Chemotherapy In Non-small Cell Lung Cancer Patients Research Articles

LncRNA SH3PXD2A-AS1 facilitates cisplatin resistance in non-small cell lung cancer by regulating FOXM1 succinylation

BackgroundLong noncoding RNAs (lncRNAs) play vital regulatory functions in non-small cell lung cancer (NSCLC). Cisplatin (DDP) resistance has significantly decreased the effectiveness of DDP-based chemotherapy in NSCLC patients. This study aimed to investigate the effects of SH3PXD2A antisense RNA 1 (SH3PXD2A-AS1) on DDP resistance in NSCLC.MethodsProliferation and apoptosis of DDP-resistant NSCLC cells were detected using cell counting kit-8 and flow cytometry assays. The interaction between SH3PXD2A-AS1 and sirtuin 7 (SIRT7) was assessed using co-immunoprecipitation (Co-IP), RNA pull-down, RNA immunoprecipitation (RIP), RNA fluorescence in situ hybridization, and immunofluorescence assays, while succinylation (SUCC) of Forkhead Box M1 (FOXM1) was analyzed by IP and Western blot assays. The role of SH3PXD2A-AS1 in vivo was explored using a xenografted tumor model.ResultsExpression of SH3PXD2A-AS1 was found elevated in DDP-resistant NSCLC cells, while it’s knocking down translated into suppression of cell viability and promotion of apoptosis. Moreover, silencing of SH3PXD2A-AS1 resulted in decreased FOXM1 protein level and enhanced FOXM1-SUCC protein level. The SIRT7 was found to interact with FOXM1, translating into inhibition of FOXM1 SUCC at the K259 site in human embryonic kidney (HEK)-293T cells. Overexpressing of SIRT7 reversed the increase of FOXM1-SUCC protein level and apoptosis, and the decrease of cell viability induced by silencing of SH3PXD2A-AS1. In tumor-bearing mice, SH3PXD2A-AS1 inhibition suppressed tumor growth and the protein levels of Ki67, SIRT7, and FOXM1.ConclusionSH3PXD2A-AS1 promoted DDP resistance in NSCLC cells by regulating FOXM1 SUCC via SIRT7, offering a promising therapeutic approach for NSCLC.

Prospect of immunotherapy alone in patients with advanced NSCLC with high btmb: a review and a meta-analysis

Lung cancer is the most prevalent cancer in the world, and the main treatment for advanced non-small cell lung cancer is immunotherapy combined with chemotherapy. In recent years, bTMB has received increasing attention as an emerging metric for monitoring the efficacy of tumour immunotherapy in terms of its operability, accessibility and real-time nature. We envisaged whether immunotherapy alone could be used to reduce the side effects of chemotherapy in patients with high bTMB lung cancer. We thus did a meta-analysis in order to show that immunotherapy alone is feasible in patients with high bTMB NSCLC.Methods This study aims to compare the efficacy of PD- 1/PD-L1 inhibitors (namely, atezolizumab, pembrolizumab, nivolumab, or tislelizumab) versus chemotherapy in NSCLC patients. The search for relevant studies was conducted in three major databases (i.e., PubMed, Embase, and Medline) up until January 2023. Specifically, we identified studies that reported risk ratios (HRs) for reporting progression-free survival (PFS) or overall survival (OS), or objective remission rates (ORs) for immunotherapy alone versus chemotherapy in high bTMB and low bTMB patient groups. Given that NSCLC represents the predominant type of lung cancer, we exclusively focused on this subtype. Our analysis encompassed a meta-analysis of the identified literature, incorporating heterogeneity analysis and sensitivity analysis. The quality of the evidence is evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to ascertain the reliability and robustness of the findings.Result-We conducted a meta-analysis of seven randomised controlled trials including 4,755 patients with advanced non-small cell lung cancer (NSCLC) evaluated the efficacy of PD- 1 or PD-L1 monotherapy compared to chemotherapy alone. All patients were randomized to receive either PD- 1/PD-L1 treatment alone or chemotherapy alone as a control. In the high bTMB patient group, PD- 1/PD-L1 monotherapy resulted in significant improvements in overall survival (HR = 0.55, 95% CI 0.49–0.61, p = 0.77) and progression-free survival (HR = 0.74, 95% CI 0.68–0.81, p = 0.78) compared to chemotherapy alone. Conversely, in the low bTMB patient group, PD- 1 monotherapy or PD-L1 monotherapy failed to demonstrate significant improvements in overall survival (HR = 0.82, 95% CI 0.73–0.92, p = 0. 13) and progression-free survival (HR = 1.22, 95% CI 1.22- 1.45, p = 0.003) in advanced NSCLC. Conclusion Our analysis suggests that monotherapy with immunotherapy is a feasible option for patients with advanced NSCLC and high bTMB. However, the results have to be construed with caution because of the small sample size and the potential bias in the studies included. Therefore, further research with larger sample sizes and rigorous study designs is necessary to confirm the observed benefits of immunotherapy in this patient population.

