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Annales de Dermatologie Et de... Dec 2020Pemetrexed is an antifolate used to treat intrathoracic cancers. We report a rare case of cutaneous toxicity of pemetrexed with inflammatory cutaneous sclerosis of the...
BACKGROUND
Pemetrexed is an antifolate used to treat intrathoracic cancers. We report a rare case of cutaneous toxicity of pemetrexed with inflammatory cutaneous sclerosis of the lower limbs.
PATIENTS AND METHODS
A 63-year-old man diagnosed with metastatic adenocarcinoma of the lung was treated with pemetrexed. Fourteen months after undergoing this chemotherapy, he developed inflammatory and fibrotic edema of the lower limbs with functional consequences on knee bending. Cardiac, renal, hepatic, thrombotic and infectious causes were ruled out. Pemetrexed was suspended and partial remission was obtained using super-potent topical corticosteroids. With the approval of the oncologist, nivolumab was introduced as a follow-on therapy after pemetrexed.
DISCUSSION
Often misdiagnosed by physicians, this form of toxicity due to pemetrexed is rare but classically described. To limit cutaneous side effects, dexamethasone may be proposed the day before, the same day as and the day after the infusion. Suspension of chemotherapy is not routine but depends on the risk-benefit ratio of the functional impact of the dermatosis and on the therapeutic alternatives available for the cancer.
Topics: Antineoplastic Agents; Humans; Lower Extremity; Lung Neoplasms; Male; Middle Aged; Pemetrexed; Sclerosis; Skin Diseases
PubMed: 32763003
DOI: 10.1016/j.annder.2020.06.016 -
International Journal of Cancer Oct 2021Pemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in...
Pemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: <45 mL/min) the approved dose of 500 mg/m would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20 mg for patients (eGFR: 20 mL/min) is shown to be neutropenic-equivalent to the approved dose in patients with adequate renal function (eGFR: 90 mL/min), but would result in an approximately 13-fold lower area under the concentration-time curve. The pemetrexed exposure-toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment.
Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dietary Supplements; Dose-Response Relationship, Drug; Female; Folic Acid Antagonists; Follow-Up Studies; Humans; Kidney Failure, Chronic; Lung Neoplasms; Male; Middle Aged; Neutropenia; Pemetrexed; Prognosis; Tissue Distribution
PubMed: 34181276
DOI: 10.1002/ijc.33721 -
Clinical Lung Cancer Sep 2023Pemetrexed-based immunochemotherapy represents an established standard of care as first line treatment for non-oncogenic driven metastatic non-small cell lung... (Randomized Controlled Trial)
Randomized Controlled Trial
Rationale and Design of the Phase II ANTELOPE Study of Atezolizumab, Carboplatin and nab-Paclitaxel vs. Pembrolizumab, Platinum and Pemetrexed in TTF-1 Negative, Metastatic Lung Adenocarcinoma (AIO-TRK-0122).
INTRODUCTION
Pemetrexed-based immunochemotherapy represents an established standard of care as first line treatment for non-oncogenic driven metastatic non-small cell lung adenocarcinoma (NSCLC/ADC). However, retrospective analyses revealed better outcomes for pemetrexed-free regimens compared to pemetrexed-containing regimens in patients with thyroid transcription factor 1 (TTF-1) negative NSCLC/ADC. The multicenter, phase II, randomized, open-label ANTELOPE trial evaluates whether atezolizumab, carboplatin and nab-paclitaxel is superior to pembrolizumab, cis-/carboplatin and pemetrexed in TTF-1 negative NSCLC/ADC.
METHODS
Eligible participants are ≥18 years of age, with histologically or cytologically confirmed, treatment-naïve stage IV TTF-1 negative NSCLC/ADC without actionable genomic alterations or PD-L1-overexpression (TPS ≥50%) and will be randomized in a 1:1 fashion to pemetrexed-free (group A) vs. pemetrexed-based (group B) immunochemotherapy. The primary endpoint of this trial is overall survival (OS).
RESULTS
Enrollment will start in Q2 2023 at 30 sites in Germany with a planned inclusion of 136 participants.
CONCLUSION
ANTELOPE will provide efficacy outcomes of the current standard-of-care for the specific subset of TTF-1 negative NSCLC/ADC in a head-to-head comparison of approved immunochemotherapy regimens.
