A retrospective study of the efficacy and safety of immune checkpoint inhibitors combined with chemotherapy for the treatment of SMARCA4-deficient thoracic tumors

Introduction

Lung cancer ranks as the leading cause of both incidence and mortality for malignant tumors on a global scale as well as in China (1). Non-small cell lung cancer (NSCLC) represents about 80 to 85 percent of all lung cancer diagnoses, with the majority of patients being diagnosed at advanced stages. Even with intensive treatment approaches, including surgery, chemotherapy, radiation, and targeted therapies, the survival rates for NSCLC continue to be disappointingly low (2). Approximately 15–50% of human primary NSCLC samples lack BRG1 subunit expression, and mutations in the BRG1 gene are identified in around 35% of NSCLC cell lines (3-6). Additionally, 4% to 6% of NSCLC cases are found to have SMARCA4 expression deficiency (7). SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC) was identified by Wong et al. (8) in 2000 for the first time who reported that BRG1 might act as a tumor suppressor and represent a target for tumor cell destruction. In 2015, Le Loarer and colleagues proposed the term “SMARCA4-deficient thoracic sarcoma (DTS)”, and indicated these type of tumors have distinct histologic, immunohistochemical and clinical characteristics compared to SMARCA4-dNSCLC (9).

In the 5th edition of the World Health Organization (WHO) classification of thoracic tumors, this category is delineated into two distinct groups: SMARCA4-deficient undifferentiated tumors (SMARCA4-dUT) and SMARCA4-dNSCLC (10). SMARCA4-dUT is a type of tumor predominantly found in adults, with significant involvement in the thoracic region. Immunohistochemical analysis typically reveals a deficiency in SMARCA4 (BRG1). In contrast, SMARCA4-dNSCLC is a subtype of NSCLC that displays a wide range of histological features. The classification covers a spectrum of malignant thoracic tumors, ranging from well-differentiated to poorly-differentiated, encompassing various subtypes such as solid and mucinous adenocarcinomas, acinar and papillary adenocarcinomas, squamous cell carcinomas, large cell carcinomas, rhabdoid tumors, as well as malignancies with spindle or signet ring cell features (11-14). Both SMARCA4-dUT and SMARCA4-dNSCLC are associated with a history of smoking and are more prevalent in males (15). Genetically, tumors deficient in SMARCA4 are often characterized by the presence of mutations in the KRAS, TP53, and KEAP1 genes, mutations involving EGFR, ALK fusions, or ROS1 rearrangements are infrequently identified within these tumors (6,16). The efficacy of targeted therapies for such genetic alterations remains largely unknown and requires further investigation. The unique clinical and pathological characteristics of these tumors highlight the necessity for precise diagnosis and suggest the possibility of personalized therapeutic approaches. Understanding the molecular underpinnings of these tumors is crucial for developing effective therapeutic approaches and improving patient outcomes. Indeed, several case studies have suggested that patients with SMARCA4 deficiency may derive benefits from immune checkpoint inhibitors (ICIs) (17-20). Certain individuals with SMARCA4-dNSCLC exhibit sustained responses to treatment with nivolumab or pembrolizumab (21-23). Kawachi and colleagues documented three instances of SMARCA4-deficient thoracic tumors (SMARCA4-dTT) treated initially with the combination of atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP), resulting in partial responses (PRs), a median progression-free survival (PFS) (mPFS) of over 6 months, and a sustained response exceeding one year in one patient (24). Yang et al. reported a 51-year-old Chinese man who was diagnosed with a SMARCA4-dUT. The patient who was treated with a second-line regimen containing tislelizumab, etoposide, and carboplatin (TEC) seemed to have a reduction in tumor burden observed for more than 10 months (25). ICIs could be a new treatment option for patients with SMARCA4-dUT and SMARCA4-dNSCLC. In this observational study, we enrolled a cohort of 59 patients presenting with SMARCA4 (BRG1) deletions in Second Affiliated Hospital of Army Medical University from January 2020 to March 2024. This group included 35 patients with SMARCA4-dUT and 24 patients with SMARCA4-dNSCLC, we compared the molecular, clinicopathological characteristics and survival, as well as safety. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-691/rc).