CRTAC1 enhances the chemosensitivity of non-small cell lung cancer to cisplatin by eliciting RyR-mediated calcium release and inhibiting Akt1 expression

Sensitivity to platinum-based combination chemotherapy is associated with a favorable prognosis in patients with non-small cell lung cancer (NSCLC). Here, our results obtained from analyses of the Gene Expression Omnibus database of NSCLC patients showed that cartilage acidic protein 1 (CRTAC1) plays a role in the response to platinum-based chemotherapy. Overexpression of CRTAC1 increased sensitivity to cisplatin in vitro, whereas knockdown of CRTAC1 decreased chemosensitivity of NSCLC cells. In vivo mouse experiments showed that CRTAC1 overexpression increased the antitumor effects of cisplatin. CRTAC1 overexpression promoted NFAT transcriptional activation by increasing intracellular Ca2+ levels, thereby inducing its regulated STUB1 mRNA transcription and protein expression, accelerating Akt1 protein degradation and, in turn, enhancing cisplatin-induced apoptosis. Taken together, the present results indicate that CRTAC1 overexpression increases the chemosensitivity of NSCLC to cisplatin treatment by inducing Ca2+-dependent Akt1 degradation and apoptosis, suggesting the potential of CRTAC1 as a biomarker for predicting cisplatin chemosensitivity. Our results further reveal that modulating the expression of CRTAC1 could be a new strategy for increasing the efficacy of cisplatin in chemotherapy of NSCLC patients.

PHF23 promotes NSCLC proliferation, metastasis, and chemoresistance via stabilization of ACTN4 and activation of the ERK pathway.

At present, non-small cell lung cancer (NSCLC) is still one of the leading causes of cancer-related deaths. Chemotherapy remains the standard treatment for NSCLC. However, the emergence of chemoresistance is one of the major obstacles to lung cancer treatment. Plant homologous structural domain finger protein 23 (PHF23) plays crucial roles in multiple cell fates. However, the clinical significance and biological role of PHF23 in NSCLC remain elusive. The Cancer Genome Atlas data mining, NCBI/GEO data mining, and western blotting analysis were employed to characterize the expression of PHF23 in NSCLC cell lines and tissues. Statistical analysis of immunohistochemistry and the Kaplan-Meier Plotter database were used to investigate the clinical significance of PHF23. A series of in vivo and in vitro assays, including assays for colony formation, cell viability, 5-ethynyl-2'-deoxyuridine (EDU incorporation) and Transwell migration, flow cytometry, RT-PCR, gene set enrichment analysis, co-immunoprecipitation analysis, and a xenograft tumor model, were performed to demonstrate the effects of PHF23 on the chemosensitivity of NSCLC cells and to clarify the underlying molecular mechanisms. PHF23 is overexpressed in NSCLC cell lines and tissues. High PHF23 levels correlate with short survival times and a poor response to chemotherapy in NSCLC patients. PHF23 overexpression facilitates cell proliferation, migration and sensitizes NSCLC cells to Cisplatin and Docetaxel by promoting DNA damage repair. Alpha-actinin-4 (ACTN4), as a downstream regulator, interacts with PHD domain of PHF23. Moreover, PHF23 is involved in ACTN4 stabilization by inhibiting its ubiquitination level. These results show that PHF23 plays an important role in the development and progression of NSCLC and suggest that PHF23 may serve as a therapeutic target in NSCLC patients.

The Survival Effect of Metformin on Non-Small Cell Lung Cancer Treated with Chemotherapy: A Systematic Review

Objective. Metformin is a common antidiabetic drug that has been reported to serve as an anticancer agent in combination with other therapies. But the effect of the addition of metformin on the survival of non-small cell lung cancer (NSCLC) patients undergoing chemotherapy is still controversial. We conducted this systematic review to evaluate the survival effect of metformin added to chemotherapy in NSCLC patients. Methods. Electronic literature search was performed in the PubMed, Embase, and Web of Science databases from their inception up to April 2023. The study region, study design, histological subtype of the NSCLC, tumor stage, treatment strategy, sample size, follow-up duration, diabetes status, and HR of OS or PFS of the included studies were extracted. The quality was assessed through Cochrane collaboration’s tool for RCT and the Newcastle–Ottawa scale (NOS) for observational studies, respectively. Results and conclusions. Eleven studies with a total of 4606 patients were finally included. Five RCTs showed a high risk of bias due to the open-label nature while six retrospective studies were of high quality. Two studies of NSCLC patients with diabetes reported significant benefits in overall survival from metformin addition, while one study of patients without diabetes reported a negative effect on the survival of metformin addition. The survival impact of metformin added to chemotherapy on unresectable NSCLC patients remains inconclusive. The survival benefit might be more prominent in patients with diabetes, awaiting further evidence.

