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In Vivo (Athens, Greece) 2024Recent lung cancer treatments include an immune checkpoint inhibitor (ICI) pembrolizumab, platinum-based agents, plus an additional cytotoxic anticancer agent....
BACKGROUND/AIM
Recent lung cancer treatments include an immune checkpoint inhibitor (ICI) pembrolizumab, platinum-based agents, plus an additional cytotoxic anticancer agent. Nutritional indices, such as the geriatric nutritional risk index (GNRI) and the prognostic nutritional index (PNI), are known to correlate with the prognosis of cancer chemotherapy. Several previous studies have investigated the relationship between PNI and treatment response in non-small cell lung cancer patients, reporting significantly increased OS and PFS in the high PNI group before treatment. However, the relationship between the three-drug combination and GNRI/PNI is unclear. The current study aimed to investigate the association of nutritional indices with duration of treatment success and occurrence of side effects in triple therapy.
PATIENTS AND METHODS
Seventy-two patients with non-small cell lung cancer, treated with combination of carboplatin, pemetrexed, and pembrolizumab from November 2019 to September 30, 2022, were classified into two groups (High and Low) for GNRI and PNI, and a retrospective study was performed.
RESULTS
In terms of time-to-treatment-failure (TTF), univariate and multivariate Cox proportional hazards regression analysis showed the Low-PNI group to have significantly shorter TTF than the High-PNI group (p=0.006); multivariate analysis results also showed PNI as a factor affecting TTF (HR=2.791, 95%CI=1.362-5.721, p=0.005). On the other hand, GNRI was not shown to be a factor affecting TTF.
CONCLUSION
PNI at the start of treatment was an independent prognostic factor affecting treatment success time (TTF) in non-small cell lung cancer patients receiving triple therapy. However, PNI was not shown to be a prognostic predictor of irAE development.
Topics: Humans; Aged; Lung Neoplasms; Nutrition Assessment; Carcinoma, Non-Small-Cell Lung; Retrospective Studies; Prognosis; Antineoplastic Agents
PubMed: 38418111
DOI: 10.21873/invivo.13512 -
Journal of Thoracic Disease Jan 2024So far, the treatment options for most advanced non-small cell lung cancer (NSCLC) with brain metastasis have been limited. Apatinib, an oral tyrosine kinase inhibitor...
BACKGROUND
So far, the treatment options for most advanced non-small cell lung cancer (NSCLC) with brain metastasis have been limited. Apatinib, an oral tyrosine kinase inhibitor (TKI) with anti-angiogenesis properties, has been approved for advanced gastric cancer in China. Clinical studies have demonstrated that apatinib also displays anticancer effects against several other human cancers, including NSCLC. We have observed that apatinib combined with pemetrexed or docetaxel shows promising efficiency for advanced NSCLC patients who have previously undergone two or more lines of treatment, we would like to further perform a retrospective efficiency analysis of apatinib combined with pemetrexed or docetaxel in advanced NSCLC patients with multiple brain metastasis in this study.
METHODS
A total of 35 patients, between 18 and 70 years old, who were clinically and pathologically confirmed as having advanced NSCLC were included in this study. All of the included patients had accepted two or more lines of treatment. These patients received apatinib combined with pemetrexed or docetaxel between January 2014 and November 2020 in Hubei Cancer Hospital.
RESULTS
The results showed that apatinib combined with pemetrexed or docetaxel could effectively delay the disease progression of brain metastasis in advanced NSCLC, with an approximate overall response rate (ORR) for measurable and non-measurable lesions of 10% and 15%, respectively. The disease control rate (DCR) for intracranial lesions was 66%, the median progression-free survival (PFS) was 4.0 months, and the median overall survival (OS) was 9.0 months. The most common treatment-related toxicities, such as fatigue, decreased appetite, and hand-foot syndrome (HFS), were either mild or moderate and tolerable.
CONCLUSIONS
Since there is currently no effective treatment for patients with advanced NSCLC patients with brain metastasis who have already undergone two or more lines of treatment, the promising efficiency of apatinib combined with pemetrexed or docetaxel would be of great significance for these heavily ill patients. The real therapeutic value of this method against brain metastasis needs to be confirmed by large, random, and prospective clinical trials in the future.
