ABSTRACT
Background: Numerous first-line immune checkpoint inhibitors (ICI) were developed for patients with advanced non-small cell lung cancer (NSCLC) lacking driver gene mutations. However, this group consists of a heterogeneous patient population, for whom the optimal therapeutic choice is yet to be confirmed. Objective: To identify the best first-line immunotherapy regimen for overall advanced NSCLC patients and different subgroups. Design: Systematic review and Bayesian network meta-analysis (NMA). Methods: We searched several databases to retrieve relevant literature. We performed Bayesian NMA for the overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (tr-AEs) with a grade equal or more than 3 (grade ⩾ 3 tr-AEs). Subgroup analysis was conducted according to programed death ligand 1 (PD-L1) levels, histologic type, central nervous system (CNS) metastases and tobacco use history. Results: For the PD-L1 non-selective patients, sintilimab plus chemotherapy (sinti-chemo) provided the best OS [hazard ratio (HR) = 0.59, 95% confidence interval (CI):0.42-0.83]. Nivolumab plus bevacizumab plus chemotherapy (nivo-bev-chemo) was comparable to atezolizumab plus bevacizumab plus chemotherapy (atezo-bev-chemo) in prolonging PFS (HR = 0.99, 95% CI: 0.51-1.91). Atezo-bev-chemo remarkably elevated the ORR than chemotherapy (OR = 3.13, 95% CI: 1.51-6.59). Subgroup analysis showed pembrolizumab plus chemotherapy (pembro-chemo) ranked first in OS in subgroups of PD-L1 < 1%, non-squamous, no CNS metastases, with or without smoking history, and ranked second in OS in subgroups of PD-L1 ⩾ 1% and PD-L1 1-49%. Cemiplimab and sugemalimab plus chemotherapy ranked first in OS and PFS for squamous subgroup, respectively. For patients with CNS metastases, nivolumab plus ipilimumab plus chemotherapy (nivo-ipili-chemo) and camrelizumab plus chemotherapy provided the best OS and PFS, respectively. Conclusions: Sinti-chemo and nivo-bev-chemo were two effective first-line regimens ranked first in OS and PFS for overall patients, respectively. Pembro-chemo was favorable for patients in subgroups of PD-L1 < 1%, PD-L1 ⩾ 1%, PD-L1 1-49%, non-squamous, no CNS metastases, with or without smoking history. Addition of bevacizumab consistently provided with favorable PFS results in patients of all PD-L1 levels. Cemiplimab was the best option in squamous subgroup and nivo-ipili-chemo in CNS metastases subgroup due to their advantages in OS.
First-line PD-1/PD-L1 inhibitors for advanced NSCLC patients lacking driver gene mutations Patients with advance non-small cell lung cancer (NSCLC) lacking driver gene mutations are a group of heterogeneous people. Although numerous therapeutic regimens were developed, the optimal choice for advanced NSCLC patients and specific subgroups is yet to be identified.We conducted a Bayesian network meta-analysis with the currently available data, and performed subgroup analyses according to programed death ligand 1 (PD-L1) levels, histologic type, CNS metastases and tobacco use history.Our key findings were as follows: (1) in non-selective PD-L1 groups, sinti-chemo and pembro-chemo provided the best OS outcome; nivo-bev-chemo and atezo-bev-chemo resulted in the most prolonged PFS; atezo-bev-chemo and pembro-chemo yielded significantly improved ORR; (2) pembro-chemo was favorable for patients in subgroups of PD-L1 < 1%, PD-L1 ⩾ 1%, PD-L1 149%, non-squamous, no CNS metastases, with or without smoking history; (3) immunochemotherapies involving anti-PD-1 agents generally exhibited potential advantages over those with anti-PD-L1 drugs; (4) addition of anti-VEGF drugs to immunochemotherapies consistently provided with favorable PFS results in advanced NSCLC patients with or without PD-L1 selection; (5) in patients with squamous NSCLC, cemiplimab and suge-chemo were the optimal drugs for improving OS and PFS, respectively; in patients with non-squamous NSCLC, pembro-chemo provided the best OS, while nivo-bev-chemo, atezo-bev-chemo, sinti-chemo, and pembro-chemo showed comparable advantages in improving PFS; (6) for patients with CNS metastases, nivo-ipili-chemo and camre-chemo provided the best OS and PFS, respectively.Our findings provide evidence for a more precise selection of first-line immunotherapy regimen for advanced NSCLC patients.
