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Orphanet Journal of Rare Diseases Oct 2023The regimen of nivolumab plus ipilimumab (NI) has been recommended by the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology-Malignant...
BACKGROUND
The regimen of nivolumab plus ipilimumab (NI) has been recommended by the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology-Malignant Pleural Mesothelioma (Version 1.2022) and Chinese Guidelines for the Clinical Diagnosis and Treatment of Malignant Pleural Mesothelioma (2021 edition) as the first-line treatment for Malignant Pleural Mesothelioma (MPM). But whether immunotherapy has a financial advantage over conventional chemotherapy (pemetrexed plus cisplatin/carboplatin, C) is uncertain.
METHODS
Based on survival and safety data from the CheckMate 743 clinical trial (NCT02899299), a partitioned survival model was constructed using TreeAge Pro2022 software. The model cycle was set to 1 month and the study period was 10 years. The output indicators included total cost, quality-adjusted life year (QALY) and incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were used to assess the robustness of the results, considering only direct medical costs.
RESULTS AND DISCUSSION
The ICER for group NI versus Group C was $375,656/QALY in all randomized patients, $327,943/QALY in patients with epithelioid histology, and $115,495/QALY in patients with non-epithelioid histology. The ICERs of all three different populations all exceeded the willingness-to-pay threshold (three times the per capita gross domestic product of China in 2021). The results of univariate sensitivity analysis showed that the price of pemetrexed and nivolumab had great influence on the analysis results. The results of the probabilistic sensitivity analysis show that the probability of the NI scheme being more economical in all three different populations was 0.
WHAT IS NEW AND CONCLUSION
From the perspective of the Chinese healthcare system, in patients with unresectable MPM, NI has no economic advantage over C.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Cost-Effectiveness Analysis; Ipilimumab; Mesothelioma, Malignant; Nivolumab; Pemetrexed; Randomized Controlled Trials as Topic
PubMed: 37845696
DOI: 10.1186/s13023-023-02925-w -
Cancers Aug 2023Pemetrexed is used for the chemotherapy of advanced thymoma. Exceptional responses of thymoma to pemetrexed treatment are not frequently observed. The underlying genetic...
BACKGROUND
Pemetrexed is used for the chemotherapy of advanced thymoma. Exceptional responses of thymoma to pemetrexed treatment are not frequently observed. The underlying genetic mechanism of the exceptional responses remains unclear. We used whole-exome sequencing to explore the specific genomic aberrations that lead to an extreme and durable response.
METHODS
Whole-exome sequencing using NovaSeq6000 (150 bp paired-end sequencing) was performed on nine formalin-fixed paraffin-embedded tissues from patients with advanced thymomas treated with pemetrexed (two exceptional responders and seven typical responders).
RESULTS
We identified 284 somatic single-nucleotide variants (SNVs; 272 missense, 8 missense/splice-site, 3 stop-gain, and 1 stop-gain/splice-site), 34 insertions and deletions (Indels; 33 frameshift and one splice region), and 21 copy number variations (CNVs; 15 gains and six losses). No difference in the number of SNVs variants and distribution of deleterious Indels was observed between the exceptional and typical responders. Interestingly, arm-level chromosomal CNVs (15 gains and six losses) were detected in four patients, including an exceptional responder. The highest number of arm-level CNVs was observed in an exceptional responder.
CONCLUSION
Exceptional responders to pemetrexed for metastatic thymomas may be characterized by arm-level CNVs. Further, whole-genome and RNA sequencing studies should be performed.
PubMed: 37627046
DOI: 10.3390/cancers15164018 -
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 -
Medicine Aug 2023With the advancement of targeted therapies, epidermal growth factor receptor tyrosine kinase inhibitors have become the preferred initial treatment for patients with... (Review)
Review
RATIONALE
With the advancement of targeted therapies, epidermal growth factor receptor tyrosine kinase inhibitors have become the preferred initial treatment for patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer. Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is effective against exon 19 and 21 mutations as well as the T790M mutation. It has been approved by both the food and drug administration and European Medicines Agency for the treatment of non-small cell lung cancer patients with locally advanced or metastatic EGFR-mutated tumors, including those who have acquired T790M mutations.
PATIENT CONCERNS
To evaluate the effectiveness of osimertinib in treating patients with EGFR-mutated advanced lung adenocarcinoma and bone metastases, we present the treatment outcomes of 3 patients with EGFR 19 deletion-mutated advanced lung adenocarcinoma and bone metastases who received osimertinib treatment in recent years. All 3 cases involved elderly female patients, aged 62, 62, and 54, respectively.
DIAGNOSES
All 3 cases exhibited a diagnosis of pulmonary adenocarcinoma accompanied by osseous metastases, with genetic testing revealing the presence of an EGFR 19del mutation.