PubMed: 38410538
DOI: 10.21037/jtd-23-1860 -
Cureus Jan 2024Malignant peritoneal mesothelioma (MPeM) is a rare cancer of the peritoneum with a poor prognosis and nonspecific clinical course. We discuss a case of MPeM in a...
Malignant peritoneal mesothelioma (MPeM) is a rare cancer of the peritoneum with a poor prognosis and nonspecific clinical course. We discuss a case of MPeM in a 59-year-old male who presented with abdominal pain and distension, without any known previous asbestos exposure. The diagnosis was made after a second biopsy finally confirmed epithelioid MPeM in an advanced stage with pleural effusion. The patient underwent six cycles of chemotherapy with cisplatin and pemetrexed, experienced disease progression, and was then started on pembrolizumab as a second-line treatment. The patient achieved a complete response after two years of treatment with pembrolizumab and has been disease-free for almost four years with an Eastern Cooperative Oncology Group (ECOG) performance status of 0. Despite the lack of evidence to support the treatment with immunotherapy for MPeM, our case report encourages its use, highlighting its ability to enable a complete response with pembrolizumab with an excellent quality of life.
PubMed: 38384604
DOI: 10.7759/cureus.52716 -
ESMO Open Apr 2024This study aimed to evaluate the efficacy and safety of intrathecal pemetrexed (IP) for treating patients with leptomeningeal metastases (LM) from non-small-cell lung...
BACKGROUND
This study aimed to evaluate the efficacy and safety of intrathecal pemetrexed (IP) for treating patients with leptomeningeal metastases (LM) from non-small-cell lung cancer (NSCLC) who progressed from epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment in an expanded, prospective, single-arm, phase II clinical study (ChiCTR1800016615).
PATIENTS AND METHODS
Patients with confirmed NSCLC-LM who progressed from TKI received IP (50 mg, day 1/day 5 for 1 week, then every 3 weeks for four cycles, and then once monthly) until disease progression or intolerance. Objectives were to assess overall survival (OS), response rate, and safety. Measurable lesions were assessed by investigator according to RECIST version 1.1. LM were assessed according to the Response Assessment in Neuro-Oncology (RANO) criteria.
RESULTS
The study included 132 patients; 68% were female and median age was 52 years (31-74 years). The median OS was 12 months (95% confidence interval 10.4-13.6 months), RANO-assessed response rate was 80.3% (106/132), and the most common adverse event was myelosuppression (n = 42; 31.8%), which reversed after symptomatic treatment. The results of subgroup analysis showed that absence of brain parenchymal metastasis, good Eastern Cooperative Oncology Group score, good response to IP treatment, negative cytology after treatment, and patients without neck/back pain/difficult defecation had longer survival. Gender, age, previous intrathecal methotrexate/cytarabine, and whole-brain radiotherapy had no significant influence on OS.
CONCLUSIONS
This study further showed that IP is an effective and safe treatment method for the EGFR-TKI-failed NSCLC-LM, and should be recommended for these patients in clinical practice and guidelines.
Topics: Humans; Female; Male; Middle Aged; Aged; Carcinoma, Non-Small-Cell Lung; Pemetrexed; Lung Neoplasms; Adult; ErbB Receptors; Injections, Spinal; Prospective Studies; Meningeal Neoplasms; Protein Kinase Inhibitors; Meningeal Carcinomatosis; Treatment Outcome
PubMed: 38377785
DOI: 10.1016/j.esmoop.2024.102384 -
JTO Clinical and Research Reports Feb 2024Acquired gene amplification, exon 14 skip mutations, or fusions can emerge as resistance mechanisms to tyrosine kinase inhibitors (TKIs) in patients with lung cancer....
The Efficacy and Safety of Treating Acquired MET Resistance Through Combinations of Parent and MET Tyrosine Kinase Inhibitors in Patients With Metastatic Oncogene-Driven NSCLC.
INTRODUCTION
Acquired gene amplification, exon 14 skip mutations, or fusions can emerge as resistance mechanisms to tyrosine kinase inhibitors (TKIs) in patients with lung cancer. The efficacy and safety of combining MET TKIs (such as crizotinib, capmatinib, or tepotinib) with parent TKIs to target acquired MET resistance are not well characterized.