Deep radiomic model based on the sphere–shell partition for predicting treatment response to chemotherapy in lung cancer

BackgroundThe prognosis of chemotherapy is important in clinical decision-making for non-small cell lung cancer (NSCLC) patients. ObjectivesTo develop a model for predicting treatment response to chemotherapy in NSCLC patients from pre-chemotherapy CT images. Materials and MethodsThis retrospective multicenter study enrolled 485 patients with NSCLC who received chemotherapy alone as a first-line treatment. Two integrated models were developed using radiomic and deep-learning-based features. First, we partitioned pre-chemotherapy CT images into spheres and shells with different radii around the tumor (0–3, 3–6, 6–9, 9–12, 12–15 mm) containing intratumoral and peritumoral regions. Second, we extracted radiomic and deep-learning-based features from each partition. Third, using radiomic features, five sphere–shell models, one feature fusion model, and one image fusion model were developed. Finally, the model with the best performance was validated in two cohorts. ResultsAmong the five partitions, the model of 9–12 mm achieved the highest area under the curve (AUC) of 0.87 (95% confidence interval: 0.77–0.94). The AUC was 0.94 (0.85–0.98) for the feature fusion model and 0.91 (0.82–0.97) for the image fusion model. For the model integrating radiomic and deep-learning-based features, the AUC was 0.96 (0.88–0.99) for the feature fusion method and 0.94 (0.85–0.98) for the image fusion method. The best-performing model had an AUC of 0.91 (0.81–0.97) and 0.89 (0.79–0.93) in two validation sets, respectively. ConclusionsThis integrated model can predict the response to chemotherapy in NSCLC patients and assist physicians in clinical decision-making.

Prognostic Impact of Dihydropyrimidine Dehydrogenase Germline Variants in Unresectable Non-Small Cell Lung Cancer Patients Treated with Platin-Based Chemotherapy.

Platin-based chemotherapy is the standard treatment for patients with non-small cell lung cancer (NSCLC). However, resistance to this therapy is a major obstacle in successful treatment. In this study, we aimed to investigate the impact of several pharmacogenetic variants in patients with unresectable NSCLC treated with platin-based chemotherapy. Our results showed that DPYD variant carriers had significantly shorter progression-free survival and overall survival compared to DPYD wild-type patients, whereas DPD deficiency was not associated with a higher incidence of high-grade toxicity. For the first time, our study provides evidence that DPYD gene variants are associated with resistance to platin-based chemotherapy in NSCLC patients. Although further studies are needed to confirm these findings and explore the underlying mechanisms of this association, our results suggest that genetic testing of DPYD variants may be useful for identifying patients at a higher risk of platin-based chemotherapy resistance and might be helpful in guiding future personalized treatment strategies in NSCLC patients.

Correlation of homologous recombination deficiency (HRD) score with response to the first-line treatment of immune checkpoint inhibitors plus chemotherapy in non-small cell lung cancer.

e21121 Background: Homologous recombination (HR) gene mutations were reported to be associated with efficiency of immune checkpoint inhibitors (ICIs). However, up to date, no recognized standard has been set up for definition of HR mutation (+), which limited its clinical application. Homologous recombination deficiency (HRD) score reflects genomic scar induced by HR genes alteration and disfunction. Thus, it may be worth to explore whether HRD score could predict the efficacy of ICIs-based therapy. Methods: We collected tumor tissues from metastatic non-small cell lung cancer (NSCLC) patients who received first-line treatment of ICIs combined with platinum-based chemotherapy. HRD score testing were carried by BGI genomic scar analysis kit, which calculates the sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), large-scale state transitions (LST) scores, and corrected by ploidy of tumor samples, through next generation sequencing(NGS) data. The association of HRD score and response to ICIs plus chemotherapy were analyzed. Results: 22 EGFR/ALK wild-type metastatic NSCLC patients were included. The average HRD score was 24.57, varying from -26.37 to 92.34. Threshold traversal was performed based on analysis of the progression free survival (PFS) data from the included NSCLC patients. HRD score 31 or more were define as HRD (+). Kaplan-Meier PFS Survival analysis showed prolonged median PFS (mPFS) in HRD (+) versus HRD (-) NSCLC patients (N/A vs. 7.0 ms, Log-rank P = 0.029; HR 0.20, 95%CI 0.04-0.96, likelihood-ratio P = 0.03). The objective response rate (ORR) was 45.5% (5/11) in HRD(+) versus 27.2% (3/11) in HRD(-) patients. In patients with PD-L1 TPS≥1% (22C3), the mPFS was N/A vs. N/A, and the ORR was 75.0% (3/4) vs. 37.5% (3/8), in HRD (+) vs. HRD(-) patients. In patients with PD-L1 TPS < 1% (22C3), the mPFS was 8.5 ms vs.2.0 ms (Log-rank P = 0.0085; HR 0.08, 95%CI 0.01-0.82, likelihood-ratio P = 0.02), and the ORR were 28.6% (2/7) vs. 0%(0/3), in HRD (+) vs. HRD(-) patients. Conclusions: In addition to PD-L1 expression level, HRD score would be a potential promising biomarker for predicting the efficiency of ICIs plus platinum-based chemotherapy in NSCLC patients.

