Efficacy of immunotherapy in patients with oncogene-driven non-small-cell lung cancer: a systematic review and meta-analysis.

Background: Immunotherapy is an emerging antitumor therapy that can improve the survival of patients with advanced non-small-cell lung cancer (NSCLC). However, only about 20% of NSCLC patients can benefit from this treatment. At present, whether patients with driving gene-positive NSCLC can benefit from immunotherapy is one of the hot issues. Therefore, we conducted a meta-analysis to evaluate the efficacy of immunotherapy in patients with oncogene-driven NSCLC and concluded the efficacy of altered subtypes. Methods: A literature search was performed using PubMed, Web of Science, and Cochrane databases. The primary endpoints included the objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) in patients with oncogene-driven NSCLC. Results: In all, 86 studies involving 4524 patients with oncogene-driven NSCLC were included in this meta-analysis. The pooled ORRs in clinical trials treated with monoimmunotherapy of EGFR, ALK, and KRAS alteration were 6%, 0%, and 23%, respectively. In retrospective studies, the pooled ORRs of EGFR, ALK, KRAS, BRAF, MET, HER2, RET, and ROS1 alteration were 8%, 3%, 28%, 24%, 23%, 14%, 7%, and 8%, respectively. Among them, the pooled ORRs of KRAS non-G12C mutation, KRAS G12C mutation, BRAF V600E mutation, BRAF non-V600E mutation, MET-exon 14 skipping, and MET-amplification were 33% 40%, 20%, 34%, 17%, and 60%, respectively. In addition, the pooled mPFS rates of EGFR, KRAS, MET, HER2, and RET alteration were 2.77, 3.24, 2.48, 2.31, and 2.68 months, while the pooled mOS rates of EGFR and KRAS alteration were 9.98 and 12.29 months, respectively. In prospective data concerning EGFR mutation, the pooled ORR and mPFS treated with chemo-immunotherapy (IC) reached 38% and 6.20 months, while 58% and 8.48 months with chemo-immunotherapy plus anti-angiogenesis therapy (ICA). Moreover, the pooled mPFS and mOS of monoimmunotherapy was 2.33 months and 12.43 months. Conclusions: EGFR-, ALK-, HER2-, RET-, and ROS1-altered NSCLC patients have poor reactivity to monoimmunotherapy but the efficacy of immune-based combined therapy is significantly improved. KRAS G12C mutation, BRAF non-V600E mutation, and MET amplification have better responses to immunotherapy, and more prospective studies are needed for further research.

Efficacy of immunotherapy in patients with oncogene-driven non-small cell lung cancer: a systematic review and meta analysis Immunotherapy is an emerging antitumor therapy that can improve the survival of patients with advanced NSCLC. However, only about 20% of NSCLC patients can benefit from this treatment. At present, whether patients with driving gene positive NSCLC can benefit from immunotherapy is one of the hot issues. Therefore, we conducted a meta-analysis to evaluate the efficacy of immunotherapy in patients with oncogene-driven NSCLC, and concluded the efficacy of altered subtypes. 86 studies involving 4524 patients with oncogene-driven NSCLC were included in this meta-analysis. The pooled ORR in clinical trials treated with monoimmunotherapy was of EGFR, ALK and KRAS alteration was 6%, 0%, and 23%, respectively. While in retrospective studies, the pooled ORR of EGFR, ALK, KRAS, BRAF, MET, HER2, RET and ROS1 alteration was 8%, 3%, 28%, 24%, 23%, 14%, 7% and 8%, respectively. Among them, the pooled ORR of KRAS non-G12C mutation, KRAS G12C mutation, BRAF V600E mutation, BRAF non-V600E mutation, MET-exon 14 skipping and MET-amplification was 33% 40%, 20%, 34%, 17% and 60%, respectively. Additionally, the pooled mPFS of EGFR, KRAS, MET, HER2 and RET alteration was 2.77, 3.24, 2.48, 2.31 and 2.68 months, while the pooled mOS of EGFR and KRAS alteration was 9.98 and 12.29 months. In prospective data concerning EGFR mutation, the pooled ORR and mPFS treated with chemo-immunotherapy (IC) was reached 38% and 6.20 months, while 58% and 8.48 months with chemo-immunotherapy plus anti-angiogenesis therapy (ICA). Moreover, the pooled mPFS and mOS of monoimmunotherapy was 2.33 months and 12.43 months. EGFR, ALK, HER2, RET and ROS1-altered NSCLC patients have poor reactivity to monoimmunotherapy, but the efficacy of immune-based combined therapy is significantly improved. KRAS G12C mutation, BRAF non-V600E mutation and MET amplification have better response to immunotherapy, and more prospective studies are needed for further research.

Exploration on the first-line treatment of ERBB2-altered advanced non-small cell lung cancer: A multicenter retrospective study.

