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. 2024 Dec 31;13(12):3460-3472.
doi: 10.21037/tlcr-24-691. Epub 2024 Dec 27.

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

Bin Wang #  1   2 , Heng You #  1   2   3 , Dongfan Ye #  1   2 , Yuanyue Yi  4 , Yu Liu  1   2 , Bin Qing  1   2 , Chuangye Wang  1   2 , Jincheng Liu  1   2 , Jian Zhang  1   2 , Nanbo Wang  1   2 , Pengfei Wan  1   2 , Linlin Shen  1   2 , Zhi Xu  1   2
Affiliations

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

Bin Wang et al. Transl Lung Cancer Res. .

Abstract

Background: Thoracic tumors characterized by a deficiency in SMARCA4 are highly aggressive and linked to a poor prognosis. This retrospective study explores the efficacy and safety of immune checkpoint inhibitors (ICIs) in combination with chemotherapy for SMARCA4-deficient undifferentiated tumors (SMARCA4-dUT) and SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC).

Methods: A cohort of 59 individuals was analyzed, including 35 patients with SMARCA4-dUT and 24 with SMARCA4-dNSCLC.

Results: Clinical characteristics as gender, age, smoking status, and metastatic sites did not significantly vary between SMARCA4-dUT and SMARCA4-dNSCLC. Nonsense and frameshift mutations in the SMARCA4 gene can result in the loss of its protein expression. Following a median follow-up of 7.6 months, the median progression-free survival (mPFS) notably increased with ICIs-based combination therapy compared to chemotherapy, the mPFS was 12.60 vs. 4.03 months in the SMARCA4-dUT subgroup (P=0.007) and not reached vs. 3.42 months in the SMARCA4-dNSCLC subgroup (P=0.03). In stage IV patients, the risk of disease progression and death decreased with ICIs-based combination therapy vs. chemotherapy [ICIs-based therapy vs. chemotherapy: hazard ratio (HR) =0.076; 95% confidence interval (CI): 0.009-0.624]. The most prevalent grade 3 or higher adverse events (AEs) in both groups were hematologic decreases, consistent with typical chemotherapy AEs. No treatment-related AEs led to patient fatalities.

Conclusions: The combination of ICIs and chemotherapy is more effective than chemotherapy for patients with advanced SMARCA4-deficient thoracic tumors (SMARCA4-dTT), and the safety is manageable.

Keywords: SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC); SMARCA4-deficient thoracic tumors (SMARCA4-dTT); SMARCA4-deficient undifferentiated tumors (SMARCA4-dUT); chemotherapy; immune checkpoint inhibitors (ICIs).

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Conflict of interest statement

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.

Figures

Figure 1
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.
Figure 2
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.
Figure 3
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.
Figure 4
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.
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.
Figure 6
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.
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