METHODS
Multi-institutional retrospective chart review identified 83 patients with metastatic oncogene-driven NSCLC that were separated into the following two pairwise matched cohorts: (1) MET cohort (n = 41)-patients with acquired MET resistance continuing their parent TKI with a MET TKI added or (2) Chemotherapy cohort (n = 42)-patients without any actionable resistance continuing their parent TKI with a platinum-pemetrexed added. Clinicopathologic features, radiographic response (by means of Response Evaluation Criteria in Solid Tumors version 1.1), survival outcomes, adverse events (AEs) (by means of Common Terminology Criteria for Adverse Events version 5.0), and genomic data were collected. Survival outcomes were assessed using Kaplan-Meier methods. Multivariate modeling adjusted for lines of therapy, brain metastases, TP53 mutations, and oligometastatic disease.
RESULTS
Within the MET cohort, median age was 56 years (range: 36-83 y). Most patients were never smokers (28 of 41, 68.3%). Baseline brain metastases were common (21 of 41, 51%). The most common oncogenes in the MET cohort were (30 of 41, 73.2%), (seven of 41, 17.1%), and (two of 41, 4.9%). Co-occurring TP53 mutations (32 of 41, 78%) were frequent. Acquired MET alterations included gene amplification (37 of 41, 90%), MET exon 14 mutations (two of 41, 5%), and gene fusions (two of 41, 5%). After multivariate adjustment, the objective response rate (ORR) was higher in the MET cohort versus the chemotherapy cohort (ORR: 69.2% versus 20%, < 0.001). Within the MET cohort, gene copy number (≥10 versus 6-10) did not affect radiographic response (54.5% versus 68.4%, = 0.698). There was no difference in ORR on the basis of MET TKI used (F [2, 36] = 0.021, = 0.978). There was no difference in progression-free survival (5 versus 6 mo; hazard ratio = 0.64; 95% confidence interval: 0.34-1.23, = 0.18) or overall survival (13 versus 11 mo; hazard ratio = 0.75; 95% confidence interval: 0.42-1.35, = 0.34) between the MET and chemotherapy cohorts. In the MET cohort, dose reductions for MET TKI-related toxicities were common (17 of 41, 41.4%) but less frequent for parent TKIs (two of 41, 5%). Grade 3 AEs were not significant between crizotinib, capmatinib, and tepotinib ( = 0.3). The discontinuation rate of MET TKIs was 17% with no significant differences between MET TKIs ( = 0.315). Among pre- and post-treatment biopsies (n = 17) in the MET cohort, the most common next-generation sequencing findings were loss of gene amplification (15 of 17, 88.2%), MET on-target mutations (seven of 17, 41.2%), new Ras-Raf-MAPK alterations (three of 17, 17.6%), and gene amplification (two of 17, 11.7%).
CONCLUSIONS
The efficacy and safety of combining MET TKIs (crizotinib, capmatinib, or tepotinib) with parent TKIs for acquired MET resistance are efficacious. Radiographic response and AEs did not differ significantly on the basis of the underlying MET TKI used. Loss of gene amplification, development of MET on-target mutations, Ras-Raf-MAPK alterations, and gene amplification were molecular patterns found on progression with dual parent and MET TKI combinations.
PubMed: 38361741
DOI: 10.1016/j.jtocrr.2024.100637 -
JAMA Oncology Apr 2024Arginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Arginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma.
OBJECTIVE
To determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumor.
DESIGN, SETTING, AND PARTICIPANTS
This was a phase 2-3, double-blind randomized clinical trial conducted at 43 centers in 5 countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months' follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023.
INTERVENTION
Patients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8 mg/m2) or placebo. All patients received intravenous pemetrexed (500 mg/m2) and platinum (75-mg/m2 cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months.
MAIN OUTCOMES AND MEASURES
The primary end point was overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only.
RESULTS
Among 249 randomized patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95% CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95% CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95% CI, 0.55-0.93; P = .02). The median progression-free survival was 6.2 months (95% CI, 5.8-7.4 months) with pegargiminase-chemotherapy as compared with 5.6 months (95% CI, 4.1-5.9 months) with placebo-chemotherapy (HR, 0.65; 95% CI, 0.46-0.90; P = .02). Grade 3 to 4 adverse events with pegargiminase occurred in 36 patients (28.8%) and with placebo in 21 patients (16.9%); drug hypersensitivity and skin reactions occurred in the experimental arm in 3 patients (2.4%) and 2 patients (1.6%), respectively, and none in the placebo arm. Rates of poststudy treatments were comparable in both arms (57 patients [45.6%] with pegargiminase vs 58 patients [46.8%] with placebo).
