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Lung Cancer (Amsterdam, Netherlands) Jan 2021To characterize the benefit-risk profile of pemetrexed and platinum in combination with pembrolizumab in patients with non-squamous non-small cell lung cancer in the... (Meta-Analysis)
Meta-Analysis
Pemetrexed maintenance with or without pembrolizumab in non-squamous non-small cell lung cancer: A cross-trial comparison of KEYNOTE-189 versus PARAMOUNT, PRONOUNCE, and JVBL.
OBJECTIVE
To characterize the benefit-risk profile of pemetrexed and platinum in combination with pembrolizumab in patients with non-squamous non-small cell lung cancer in the KEYNOTE-189 study, with reference to historical pemetrexed maintenance data from the PARAMOUNT, PRONOUNCE, and JVBL randomized studies.
MATERIALS AND METHODS
To harmonize the treatment setting across the studies in our comparative analysis, we selected patients from KEYNOTE-189 who received ≥5 cycles of pemetrexed (pembrolizumab/pemetrexed/platinum, N = 310; placebo/pemetrexed/platinum, N = 135) and pooled data from PARAMOUNT (N = 359), PRONOUNCE (N = 98), and JVBL (N = 29) who received ≥5 cycles of pemetrexed (total, N = 486). For the 2 selected populations from KEYNOTE-189 and the pooled historical data, progression-free survival (PFS) was evaluated by Kaplan-Meier estimator and Cox proportional hazards model. Tumor response and grade ≥3 treatment-emergent adverse events (TEAEs) for the aforementioned population were summarized by descriptive statistics.
RESULTS
In the selected KEYNOTE-189 population with ≥5 cycles pemetrexed, median PFS was 9.3 months (95 % confidence interval [CI]: 9.0-11.1) in the pembrolizumab/pemetrexed/platinum arm and 6.6 months (95 % CI: 5.4-7.1) in the placebo/pemetrexed/platinum arm (unstratified hazard ratio: 0.53; 95 % CI: 0.42‒0.68; p ≤ 0.0001). In the pooled population with ≥5 cycles pemetrexed from historical trials, median PFS was 5.6 months (95 % CI: 4.6-5.8). Objective response rates were 58.7 % and 28.9 % in the pembrolizumab/pemetrexed/platinum and placebo/pemetrexed/platinum arms, respectively, of KEYNOTE-189 and 42.4 % in the pooled historical studies. The incidence of grade ≥3 TEAEs was similar in both arms of KEYNOTE-189 and in the pooled historical studies.
CONCLUSION
Improved PFS was shown with pembrolizumab/pemetrexed/platinum compared with placebo/pemetrexed/platinum in the patient group with pemetrexed maintenance (≥5 cycles) in KEYNOTE-189. The PFS and safety profile of the control arm in KEYNOTE-189 were comparable with historical pemetrexed maintenance data.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Pemetrexed
PubMed: 33285468
DOI: 10.1016/j.lungcan.2020.11.018 -
Cellular Oncology (Dordrecht) Dec 2023Chemoresistance is a primary factor for treatment failure and tumor recurrence in non-small cell lung cancer (NSCLC) patients. The oncoprotein survivin is commonly...
PURPOSE
Chemoresistance is a primary factor for treatment failure and tumor recurrence in non-small cell lung cancer (NSCLC) patients. The oncoprotein survivin is commonly upregulated in human malignancies and is associated with poor prognosis, but its effect on carcinogenesis and chemoresistance in NSCLC is not yet evident, and to explore an effective inhibitor targeting survivin expression is urgently needed.
METHODS
The protumor characteristics of survivin and antitumor activities of bergenin in NSCLC cells were examined by MTS, colony formation assays, immunoblot, immunohistochemistry, and in vivo xenograft development.