INTERVENTIONS
In the first case, following 17 months of gefitinib therapy, disease progression prompted a switch to osimertinib treatment. In the second case, bone metastases were detected after 20 months of pemetrexed-carboplatin chemotherapy, leading to a transition to osimertinib therapy. In the third case, after 11 months of erlotinib treatment, bone metastases were identified. Subsequent interventions, including radiation therapy, pemetrexed-carboplatin chemotherapy, pemetrexed-bevacizumab maintenance therapy, and docetaxel chemotherapy, failed to arrest the progression of bone metastases. As a result, a combination of osimertinib and anlotinib targeted therapy was administered.
OUTCOMES
All 3 patients experienced relatively good and favorable survival outcomes, with a progression-free survival of 22.7 months, 12 months, and 17.7 months, respectively.
LESSONS
These cases suggest that osimertinib is a promising treatment option for patients with EGFR 19 deletion-mutated lung adenocarcinoma and bone metastases, although further clinical studies are needed to confirm its efficacy.
Topics: Aged; Female; Humans; Adenocarcinoma of Lung; Bone Neoplasms; Carboplatin; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Lung Neoplasms; Mutation; Pemetrexed; Protein Kinase Inhibitors; United States; Tyrosine Kinase Inhibitors
PubMed: 37653755
DOI: 10.1097/MD.0000000000034545 -
JTO Clinical and Research Reports Dec 2023We hypothesized that ramucirumab could increase previously reported objective response rate (ORR) of 11% of single-agent nivolumab in the second-line therapy of...
INTRODUCTION
We hypothesized that ramucirumab could increase previously reported objective response rate (ORR) of 11% of single-agent nivolumab in the second-line therapy of unresectable mesothelioma.
METHODS
This was a cooperative group, single-arm, phase 2 trial enrolling patients with unresectable mesothelioma after progression on more than or equal to one pemetrexed-containing regimen. Ramucirumab and nivolumab were given intravenously every 14 days for up to 24 months. The primary end point was ORR; secondary end points were progression-free survival (PFS) rate at 24 weeks and overall survival (OS).
RESULTS
Between April 2018 and October 2021, 34 patients were recruited. Median age was 72 (range: 40-89) years, 12% were women, and 79% of tumors had epithelial histology. Median follow-up was 10.2 months (interquartile range 19.6 mo [4.3-23.8]). ORR was 22.6% (95% confidence interval [CI]: 9.6%-41.1%) in all population and 43% (95% CI: 10%-82%) in patients with nonepithelioid histology. Of all patients, 45.2% (95% CI: 27.3%-64.0%) had stable disease. PFS rate at 24 weeks was 32% (95% CI: 17%-51%). Median PFS was 4.2 months (95% CI: 1.9-6.4 mo). Median OS was 12.5 months (95% CI: 6.3-23.5 mo). There was no grade greater than or equal to four toxicity. Programmed death-ligand 1 expression in the tumor did not correlate with benefit from treatment. Activation of tumor-infiltrating lymphocytes in response to treatment was associated with a trend toward improvement in PFS.
CONCLUSIONS
Nivolumab and ramucirumab combination was safe and generated PFS and OS rates and ORR that compare favorably with single-agent nivolumab in a similar patient population. The primary end point of 40% ORR was not reached. Further investigation of this regimen in mesothelioma with nonepithelioid histology may be warranted. Clinical Trial Information: NCT03502746.
PubMed: 38046376
DOI: 10.1016/j.jtocrr.2023.100584 -
Asian Pacific Journal of Cancer... Jun 2024Lung cancer is the most common malignancy and among the leading cause of cancer death worldwide. Therefore, there is an important need for biomarkers that can be used in...
OBJECTIVE
Lung cancer is the most common malignancy and among the leading cause of cancer death worldwide. Therefore, there is an important need for biomarkers that can be used in the early diagnosis of the disease and in the follow-up of treatment. Circular RNAs (circRNAs) have a covalently closed circular structure that lacks 3' and 5' polar ends and is resistant to RNAase enzymes. Due to these properties, they can be stably found in body fluids. Therefore, they can serve as potential biomarkers in the diagnosis, monitoring of therapeutic response and prognosis of cancer. In our study, we aimed to investigate the expression levels of circRNA molecules in the treatment of lung cancer and to determine those that have the potential to be biomarkers.
METHODS
In this in vitro study, expression levels of 163 circRNAs were investigated in A549 cells, a non-small cell lung cancer cell line, before and after treatment with carboplatin and pemetrexed. Total RNA isolation and cDNA synthesis were performed after treatments. Expression levels of circRNA genes were determined by RT-qPCR method with the designed divergent primer sequences.
