Effective treatment strategies and key factors influencing therapeutic efficacy in advanced SMARCA4-deficient non-small cell lung cancer.

SMARCA4/BRG1-deficient non-small cell lung cancer (SD-NSCLC) with high invasiveness and poor prognosis is associated with primary resistance to standard treatment, especially in late-stage patients. This study aimed to explore effective treatments and identify critical factors impacting therapeutic efficacy to enhance outcomes for SD-NSCLC patients. 103 SD-NSCLC patients in stage III/IV diagnosed by immunohistochemistry from May 2019 to March 2024 were included in this study. We assessed the patients' clinical and genetic features, analyzed the clinical outcomes of local treatment and immunotherapy according to the TNM stage, and further evaluated the factors impacting therapeutic efficacy. In stage III patients, no significant differences in the median progression-free survival (mPFS) and median overall survival (mOS) were observed between patients receiving local treatment at the primary site and those who did not (p > 0.05), while adding ICIs (immune checkpoint inhibitors) to local treatment significantly improved mPFS compared with non-ICIs (15.0 vs. 7.7 months, p = 0.033), though not mOS (p > 0.05). For stage IV patients, ICIs significantly improved mPFS (8.9 vs. 4.2 months, p = 0.006) and mOS (19.7 vs. 13.1 months, p = 0.007) compared to non-ICIs treatments. However, among ICIs-treated patients, the addition of local treatment to the primary lesion did not significantly affect mPFS and mOS (p > 0.05). Patients with STK11/KEAP1 mutations had significantly shorter mPFS (3.6 vs. 16.2 months, p = 0.001) and mOS (17.7 vs. 31.3 months, p = 0.002), while no significant difference was observed in mPFS and mOS in patients with different tumor mutation burden (TMB) and PD-L1 expression levels. The addition of ICIs to local treatment shows promising results for locally advanced patients with SD-NSCLC, and first-line ICIs are associated with improved survival in metastatic SD-NSCLC. STK11/KEAP1 mutations may be linked to reduced efficacy of immunotherapy.

Liu H ，Hong Q ，Zheng S ，Zhang M ，Cai L ... -  《-》

Exploration of efficacy of the first-line treatment for advanced non-small cell lung cancer with primary MET-amplification: Retrospective evaluation of 36 cases.

There are few clinical data on targeted therapy for primary mesenchymal-epidermal transforming factor amplification (METamp), unlike METamp secondary to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). First-line treatment options for patients with primary METamp NSCLC remain unclear, and in particular, the efficacy of immune checkpoint inhibitors (ICIs) in these patients is controversial. We retrospectively included primary METamp patients who had received at least one line of systemic anticancer therapy, diagnosed at Zhejiang Cancer Hospital from June 2018 to June 2023, and analyzed the efficacies of different treatment patterns for these patients. We also evaluated the potential relationship between the tumor immune microenvironment (TIME) and the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) axis in primary METamp NSCLC patients. High-level METamp was defined as gene copy number (GCN) ≥ 10 [1]. The clinical outcomes included objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS). We screened 2016 NSCLC patients and detected 36 primary METamp, resulting in a prevalence of 1.79 %. Among the patients, the average MET GCN was 4.6, the overall ORR was 50.0 %, DCR was 77.8 %, mPFS was 5.8 months and mOS was 11.7 months. We categorized the first-line treatments that patients received as: immuno-chemotherapy (CI-group), antiangio-chemotherapy (CA-group), chemotherapy (C-group) and MET-TKIs therapy (TKI-group). The ORR of CI-group, CA-group, C-group and TKI-group was 64.3 %, 16.7 %, 33.4 % and 71.4 %, respectively. And the DCR of this four groups was 100 %, 50 %, 66.7 % and 71.4 %, respectively. CI-group achieved longer mPFS and mOS than other groups, respectively (mPFS: 8.63 vs 3.73 vs 3.53 vs 5.50 months, P = 0.021; mOS: 15.10 vs 11.73 vs 9.93 vs 13.93 months, P = 0.023). The mPFS was longer in the PD-L1-positive group than in the PD-L1 negative group (P = 0.046) and PD-L1 positivity was an independent prognostic indicator for PFS (P = 0.005). In addition, the disease remission effect was significantly lower in Foxp3-positive expressors than in negative expressors (ORR: 33.3 % vs 75.0 %, P = 0.024). Immuno-chemotherapy is a first-line optional treatment strategy in addition to targeted therapy for NSCLC patients with primary METamp. Foxp3-negative expression better predicts the near-term efficacy of immunotherapy.