Topics: Humans; Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Pemetrexed; Platinum; Retrospective Studies; Thyroid Nuclear Factor 1
PubMed: 37169628
DOI: 10.1016/j.cllc.2023.04.009 -
Angewandte Chemie (International Ed. in... Feb 2020Immunotherapy has emerged as a promising new approach for cancer treatment. However, clinically available drugs have been limited until recently, and the antitumor...
Immunotherapy has emerged as a promising new approach for cancer treatment. However, clinically available drugs have been limited until recently, and the antitumor efficacy of most cancer immunotherapies still needs to be improved. Herein, we develop diselenide-pemetrexed assemblies that combine natural killer (NK) cell-based cancer immunotherapy with radiotherapy and chemotherapy in a single system. The assemblies are prepared by co-assembly between pemetrexed and cytosine-containing diselenide through hydrogen bonds. Under γ-radiation, the hydrogen bonds are cleaved, resulting in the release of pemetrexed. At the same time, diselenide can be oxidized to seleninic acid, which suppresses the expression of human leukocyte antigen E (HLA-E) in cancer cells, thus activating the immune response of NK cells. In this way, cancer immunotherapy is combined with radiotherapy and chemotherapy, providing a new strategy for cancer treatment.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Histocompatibility Antigens Class I; Humans; Immunotherapy; Killer Cells, Natural; Molecular Structure; Organoselenium Compounds; Pemetrexed
PubMed: 31805209
DOI: 10.1002/anie.201914453 -
Cancer Science Jul 2023Chemotherapy, in combination with immune checkpoint blockade (ICB) targeting to programmed death-1 (PD-1) or its ligand PD-L1, is one of the first-line treatments for...
Chemotherapy, in combination with immune checkpoint blockade (ICB) targeting to programmed death-1 (PD-1) or its ligand PD-L1, is one of the first-line treatments for patients with advanced non-small-cell lung cancer (NSCLC). However, a large proportion of patients, especially those with PD-L1 negative tumors, do not benefit from this treatment. This may be due to the existence of multiple immunosuppressive mechanisms other than the PD-1/PD-L1 axis. Human leukocyte antigen-G (HLA-G) has been identified as an immune checkpoint protein (ICP) and a neoexpressed tumor-associated antigen (TAA) in a large proportion of solid tumors. In this study, we evaluated the induction of HLA-G as well as PD-L1 using sublethal doses of chemotherapeutics including pemetrexed in different NSCLC cell lines. Except for gefitinib, most of the chemotherapeutic agents enhanced HLA-G and PD-L1 expression in a dose-dependent manner, whereas pemetrexed and carboplatin treatments showed the most consistent upregulation of PD-L1 and HLA-G in each cell line. In addition to protein levels, a novel finding of this study is that pemetrexed enhanced the glycosylation of HLA-G and PD-L1. Pemetrexed potentiated the cytotoxicity of cytotoxic T lymphocytes (CTLs) to treat NSCLC. Both in vitro and in vivo experiments revealed that CTL-mediated cytotoxicity was most pronounced when both anti-PD-L1 and anti-HLA-G ICBs were combined with pemetrexed treatment. In conclusion, anti-HLA-G could be an intervention strategy in addition to the anti-PD-1/PD-L1 pathway for NSCLC. Moreover, dual targeting of PD-L1 and HLA-G combined with pemetrexed might have a better extent of CTL-based immunotherapy.
Topics: Humans; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; T-Lymphocytes, Cytotoxic; Pemetrexed; Immune Checkpoint Inhibitors; B7-H1 Antigen
PubMed: 37017116
DOI: 10.1111/cas.15806 -
Clinical and Experimental Dermatology Dec 2017
Topics: Aged; Antineoplastic Agents; Betamethasone Valerate; Cellulitis; Diagnosis, Differential; Diagnostic Errors; Edema; Erythema; Folic Acid Antagonists; Glucocorticoids; Humans; Lower Extremity; Lung Neoplasms; Male; Middle Aged; Pemetrexed; Treatment Outcome
PubMed: 28815694
DOI: 10.1111/ced.13202 -
Journal of Thoracic Oncology : Official... Jan 2020
Topics: Biomarkers; ErbB Receptors; Gefitinib; Humans; Lung Neoplasms; Mutation; Pemetrexed
PubMed: 31864546
DOI: 10.1016/j.jtho.2019.10.017 -
Journal of Thoracic Oncology : Official... Apr 2021We report the final results of the phase 3 IMpower132 study evaluating atezolizumab plus carboplatin or cisplatin plus pemetrexed (APP) in patients with nonsquamous... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
We report the final results of the phase 3 IMpower132 study evaluating atezolizumab plus carboplatin or cisplatin plus pemetrexed (APP) in patients with nonsquamous NSCLC.