Methods

Patients cohort

This study conducted a retrospective analysis of patients diagnosed with SMARCA4-dUT and SMARCA4-dNSCLC at Second Affiliated Hospital of Army Medical University from January 2020 to March 2024. To be eligible for inclusion, patients must meet the following specific criteria: (I) they must have a pathological or cytological diagnosis indicating a deficiency in SMARCA4 (BRG1); (II) they must be 30 years of age or older. These criteria were essential for study participation; (III) they had not previously enrolled in other clinical trials. Patients were excluded if there were significant gaps in their medical records, such as incomplete treatment details or a lack of necessary follow-up data, including the absence of imaging study dates and results needed to evaluate disease progression or treatment efficacy. Furthermore, patients who did not have measurable lesions as per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were also excluded from the study. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013), and the protocol was approved by the Second Affiliated Hospital Medical Ethics Committee of Army Medical University (No. 2024-210). Given the retrospective nature of this study, the requirement for obtaining informed consent was dispensed with.

Data collection and clinicopathological evaluation

Our database was carefully reviewed to assess various parameters including age, gender, smoking status, clinical T and N stages, histological subtypes, molecular profiles, treatment plans, and survival outcomes. Survival status data were extracted from patients’ clinical records. Tumor node metastasis (TNM) staging followed the 8th edition guidelines of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual. Histopathological diagnosis criteria were based on the 2021 WHO classification for lung tumors. Molecular test findings, whether performed in-house or in collaboration with other institutions, were systematically collected and analyzed.

Statistical analyses

The interval defined as PFS spanned from the initial diagnosis to either the detection of disease progression or the date of death due to any cause. Overall survival (OS) was characterized as the duration from the point of diagnosis to the date of death. The combined objective response rate (ORR) and disease control rate (DCR) were assessed according to the RECIST version 1.1, with ORR representing the percentage of patients achieving a complete response (CR) or PR and DCR indicating the proportion of patients with CR, PR, or stable disease (SD). For the analysis of categorical variables, we utilized either the Chi-squared test or Fisher’s exact test. In contrast, the comparison of continuous data between the two groups was performed using the Student’s t-test for parametric data or the Wilcoxon rank-sum test for non-parametric data. The estimation of PFS and OS was accomplished through the Kaplan-Meier method. The log-rank test was utilized to appraise the disparities in PFS and OS among different histological groups in a univariate analysis framework. Both univariate and multivariate analyses were conducted using the Cox proportional hazards model to determine the statistical significance. A P value of less than 0.05 was considered the threshold for statistical significance in pooled analyses. Statistical computations were carried out using SPSS software (version 26; IBM Corp, Armonk, NY, USA) in conjunction with GraphPad Prism (version 9.5) for comprehensive data analysis and interpretation.

Results

Clinicopathologic characteristics in SMARCA4-dUT and SMARCA4-dNSCLC

A total of 59 patients were enrolled in the study, with 35 cases diagnosed with SMARCA4-dUT and 24 with SMARCA4-dNSCLC. The patient selection process is illustrated in Figure 1. Some patients did not receive systematic treatment due to economic reasons. The detailed clinicopathological characteristics of these individuals are available in Table 1. The average age at disease onset was similar between the SMARCA4-dUT group (64.46±9.42 years) and the SMARCA4-dNSCLC group (61.92±8.41 years). Both groups predominantly consisted of male patients, with 34 (97.14%) in the SMARCA4-dUT group and 22 (91.67%) in the SMARCA4-dNSCLC group. The average pack-year smoking history was 39.29 pack-years for SMARCA4-dUT and 35.27 pack-years for SMARCA4-dNSCLC.

Figure 1 The selection process of eligible patients. SMARCA4-dUT, SMARCA4-deficient undifferentiated tumors; SMARCA4-dNSCLC, SMARCA4-deficient non-small cell lung cancer; ICIs, immune checkpoint inhibitors; Chemo, chemotherapy.

Upon initial diagnosis, most patients were found to have stage III or advanced disease, with 29 (82.86%) in the SMARCA4-dUT group and all 24 (100.00%) in the SMARCA4-dNSCLC group, indicating that many were not eligible for surgery. The patterns of metastasis observed in both groups were similar, with bone being the primary site of metastasis. Despite the significantly higher tumor mutational burden (TMB) in SMARCA4-dUT patients compared to SMARCA4-dNSCLC patients (19.81 vs. 8.38 mean/Mb, P=0.03), no significant difference was observed in the expression of programmed cell death ligand 1 (PD-L1) between the two groups.