Ding K ，Liu D ，Jin X ，Xu Y ... -  《-》

Recurrence Risk and Its Impact on Current Treatment Strategies in Early and Locally Advanced NSCLC.

Recurrence rates in early and locally advanced non-small-cell lung cancer (NSCLC) remain high despite curative treatment. Recently, the survival benefit of immune checkpoint inhibitors (ICI) in the (neo)adjuvant setting in patients with stage II-III NSCLC has been demonstrated. This study aimed to identify predisposing factors for disease recurrence to select patients who would benefit from multimodality treatment. This retrospective observational study included patients with stage I-IIIA NSCLC discussed at the Thoracic Multidisciplinary Tumour Board of the University Hospital, Brussels, between 2017 and 2021. Of the 167 patients, 34% had a recurrence, with a median time to recurrence of 9.1 months [272 (interquartile range=175-621.5) days]. The highest recurrence rate (56.5%) was observed in cTNM stage IIIA. Of surgical patients who were not eligible for (neo)adjuvant ICI according to current European reimbursement criteria, 21.7% developed disease recurrence. Twelve out of 20 patients eligible for ICI had no recurrence at a median follow-up of 34.1 months and would have been overtreated if they had received ICI therapy. Treatment modality and TNM stage were significantly associated with recurrence and worse progression-free survival (p<0.05). Stereotactic body radiotherapy, higher TNM stage and the presence of serine/threonine kinase 11 (STK11) mutation were significantly associated with worse overall survival. European reimbursement criteria for (neo)adjuvant ICI in surgical patients are based on TNM stage (T≥4 cm or N1/N2 disease). However, TNM stage alone does not give the full picture. In patients undergoing surgery, the presence of the STK11 mutation was significantly associated with worse overall survival. We suggest the integration of analysis of circulating tumour DNA into perioperative strategies to reduce over- and undertreatment.

Tegenbosch C ，Vekens K 《-》

Promising efficacy of immune checkpoint inhibitor plus chemotherapy for thoracic SMARCA4-deficient undifferentiated tumor.

Thoracic SMARCA4-deficient undifferentiated tumor (SD-UT) is a highly aggressive disease that is nosologically related to but distinct from SMARCA4-deficient non-small cell lung cancer (SD-NSCLC). No standard treatment guidelines were established for SD-UT. This research explored the efficacy of different treatments in SD-UT, and the prognostic, clinicopathologic and genomic difference between SD-UT and SD-NSCLC. Information of 25 SD-UT and 22 SD-NSCLC patients diagnosed and treated in Fudan University Shanghai Cancer Center from January, 2017 to September, 2022 was analyzed. SD-UT was similar to SD-NSCLC in characteristics of onset age, male prevalence, heavy smoking history and metastatic pattern. SD-UT showed a rapid relapse pattern after radical therapy. For Stage IV SD-UT patients, immune checkpoint inhibitor (ICI) plus chemotherapy significantly improved median progression-free survival (PFS) compared to traditional chemotherapy as first-line treatment (26.8 vs. 2.73 months, p = 0.0437), while objective response rates of two arms were comparable (71.4% vs. 66.7%). No significant survival differences were observed between SD-UT and SD-NSCLC under similar treatment settings. SD-UT or SD-NSCLC patients receiving ICI in the first line had significantly prolonged OS than those with ICI in the latter lines or without ICI treatment throughout clinical courses. Genetic study found frequent SMARCA4, TP53 and LRP1B mutations in SD-UT. To the best of our knowledge, this is the largest series to date to compare the efficacy of ICI-based treatment to chemotherapy and document frequent mutations of LRP1B in SD-UT. ICI plus chemotherapy is an effective strategy for Stage IV SD-UT.