BACKGROUND: Although the treatment of ERBB2-altered non-small cell lung cancer (NSCLC) has been studied for many years, there are no comprehensive studies to evaluate the benefits of various therapies as first-line treatment. Through the development of immunotherapy, more and more different combination treatments were applicated in clinical practice, therefore, we conducted a multicenter retrospective study to evaluate the efficacy of different treatments. METHODS: We enrolled patients with ERBB2-altered NSCLC who had undergone at least one-line systemic anticancer treatment to evaluate the efficacy of first-line chemotherapy alone (Chemo), anti-ERBB2 tyrosine kinase inhibitor (TKI), chemotherapy plus immunotherapy (Chemo + Immuno), chemotherapy plus anti-angiogenesis therapy (Chemo + Antiangio) and chemotherapy combined with immunotherapy and anti-angiogenesis therapy (Chemo + Immuno + Antiangio). The clinical outcomes included objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), one-year and three-year survival rate. RESULTS: We enroll 36 patients harboring ERBB2 mutation and 29 with ERBB2 amplification. The overall ORR was 30.8%, DCR was 69.2% and mPFS was 5.7 months. Chemo + Immuno and Chemo + Antiangio both achieved longer mPFS than TKI (7.8 vs 3.6 months, HR: 0.24, 95 %CI: 0.09-0.64, P = 0.002; 5.9 vs 3.6 months, HR: 0.36, 95 %CI: 0.15-0.88, P = 0.019; respectively), while there was no significant difference in mPFS between Chemo + Immuno or Chemo + Antiangio and Chemo (both P > 0.05), the mPFS of the first two was longer. For ERBB2-mutant patients, the mPFS was 5.9 months, and Chemo + Immuno and Chemo + Antiangio both achieved longer mPFS than TKI (12.9 vs 2.9 months, HR: 0.15, 95 %CI: 0.03-0.68, P = 0.005; 7.1 vs 2.9 months, HR: 0.50, 95 %CI: 0.29-0.88, P = 0.009, respectively). In the same therapies, patients with ERBB2 mutation or ERBB2 amplification showed no statistical significance in PFS (both P > 0.05). CONCLUSIONS: In the first-line treatment of ERBB2-altered NSCLC, chemotherapy combined with immunotherapy or anti-angiogenesis therapy may have greater survival benefits than ERBB2-target therapy, but the efficacy may not be better than that of chemotherapy.

[Effect of Different Antitumor Regimens on Incidence and Severity of Corona Virus 
Disease 2019 Pneumonia in Lung Cancer Patients: 
A Single-center Retrospective Study].

BACKGROUND: Studies have shown that the incidence and severity of corona virus disease 2019 (COVID-19) in patients with lung cancer are higher than those in healthy people. At present, the main anti-tumor treatments for lung cancer include surgery, immunotherapy, chemotherapy, radiotherapy, targeted therapy and anti-angiogenesis therapy. While the effects of different anti-tumor treatments on the occurrence and severity of COVID-19 pneumonia are not uniform. Therefore, we aimed to describe clinical characteristics and antitumor therapy of patients with lung cancer and COVID-19 pneumonia, and examined risk factors for severity in this population. METHODS: From December 1, 2022 to February 15, 2023, a retrospective study was conducted in 217 patients diagnosed with COVID-19 and pathologically confirmed lung cancer in the Jinling Hospital. We collected data about patients' clinical features, antitumor treatment regimen within 6 months, and the diagnosis and treatment of COVID-19. Risk factors for occurrence and severity of COVID-19 pneumonia were identified by univariable and multivariable Logistic regression models. RESULTS: (1) Among the 217 patients included, 51 (23.5%) developed COVID-19 pneumonia, of which 42 (82.4%) were classified as medium and 9 (17.6%) were classified as severe; (2) Univariate and multivariate analysis revealed overweight (OR=2.405, 95%CI: 1.095-5.286) and intrapulmonary focal radiotherapy (OR=2.977, 95%CI: 1.071-8.274) are risk factors for increasing occurrence of COVID-19 pneumonia, while other therapies are not; (3) Chronic obstructive pulmonary disease (COPD) history (OR=7.600, 95%CI: 1.430-40.387) was more likely to develop severe pneumonia and anti-tumor therapies such as intrapulmonary focal radiotherapy, chemotherapy, targeted therapy and immunotherapy did not increase severity. CONCLUSIONS: Intrapulmonary focal radiation therapy within 6 months increased the incidence of COVID-19 pneumonia, but did not increase the severity. However, there was no safety concern for chemotherapy, targeted therapy, surgery and immunotherapy.

Clinical characteristics and targeted therapy of different gene fusions in non-small cell lung cancer: a narrative review.