Genomic alterations in patients

Of the 59 patients, 24 underwent next-generation sequencing using the Illumina NovaSeq 6000 platform, or target gene capture sequencing through circulating single-molecule amplification and resequencing technology (cSMART), as well as the ANDiS 500 fully automated closed-tube gene sequencing library preparation instrument. Among these, 10 were diagnosed with SMARCA4-dUT, and 14 were diagnosed with SMARCA4-dNSCLC. The SMARCA4 gene mutations observed in these patients included nonsense and frameshift mutations, along with some missense and synonymous mutations. KRAS mutations were identified in five patients, with specific mutations such as Q61H, G12C, G12V, G12S, and an indeterminate mutation in exon two. Among potential targetable driver genes, three patients had ALK missense mutations, three had EGFR mutations (two missense mutations and one EGFR p.L858R mutation), a MET copy number gain, a MET missense mutation, and three cases with ROS1 missense mutations were detected (Figure 2A). Notably, only the EGFR p.L858R mutation is considered to have clinical significance.

Figure 2 Genetic alterations of SMARCA4-dUT and SMARCA4-dNSCLC. (A) Mutation type of selected genes of SMARCA4-deficient tumors. (B) Genetic alterations of thoracic SMARCA4-dUT and SMARCA4-dNSCLC. A column represents a case and each row represents a gene. SMARCA4-dUT, SMARCA4-deficient undifferentiated tumors; SMARCA4-dNSCLC, SMARCA4-deficient non-small cell lung cancer.

The most commonly mutated genes were TP53 (19 of 21 patients, 90%), RB1 (2 of 4 patients, 50%), LRP1B (4 of 8 patients, 50%), SPTA1 (3 of 6 patients, 50%), and STK11 (3 of 7 patients, 43%) (Figure 2B). This in-depth molecular analysis offers a comprehensive view of the genetic abnormalities in SMARCA4-deficient tumors and can guide tailored therapeutic strategies for these individuals. The presence of targetable mutations like ALK, EGFR, and ROS1 highlights the crucial role of genetic testing in directing personalized treatment plans for patients with these tumor types (Figure 2B).

ICIs-based therapy shows good results in SMARCA4-dUT and SMARCA4-dNSCLC

Twenty-six patients with locally advanced (stage IIIB) or metastatic (stage IV) disease were treated. Among them, 18 had SMARCA4-dUT, and eight had SMARCA4-dNSCLC. Of these, 17 patients were treated with ICIs-based therapy, while nine patients received chemotherapy. There were no significant differences in clinical baseline characteristics between patients receiving ICI-based therapy and those undergoing chemotherapy, as detailed in Table S1. Among patients receiving ICI-based therapy, the most commonly used immune agent was tislelizumab (35.3%), while the chemotherapeutic agents were paclitaxel and nedaplatin. After observing a median follow-up time of 7.6 months [95% confidence interval (CI): 4.8–10.4 months]. While there was no significant difference in DCR between ICIs-based therapy and chemotherapy (76.5% vs. 66.7%), a marked difference was observed in the ORR, favoring ICI-based therapy (52.9% vs. 22.2%) (Table 2).

ICIs-based therapy compared to chemotherapy markedly extended mPFS (31.37 vs. 3.87 months, P=0.001; Figure 3A). A similar noteworthy improvement in mPFS was observed in the SMARCA4-dUT subgroup (12.60 vs. 4.03 months, P=0.007; Figure 3B) and SMARCA4-dNSCLC subgroup (not reached vs. 3.42 months; P=0.03; Figure 3B) with ICIs-based therapy and chemotherapy.

Figure 3 PFS between ICIs-based therapy and chemotherapy. (A) Kaplan-Meier plots of PFS in patients with SMARCA4-dUT/SMARCA4-dNSCLC treated with ICIs-based therapy and those treated with chemotherapy. (B) Kaplan-Meier plots of PFS in patients with SMARCA4-dUT and SMARCA4-dNSCLC treated with ICIs-based therapy and those treated with chemotherapy. PFS, progression-free survival; ICIs, immune checkpoint inhibitors; SMARCA4-dUT, SMARCA4-deficient undifferentiated tumors; SMARCA4-dNSCLC, SMARCA4-deficient non-small cell lung cancer.

Regarding OS, with a median follow-up of 6 months, the OS data were not yet mature, showing no significant differences between ICIs-based therapy and chemotherapy (P=0.06; Figure 4A). Similarly, no distinctions were noted in the SMARCA4-dUT (P=0.17; Figure 4B) and SMARCA4-dNSCLC (P=0.16; Figure 4B) subgroups. Nevertheless, patients undergoing long-term treatment with platinum-based therapy demonstrated a notably prolonged survival, with the longest survivor reaching 44 months. These results highlight the potential advantages of ICIs-based therapy for managing SMARCA4-dUT and SMARCA4-dNSCLC, emphasizing the need for further exploration to optimize treatment strategies for these individuals.