On-treatment lung immune prognostic index is predictive for first-line PD-1 inhibitor combined with chemotherapy in patients with non-small cell lung cancer.

Inflammation is a factor that promotes tumor progression and immunosuppression. Lung immune prognostic index (LIPI) is a non-invasive and easily calculated indicator of inflammation. This study aimed to investigate whether continuous assessment of LIPI has predictive value for chemoimmunotherapy in non-small cell lung cancer (NSCLC) patients receiving first-line programmed cell death 1 (PD-1) inhibitor plus chemotherapy. In addition, the predictive value of LIPI in patients with the negative or low programmed death-ligand (PD-L1) expression level was also explored. Totally, 146 stage IIIB to IV or recurrent NSCLC patients who received first-line PD-1 inhibitor combined with chemotherapy were enrolled in this study. The LIPI scores were calculated at baseline (PRE-LIPI) and after two cycles of the combined administration (POST-LIPI). This study analyzed the relationship between good/intermediate/poor PRE (POST)-LIPI and objective response rate (ORR), as well as progression-free survival (PFS) using logistic and Cox regression models. In addition, the predictive value of LIPI in patients with the negative or low PD-L1 expression level was explored. To further assess the potential predictive value of continuous assessment of LIPI, the association of sum (LIPI) [sum(LIPI) = PRE-LIPI + POST-LIPI] and PFS was analyzed in the 146 patients. Compared with good POST-LIPI group, significantly lower ORRs were found in intermediate POST-LIPI (P = 0.005) and poor POST-LIPI (P = 0.018) groups. Moreover, intermediate POST-LIPI (P =0.003) and poor POST-LIPI (P < 0.001) were significantly associated with a shorter PFS than good POST-LIPI. Additionally, a higher POST-LIPI score was still significantly associated with poorer treatment efficacy in patients with the negative or low PD-L1 expression level. Moreover, a higher sum (LIPI) score was significantly correlated with a shorter PFS (P = 0.001). Continuous assessment of LIPI might be an effective method for predicting the efficacy of PD-1 inhibitor plus chemotherapy in NSCLC patients. In addition, in patients with the negative or low PD-L1 expression level, it might also have a potential predictive value for therapeutic efficacy to continuously assess LIPI during the treatment.

A miR-15a related polymorphism affects NSCLC prognosis via altering ERCC1 repair to platinum-based chemotherapy.

Platinum-based chemotherapy is regarded as a preferential curative-intent option for non-small cell lung cancer (NSCLC), while the acquired drug resistance has become a major obstacle that limits its clinical application. Since the repair efficiency of tumour cells to platinum-DNA adducts plays a crucial role in chemotherapy resistance, we aimed to explore whether several meaningful polymorphisms of DNA repair genes were associated with the benefits of platinum-based chemotherapy in NSCLC patients. Firstly, six single nucleotide polymorphisms (SNPs) located in the 3'untranslated region (3'UTR) of three DNA repair genes were detected in 246 NSCLC patients receiving platinum-based chemotherapy and analysed the correlation of these candidate SNPs with the overall survival. Cox proportional hazard model showed that NSCLC patients carrying ERCC1 rs3212986 AA genotype had a shorter overall survival compared to those with CC. Mechanistically, we performed tumour chemosensitivity assay to observe the convincing linkage of rs3212986 polymorphism with ERCC1 expression and cisplatin sensitivity. The subsequent in vitro experiments identified that rs3212986 polymorphism altered the post-transcriptional regulation of ERCC1 via affecting the binding of miR-15a, and further changed the sensitivity to platinum analogue. It reminded that patients carrying ERCC1 rs3212986 CC homozygote were expected to respond better to platinum-based chemotherapy due to a lower expression of ERCC1. Compared with previous studies, our current comprehensive study suggested that rs3212986, a 3'UTR polymorphism in ERCC1, might have clinical relevance in predicting the prognosis of NSCLC patients receiving platinum-based chemotherapy.

