLC and SMARCA4-deficient UT were statistically analyzed for first-line treatment strategies. We found that immune-based therapies should be used early to treat patients with SMARCA4 deletion, which is in line with a previous study (12).

However, the study conducted had certain limitations that need to be considered when interpreting the results. Firstly, it was a retrospective single-center study, which could have led to selection bias. Secondly, the type of lung cancer that was the focus of this study is rare. We were only able to collect a small number of cases. In particular, there were only five cases of patients receiving the anlotinib combined with immunotherapy as first-line therapy. This led to our analysis of the first-line treatment was not convincing enough. However, a recently published multicenter retrospective study demonstrated that combining ICIs with anti-angiogenic agents significantly prolonged PFS in patients with advanced PSC—a finding consistent with our swimmer plot and survival analysis (25). Based on these results, the combination of anti-angiogenic therapy and immunotherapy may help improve PFS. Moreover, as a rare tumor type with limited sample size and insufficient follow-up duration, these factors may introduce potential bias in the results. Therefore, longer follow-up periods and larger sample sizes are warranted to validate our findings.

Lastly, our study did not identify a strong correlation between PD-L1 expression and response to ICIs. In a recent retrospective study on SMARCA4-related clinical cases, patients with high PD-L1 expression (≥50%) showed a trend toward better ICIs efficacy, but the difference was not statistically significant (20). Bioinformatics analysis of the TME in SMARCA4-mutated lung cancer revealed a significant decrease in the level of infiltrating cytotoxic T cells, indicating an ‘immune cold’ characteristic, which is consistent with the lack of clinical response to immunotherapy (3). The latest mechanism-based research has found that models lacking SMARCA4 show reduced responses to anti-PD-1 immunotherapy, which is linked to a significant reduction in the infiltration of dendritic cells and CD4⁺ T cells into the TME (35). These findings provide a mechanistic basis for the poor response of SMARCA4-mutated tumors to immunotherapy. Overall, due to the limited data, larger samples are needed to better assess its impact. It is important to identify other useful predictors, such as tumor mutation burden (TMB), genetic mutations, in addition to the expression level of PD-L1, to evaluate the response of BRG1-deficient NSCLC to immunotherapy (3,11,36). We hope that more multicenter prospective studies will be conducted in the future to provide more effective and comprehensive insights for patients with advanced lung cancer with SMARCA4 deficiency.

Conclusions

In conclusion, our real-world evidence study supports that the early use of ICI-based treatment may result in superior survival outcomes for these patients with advanced lung cancer with SMARCA4-deficient compared to other treatment modalities. Besides, ICIs combined with anti-angiogenesis therapy may be a potential first-line treatment. We believe that our findings could be an important reference for future studies.

Acknowledgments

The authors thank the study participants for their contribution to the research.

Our abstract had been accepted for presentation at the 2024 World Conference on Lung Cancer (WCLC), which was held from September 7 to 10, 2024, in San Diego, USA.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-556/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-556/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-556/prf

Funding: This research was supported by grants from the National Natural Science Foundation of China (No. 82272665, No. 82273124) and the Hospital Management Research Foundation of Shanghai Hospital Association (No. 202240019).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-556/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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Shanghai Chest Hospital (No. IS23093) and individual consent for this retrospective analysis was waived.

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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