RESULTS
Survivin was upregulated in non-small cell lung cancer (NSCLC) tissues, while its depletion inhibited NSCLC tumorigenesis. The current study focused on bergenin, identifying its effective antitumor effect on NSCLC cells both in vivo and in vitro. The results showed that bergenin could inhibit cell proliferation and induce the intrinsic pathway of apoptosis via downregulating survivin. Mechanistically, bergenin reduced the phosphorylation of survivin via inhibiting the Akt/Wee1/CDK1 signaling pathway, thus resulting in enhanced interaction between survivin and E3 ligase Fbxl7 to promote survivin ubiquitination and degradation. Furthermore, bergenin promoted chemoresistance in NSCLC cells re-sensitized to pemetrexed treatment.
CONCLUSIONS
Survivin overexpression is required for maintaining multiple malignant phenotypes of NSCLC cells. Bergenin exerts a potent antitumor effect on NSCLC via targeting survivin, rendering it a promising agent for the treatment of NSCLC.
Topics: Humans; Survivin; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Pemetrexed; Inhibitor of Apoptosis Proteins; Proto-Oncogene Proteins c-akt; Apoptosis; Cell Proliferation; Cell Line, Tumor
PubMed: 37542022
DOI: 10.1007/s13402-023-00850-5 -
British Journal of Clinical Pharmacology Feb 2022Pemetrexed is a cytotoxic drug for first-line treatment of lung cancer. It is often combined with other anticancer drugs such as cisplatin or carboplatin. In clinical...
Pemetrexed is a cytotoxic drug for first-line treatment of lung cancer. It is often combined with other anticancer drugs such as cisplatin or carboplatin. In clinical practice, hyperhydration regimens are applied to overcome cisplatin-related nephrotoxicity. As pemetrexed is almost completely eliminated from the body by the kidneys, hyperhydration can result in augmented clearance. Furthermore, administration of large quantities of fluid may increase the volume of distribution of pemetrexed. Pharmacokinetics and, thus, efficacy and toxicity may be influenced by hyperhydration. This has not yet been properly studied. We performed a population pharmacokinetic analysis to assess hyperhydration as a covariate for pemetrexed clearance and for volume of distribution A relevant change was defined as >25% increase in clearance or volume of distribution. In our extensive dataset of 133 individuals, we found that hyperhydration did not significantly or relevantly explain variability in pemetrexed clearance (unchanged, P = .196) or volume of distribution (+7% change, P = .002), despite a power of >99% to detect a relevant change. Therefore, dose adjustments of pemetrexed are not required during hyperhydration with cisplatin.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Humans; Lung Neoplasms; Pemetrexed
PubMed: 34374116
DOI: 10.1111/bcp.15031 -
Journal For Immunotherapy of Cancer Sep 2023ONCOS-102, an oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor, can alter the tumor microenvironment to an immunostimulatory state.... (Randomized Controlled Trial)
Randomized Controlled Trial
ONCOS-102 plus pemetrexed and platinum chemotherapy in malignant pleural mesothelioma: a randomized phase 2 study investigating clinical outcomes and the tumor microenvironment.
BACKGROUND
ONCOS-102, an oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor, can alter the tumor microenvironment to an immunostimulatory state. Combining ONCOS-102 with standard-of-care chemotherapy for malignant pleural mesothelioma (MPM) may improve treatment outcomes.
METHODS
In this open-label, randomized study, patients with unresectable MPM received intratumoral ONCOS-102 (3×10 virus particles on days 1, 4, 8, 36, 78, and 120) and pemetrexed plus cisplatin/carboplatin (from day 22), or pemetrexed plus cisplatin/carboplatin alone. The primary endpoint was safety. Overall survival (OS), progression-free survival, objective response rate, and tumor immunologic activation (baseline and day 36 biopsies) were also assessed.
RESULTS
In total, 31 patients (safety lead-in: n=6, randomized: n=25) were enrolled. Anemia (15.0% and 27.3%) and neutropenia (40.0% and 45.5%) were the most frequent grade ≥3 adverse events (AEs) in the ONCOS-102 (n=20) and chemotherapy-alone (n=11) cohorts. No patients discontinued ONCOS-102 due to AEs. No statistically significant difference in efficacy endpoints was observed. There was a numerical improvement in OS (30-month OS rate 34.1% vs 0; median OS 20.3 vs 13.5 months) with ONCOS-102 versus chemotherapy alone in chemotherapy-naïve patients (n=17). By day 36, ONCOS-102 was associated with increased T-cell infiltration and immune-related gene expression that was not observed in the control cohort. Substantial immune activation in the tumor microenvironment was associated with survival at month 18 in the ONCOS-102 cohort.
