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Journal of Managed Care & Specialty... Jun 2024Larotrectinib is approved for patients with advanced gene fusion-positive solid tumors. Prior studies demonstrated promising results with larotrectinib compared with... (Comparative Study)
Comparative Study
Projecting long-term clinical outcomes with larotrectinib compared with immune checkpoint inhibitors in metastatic nonsmall cell lung cancer and differentiated thyroid cancer.
BACKGROUND
Larotrectinib is approved for patients with advanced gene fusion-positive solid tumors. Prior studies demonstrated promising results with larotrectinib compared with other systemic therapy. However, comparisons to checkpoint inhibitors, such as nivolumab or pembrolizumab, have not been done.
OBJECTIVE
To estimate and compare expected life-years (LYs) and quality-adjusted LYs (QALYs) for patients with nonsmall cell lung cancer (NSCLC) eligible for larotrectinib vs patients with unknown gene fusion status on nivolumab or pembrolizumab. We also assessed patients with metastatic differentiated thyroid cancer (DTC), as pembrolizumab may be considered in certain circumstances.
METHODS
We developed partitioned survival models to project long-term comparative effectiveness of larotrectinib vs nivolumab or pembrolizumab. Larotrectinib survival data were derived from an updated July 2021 analysis of 21 adult patients (≥18 years of age) with metastatic gene fusion-positive NSCLC and 21 with DTC. Survival inputs for nivolumab and pembrolizumab were obtained from published articles. Progression-free and overall survival were estimated using survival distributions (Exponential, Weibull, Log-logistic, and Log-normal). Exponential fits were chosen based on goodness-of-fit and clinical plausibility.
RESULTS
In NSCLC, larotrectinib resulted in gains of 5.87 and 5.91 LYs compared to nivolumab and pembrolizumab, respectively, which translated to gains of 3.53 and 3.56 QALYs. In DTC, larotrectinib resulted in a gain of 5.23 LYs and 4.24 QALYs compared to pembrolizumab.
CONCLUSIONS
In metastatic NSCLC and DTC, larotrectinib may produce substantial life expectancy and QALY gains compared to immune checkpoint inhibitors. Additional data with longer follow-up will further inform this comparison.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Immune Checkpoint Inhibitors; Thyroid Neoplasms; Quality-Adjusted Life Years; Nivolumab; Pyrimidines; Pyrazoles; Male; Female; Antibodies, Monoclonal, Humanized; Middle Aged; Adult; Aged; Treatment Outcome
PubMed: 38824630
DOI: 10.18553/jmcp.2024.30.6.581 -
Molecular Biology Reports Jun 2024Non-small cell lung cancer (NSCLC) is the leading cause of cancer morbidity and mortality worldwide, and new diagnostic markers are urgently needed. We aimed to...
BACKGROUND
Non-small cell lung cancer (NSCLC) is the leading cause of cancer morbidity and mortality worldwide, and new diagnostic markers are urgently needed. We aimed to investigate the mechanism by which hsa_circ_0096157 regulates autophagy and cisplatin (DDP) resistance in NSCLC.
METHODS
A549 cells were treated with DDP (0 μg/mL or 3 μg/mL). Then, the autophagy activator rapamycin (200 nm) was applied to the A549/DDP cells. Moreover, hsa_circ_0096157 and Nrf2 were knocked down, and Nrf2 was overexpressed in A549/DDP cells. The expression of Hsa_circ_0096157, the Nrf2/ARE pathway-related factors Nrf2, HO-1, and NQO1, and the autophagy-related factors LC3, Beclin-1, and p62 was evaluated by qRT‒PCR or western blotting. Autophagosomes were detected through TEM. An MTS assay was utilized to measure cell proliferation. The associated miRNA levels were also tested by qRT‒PCR.
RESULTS
DDP (3 μg/mL) promoted hsa_circ_0096157, LC3 II/I, and Beclin-1 expression and decreased p62 expression. Knocking down hsa_circ_0096157 resulted in the downregulation of LC3 II/I and Beclin-1 expression, upregulation of p62 expression, and decreased proliferation. Rapamycin reversed the effect of interfering with hsa_circ_0096157. Keap1 expression was lower, and Nrf2, HO-1, and NQO1 expression was greater in the A549/DDP group than in the A549 group. HO-1 expression was repressed after Nrf2 interference. In addition, activation of the Nrf2/ARE pathway promoted autophagy in A549/DDP cells. Moreover, hsa_circ_0096157 activated the Nrf2/ARE pathway. The silencing of hsa_circ_0096157 reduced Nrf2 expression by releasing miR-142-5p or miR-548n. Finally, we found that hsa_circ_0096157 promoted A549/DDP cell autophagy by activating the Nrf2/ARE pathway.