Figure 4 OS between ICIs-based therapy and chemotherapy. (A) Kaplan-Meier plots of OS in patients with SMARCA4-dUT/SMARCA4-dNSCLC treated with ICIs-based therapy and those treated with chemotherapy. (B) Kaplan-Meier plots of OS in patients with SMARCA4-dUT and SMARCA4-dNSCLC treated with ICIs-based therapy and those treated with chemotherapy. OS, overall survival; ICIs, immune checkpoint inhibitors; SMARCA4-dUT, SMARCA4-deficient undifferentiated tumors; SMARCA4-dNSCLC, SMARCA4-deficient non-small cell lung cancer.

Under the same treatment protocols, the prognostic analysis revealed no significant differences in PFS and OS between the SMARCA4-dUT and SMARCA4-dNSCLC groups, as shown in Figure 5.

Figure 5 ICIs-based therapy vs. chemotherapy in SMARCA4-dUT and SMARCA4-dNSCLC. (A) Kaplan-Meier plots of PFS in SMARCA4-dUT and SMARCA4-dNSCLC patients receiving ICIs-based therapy, and patients receiving chemotherapy. (B) Kaplan-Meier plots of OS in SMARCA-dUT and SMARCA-dNSCLC patients receiving ICIs-based therapy, and patients receiving chemotherapy. PFS, progression-free survival; ICIs, immune checkpoint inhibitors; SMARCA4-dUT, SMARCA4-deficient undifferentiated tumors; SMARCA4-dNSCLC, SMARCA4-deficient non-small cell lung cancer; OS, overall survival.

Due to the limited follow-up duration and small sample size, in most subgroups, the addition of ICIs to chemotherapy did not lead to a PFS extension compared to chemotherapy (Figure 6). However, in patients with stage IV disease, the risk of disease progression and mortality was lower in those receiving ICIs than in those undergoing chemotherapy [ICIs-based therapy vs. chemotherapy: hazard ratio (HR) =0.076; 95% CI: 0.009–0.624].

Figure 6 Subgroup analysis of ICIs-based therapy vs. chemotherapy in SMARCA4-deficient thoracic tumors. Forest plots showing hazard ratios of ICIs-based therapy for progression-free survival in different subgroups. HR, hazard ratio; PD, progressive disease; CI, confidence interval; PD-L1, programmed death-ligand 1; TMB, tumor mutational burden; ICIs, immune checkpoint inhibitors.

Almost all patients experienced treatment-related adverse events (AEs) (Table 3). The most prevalent treatment-related AEs in all groups were hypoalbuminemia and anemia. Grade 3 or higher AEs mainly occurred in the group receiving ICIs combined with chemotherapy, presenting as declines in the blood system, such as neutrophil, leukopenia, and neutropenia, consistent with known chemotherapy-related AEs. Following dose adjustment or symptomatic management, AEs were effectively controlled, with no patient fatalities attributed to the treatment. Furthermore, one patient developed immune-related pneumonitis, graded as mild to moderate (grade 1–2), and did not necessitate discontinuation of subsequent treatment.

Discussion

In this retrospective study, frameshift and nonsense mutations in the SMARCA4 gene led to the loss of its protein expression. After a median study follow-up of 7.6 months, the combination of ICIs with chemotherapy improved the PFS of patients with locally advanced or metastatic disease.

SMARCA4-dUT is characterized by highly clinical aggressiveness, rapid progression, poor prognosis and no clear treatment. Diagnosis of SMARCA4-dTT relies on loss of SMARCA4 in immunohistochemistry, and expression of CD34, SOX2 or SALL4 expression or localized Claudin-4 expression are important markers that distinguish SMARCA4-dUT from SMARCA4-dNSCLC (26).

The mechanisms by which SMARCA4 gene mutations alter protein expression are not fully understood, with effects ranging from transcriptional issues to protein recombination (27,28). Our study found that frameshift and nonsense mutations are the main causes of SMARCA4 deficiency, which is consistent with previous research findings (29). Curiously, we encountered cases where patients exhibited a lack of protein expression despite no identifiable mutations, suggesting the involvement of alternative factors such as regulatory mechanisms or epigenetic influences. Previous studies have indicated that patients with point mutations in TP53, but without nonsense mutations, tend to have better clinical benefits when treated with PD-1/PD-L1 therapies compared to those with wild-type TP53. This aligns with our findings of a higher frequency of TP53 mutations, which provides direction for exploring the mechanisms underlying the effectiveness of ICIs in SMARCA4-deficient tumors on a molecular level (30).