CONCLUSIONS
ONCOS-102 plus pemetrexed and cisplatin/carboplatin was well tolerated by patients with MPM. In injected tumors, ONCOS-102 promoted a proinflammatory environment, including T-cell infiltration, which showed association with survival at month 18.
Topics: Humans; Pemetrexed; Platinum; Mesothelioma, Malignant; Cisplatin; Tumor Microenvironment; Carboplatin
PubMed: 37661097
DOI: 10.1136/jitc-2023-007552 -
Biomaterials Jan 2022NK cell-based immunotherapy and pemetrexed (Pem)-based chemotherapy have broad application prospects in cancer treatment. However, the over-expressed NK cell inhibitory...
NK cell-based immunotherapy and pemetrexed (Pem)-based chemotherapy have broad application prospects in cancer treatment. However, the over-expressed NK cell inhibitory receptor on the surface of cancer cells and the low cell internalization efficiency of Pem greatly limit their clinical application. Herein, we construct a series of selenium-containing nanoparticles to synergistically enhance Pem-based chemotherapy and NK cell-based immunotherapy. The nanoparticles could deliver Pem to tumor sites and strengthen the chemotherapy efficiency of Pem by seleninic acid, which is produced by the oxidation of β-seleno ester. Moreover, seleninic acid can block the expression of inhibitory receptors against NK cells, thereby activating the immunocompetence of NK cells. The in vitro and in vivo experiments reveal the potential chemo-enhancing and immune-activating mechanism of seleninic acid, emphasizing the promising prospects of this strategy in effective chemoimmunotherapy.
Topics: Immunotherapy; Killer Cells, Natural; Nanoparticles; Pemetrexed; Selenium
PubMed: 34922271
DOI: 10.1016/j.biomaterials.2021.121321 -
Journal of Cellular and Molecular... Jul 2023Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are strongly recommended for non-small-cell lung cancer (NSCLC) patients harbouring active EGFR...
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are strongly recommended for non-small-cell lung cancer (NSCLC) patients harbouring active EGFR mutations, while drug resistance makes exploring resistance mechanisms and seeking effective therapeutic strategies urgent endeavours. Thymidylate synthetase (TYMS or TS) is a dominant enzyme in thymidylate nucleotide metabolism. In this study, we found a positive correlation between TS expression and overall survival (OS) and disease-free survival (DFS) in lung adenocarcinoma. The examination of gene sets from 140 NSCLC patients received EGFR-TKI therapy demonstrated a negative correlation between high TS expression and the efficacy of EGFR-TKI therapy. 24 tissue specimens from NSCLC patients exhibited upregulated TS mRNA expression in NSCLC patients resistant to gefitinib. The NSCLC cell PC9 and HCC827 sensitive to gefitinib and relatively resistant PC9/GR and HCC827/GR cells were used to demonstrate the knockdown of TS restored the sensitivity of resistant cells to gefitinib. Furthermore, pemetrexed effectively suppressed TS-mediated thymidylate metabolism and induced ROS generation, DNA damage and cellular senescence, thereby hampering cancer progression and restoring sensitivity to gefitinib. Our findings illuminate the potential mechanism of TS-triggered gefitinib resistance and indicate inhibition of TS by pemetrexed can potentiate the effect of gefitinib in NSCLC. Pemetrexed combined with gefitinib has potent anti-progression potential in gefitinib-resistant NSCLC. This study suggests that NSCLC patients with both high TS expression and EGFR-driving mutations might benefit more from a combination strategy of EGFR-TKI and pemetrexed-based chemotherapy than EGFR-TKI monotherapy, which has profound clinical implications and therapeutic value.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Gefitinib; Pemetrexed; Reactive Oxygen Species; Lung Neoplasms; ErbB Receptors; Quinazolines; Drug Resistance, Neoplasm; Cell Line, Tumor; Cellular Senescence; Mutation; Protein Kinase Inhibitors
PubMed: 37278440
DOI: 10.1111/jcmm.17799 -
Lung Cancer (Amsterdam, Netherlands) Aug 2020Pemetrexed is a pharmacotherapeutic cornerstone in the treatment of non-small cell lung cancer. As it is primarily eliminated by renal excretion, adequate renal function...