BRCA1 expression associated with the prognostic value of platinum-based chemotherapy for stage II-IV non-small cell lung cancer: A meta-analysis.

To explore the relationship between breast cancer susceptibility gene 1 (BRCA1) expression and the prognostic value of platinum-based chemotherapy for stage II-IV non-small cell lung cancer (NSCLC). PubMed, Web of Science, Embase, and Cochrane Library were searched from inception to August 2021, for retrieving literature related to BRCA1 expression and prognostic value of platinum-based chemotherapy in NSCLC patients. Stata 15.0 was employed for statistical analysis. A total of 15 articles were included. Compared with the low BRCA1 expression, its high expression negatively affected the overall survival of NSCLC patients treated with platinum-based chemotherapy (hazard ratio (HR) = 1.53, 95% confidence interval (CI): 1.01-2.31, P < 0.05). No significant difference was identified in the effect of both low and high BRCA1 expression on event-free survival (HR = 1.73, 95% CI: 0.98-3.05, P > 0.05). Subgroup analysis showed that significant differences existed in overall survival and event-free survival in Caucasian population; that is, compared with low BRCA1 expression, its high expression negatively affected the overall survival (HR = 1.79, 95% CI: 1.15-2.79, P < 0.05) and event-free survival (HR = 2.39, 95% CI: 1.43-3.97, P < 0.05). Nevertheless, there were no significant differences in overall survival and event-free survival in China. BRCA1 expression is correlated with the prognostic value of platinum-based chemotherapy for stage II-IV NSCLC patients. In Caucasian population, compared with low BRCA1 expression, its high expression has a negative effect on the overall survival and event-free survival in stage II-IV NSCLC patients after platinum-based chemotherapy; however, this correlation was not found in China.

Immunotherapy plus chemotherapy showed superior clinical benefit to chemotherapy alone in advanced NSCLC patients after progression on osimertinib.

BackgroundOsimertinib is the standard first‐line treatment for non‐small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation. Resistance to osimertinib remains a clinical challenge. However, the optimal therapy for these patients is still controversial. In this study, we aimed to assess the efficacy and safety of immunotherapy plus chemotherapy (IO+C) compared with chemotherapy (C) in NSCLC patients after progression on osimertinib.MethodsAdvanced NSCLC patients after progression on osimertinib were retrospectively reviewed. Progression‐free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were evaluated between the patients treated with IO+C and C.ResultsA total of 40 patients were included in the study. There were 20 patients each in the IO+C group or C group. The ORR was significantly higher in patients in the IO+C group (45% vs. 25%, p < 0.01). The median PFS was 6.4 months for patients in the IO+C group compared to 2.8 months for patients in C group (HR: 0.41, 95% confidence interval [CI]: 0.20–0.82, p < 0.01). The median OS was significantly longer in the IO+C group than the C group (OS: 12.8 vs. 10.5 months, HR: 0.39, 95% CI: 0.19–0.80, p < 0.01). In subgroup analysis, patients of both sexes, age ≤ 65, bone or adrenal metastasis, exon19 del mutation, and third‐line treatment obtained more OS benefits from immunotherapy. The safety profile of both groups was comparable.ConclusionsOur study provides the clinical evidence of favoring immunotherapy plus chemotherapy in NSCLC patients after progression on osimertinib.

Molecular profiles of predictive biomarkers for platinum-based chemotherapy in Non-Small Cell Lung Cancer (NSCLC)