These genetic insights may elucidate the suboptimal efficacy of certain NSCLC treatments. The research further indicates the potential for employing immunosuppressive therapies irrespective of modest PD-L1 expression levels. This idea makes us think again about how we treat NSCLC and look into using immunomodulatory therapies for more patients, regardless of their PD-L1 status.

Grasp of the intricate interplay between genetic alterations and protein levels is essential for crafting tailored and potent therapeutic strategies against NSCLC. This deeper knowledge could lead to better strategies for patients in the future. Our research identified a case where an individual was initially diagnosed with SMARCA4-dNSCLC and subsequently received a revised diagnosis of SMARCA4-dUT at our institution. It shows that there are some close connections between SMARCA4-dUT and SMARCA4-dNSCLC that we do not know yet. In the study by Lin et al. a case was described where a patient presented with SMARCA4-dNSCLC at the primary tumor site and SMARCA4-dUT at the metastatic site. This finding hints at a potential link between the emergence of SMARCA4-dUT and SMARCA4-dNSCLC, shedding additional light on the intricate interplay between these two unique malignancies (19). As reported by Rekhtman et al. the initial co-deletion of SMARCA4 and SMARCA2, or the subsequent loss of SMARCA2 on the basis of SMARCA4 deficiency, represents a potential pattern of evolution for SMARCA4-dUT (15).

Regarding potential targetable driver genes, in contrast to previous reports (31) we have identified the presence of driver gene mutations in SMARCA4-dTT. Patients diagnosed with SMARCA4-deficient tumors still need to undergo potential targetable driver genes testing. Although the patient with EGFR (p.L858R) mutation in our study did not receive treatment, it could provide a new therapeutic option. Additionally, we have observed the loss of SMARCA in small cell lung cancer, which is a distinct finding.

In the context of limited-stage patients who receive radical treatment, a rapid relapse pattern was observed in those with SMARCA4-dUT. Nevertheless, these patients exhibited a 13-month long-term survival rate, which was higher than those untreated or treated solely with chemotherapy. This discrepancy, while promising, should be interpreted with caution due to the small sample size and the possibility that patients who underwent surgery may still be in the early phases of follow-up. Despite these limitations, surgery continues to be regarded as the optimal primary treatment for thoracic tumors characterized by SMARCA4 deficiency. The aggressive nature of SMARCA4-dUT necessitates a multidisciplinary approach, and surgery (17,32), when feasible, offers the best chance for disease control and potential cure. Additional studies are vital for enhancing and tailoring treatment approaches to better outcomes, particularly in pinpointing biomarkers that forecast the efficacy of treatments and facilitate customized medical care. There was a notable enhancement in mPFS among patients on ICIs-based therapies compared with chemotherapy, evident in both the SMARCA4-dUT and SMARCA4-dNSCLC subgroups. The majority achieved PR or SD swiftly after two cycles of ICIs-based therapies, leading to sustained disease management.

Although good therapeutic effects were observed in patients receiving immunosuppressive agents, patients having low levels of PD-L1 expression, and no efficacy of ICIs were observed in all TMB subgroups. Extended monitoring and an expanded data pool are necessary to validate the enduring efficacy of this therapeutic strategy.

In terms of AEs, ICIs-based therapy is consistent with the established safety profile of previously reported PD-1/PD-L1 inhibitors (18) and chemotherapy (33,34). Most AEs were hematological in nature, aligning with the known toxicities of the chemotherapy backbone; however, treatment discontinuations due to treatment-emergent AEs were not observed in our study.

Due to reliance on historical data, there may be issues with incomplete or inaccurate records. Some patients discontinued follow-up treatment for economic reasons, leading to missing data. Since SMARCA4-dTT are a rare disease, our study had a small number of cases, the PFS and subgroup analyses may be biased due to individual cases.

Conclusions

Our study provides compelling evidence for the potential of ICI-based therapy compared to conventional chemotherapy in the treatment of SMARCA4-dTT. Additionally, our research is dedicated to exploring the heterogeneity of genetic mutations in patients with SMARCA4-dTT. We have conducted an in-depth analysis of clinical characteristics, tumor classification, and gene expression. Although the ICI-based treatment protocol has shown positive effects in treating SMARCA4-dTT, these findings are preliminary and require further validation through larger-scale, prospective studies.

Acknowledgments

The authors would like to thank the patients and their families for giving their time and commitment to participate in this study.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-691/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-691/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-691/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-691/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 conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Second Affiliated Hospital Medical Ethics Committee of Army Medical University (No. 2024-210). The need for obtaining informed consent was waived because of the retrospective nature of the study.

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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