METHODS
Chemotherapy-naive patients with stage IV nonsquamous NSCLC without sensitizing EGFR or ALK genetic alterations were randomized in a one-to-one ratio to receive four or six cycles of carboplatin or cisplatin plus pemetrexed (PP) or APP every 3 weeks, followed by maintenance therapy with atezolizumab plus pemetrexed or pemetrexed alone. Co-primary end points were overall survival (OS) and investigator-assessed progression-free survival (PFS).
RESULTS
The intention-to-treat population included 578 patients (APP, n = 292; PP, n = 286). At the primary PFS analysis (May 22, 2018; median follow-up, 14.8 mo), APP exhibited significant PFS improvement versus PP (median = 7.6 versus 5.2 mo, stratified hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.49-0.72, p < 0.0001). OS for the APP group was numerically better but not statistically significant at the interim (May 22, 2018; median = 18.1 versus 13.6 mo, stratified HR = 0.81, 95% CI: 0.64-1.03, p = 0.0797) and final analyses (July 18, 2019; median = 17.5 versus 13.6 mo; stratified HR = 0.86, 95% CI: 0.71-1.06, p = 0.1546). The OS and PFS results favored APP versus PP across subgroups. Grade 3 or 4 treatment-related adverse events occurred in 54.6% (APP) and 40.1% (PP) of patients; grade 5 treatment-related events occurred in 3.8% and 2.9%, respectively.
CONCLUSIONS
IMpower132 met its co-primary PFS end point but not its co-primary OS end point, with numerical improvement for OS in the APP arm. APP had a manageable safety profile, with no new or unexpected safety signals identified.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Humans; Lung Neoplasms; Pemetrexed
PubMed: 33333328
DOI: 10.1016/j.jtho.2020.11.025 -
American Journal of Kidney Diseases :... Oct 2016Pemetrexed is an approved antimetabolite agent, now widely used for treating locally advanced or metastatic nonsquamous non-small cell lung cancer. Although no...
Pemetrexed is an approved antimetabolite agent, now widely used for treating locally advanced or metastatic nonsquamous non-small cell lung cancer. Although no electrolyte abnormalities are described in the prescribing information for this drug, several case reports have noted nephrogenic diabetes insipidus with associated acute kidney injury. We present a case of nephrogenic diabetes insipidus without severely reduced kidney function and propose a mechanism for the isolated finding. Severe hypernatremia can lead to encephalopathy and osmotic demyelination, and our report highlights the importance of careful monitoring of electrolytes and kidney function in patients with lung cancer receiving pemetrexed.
Topics: Adult; Antineoplastic Agents; Diabetes Insipidus, Nephrogenic; Humans; Male; Pemetrexed
PubMed: 27241854
DOI: 10.1053/j.ajkd.2016.04.016 -
Head & Neck Jun 2019There are no proven systemic therapies for metastatic adenocarcinoma of the salivary glands. Pemetrexed use in adenocarcinoma of the salivary glands has not been... (Review)
Review
BACKGROUND
There are no proven systemic therapies for metastatic adenocarcinoma of the salivary glands. Pemetrexed use in adenocarcinoma of the salivary glands has not been previously described.
METHODS
Retrospective case reports and literature review.
RESULTS
Two patients with metastatic salivary gland adenocarcinoma were treated with single-agent pemetrexed with marked response and clinical benefit. Case 1 describes a sustained clinical response for 8 months after failing several lines of chemotherapy. Case 2 describes a marked interval response of diffuse metastatic disease at 2 months with resolution of bone pain and sustained response at 8 months.
CONCLUSION
To our knowledge, this is the first report of efficacy of single-agent pemetrexed for metastatic salivary gland adenocarcinoma. Given the significant and sustained responses in heavily pretreated patients, further investigation of pemetrexed for salivary cancer may be warranted.
Topics: Adenocarcinoma; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Parotid Neoplasms; Pemetrexed
PubMed: 30706564
DOI: 10.1002/hed.25658