BackgroundNon-small cell lung cancer (NSCLC) is the principal subtype of lung cancer. Among all therapeutic options, platinum-based chemotherapy agents, especially Cisplatin, are still commonly used treatment for NSCLC patients. However, developing chemoresistance in NSCLC cells often gives rise to chemotherapy failure. Therefore, more studies are required to shed light on gene interaction and cellular pathways involved in initiating and developing resistance to platinum-based chemotherapy in NSCLC. Hence, it is urgent to find the key genes, microRNA (miRNAs), and potential molecular mechanisms implicated in chemoresistance and present markers to predict response to platinum-based chemotherapy in NSCLC patients. MethodsThe microarray datasets GSE6410, GSE7035, GSE14814, GSE26704, GSE73302 were downloaded from the Gene Expression Omnibus (GEO) database and were analyzed using R software. Functional and pathway enrichment analyses were performed using the Enrich R site. Then, the protein-protein interaction (PPI) network and hub genes were obtained using the Cytoscape software. Further, the miRSystem database was performed to predict the miRNAs regulating the hub genes. Moreover, Cytoscape software and the CytoHubba plugin were used to construct the miRNA-target interaction network and hub modules. Finally, the Kaplan–Meier curve was used to demonstrate the survival curves and assess the association of the genes signature with clinical outcomes. ResultsA total of 142 differentially expressed genes (DEGs) were found. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses present the p53 signaling pathway as the most significant pathway.Besides, from the top ten terms obtained of Biological Process, Molecular Function, and Cellular Component, the first ones, including cholesterol biosynthetic process, the extrinsic component of external side of plasma membrane, cytokine activity, were selected respectively. Based on the PPI network, the ten nodes with the highest degree were screened as hub genes. In addition, from the miRNA–target regulatory network in Cytoscape, ten hub nodes were found. Ultimately, according to Kaplan–Meier curve, BTG2 and TP53I3 with p-value <0.05 were associated with a better prognosis. ConclusionsIn the present study, DEGs, candidate miRNAs, and underlying mechanisms involved in chemoresistance were identified to suggest potential biomarkers to provide new clues for the prediction of response to platinum-based chemotherapy.

P48.11 ctDNA Dynamic Detection Reveals the Advantages of EGFR Tyrosine Kinase Inhibitors Combined With Chemotherapy in NSCLC Patients

EGFR is a major oncogene which frequently occurred in about 10-30% of non-small cell lung cancer (NSCLC) patients. EGFR T790M mutation is the main mechanism of acquired resistance to the first generation EGFR tyrosine kinase inhibitors (TKIs). Chemotherapy is widely used in lung cancer patients and is considered as a subsequent therapy when TKI-resistance occurred. In this study, we aimed to evaluate the effect of pemetrexed by dynamic detection of EGFR T790M in patients with TKI treatment.

VHL expression level in the pathological tissue is significantly associated with clinical outcomes of platinum-based chemotherapy in non-small cell lung cancer patients. (withdrawn 03/11/2021)

Objective To investigate the association between expression level of VHL in pathological tissue and outcomes of platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients. Methods The pathological samples of NSCLC patients were obtained for immunohistochemical staining to evaluate the expression level of VHL. Furthermore, their clinical data were collected and prognosis was traced by phone. The correlation between gene expression level and the hematotoxicity was evaluated by chi-square test. The influence of VHL expression level on the risk of hematotoxicity was tested by logistic regression model. The survival curve was plotted by Kaplan-Meier method and the survival rate between the two groups was compared by log-rank test. Results A total of 110 NSCLC patients were enrolled in this study, the median follow-up time of these patients was 27.5 months. In the whole group, 31 patients had died by the last date of follow-up to get their survival information (Nov.10,2020), with a median survival time of 24.3 months. Though immunohistochemical analysis,we found that 59 patients(53.6%) had weak expression level of VHL or lack of expression in their tumor tissues,while 51 patients(46.4%) presented moderate or high expression. We found that the patients with weak expression of VHL in their carcinoma tissue or lack of expression had more opportunities to occur neutropenia after platinum-based chemotherapy(OR=0.264,95%CI=0.085-0.818,P-value=0.021).And the expression level of VHL was correlated with OS(Logrank test：P-value= 0.007，HR= 4.219,95%CI: 1.75-10.174, P-value=0.001), while not related with DFS(Logrank test：P-value=0.256，HR= 1.334,95%CI:0.642-2.769, P-value=0.440). Conclusion The expression level of VHL gene in pathological tissue is related with Granulocytosis and leukocytotoxicity after platinum-based chemotherapy in NSCLC patients. It can be used as a biomarker to predict the risk of neutropenia and the prognosis of NSCLC patients.

Smoking status during first-line immunotherapy and chemotherapy in NSCLC patients: A case-control matched analysis from a large multicenter study.

