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Journal of Thoracic Oncology : Official... Jun 2023Immune checkpoint inhibitors have activity in mesothelioma. IND.227 was a phase 2 trial (120 patients planned) comparing progression-free survival of standard platinum... (Randomized Controlled Trial)
Randomized Controlled Trial
Immune checkpoint inhibitors have activity in mesothelioma. IND.227 was a phase 2 trial (120 patients planned) comparing progression-free survival of standard platinum and pemetrexed (CP) versus CP + pembrolizumab (pembro) versus pembro. Accrual to the pembro arm was discontinued on the basis of interim analysis (IA-16 wk disease control rate). CP + pembro was tolerable, with progression-free survival similar between arms and median survival and overall response rate higher than those of CP alone (19.8 mo [95% confidence interval or CI: 8.4-41.36] versus 8.9 mo [95% CI: 5.3-12.8] and 47% [95% CI: 24%-71%] versus 19% [95% CI: 5%-42%], respectively). The subsequent phase 3 trial has completed accrual; results are expected in 2023.
Topics: Humans; Mesothelioma, Malignant; Lung Neoplasms; Canada; Mesothelioma; Pemetrexed; Antineoplastic Combined Chemotherapy Protocols; Pleural Neoplasms
PubMed: 36841541
DOI: 10.1016/j.jtho.2023.02.003 -
Asia-Pacific Journal of Clinical... Dec 2021Carboplatin plus pemetrexed followed by maintenance pemetrexed is expected to be well-tolerated by the elderly. This multicenter, prospective study examined the efficacy...
Efficacy and safety of carboplatin and pemetrexed followed by maintenance with pemetrexed for elderly patients with advanced non-squamous non-small cell lung cancer: A single-arm, open-label, multicenter, phase II study.
PURPOSE
Carboplatin plus pemetrexed followed by maintenance pemetrexed is expected to be well-tolerated by the elderly. This multicenter, prospective study examined the efficacy and tolerability of the regimen in elderly patients with previously untreated advanced non-squamous non-small cell lung cancer.
METHODS
The primary endpoint was the 1-year survival rate, with secondary endpoints of response rate (RR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse event rate. Efficacy was compared between patients with performance status (PS) 0 and 1.
RESULTS
Forty-one patients were enrolled between March 2011 and April 2016. Median age was 76.0 years. The 1-year survival rate was 73% (95% confidence interval (CI), 56-84%). RR was 44%, DCR was 81%, median PFS was 7.2 months (95%CI, 3.98-9.20 months), and median OS was 17.4 months (95%CI, 13.60-22.83 months). Twenty-one patients (51%) transitioned to maintenance therapy. Toxicities of grade ≥ 3 during the induction phase included anemia (37%), thrombocytopenia (29%), neutropenia (22%), appetite loss (15%), nausea (10%), bacterial pneumonia (7%), febrile neutropenia (5%), and interstitial pneumonia (2%). Treatment was discontinued in two patients with interstitial pneumonia, but no deaths were encountered. During the maintenance phase, one patient needed dose reductions due to phlegmon. No significant difference in efficacy was seen between PS 0 and PS 1.
CONCLUSION
Carboplatin and pemetrexed followed by maintenance pemetrexed for non-squamous non-small cell lung cancer in elderly patients appear effective and tolerable.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Pemetrexed; Prospective Studies
PubMed: 33567165
DOI: 10.1111/ajco.13488 -
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 -
Acta Oncologica (Stockholm, Sweden) 2016
Topics: Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Pemetrexed; Retrospective Studies; Steroids
PubMed: 26366501
DOI: 10.3109/0284186X.2015.1080859 -
Journal of Controlled Release :... Jan 2023Therapeutic cancer drug efficacy can be limited by insufficient tumor penetration, rapid clearance, systemic toxicity and (acquired) drug resistance. The poor...
Therapeutic cancer drug efficacy can be limited by insufficient tumor penetration, rapid clearance, systemic toxicity and (acquired) drug resistance. The poor therapeutic index due to inefficient drug penetration and rapid drug clearance and toxicity can be improved by using a liposomal platform. Drug resistance for instance against pemetrexed, can be reduced by combination with docetaxel. Here, we developed a specific liposomal formulation to simultaneously deliver docetaxel and pemetrexed to enhance efficacy and safety. Hydrophobic docetaxel and hydrophilic pemetrexed were co-encapsulated into pH-sensitive liposomes using a thin-film hydration method with high efficiency. The physicochemical properties, toxicity, and immunological effects of liposomes were examined in vitro. Biodistribution, anti-tumor efficacy, and systemic immune response were evaluated in vivo in combination with PD-L1 immune checkpoint therapy using two murine colon cancer models. In cellular experiments, the liposomes exhibited strong cytotoxicity and induced immunogenic cell death. In vivo, the treatment with the liposome-based drug combination inhibited tumor development and stimulated immune responses. Liposomal encapsulation significantly reduced systemic toxicity compared to the delivery of the free drug. Tumor control was strongly enhanced when combined with anti-PDL1 immunotherapy in immunocompetent mice carrying syngeneic MC38 or CT26 colon tumors. We showed that treatment with liposome-mediated chemotherapy of docetaxel and pemetrexed combined with anti-PD-L1 immunotherapy is a promising strategy for the treatment of colon cancers.