Background and Objective: Lung cancer is the most fatal malignant tumor in the world. Since the discovery of driver genes, targeted therapy has been demonstrated to be superior to traditional chemotherapy and has revolutionized the therapeutic landscape of non-small cell lung cancer (NSCLC). The remarkable success of tyrosine kinase inhibitors (TKIs) in patients with epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusions has shifted the treatment from platinum-based combination chemotherapy to targeted therapy. Although the incidence rate of gene fusion is low in NSCLC, it is of great significance in advanced refractory patients. However, the clinical characteristics and the latest treatment progress of patients with gene fusions in lung cancer have not been thoroughly explored. The objective of this narrative review was to summarize the latest research progress of targeted therapy for gene fusion variants in NSCLC to improve understanding for clinicians. Methods: We conducted a search of PubMed database and American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), and World Conference on Lung Cancer (WCLC) abstracts meeting proceedings from 1 January 2005 to 31 August 2022 with the following keywords "non-small cell lung cancer", "fusion", "rearrangement", "targeted therapy" and "tyrosine kinase inhibitor". Key Content and Findings: We comprehensively listed the targeted therapy of various gene fusions in NSCLC. Fusions of ALK, ROS proto-oncogene 1 (ROS1), and rearranged during transfection proto-oncogene (RET) are relatively more common than others (NTRK fusions, NRG1 fusions, FGFR fusions, etc.). Among ALK-rearranged NSCLC patients treated with crizotinib, alectinib, brigatinib, or ensartinib, the Asian population exhibited a slightly better effect than the non-Asian population in first-line therapy. It was revealed that ceritinib may have a slightly better effect in the non-Asian ALK-rearranged population as first-line therapy. The effect of crizotinib might be similar in Asians and non-Asians with ROS1-fusion-positive NSCLC in first-line therapy. The non-Asian population were shown to be more likely to be treated with selpercatinib and pralsetinib for RET-rearranged NSCLC than the Asian population. Conclusions: The present report summarizes the current state of fusion gene research and the associated therapeutic methods to improve understanding for clinicians, but how to better overcome drug resistance remains a problem that needs to be explored.

MicroRNA-25-3p regulates osteoclasts through nuclear factor I X.

Osteoporosis is a bone metabolic disease, characterized by loss of bone density leading to fractures. Its incidence increases with age and affects patient quality of life. Although osteoclasts play a significant role in osteoporosis, their underlying regulatory mechanisms remain unclear. In this study, we found that microRNA (miR)-25-3p negatively regulates osteoclast function through nuclear factor I X (NFIX). Overexpression of NFIX promoted osteoclast proliferation and increased the expression of the osteoclast differentiation and activity markers tartrate-resistant acid phosphatase and cathepsin K. MiR-25-3p transfection inhibited NFIX expression, which in turn inhibited osteoclast proliferation. Collectively, our results suggest that miR-25-3p promotes osteoclast activity by regulating the expression of NFIX. Therefore, targeting miR-25-3p in osteoclasts could be a promising strategy for treating skeletal disorders involving reduced bone formation.

Preparation of Decellularized Triphasic Hierarchical Bone-Fibrocartilage-Tendon Composite Extracellular Matrix for Enthesis Regeneration.

Tendon to bone (enthesis) rupture, which may cause disability and persistent pain, shows high rate of re-rupture after surgical repair. Tendon or enthesis scaffolds have been widely studied, but few of these materials can recapitulate the tissue continuity. Thus, this study is conducted to prepare a triphasic decellularized bone-fibrocartilage-tendon (D-BFT) composite scaffold. The D-BFT scaffold is developed using a combination of physical, chemical, and enzymatic treatments using liquid nitrogen, Triton-X 100, sodium-dodecyl sulfate, and DNase I, which effectively removes the cell components while preserving the biological composite and microstructure. Moreover, the mechanical properties of D-BFT are highly preserved and similar to those of the human Achilles tendon. Additionally, in vitro, mesenchymal stem cells (MSCs) adhered, proliferated, and infiltrated into the D-BFT scaffold, and MSC differentiation is confirmed by up-regulation of osteogenic-related and tenogenic-related genes. The repair outcomes are explored by applying the D-BFT scaffold in the model of femur-tibia defects in vivo, which shows good repair results. Thus, the D-BFT scaffold developed in this study is a promising graft for enthesis regeneration.

Could cell division cycle protein 42 be a target for lung cancer treatment?

Cell division cycle protein 42 (Cdc42), a member of the Rho GTPase family, which is part of the Ras superfamily, plays important roles in multiple fundamental cellular processes. Deregulation of Cdc42 may cause cellular defects that are responsible for the activation of signaling pathways, and such deregulation is related to cancer formation. Lung cancer is one of the most devastating diseases worldwide. Cdc42 is overexpressed in human lung cancer samples, which suggests that this protein is associated with lung carcinogenesis. Herein, we review the functions of Cdc42 in lung cancer and discuss potential pharmacological approaches that target Cdc42 in cancer cells.