CONCLUSION
Knockdown of hsa_circ_0096157 inhibits autophagy and DDP resistance in NSCLC cells by downregulating the Nrf2/ARE signaling pathway.
Topics: Humans; Cisplatin; NF-E2-Related Factor 2; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Autophagy; Signal Transduction; Lung Neoplasms; A549 Cells; Gene Expression Regulation, Neoplastic; MicroRNAs; Cell Proliferation; Cell Line, Tumor; Antioxidant Response Elements; Antineoplastic Agents; Heme Oxygenase-1
PubMed: 38822881
DOI: 10.1007/s11033-024-09552-z -
The American Journal of Case Reports Jun 2024BACKGROUND Various resistance mechanisms of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) have been reported, and approximately half of the...
BACKGROUND Various resistance mechanisms of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) have been reported, and approximately half of the cases show a T790M point mutation as resistance to EGFR-TKI. In addition, 3-14% of cases of non-small cell lung cancer transform into small cell lung carcinoma (SCLC) during treatment. However, there are few reported cases in which 2 mechanisms of resistance have been observed simultaneously. This report describes a 66-year-old man with initial presentation of stage IIA right-sided lung adenocarcinoma with EGFR gene exon 21 L858R mutation and 3 years of stable disease. During treatment with erlotinib, the patient developed SCLC and adenocarcinoma with EGFR exon 21 L858R and exon 20 T790M mutation. CASE REPORT A 66-year-old man underwent right pneumonectomy plus nodal dissection 2a for right hilar lung cancer and was diagnosed with an EGFR exon21 L858R mutated lung adenocarcinoma. Three years later, pleural dissemination was observed in the right chest wall. Although erlotinib was continued for 52 months, new metastases to the right ribs were detected. Chest wall tumor resection was performed. Based on the World Health Organization classification, the patient was diagnosed with combined SCLC, with EGFR exon21 L858R and exon20 T790M mutation. The patient received 4 cycles of carboplatin plus etoposide, 14 cycles of amrubicin, and 2 cycles of irinotecan. Chemotherapy continued for 25 months. CONCLUSIONS Long-term survival was achieved by chemotherapy after transformation. Since EGFR mutation-positive lung cancer shows a variety of acquired resistances, it is important to consider the treatment strategy of performing re-biopsy.
Topics: Humans; Male; Lung Neoplasms; Aged; ErbB Receptors; Adenocarcinoma; Small Cell Lung Carcinoma; Erlotinib Hydrochloride; Adenocarcinoma of Lung; Protein Kinase Inhibitors; Drug Resistance, Neoplasm; Mutation
PubMed: 38822519
DOI: 10.12659/AJCR.943466 -
Nature Communications May 2024Checkpoint kinase 1 (CHK1) is critical for cell survival under replication stress (RS). CHK1 inhibitors (CHK1i's) in combination with chemotherapy have shown promising...
Checkpoint kinase 1 (CHK1) is critical for cell survival under replication stress (RS). CHK1 inhibitors (CHK1i's) in combination with chemotherapy have shown promising results in preclinical studies but have displayed minimal efficacy with substantial toxicity in clinical trials. To explore combinatorial strategies that can overcome these limitations, we perform an unbiased high-throughput screen in a non-small cell lung cancer (NSCLC) cell line and identify thioredoxin1 (Trx1), a major component of the mammalian antioxidant-system, as a determinant of CHK1i sensitivity. We establish a role for redox recycling of RRM1, the larger subunit of ribonucleotide reductase (RNR), and a depletion of the deoxynucleotide pool in this Trx1-mediated CHK1i sensitivity. Further, the TrxR inhibitor auranofin, an approved anti-rheumatoid arthritis drug, shows a synergistic interaction with CHK1i via interruption of the deoxynucleotide pool. Together, we show a pharmacological combination to treat NSCLC that relies on a redox regulatory link between the Trx system and mammalian RNR activity.
Topics: Checkpoint Kinase 1; Humans; Oxidation-Reduction; Thioredoxins; Cell Line, Tumor; Auranofin; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Protein Kinase Inhibitors; Ribonucleoside Diphosphate Reductase; Ribonucleotide Reductases; Drug Synergism; Animals
PubMed: 38821952
DOI: 10.1038/s41467-024-48076-9 -
Nature Communications May 2024Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established...
Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.
Topics: Carcinoma, Non-Small-Cell Lung; Humans; Animals; Lung Neoplasms; Mice; Mice, Inbred NOD; Mice, SCID; Genetic Heterogeneity; Female; Exome Sequencing; Genomics; Male; Xenograft Model Antitumor Assays; Heterografts; Disease Models, Animal; Aged; Middle Aged
PubMed: 38821942
DOI: 10.1038/s41467-024-47547-3 -
Anticancer Research Jun 2024Non-small cell lung cancer (NSCLC) is the deadliest form of cancer worldwide. Understanding the mechanisms of lung cancer development is vital for targeted therapy...
BACKGROUND/AIM
Non-small cell lung cancer (NSCLC) is the deadliest form of cancer worldwide. Understanding the mechanisms of lung cancer development is vital for targeted therapy advancements. This article explores the little-known role of the guanylate kinase-associated protein (GKAP), encoded by the Disks large-associated protein 1 (DLGAP1) gene, in NSCLC along with assessing microRNA-30a-5p's influence on DLGAP1 gene expression in the A549 cell line.
MATERIALS AND METHODS
Experiments were conducted on A549 cells transfected with synthetic oligonucleotides. The luciferase assay was employed to confirm the binding site of miR-30a-5p to the 3'UTR of DLGAP1 mRNA. The role of miRNA-30a-5p mimic in regulating potential target gene expression at the protein and mRNA levels was studied by performing RT-qPCR and western blot analyses. The effects of DLGAP1 knockdown and miRNA-30a-5p mimic on cell viability and the cell cycle were evaluated using the MTT test and flow cytometry with annexin/iodide cell staining.
RESULTS
The luciferase assay indicated that miR-30a-5p has the ability to bind to the 3'UTR of DLGAP1 mRNA. RT-qPCR revealed that the overexpression of miR-30a-5p down-regulates DLGAP1 mRNA. Western blot analysis indicated that miR-30a-5p slightly reduces the level of the GKAP protein. Knockdown of DLGAP1 with synthetic oligonucleotides, as well as transfection with a miR-30a-5p mimic, significantly attenuates cell proliferation and increases the number of cells in the early and late stages of apoptosis.
CONCLUSION
Our findings reveal the antiproliferative effect of miR-30a-5p and DLGAP1 gene knockdown on A549 cancer cells, implying that these elements could be considered as therapeutic targets for personalized medicine in NSCLC patients.
Topics: Humans; MicroRNAs; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Gene Expression Regulation, Neoplastic; Cell Proliferation; A549 Cells; 3' Untranslated Regions; Apoptosis; SAP90-PSD95 Associated Proteins; GTPase-Activating Proteins; Cell Survival; Cell Line, Tumor
PubMed: 38821626
DOI: 10.21873/anticanres.17051 -
Anticancer Research Jun 2024Atezolizumab, an anti-PD-L1 antibody, has been increasingly administered in combination with chemotherapy to patients with small cell lung cancer (SCLC). This study...
BACKGROUND/AIM
Atezolizumab, an anti-PD-L1 antibody, has been increasingly administered in combination with chemotherapy to patients with small cell lung cancer (SCLC). This study aimed to determine how patients with extensive disease (ED) -SCLC responded to atezolizumab with chemotherapy and found factors affecting long-term response and survival.
PATIENTS AND METHODS
This study focused on patients with SCLC who were treated with a combination of atezolizumab and chemotherapy in Japan between 2019 and 2023. Patient information and tumor response were analyzed, along with adverse events. We compared data and estimated survival probabilities.
RESULTS
In our clinical trial, 95 patients with SCLC who received this treatment had a median progression-free survival of 6.0 months and a median overall survival of 15.0 months. Immune-related adverse events were observed in 13.7% of the patients, with grade 3 or higher in 5.3%. The efficacy and immune-related adverse events associated with this treatment regimen were comparable to those reported in previous clinical trials. Progression-free survival >2 years was observed in a small number of patients (5.3%).
CONCLUSION
Our research will offer important insights for the future care of patients with extensive-stage SCLC by utilizing atezolizumab in combination with chemotherapy. Accumulation and confirmation of clinical practice results will have important implications for the future implementation of this therapy.