Topics: Animals; Mice; Liposomes; Docetaxel; Pemetrexed; Tissue Distribution; Colonic Neoplasms; Cell Line, Tumor
PubMed: 36460179
DOI: 10.1016/j.jconrel.2022.11.049 -
BMC Cancer Apr 2022Malignant pleural mesothelioma (MPM) is a rare, aggressive malignancy of the pleural cavity linked to asbestos exposure. The combination of pemetrexed and platinum is a...
BACKGROUND
Malignant pleural mesothelioma (MPM) is a rare, aggressive malignancy of the pleural cavity linked to asbestos exposure. The combination of pemetrexed and platinum is a standard first-line therapy for malignant pleural mesothelioma. Despite some progress, almost all MPM patients experience progression after first-line therapy. The second-line treatment is still being under discussion and there are very limited data available on the second-line and subsequent treatments.
METHODS
The retrospective analysis included 57 patients (16 females and 41 males) from two Polish oncological institutions treated for advanced mesothelioma between 2013 and 2019. We analysed the efficacy of first-line and second-line therapy: progression-free survival (PFS), overall survival (OS), overall response rate (ORR).
RESULTS
In the first-line treatment, 55 patients received pemetrexed-based chemotherapy (PBC) and two cisplatin in monotherapy. Patients' characteristics at baseline: median age was 64.2 years, ECOG PS ≤ 1 (86.2%), epithelial histology (85.7%). Median PFS and OS were 7.6 months and 14 months, respectively. Patients with ECOG PS ≤ 1 vs > 1 had a longer median OS (14.8 months vs 9.7 months, p = 0.057). One-year OS and PFS were 60.9% and 32.0%, respectively. Disease control rate (DCR) was 82.5%. Response to first-line therapy: PFS ≥ 6 months and PFS ≥ 12 months had a significant impact on median OS. Twelve patients received second-line therapy (seven PBC and five other cytotoxic single agents: navelbine, gemcitabine, or adriamycin/vincristine/methotrexate triplet). Median PFS and OS were 3.7 months and 7.2 months, respectively. DCR was 83%. One-year OS and PFS were 37% and 16.7%, respectively. In the group receiving PBC, OS was prolonged by 4.5 months compared to the non-PBC group (6.0 months vs 10.5 months, p = 0.47).
CONCLUSION
Patients who benefited from first-line therapy and had prolonged PFS at first-line and achieve PFS longer than 6 months at first-line should be offered second-line treatment. Consideration of retreatment with the same cytotoxic agent could to be a viable option when no other treatment are available.
Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Middle Aged; Pemetrexed; Pleural Neoplasms; Retrospective Studies; Treatment Outcome
PubMed: 35443624
DOI: 10.1186/s12885-022-09490-8 -
Journal For Immunotherapy of Cancer Nov 2020The immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) has been proved beneficial for numerous types of cancers, including...
BACKGROUND
The immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) has been proved beneficial for numerous types of cancers, including non-small-cell lung cancer (NSCLC). However, a significant number of patients with NSCLC still fail to respond to ICB due to unfavorable tumor microenvironment. To improve the efficacy, the immune-chemotherapy combination with pemetrexed, cis/carboplatin and pembrolizumab (anti-PD-1) has been recently approved as first-line treatment in advanced NSCLCs. While chemotherapeutic agents exert beneficial effects, the underlying antitumor mechanism(s) remains unclear.
METHODS
Pemetrexed, cisplatin and other chemotherapeutic agents were tested for the potential to induce PD-L1 expression in NSCLC cells by immunoblotting and flow cytometry. The ability to prime the tumor immune microenvironment was then determined by NSCLC/T cell coculture systems and syngeneic mouse models. Subpopulations of NSCLC cells responding differently to pemetrexed were selected and subjected to RNA-sequencing analysis. The key signaling pathways were identified and validated in vitro and in vivo.
RESULTS
Pemetrexed induced the transcriptional activation of (encoded by ) by inactivating thymidylate synthase (TS) in NSCLC cells and, in turn, activating T-lymphocytes when combined with the anti-PD-1/PD-L1 therapy. Nuclear factor κB (NF-κB) signaling was activated by intracellular reactive oxygen species (ROSs) that were elevated by pemetrexed-mediated TS inactivation. The TS-ROS-NF-κB regulatory axis actively involves in pemetrexed-induced PD-L1 upregulation, whereas when pemetrexed fails to induce PD-L1 expression in NSCLC cells, NF-κB signaling is unregulated. In syngeneic mouse models, the combinatory treatment of pemetrexed with anti-PD-L1 antibody created a more favorable tumor microenvironment for the inhibition of tumor growth.