BackgroundImproved outcome in tobacco smoking patients with non‐small cell lung cancer (NSCLC) following immunotherapy has previously been reported. However, little is known regarding this association during first‐line immunotherapy in patients with high PD‐L1 expression. In this study we compared clinical outcomes according to the smoking status of two large multicenter cohorts.MethodsWe compared clinical outcomes according to the smoking status (never smokers vs. current/former smokers) of two retrospective multicenter cohorts of metastatic NSCLC patients, treated with first‐line pembrolizumab and platinum‐based chemotherapy.ResultsA total of 962 NSCLC patients with PD‐L1 expression ≥50% who received first‐line pembrolizumab and 462 NSCLC patients who received first‐line platinum‐based chemotherapy were included in the study. Never smokers were confirmed to have a significantly higher risk of disease progression (hazard ratio [HR] = 1.49 [95% CI: 1.15–1.92], p = 0.0022) and death (HR = 1.38 [95% CI: 1.02–1.87], p = 0.0348) within the pembrolizumab cohort. On the contrary, a nonsignificant trend towards a reduced risk of disease progression (HR = 0.74 [95% CI: 0.52–1.05], p = 0.1003) and death (HR = 0.67 [95% CI: 0.45–1.01], p = 0.0593) were reported for never smokers within the chemotherapy cohort. After a random case–control matching, 424 patients from both cohorts were paired. Within the matched pembrolizumab cohort, never smokers had a significantly shorter progression‐free survival (PFS) (HR = 1.68 [95% CI: 1.17–2.40], p = 0.0045) and a nonsignificant trend towards a shortened overall survival (OS) (HR = 1.32 [95% CI: 0.84–2.07], p = 0.2205). On the contrary, never smokers had a significantly longer PFS (HR = 0.68 [95% CI: 0.49–0.95], p = 0.0255) and OS (HR = 0.66 [95% CI: 0.45–0.97], p = 0,0356) compared to current/former smoker patients within the matched chemotherapy cohort. On pooled multivariable analysis, the interaction term between smoking status and treatment modality was concordantly statistically significant with respect to ORR (p = 0.0074), PFS (p = 0.0001) and OS (p = 0.0020), confirming the significantly different impact of smoking status across the two cohorts.ConclusionsAmong metastatic NSCLC patients with PD‐L1 expression ≥50% receiving first‐line pembrolizumab, current/former smokers experienced improved PFS and OS. On the contrary, worse outcomes were reported among current/former smokers receiving first‐line chemotherapy.

Is there a role for dacomitinib, a second-generation irreversible inhibitor of the epidermal-growth factor receptor tyrosine kinase, in advanced non-small cell lung cancer?

ABSTRACT Introduction Non-small cell lung cancer (NSCLC) is a highly lethal disease. During the past 20 years, the epidermal growth factor receptor (EGFR) has been a relevant target for anticancer drug-design, and a large family of EGFR tyrosine kinase inhibitors (TKI) were designed, which improved therapeutic outcomes compared to conventional chemotherapy in NSCLC patients with specific EGFR mutations. However, resistance to these inhibitors occurs; therefore, the debate on which inhibitor should be used first is still open. Dacomitinib was approved in 2018 for the first-line treatment of NSCLC with EGFR activating mutations. Areas covered This manuscript reviews the properties of dacomitinib, including the current information from clinical trials and its potential application as stand-alone therapy, or in combination. Expert opinion Dacomitinib is a second-generation EGFR-TKI that has demonstrated significant improvement in overall survival in a phase III randomized study compared with gefitinib, a first-generation TKI. However, the rapid development and approval of a new generation of TKIs (osimertinib), with better clinical profiles, raises the question of which role can dacomitinib play in NSCLC. Further studies are required to evaluate the efficacy of this drug on brain metastases, as a second-line treatment after third-generation TKIs, or in combination with other types of treatments.

Cost-effectiveness of icotinib versus whole-brain irradiation with or without chemotherapy in EGFR-mutant NSCLC patients with brain metastases.

Nonsmall cell lung cancer (NSCLC) patients with brain metastases (BM) have a poor prognosis. Despite the traditional methods including radiotherapy and chemotherapy, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) might benefit patients on survival and quality of life. We investigated the cost-effectiveness of icotinib compared with whole-brain irradiation (WBI) with or without chemotherapy for NSCLC patients with BM. A Markov model was conducted based on the data of BRAIN trial. We compared the economic benefit between icotinib and the combination of WBI and WBI plus chemotherapy group. We considered disease progression as intracranial progression and overall progression separately. Sensitivity analyses were performed to observe the stability of the model. The willingness-to-pay (WTP) was set as 3× per capita gross domestic product ($25929/quality-adjusted life year [QALY]) from the Chinese healthcare perspective. When considering progression as intracranial progression and overall progression, respectively, the incremental cost-effectiveness ratio was $14882.64/QALY and $13484.21/QALY between icotinib and WBI/WBI-chemotherapy. Besides, both of the average cost-effective ratio (ACER) and net benefit showed advantage of icotinib (ACER: $34521.42/QALY for intracranial progression and $36562.63/QALY for overall progression; net benefit: -$8407.36 for intracranial progression and -$9836.41 for overall progression). One-way sensitivity analyses demonstrated that no thresholds were encountered. The probabilistic sensitivity analyses showed even at a WTP under $18000/QALY, icotinib could be cost-effective. Icotinib was cost-effective compared with WBI with or without chemotherapy.