Topics: Humans; Small Cell Lung Carcinoma; Antibodies, Monoclonal, Humanized; Male; Lung Neoplasms; Female; Antineoplastic Combined Chemotherapy Protocols; Aged; Middle Aged; Aged, 80 and over; Adult; Progression-Free Survival
PubMed: 38821613
DOI: 10.21873/anticanres.17080 -
Anticancer Research Jun 2024There have been advances in the development of immune checkpoint inhibitors for monotherapy and combination therapy with other anticancer agents in recent years. The...
BACKGROUND/AIM
There have been advances in the development of immune checkpoint inhibitors for monotherapy and combination therapy with other anticancer agents in recent years. The combination of bevacizumab, carboplatin, and paclitaxel with atezolizumab, an anti-programmed death ligand 1 antibody (ABCP therapy), has been reported to be effective for treating non-small cell lung cancer. However, reports on its adverse events are limited. In this study, a survey and disproportionality analysis based on the Japanese Adverse Drug Event Report (JADER) database was conducted to elucidate the adverse event profile of ABCP therapy.
MATERIALS AND METHODS
The reporting odds ratio (ROR) and information component were used as indicators for the disproportionality analysis. The ROR was also used to assess the changes in the reporting intensity with combination therapy, and the mutual exclusivity of the 95% confidence interval between the compared groups was considered.
RESULTS
The reported adverse events of ABCP therapy mirrored those of the individual drugs that constituted it. ABCP therapy enhanced the reporting intensity of adverse events related to leukocytes and the skin, while decreased those related to interstitial lung disease and hepatic function abnormality as immune-related adverse events caused by atezolizumab, and gastrointestinal perforation caused by bevacizumab.
CONCLUSION
Our analysis of data from the JADER database has revealed the adverse event profile of ABCP therapy. Our findings emphasize the importance of effectively managing febrile neutropenia and skin-related adverse events in ABCP therapy.
Topics: Humans; Carboplatin; Bevacizumab; Paclitaxel; Antineoplastic Combined Chemotherapy Protocols; Antibodies, Monoclonal, Humanized; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Female; Male
PubMed: 38821611
DOI: 10.21873/anticanres.17072 -
Anticancer Research Jun 2024This study analyzed the effect of epidermal growth factor receptor (EGFR) mutations on fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography...
BACKGROUND/AIM
This study analyzed the effect of epidermal growth factor receptor (EGFR) mutations on fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) results in lung cancer and the pathological findings in patients subjected to surgery.
PATIENTS AND METHODS
A total of 210 patients diagnosed with lung cancer by F-18 FDG PET/CT at Inje University Busan Paik Hospital between January 2018 and December 2023 were recruited. EGFR mutation tests were performed on biopsy specimens. Overall, 78 patients (37.1%) with EGFR mutations were included in this study. Twenty-seven patients (12.9%) had distant metastases at the time of diagnosis. Of all patients, 69 (32.9%) underwent surgery at our hospital, and their pathological findings were analyzed.
RESULTS
The maximum standardized uptake value (SUVmax) of F-18 FDG PET/CT was <10 in patients with EGFR mutations. Patients with EGFR mutations were not commonly diagnosed with diabetes. When analyzing the pathological findings after surgery in the 69 patients, adenocarcinoma was more common in those with EGFR mutations. In contrast, perineural invasion was more common in patients without EGFR mutations. When analyzing the results of 69 patients with postoperative pathology, 25 relapsed during the median follow-up of 21.7 months (range=0.9-58.4 months). Patients who underwent surgery and had EGFR mutations (n=26) exhibited lower recurrence rates compared to those without EGFR mutations. Disease-free survival was longer in patients with EGFR mutations.
CONCLUSION
In non-small-cell lung cancer with an EGFR mutation, the F-18 FDG PET/CT SUVmax value and the probability of recurrence were lower. EGFR mutations are associated with low-glucose metabolism.
Topics: Humans; Lung Neoplasms; ErbB Receptors; Positron Emission Tomography Computed Tomography; Male; Female; Mutation; Middle Aged; Aged; Fluorodeoxyglucose F18; Adult; Aged, 80 and over; Radiopharmaceuticals; Carcinoma, Non-Small-Cell Lung
PubMed: 38821597
DOI: 10.21873/anticanres.17075 -
The Lancet. Oncology Jun 2024
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; B7-H1 Antigen; Biomarkers, Tumor; Prognosis; Immune Checkpoint Inhibitors
PubMed: 38821094
DOI: 10.1016/S1470-2045(24)00186-4