RESULTS
The study revealed the characterisation of differentially expressed circRNAs by treatment in lung cancer cells. Of them, hsa_circ_0001320 is not expressed in cancer cells, is expressed only after treatment, and increased the level of its expression in response to combination therapy.
CONCLUSION
As a result, while carboplatin, pemetrexed, and combined drug applications changed the expression levels of some circRNAs in lung cancer cells, some circRNAs were expressed only after treatment. In treatment follow-up and management, hsa_circ_0001320 has been identified as potential biomarker candidate.
Topics: Humans; RNA, Circular; Lung Neoplasms; Biomarkers, Tumor; Prognosis; Carcinoma, Non-Small-Cell Lung; Carboplatin; Pemetrexed; Gene Expression Regulation, Neoplastic; Tumor Cells, Cultured
PubMed: 38918678
DOI: 10.31557/APJCP.2024.25.6.2147 -
JAMA Network Open May 2024Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to assess therapeutic response in clinical trials but not in routine care; thus, RECIST-based end... (Observational Study)
Observational Study
IMPORTANCE
Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to assess therapeutic response in clinical trials but not in routine care; thus, RECIST-based end points are difficult to include in observational studies. Clinician-anchored approaches for measuring clinical response have been validated but not widely compared with clinical trial data, limiting their use as evidence for clinical decision-making.
OBJECTIVE
To compare response- and progression-based end points in clinical trial and observational cohorts of patients with non-small cell lung cancer (NSCLC).
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study used patient-level data from the IMpower132 trial (conducted April 7, 2016, to May 31, 2017) and a nationwide electronic health record (EHR)-derived deidentified database (data collected January 1, 2011, to March 31, 2022). Patients in the observational cohort were selected according to the inclusion and exclusion criteria of the IMpower132 trial. All patients in the observational cohort had stage IV NSCLC.
EXPOSURE
All patients were randomized to or received first-line carboplatin or cisplatin plus pemetrexed.
MAIN OUTCOMES AND MEASURES
End points included response rates, duration of response, and progression-free survival, compared between the trial and observational cohorts before and after weighting. Response rates for the observational cohort were derived from the EHR.
RESULTS
A total of 769 patients met inclusion criteria, 494 in the observational cohort (median [IQR] age, 67 [60-74] years; 228 [46.2%] female; 45 [9.1%] Black or African American; 352 [71.3%] White; 53 [10.7%] American Indian or Alaska Native, Asian, Hawaiian or Pacific Islander, or multiracial) and 275 in the trial cohort (median [IQR] age, 63 [56-68] years; 90 [32.7%] female; 4 [1.5%] Black or African American; 194 [70.5%] White; 65 [23.6%] American Indian or Alaska Native, Asian, Hawaiian or Pacific Islander, or multiracial). All 3 end points were comparable between the study cohorts. Trial patients had a higher number of response assessments compared with patients in the weighted observational cohort. The EHR-derived response rate was numerically higher than the objective response rate after weighting (100.3 of 249.3 [40.2%] vs 105 of 275 [38.2%]) due to higher rates of observed partial response than RECIST-based partial response. Among patients with at least 1 response assessment, the EHR-derived response rate remained higher than the objective response rate (100.3 of 193.4 [51.9%] vs 105 of 256 [41.0%]) due to a higher proportion of patients in the observational cohort with no response assessment.
CONCLUSIONS AND RELEVANCE
In this study, response- and progression-based end points were similar between clinical trial and weighted observational cohorts, which increases confidence in the reliability of observational end points and can inform their interpretation in relation to trial end points. Additionally, the difference observed in response rates (including vs excluding patients with no response assessment) highlights the importance of future research adopting this 2-way approach when evaluating the relationship of EHR-derived and objective response rates.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Female; Male; Lung Neoplasms; Middle Aged; Aged; Retrospective Studies; Carboplatin; Disease Progression; Cisplatin; Pemetrexed; Cohort Studies; Response Evaluation Criteria in Solid Tumors; Antineoplastic Combined Chemotherapy Protocols; Progression-Free Survival
PubMed: 38700864
DOI: 10.1001/jamanetworkopen.2024.9286 -
International Journal of Molecular... May 2024Malignant pleural mesothelioma (MPM) remains an incurable disease. This is partly due to the lack of experimental models that fully recapitulate the complexity and...