Lin Y ，Yu B ，Sun H ，Zhang H ，Hu Z ，Zhang Y ，Wu Z ，Sun S ，Zhao X ，Yu H ，Wu X ，Li Y ，Wang J ，Wang H ... -  《-》

Comparison of efficacy and safety of PD-1/PD-L1 combination therapy in first-line treatment of advanced NSCLC: an updated systematic review and network meta-analysis.

The use of immune checkpoint inhibitors has led to an increase in randomized controlled trials exploring various first-line combination treatment regimens. With the introduction of new PD-1/PD-L1 inhibitors, there are now more clinical options available. For the first time, the AK105 monoclonal antibody Penpulimab, developed in China, was included. The AK105-302 Phase III trial studied the efficacy and safety of Penpulimab combined with chemotherapy in patients with advanced or metastatic squamous NSCLC. To determine the optimal treatment options, we conducted an updated network meta-analysis to compare the effectiveness and safety of these regimens. The system retrieves data from Chinese and English electronic databases, Clinical Trials, and the gov Clinical Trial Registration website up to September 6, 2023. The study indirectly compared the efficacy and safety of PD-1/PD-L1 combination regimens, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), all-grade adverse events, and above-grade III adverse events. Subgroup analyses were conducted based on programmed death ligand 1 (PD-L1) level, histological type, ECOG score, sex, and smoking history. Nineteen RCTS were included, with a total of ten thousand eight hundred patients. Penpulimab plus chemotherapy (Pen + CT) provided the best OS (HR = 0.55, 95% CI 0.38-0.81) for PD-L1 patients with non-selective advanced NSCLC. Except Nivolumab plus Ipilimumab (Niv + Ipi), other PD-1/PD-L1 combination therapies significantly extended PFS compared with CT, and Nivolumab plus Bevacizumab combined with chemotherapy (Niv + Bev + CT) (HR = 0.43, 95% CI 0.26-0.74) provided the best PFS benefit and was comparable to Pen + CT (HR = 1.0) for PFS prolongation. For ORR, except Niv + Ipi, all the other regimens significantly improved ORR compared with CT. In terms of safety, except Tor + CT, the incidence of any-grade AEs or grade ≥ 3 adverse events may be higher than those of chemotherapy. The subgroup analysis revealed that for patients with PD-L1 levels below 1%, treatment with Tor + CT resulted in the best progression-free survival (HR = 0.47, 95% CI 0.25-0.86). For patients with PD-L1 levels of 1% or higher, Sintilimab plus chemotherapy (Sin + CT) (HR = 0.56, 95% CI 0.31-0.99) and Camrelizumab plus chemotherapy (Cam + CT) (HR = 0.43, 95% CI 0.28-0.64) were associated with the best overall survival and progression-free survival, respectively. For patients with SqNSCLC, combined immunotherapy may provide greater survival benefits. For patients with Non-sqNSCLC, Niv + Bev + CT and Tor + CT were associated with optimal PFS and OS, respectively. Cam + CT provided the best PFS in male patients with a history of smoking and an ECOG score of 0. In both female and non-smoking patient subgroups, Pem + CT was associated with the best PFS and OS benefits. For patients with advanced non-selective PD-L1 NSCLC, two effective regimens are Pen + CT and Niv + Bev + CT, which rank first in OS and PFS among all patients. Cam + CT and Tor + CT have advantages for OS in patients with SqNSCLC and Non-sqNSCLC, respectively. Niv + Ipi + CT provided the best OS benefit for patients with an ECOG score of 0, while Pem + CT may be the most effective treatment for patients with an ECOG score of 1. Pem + CT has a better effect on female patients and non-smokers. Sin + CT was found to be the most effective treatment for male patients and the smoking subgroup, while Cam + CT was found to be the most effective for PFS. In addition, Tor + CT was associated with the best PFS for patients with negative PD-L1 expression. Pem + CT was found to significantly improve both PFS and OS compared to CT alone. For patients with positive PD-L1 expression, Sin + CT and Cam + CT were found to be optimal for OS and PFS, respectively. It is important to note that, with the exception of Tor + CT, the toxicity of the other combinations was higher than that of CT alone.

Yang Y ，Chen W ，Dong L ，Duan L ，Gao P ... -  《-》