ABSTRACT
Objective To detect the expressions of nm23-H1 and heat shock protein 27 (HSP27) and their clinical significance on development and metastasis in non-small cell lung carcinoma (NSCLC).Methods 75 tumor tissues from patients with NSCLC were included as experimental group and 28 pulmonary benign lesion tissues were as control group.The expressions of nm23-H1 and HSP27 in patients with different clinical and pathological characters were detected by immunohistochemistry.Results nm23-H1 and HSP27 were mainly expressed in cytoplasm,the positive rates of nm23-H1 and HSP27 were significantly higher in the experimental group than that in control group [41.3 ％ (31/75) vs 7.1％ (2/28),x2 =10.946,P =0.001,80.0 ％ (60/75) vs 46.4 ％ (13/28),x2 =11.131,P =0.001].Compared with control group,the positive rate of HSP27 was correlated with the degree of tumor differentiation (x2 =4.191,P =0.041).nm23-H1 was related with HSP27 in lung cancer (r =0.284,P =0.013).Conclusion nm23-H1 and HSP27 are related to the occurrence and development of NSCLC.The joint detection of nm23-H1 and HSP27 should be helpful to the diagnosis and judge the biological behavior of NSCLC.
ABSTRACT
Objective To analyze the differences in microRNA (miRNA) expression between A549 and A549/DDP cells and explore the association between miRNA expression and drug resistance in non-small cell lung cancer (NSCLC).Methods The drug resistance of A549/DDP cells was evaluated using CCK-8 assay and flow cytometry.Microarray technique and RT-PCR were used to analyze the differential expression of the miRNA between A549 and A549/DDP cells.Enforced or inhibited target miRNA expression in cisplatin resistant cell was used to investigate whether miRNA involve in modulating the sensitivity of NSCLC cells to chemotherapeutic agent,exploiting the emerging knowledge of miRNA for the development of new human therapeutic applications for overcoming anticancer drug resistance and trying to discover biomarkers that were better able to predict the cancer chemotherapy sensitivity.Results The drug resistance index of A549/DDP cells relative to the parental A549 cells was 18.Microarray analysis of A549 and A549/DDP cells identified 51 differentially expressed genes (≥4-fold),including 24 up-regulated and 27 down-regulated genes in A549/DDP cells.RT-PCR identified 9 miRNA that were differentially expressed between A549 and A549/DDP cells.Of these differentially expressed miRNA,miR-376c,miR-31,miR-29a,miR-221 showed significantly increased expression,and miR-196a,miR-20a,miR-20b,miR-17,miR-451 showed significantlylowered expression in A549/DDP cells as indicated by the results of microarray analysis and RT-PCR.DDP sensitivity was increased 11.7 ％ in A549/DDP cells transfected with miR-17,but the chemosensitivity was decreased when miR-451 was over-expressed or miR-29a was inhibited by selective inhibitor,the reduction was 15.5 ％,12.9 ％,respectively,whereas chemosensitivity did not change when miR-376c,miR-31,miR-221 were inhibited or miR-196a,miR-20b,miR-20a were over-expressed.Conclusion A549/DDP cells show a different miRNA expression profile from its parental A549 cells,suggesting the involvement of miRNA in tumor cell drug resistance.miR-17 has the potential to be an efficient agent for preventing and reversing DDP-resistance in NSCLC.These results provide a strong rationale for the development of miRNA-based therapeutic strategies aiming to overcome cancer cell resistance.