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial of arginine depletion with pegargiminase plus chemotherapy, survival was extended beyond standard chemotherapy with a favorable safety profile in patients with nonepithelioid pleural mesothelioma. Pegargiminase-based chemotherapy as a novel antimetabolite strategy for mesothelioma validates wider clinical testing in oncology.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02709512.
Topics: Aged; Female; Humans; Male; Antineoplastic Combined Chemotherapy Protocols; Arginine; Hydrolases; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Pleural Neoplasms; Polyethylene Glycols
PubMed: 38358753
DOI: 10.1001/jamaoncol.2023.6789 -
PloS One 2024Timeless is well-known for its key role in replication checkpoints. Recent studies reveal the involvement of Timeless and specificity protein (SP) 1 in human...
BACKGROUND
Timeless is well-known for its key role in replication checkpoints. Recent studies reveal the involvement of Timeless and specificity protein (SP) 1 in human malignancies. However, no evidence proved the interaction between SP3 and Timeless in lung adenocarcinoma (LUAD).
METHODS
The expression and clinical significance of Timeless were analyzed using the LUAD dataset downloaded from the Cancer Genome Atlas (TCGA). Lentivirus-mediated Timeless knockdown in A549 cells was used to examine the role of Timeless in cell proliferation and pemetrexed (PEM) resistance. Transcription factors (TFs) bound to the Timeless promoter were identified by DNA pull-down technology with HPLC-MS/MS analysis and analyzed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Dual-luciferase reporter assay was used to determine the activity of SP3 in Timeless transcription.
RESULTS
Timeless was overexpressed in LUAD samples, and it could serve as a potential diagnostic or prognostic biomarker for LUAD patients. shTimeless-mediated knockdown of Timeless reduced cell viability and proliferation and sensitized PEM-resistant A549 cells to PEM. Four fragments (F1: 1-373 bp), (F2: 374-962 bp), (F4: 1274-1645 bp), and (F5: 1646-2000bp) were confirmed as the TF binding profiles of the Timeless promoter. KEGG analysis showed that the TFs bound to the Timeless promoter had relevance to spliceosome, RNA transport, and mRNA surveillance pathways. SP3 promoted the transcription of Timeless via the F2 fragment (374-962 bp) binding motif.
CONCLUSION
Upregulation of Timeless mediated by SP3 promotes LUAD cell proliferation, providing evidence to support that targeting the SP3/Timeless axis may be a potential therapeutic strategy against LUAD.
Topics: Humans; Adenocarcinoma of Lung; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Lung Neoplasms; Tandem Mass Spectrometry
PubMed: 38354174
DOI: 10.1371/journal.pone.0298295 -
Amino Acids Feb 2024The advance of high-throughput sequencing enhances the discovery of short ORFs embedded in long non-coding RNAs (lncRNAs). Here, we uncovered the production and...
The advance of high-throughput sequencing enhances the discovery of short ORFs embedded in long non-coding RNAs (lncRNAs). Here, we uncovered the production and biological activity of lncRNA-hidden polypeptides in lung adenocarcinoma (LUAD). In the present study, bioinformatics was used to screen the lncRNA-hidden polypeptides in LUAD. Analysis of protein expression was done by western blot or immunofluorescence assay. The functions of the polypeptide were determined by detecting its effects on cell viability, proliferation, migration, invasion, and pemetrexed (PEM) sensitivity. The protein interactors of the polypeptide were analyzed by mass spectrometry after Co-immunoprecipitation (Co-IP) assay. The results showed that the lncRNA LINC00954 was confirmed to encode a novel polypeptide LINC00954-ORF. The polypeptide had tumor-suppressor features in A549 cells by repressing cell growth, motility and invasion. Moreover, the polypeptide enhanced PEM sensitivity and suppressed growth in A549/PEM cells. The protein interactors of this polypeptide had close correlations with RNA processing, amide metabolic process, translation, RNA binding, RNA transport, and DNA replication. As a conclusion, the LINC00954-ORF polypeptide embedded in lncRNA LINC00954 possesses tumor-suppressor features in A549 and PEM-resistant A549 cells and sensitizes PEM-resistant A549 cells to PEM, providing evidence that the LINC00954-ORF polypeptide is a potential anti-cancer agent in LUAD.