INTRODUCTION
Pemetrexed is a pharmacotherapeutic cornerstone in the treatment of non-small cell lung cancer. As it is primarily eliminated by renal excretion, adequate renal function is essential to prevent toxic exposure. There is growing evidence for the nephrotoxic potential of pemetrexed, which even becomes a greater issue now combined immuno-chemotherapy prolongs survival. Therefore, the aim of this study was to describe the incidence of nephrotoxicity and related treatment consequences during pemetrexed-based treatment.
METHODS
A retrospective cohort study was conducted in the Jeroen Bosch Hospital, Den Bosch, the Netherlands. All patients that received at least 1 cycle of pemetrexed based therapy were included in the dataset. The primary outcome was defined as a ≥25 % reduction in eGFR. Additionally, the treatment consequences of decreased renal function were assessed. Logistic regression was used to identify risk factors for nephrotoxicity during treatment with pemetrexed.
RESULTS
Of the 359 patients included in this analysis, 21 % patients had a clinically relevant decline in renal function after treatment and 8.1 % of patients discontinued treatment due to nephrotoxicity. Cumulative dose (≥10 cycles of pemetrexed based therapy) was identified as a risk factor for the primary outcome measure (adjusted OR 5.66 (CI 1.73-18.54)).
CONCLUSION
This study shows that patients on pemetrexed-based treatment are at risk of developing renal impairment. Risk significantly increases with prolonged treatment. Renal impairment is expected to become an even greater issue now that pemetrexed-based immuno-chemotherapy results in longer survival and thus longer treatment duration.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Netherlands; Pemetrexed; Retrospective Studies
PubMed: 32505078
DOI: 10.1016/j.lungcan.2020.05.022 -
Anticancer Research Sep 2023No standard treatment is currently recommended for advanced biliary tract cancer (BTC) after first-line therapy with gemcitabine plus cisplatin. We aimed to evaluate the...
Pemetrexed and Erlotinib as a Salvage Treatment in Patients With Metastatic Biliary Tract Cancer Who Failed Gemcitabine-containing Chemotherapy: A Phase II Single-arm Prospective Study.
BACKGROUND/AIM
No standard treatment is currently recommended for advanced biliary tract cancer (BTC) after first-line therapy with gemcitabine plus cisplatin. We aimed to evaluate the efficacy and safety of a pemetrexed and erlotinib combination in patients with BTC previously treated with gemcitabine.
PATIENTS AND METHODS
This phase II, open-label, single-arm study enrolled patients with BTC who had previously failed gemcitabine-based first-line chemotherapy. Patients were treated with pemetrexed as a 500 mg/m intravenous infusion on day 1 for three weeks and erlotinib 100 mg daily until disease progression or unacceptable toxicity. The primary endpoint was the overall response rate (ORR).
RESULTS
The study enrolled 20 patients with BTC, including 12 (60%) with intrahepatic cholangiocarcinoma (IHCC), 3 (15%) with extrahepatic cholangiocarcinoma (EHCC), and 5 (25%) with gallbladder cancer (GBC). The ORR was 5%, and the disease control rate (DCR) was 55%. As of the cutoff point of March 31, 2023, the median progression-free survival (PFS) was 2.3 months [95% confidence interval (CI)=0.00-4.74] and the median overall survival (OS) was 5.6 months (95%CI=2.28-8.87). Patients with EHCC showed longer PFS and OS compared to patients with IHCC or GBC, but the differences were not significant. A baseline CEA greater than the upper normal limit was the only significant prognostic factor for a worse OS rate. The only treatment-related adverse event (TRAE) with severity grade ≥3 was anemia (5%).