The efficacy and safety of immune checkpoint inhibitors in non-small cell lung cancer patients of different age groups: a meta-analysis

BackgroundAge is closely related to the efficacy of treatment for non-small cell lung cancer (NSCLC) patients. Latest clinical trials have proved the better overall survival (OS) for the use of immune checkpoint inhibitors verse chemotherapy in NSCLC patients. However, we had no clear idea of the efficacy of them in elderly patients. So we conducted a meta-analysis to compare the efficacy of immune checkpoint inhibitors for NSCLC patients of different age groups and summarized overall treatment-related adverse events.Materials and methodsPubMed, EMBASE, Web of Science and the Cochrane Library were searched for all clinical trials in NSCLC until 30th of April 2019. Eligible studies included randomized controlled trials (RCTs) comparing immune checkpoint inhibitors with chemotherapy in NSCLC patients. The hazard ratio (HRs) and 95% confidence intervals (CIs) of OS, progression-free survival or adverse events (AEs) were used.ResultsA total of 4994 patients from 8 RCTs were included. Immune checkpoint inhibitors significantly prolonged the OS (HR, 0.73; 95% CI, 0.61–0.89) versus chemotherapy in NSCLC patients who were less than 65 years old. Also, they prolonged the OS (HR, 0.74; 95% CI, 0.59–0.93) in NSCLC patients who were more than 65 years old. However, there was no statistical significance of OS (HR, 0.87; 95% CI, 0.57–1.30) among NSCLC patients who were more than 75 years old. It also showed that the single use of immune checkpoint inhibitors had fewer all-grade AEs.ConclusionRegardless of the NSCLC patients who were less or more than 65 years, immune checkpoint inhibitors could achieve better OS than chemotherapy. But there was no significant difference when NSCLC patients who were more than 75 years old. Older patient should be offered immune therapies if it is possible and the mechanism in old age treatment should be further studied.

1254P - Efficacy of PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer patients with sensitive genes mutation

BackgroundAs we all know, patients with sensitive genes mutation could achieve better overall survival by taking targeted drugs. Many trials showed that non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EFGR) mutation responded to PD-1/PD-L1 inhibitors worse than EGFR wild-type. And subgroups of trials also reported the efficacy of PD-1/PD-L1 inhibitors in the treatment of NSCLC patients with other sensitive genes mutation. So we conducted a complementary systematic review and meta-analysis to compare efficacy of PD-1/PD-L1 inhibitors for NSCLC patients with sensitive genes mutation. MethodsPubMed, EMBASE, Web of Science and the Cochrane Central Register of Controlled Trials (Central) databases were searched for all clinical trials in NSCLC until 5th of January 2019. Eligible studies included randomized controlled trials (RCTs) comparing PD-1/PD-L1 inhibitors with chemotherapy in NSCLC patients with sensitive genes mutation. The hazard ratio (HR) and 95% confidence intervals (CIs) of overall survival (OS) or progression-free survival (PFS) were used. ResultsA total of 2419 patients from 4 RCTs (2 with PD-1 inhibitors; 2 with PD-L1 inhibitors) were included. PD-1/PD-L1 inhibitors significantly prolonged the OS (HR, 0.67; 95% CI, 0.60–0.67) and PFS (HR, 0.46; 95% CI, 0.36–0.60) in NSCLC patients with EGFR wild-type versus chemotherapy. Meanwhile, PD-1/PD-L1 inhibitors prolonged the OS (HR, 0.61; 95% CI, 0.39–0.94) in NSCLC patients with KRAS mutation versus chemotherapy. However, for NSCLC patients with EGFR mutation (the OS of HR, 1.11; 95% CI, 0.80–1.55; the PFS of HR, 0.76; 95% CI, 0.35–1.64) and KRAS wild-type (the OS of HR, 0.89; 95% CI, 0.68–1.17), there were no significant differences between PD-1/PD-L1 inhibitors and chemotherapy. ConclusionsPD-1/PD-L1 inhibitors are more efficacious in NSCLC patients with EGFR wild-type and KRAS mutation compared with chemotherapy. There was no significant difference between PD-1/PD-L1 inhibitors and chemotherapy in NSCLC patients with EGFR mutation and KRAS wild-type. Legal entity responsible for the studyThe authors. FundingNational Natural Science Foundation of China (No. 81873396). DisclosureAll authors have declared no conflicts of interest.