Topics: Humans; Pemetrexed; RNA, Long Noncoding; A549 Cells; Lung Neoplasms; Cell Line, Tumor; Cell Proliferation; Phenotype; Adenocarcinoma; Peptides; Gene Expression Regulation, Neoplastic
PubMed: 38351332
DOI: 10.1007/s00726-023-03361-7 -
Journal For Immunotherapy of Cancer Feb 2024In CheckMate 9LA, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy regardless of tumor PD-L1 expression or histology. We... (Randomized Controlled Trial)
Randomized Controlled Trial
Four-year clinical update and treatment switching-adjusted outcomes with first-line nivolumab plus ipilimumab with chemotherapy for metastatic non-small cell lung cancer in the CheckMate 9LA randomized trial.
BACKGROUND
In CheckMate 9LA, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy regardless of tumor PD-L1 expression or histology. We report updated efficacy and safety in all randomized patients with a minimum 4-year follow-up and an exploratory treatment-switching adjustment analysis in all treated patients who received chemotherapy and subsequent immunotherapy.
METHODS
Adults with stage IV/recurrent non-small cell lung cancer (NSCLC), no sensitizing alterations, and ECOG performance status ≤1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy (four cycles, with optional maintenance pemetrexed for the nonsquamous population). Assessments included OS, progression-free survival, and objective response rate. Exploratory analyses included efficacy by tumor PD-L1 expression and histology and in patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events (TRAEs), and a treatment-switching adjustment analysis using inverse probability of censoring weighting.
RESULTS
With a 47.9-month minimum follow-up for OS, nivolumab plus ipilimumab with chemotherapy continued to prolong OS over chemotherapy in all randomized patients (HR 0.74, 95% CI 0.63 to 0.87; 4-year OS rate: 21% versus 16%), regardless of tumor PD-L1 expression (HR (95% CI): PD-L1<1%, 0.66 (0.50 to 0.86) and ≥1%, 0.74 (0.60 to 0.92)) or histology (squamous, 0.64 (0.48 to 0.84) and non-squamous, 0.80 (0.66 to 0.97)). In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy due to TRAEs (n=61), the 4-year OS rate was 41%. With treatment-switching adjustment for the 36% of patients receiving subsequent immunotherapy in the chemotherapy arm, the estimated HR of nivolumab plus ipilimumab with chemotherapy versus chemotherapy was 0.66 (95% CI 0.55 to 0.80). No new safety signals were observed.
CONCLUSIONS
In this 4-year update, patients treated with nivolumab plus ipilimumab with chemotherapy continued to have long-term, durable efficacy benefit over chemotherapy regardless of tumor PD-L1 expression and/or histology. A greater estimated relative OS benefit was observed after adjustment for subsequent immunotherapy use in the chemotherapy arm. These results further support nivolumab plus ipilimumab with chemotherapy as a first-line treatment for patients with metastatic/recurrent NSCLC, including those with tumor PD-L1<1% or squamous histology, populations with high unmet needs.
Topics: Adult; Humans; Nivolumab; Carcinoma, Non-Small-Cell Lung; Ipilimumab; B7-H1 Antigen; Treatment Switching; Lung Neoplasms; Neoplasm Recurrence, Local; Carcinoma, Squamous Cell
PubMed: 38346853
DOI: 10.1136/jitc-2023-008189 -
Cureus Jan 2024Pemetrexed, an anti-folate, antineoplastic agent, effectively treats various malignancies such as non-small cell lung cancer (NSCLC) and mesothelioma. Here, we report...
Pemetrexed, an anti-folate, antineoplastic agent, effectively treats various malignancies such as non-small cell lung cancer (NSCLC) and mesothelioma. Here, we report two cases of recurrent pemetrexed-induced lower extremity erythema and edema, one in a 60-year-old male and the other in a 47-year-old male, who were both treated for recurrent cellulitis on multiple occasions before finally being diagnosed with pemetrexed-induced pseudocellulitis (PIP), a rarely reported adverse effect. This is an important diagnostic pitfall for clinicians to be aware of, as early recognition may minimize patient morbidity and prevent unnecessary hospitalization and antibiotic use for presumed cellulitis.
PubMed: 38344595
DOI: 10.7759/cureus.52114