CONCLUSION
Salvage chemotherapy with pemetrexed plus erlotinib was well-tolerated and showed marginal clinical activity in BTC patients after failure to gemcitabine-based chemotherapy.
Topics: Humans; Salvage Therapy; Gemcitabine; Erlotinib Hydrochloride; Pemetrexed; Prospective Studies; Bile Duct Neoplasms; Carcinoma in Situ; Cholangiocarcinoma; Gallbladder Neoplasms; Bile Ducts, Intrahepatic
PubMed: 37648323
DOI: 10.21873/anticanres.16607 -
Journal of Thoracic Oncology : Official... Sep 2020The combination of chemotherapy and immune checkpoint inhibition (ICI) therapy is the current standard of care for most patients who are fit to undergo treatment for... (Review)
Review
The combination of chemotherapy and immune checkpoint inhibition (ICI) therapy is the current standard of care for most patients who are fit to undergo treatment for metastatic NSCLC. With this combination, renal toxicity was slightly higher than with chemotherapy alone in initial clinical trials. However, in recent real-world data, loss of kidney function is reported to be more frequent. Both chemotherapy and ICI therapy can induce renal impairment, although the mechanism of renal damage is different. Renal injury from chemotherapy is often ascribed to acute tubular injury and necrosis, whereas the main mechanism of injury caused by ICI therapy is acute tubulointerstitial nephritis. In cases of concomitant use of chemotherapy and ICI therapy, distinguishing the cause of renal failure is a challenge. Discriminating between these two causes is of utmost importance, as it would help assess which drug can be safely continued and which drug must be halted. This review aims to describe the underlying mechanisms of the renal adverse effects caused by chemotherapy and ICI therapy, leading to a suggested diagnostic and treatment algorithm on the basis of clinical, laboratory, radiographic, and pathologic parameters. This algorithm could serve as a supportive tool for clinicians to diagnose the underlying cause of acute kidney injury in patients treated with the combination of chemotherapy and immunotherapy.
Topics: Antibodies, Monoclonal, Humanized; Humans; Lung Neoplasms; Pemetrexed; Renal Insufficiency
PubMed: 32360753
DOI: 10.1016/j.jtho.2020.04.021 -
Scientific Reports May 2023Chordomas are rare slow growing tumors, arising from embryonic remnants of notochord with a close predilection for the axial skeleton. Recurrence is common and no...
Chordomas are rare slow growing tumors, arising from embryonic remnants of notochord with a close predilection for the axial skeleton. Recurrence is common and no effective standard medical therapy exists. Thymidylate synthase (TS), an intracellular enzyme, is a key rate-limiting enzyme of DNA biosynthesis and repair which is primarily active in proliferating and metabolically active cells. Eighty-four percent of chordoma samples had loss of TS expression which may predict response to anti-folates. Pemetrexed suppresses tumor growth by inhibiting enzymes involved in folate metabolism, resulting in decreased availability of thymidine which is necessary for DNA synthesis. Pemetrexed inhibited growth in a preclinical mouse xenograft model of human chordoma. We report three cases of metastatic chordoma that had been heavily treated previously with a variety of standard therapies with poor response. In two cases, pemetrexed was added and objective responses were observed on imaging with one patient on continuous treatment for > 2 years with continued shrinkage. One case demonstrated tumor growth after treatment with pemetrexed. The two cases which had a favorable response had a loss of TS expression, whereas the one case with progressive disease had TS present. These results demonstrate the activity of pemetrexed in recurrent chordoma and warrant a prospective clinical trial which is ongoing (NCT03955042).
Topics: Humans; Animals; Mice; Pemetrexed; Chordoma; Prospective Studies; Guanine; Glutamates; Neoplasm Recurrence, Local; DNA; Thymidylate Synthase
PubMed: 37147496
DOI: 10.1038/s41598-023-34404-4