Malignant pleural mesothelioma (MPM) remains an incurable disease. This is partly due to the lack of experimental models that fully recapitulate the complexity and heterogeneity of MPM, a major challenge for therapeutic management of the disease. In addition, the contribution of the MPM microenvironment is relevant for the adaptive response to therapy. We established mesothelioma patient-derived organoid (mPDO) cultures from MPM pleural effusions and tested their response to pemetrexed and cisplatin. We aimed to evaluate the contribution of mesothelioma-associated fibroblasts (MAFs) to the response to pemetrexed and cisplatin (P+C). Organoid cultures were obtained from eight MPM patients using specific growth media and conditions to expand pleural effusion-derived cells. Flow cytometry was used to verify the similarity of the organoid cultures to the original samples. MAFs were isolated and co-cultured with mPDOs, and the addition of MAFs reduced the sensitivity of mPDOs to P+C. Organoid formation and expression of cancer stem cell markers such as ABCG2, NANOG, and CD44 were altered by conditioned media from treated MAFs. We identified IL-6 as the major contributor to the attenuated response to chemotherapy. IL-6 secretion by MAFs is correlated with increased resistance of mPDOs to pemetrexed and cisplatin.
Topics: Humans; Organoids; Interleukin-6; Cisplatin; Pemetrexed; Mesothelioma, Malignant; Cancer-Associated Fibroblasts; Mesothelioma; Tumor Microenvironment; Male; Female; Fibroblasts; Middle Aged; Aged; Antineoplastic Agents; Neoplastic Stem Cells; Lung Neoplasms
PubMed: 38791392
DOI: 10.3390/ijms25105355 -
Scientific Reports Oct 2023This study aims to investigate the effects of hyperthermia on intestinal microecology, immune function, and progression-free survival of patients with advanced...
This study aims to investigate the effects of hyperthermia on intestinal microecology, immune function, and progression-free survival of patients with advanced unresectable lung adenocarcinoma. A total of twenty patients with lung adenocarcinoma in the study group received the advanced standard first-line treatment protocol, which included pemetrexed + cisplatin combined with sintilimab immunotherapy and hyperthermia. Additionally, twenty patients with lung adenocarcinoma in the control group received the advanced standard first-line treatment protocol, which included pemetrexed + cisplatin combined with sintilimab immunotherapy. The T-lymphocyte subpopulation and CD4/CD8 cell ratio of each sample were detected using flow cytometry. The intestinal flora was evaluated using 16S rRNA gene sequencing. The study observed the changes in the abundance, distribution, composition, and structure of fecal gut microorganisms before and after the treatment in both groups of patients. Significant differences were observed in the intestinal flora between the two groups. The patients in the study group showed improved immunity after treatment, whereas there was no significant change in the immunity of the control group before and after treatment. However, the difference in progression-free survival between the two groups was not statistically significant. Hyperthermia has a significant impact on improving the microecology of intestinal flora and the immunity of patients, but it does not have a significant effect on prolonging the progression-free survival of patients.
Topics: Humans; Pemetrexed; Cisplatin; Lung Neoplasms; Progression-Free Survival; RNA, Ribosomal, 16S; Adenocarcinoma of Lung; Immunity; Hyperthermia, Induced; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37821661
DOI: 10.1038/s41598-023-44350-w -
International Journal of Molecular... Oct 2023To promote the preclinical development of new treatments for non-small cell lung cancer (NSCLC), we established NSCLC xenograft tumor assays on the chorioallantoic...
To promote the preclinical development of new treatments for non-small cell lung cancer (NSCLC), we established NSCLC xenograft tumor assays on the chorioallantoic membrane (CAM) of chicken embryos. Five NSCLC cell lines were compared for tumor take rate, tumor growth, and embryo survival. Two of these, A549 and H460 CAM tumors, were histologically characterized and tested for susceptibility to systemic chemotherapy and gene delivery using viral vectors. All cell lines were efficiently engrafted with minimal effect on embryo survival. The A549 cells formed slowly growing tumors, with a relatively uniform distribution of cancer cells and stroma cells, while the H460 cells formed large tumors containing mostly proliferating cancer cells in a bed of vascularized connective tissue. Tumor growth was inhibited via systemic treatment with Pemetrexed and Cisplatin, a chemotherapy combination that is often used to treat patients with advanced NSCLC. Lentiviral and adenoviral vectors expressing firefly luciferase transduced NSCLC tumors in vivo. The adenovirus vector yielded more than 100-fold higher luminescence intensities after a single administration than could be achieved with multiple lentiviral vector deliveries. The adenovirus vector also transduced CAM tissue and organs of developing embryos. Adenovirus delivery to tumors was 100-10,000-fold more efficient than to embryo organs. In conclusion, established human NSCLC-CAM tumor models provide convenient in vivo assays to rapidly evaluate new cancer therapies, particularly cancer gene therapies.
Topics: Animals; Humans; Chick Embryo; Carcinoma, Non-Small-Cell Lung; Chickens; Lung Neoplasms; Chorioallantoic Membrane; Cell Line, Tumor; Xenograft Model Antitumor Assays
PubMed: 37895104
DOI: 10.3390/ijms242015425