Original Article Efficacy and safety analysis of immune checkpoint inhibitor rechallenge therapy in locally advanced and advanced non-small cell lung cancer: a retrospective study Xiaoqi Yan, Luqing Zhao, Fei Wu, Bo Shen, Guoren Zhou, Jifeng Feng, Chao Yue, Jingni Zhu, Shaorong Yu

Since TNM staging has limitations for predicting post-operative outcomes and relapse, more effective prediction tools need to be researched and developed. Lymphovascular invasion, LVI, as a histopathological feature, has been widely shown to have a correlation with poor prognosis and early recurrence of lung adenocarcinoma (LUAD). However, LVI assessment is limited by subjective bias, and therefore its efficacy in practical clinical application needs further clarification. The aim of this study was to formulate a new signature based on LVI-related genes to predict prognosis and recurrence in patients with lung adenocarcinoma. Clinicopathological information, gene sequencing data and whole slide images (WSIs) of LUAD patients were downloaded from the Cancer Genome Atlas (TCGA) databases. LVI statue were evaluated by professional pathologists, and then the differentially expressed genes (LVI DEGs) associated with LVI were screened. The least absolute shrinkage and selection operator (LASSO) and Step Cox regression models were used to construct LVI-associated risk scores (LVRS), including PAQR4, ARGHEF6, CKS1B, CFTR and SEC14L4. The validity of the LVRS score was evaluated on multiple external datasets and our JSSZL cohort dataset. Using LVRS scores and clinical information, nomogram were constructed for use by clinicians. In addition, we further explored the relationship between LVRS score and clinicopathological features, immune infiltration, tumor mutational load, and immunotherapy response, and confirmed the expression of key genes in LVRS score in lung adenocarcinoma tissues using qRT-PCR and immunohistochemistry (IHC) techniques. Based on the LVRS, patients could be classified into high-LVRS and low-LVRS groups. It was found that OS and PFS were significantly worse in the high-LVRS group than in the low-LVRS group (p < 0.001). By ROC curve analysis, it could be found that the nomogram combining LVRS and clinical information could accurately predict the prognosis of LUAD patients with the area under the curve of 1,3,5-year survival rate could reach 0.754, 0.741 and 0.735. The results of univariate and multivariate analysis showed that LVRS was an independent prognostic factor. At the same time, there were significant differences in the mutation profiles and immune microenvironment between the high-LVRS and low-LVRS groups, with the high-LVRS group having a significantly higher mutation rate than the low-LVRS group and exhibiting immunological "cold" features. By the experimental results, higher expression levels of PAQR4 and CKS1B were found in LUAD tissues, while lower expression levels of ARGHEF6, CFTR and SEC14L4 were observed. The LVRS established in this study serves as a valid tool to predict the prognosis and recurrence status of lung adenocarcinoma patients and has a predictive effect on the response to postoperative treatment. The establishment of LVRS may offer some theoretical support to clinical treatment strategies for patients with lung adenocarcinoma following surgical intervention.

Background: Bevacizumab has played an important role in the systemic treatment of patients with advanced non-small-cell lung cancer (NSCLC) without gene mutation. In recent years, bevacizumab biosimilar has received marketing approval based on the results of phase III clinical studies. However, more clinical data are needed to verify the efficacy and safety of bevacizumab biosimilar in clinical application.Materials and methods: We identified 946 patients with locally advanced or metastatic NSCLC who were treated with bevacizumab biosimilar or bevacizumab from January 1, 2019 to November 30, 2021. Comparisons and statistical analyses of bevacizumab biosimilar and bevacizumab were made in terms of efficacy and safety. Efficacy evaluation was performed directly in accordance with RECIST v1.1. Adverse events were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0.Results: The objective response rates (ORRs) were 28.9% in the biosimilar group (n=551) and 30.9% in the reference group (n=395; unstratified ORR risk ratio: 0.934, 95% confidence interval [CI]: 0.677–1.138; unstratified ORR risk difference: −0.020, 95% CI: −0.118–0.035). The estimated median progression-free survival (mPFS) were 6.27 (95% CI: 5.53–7.01) and 4.93 (95% CI: 4.24–5.62) months in the biosimilar and reference groups, respectively (P=0.296). The number of treatment lines, combined treatment regimens and with or without radiotherapy were significant factors affecting the PFS of both groups (P<0.001, P=0.001, P=0.039). Different genetic mutations and dose intensity were not the main factors affecting PFS (P=0.627, P=0.946). The incidences of treatment-emergent adverse events (TEAEs) were 76.41% in the biosimilar group and 71.65% in the reference group (P=0.098). The incidences of grade 3 or higher TEAEs were 22.14% and 19.49% in the biosimilar and reference groups, respectively (P=0.324).Conclusions: Bevacizumab biosimilar is equivalent in efficacy to bevacizumab in patients with locally advanced and advanced NSCLC. It showed acceptable toxicity profile and no new adverse events. Patients who were excluded by clinical trials can also benefit from bevacizumab biosimilar.