CONCLUSIONS
Our findings reveal novel mechanisms showing that pemetrexed upregulates PD-L1 expression and primes a favorable microenvironment for ICB, which provides a mechanistic basis for the combinatory chemoimmunotherapy in NSCLC treatment.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Humans; Immune Checkpoint Inhibitors; Mice; Mice, Nude; Pemetrexed; Signal Transduction; Tumor Microenvironment
PubMed: 33243934
DOI: 10.1136/jitc-2020-001392 -
Seminars in Respiratory and Critical... Oct 2016Therapy of non-small cell lung cancer (NSCLC) patients has evolved over the past few years with the incorporation of targeted therapy and immune therapy. These changes... (Review)
Review
Therapy of non-small cell lung cancer (NSCLC) patients has evolved over the past few years with the incorporation of targeted therapy and immune therapy. These changes have increased the importance of prognostic and predictive biomarkers to enable practicing physicians in making the most appropriate treatment decisions for NSCLC patients. A variety of prognostic factors based on clinical and pathologic features determine the overall outcome of the patient and these factors do influence decisions regarding initiation of therapy. The most important prognostic factors remain stage of the disease at diagnosis and performance status. For years, the only approved systemic therapy for NSCLC patients was chemotherapy. Despite attempts at defining factors that influence efficacy of chemotherapeutic agents, pemetrexed is the only chemotherapy drug that has differential activity based on a specific factor. In recent years, there is increasing focus on defining the molecular alterations critical to the oncogenic phenotype of NSCLC and targeting these alterations for therapeutic benefit. In addition, there is increasing use of immune-modulating drugs, specifically anti-PD-1 drugs, in advanced NSCLC patients. Several studies have shown that the probability of clinical benefit from these agents is greater in patients with NSCLCs that express PD-L1. The totality of these data suggests that determination of predictive markers prior to initiation of therapy is critical.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Pemetrexed; Prognosis; Severity of Illness Index
PubMed: 27732997
DOI: 10.1055/s-0036-1592337 -
Journal of Thoracic Oncology : Official... Dec 2021Sintilimab plus chemotherapy significantly prolonged progression-free survival (PFS) compared with chemotherapy alone in nonsquamous NSCLC in the ORIENT-11 study....
Updated Overall Survival Data and Predictive Biomarkers of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC in the Phase 3 ORIENT-11 Study.
INTRODUCTION
Sintilimab plus chemotherapy significantly prolonged progression-free survival (PFS) compared with chemotherapy alone in nonsquamous NSCLC in the ORIENT-11 study. Updated overall survival (OS) and PFS data and corresponding biomarker analyses are reported here.
METHODS
In this study, a total of 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC were assigned to sintilimab plus chemotherapy combination treatment (combo) group or placebo plus chemotherapy treatment group. The patients were stratified by programmed death-ligand 1 (PD-L1) expression levels. Immune signature profiles from tumor RNA sequencing and PD-L1 immunohistochemistry were correlated with clinical outcome to identify predictive biomarkers.
RESULTS
As of January 2021, with median follow-up of 22.9 months, median OS was significantly improved in the combo group compared with the placebo plus chemotherapy treatment group (not reached versus 16.8 mo; hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.45-0.79, p = 0.0003). High or medium immune cell infiltration was strongly associated with improved PFS in the combo group, in contrast to absent or low immune cell infiltration, which suggests that chemotherapy could not prime "immune deserts" to obtain benefit from programmed cell death protein-1 inhibition. In particular, high major histocompatibility complex (MHC) class II presentation pathway expression was significantly correlated with prolonged PFS (HR = 0.32, 95% CI: 0.19-0.54, p < 0.0001) and OS (HR = 0.36, 95% CI: 0.20-0.64, p = 0.0005) in the combo group. Importantly, patients with low or absent PD-L1 but high MHC class II expression could still benefit from the combo treatment. In contrast, MHC class I antigen presentation pathway was less relevant in this combination setting.
CONCLUSIONS
The addition of sintilimab to chemotherapy resulted to significantly longer OS in nonsquamous NSCLC. Expression of MHC class II antigen presentation pathway could identify patients benefiting most from this combination.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Humans; Lung Neoplasms; Pemetrexed; Platinum
PubMed: 34358724
DOI: 10.1016/j.jtho.2021.07.015 -
European Journal of Paediatric Dentistry Dec 2017The aim of this study was to gather all the clinical studies regarding apexification and artificial apical barrier techniques, point out the possible differences of the... (Review)
Review
AIM
The aim of this study was to gather all the clinical studies regarding apexification and artificial apical barrier techniques, point out the possible differences of the clinical procedures and investigate how these are changing over time.
MATERIALS AND METHODS
An electronic search was carried out in PubMed, covering the period from March 1968 to July 2015. More articles were retrieved by hand-searching or by the reference section of the included articles. Specific criteria were set in order to determine the relevance of each study.
RESULTS
One hundred and thirty eight articles were included, 53% of them concerned apexification with MTA plug. Long term apexification studies demonstrated 13% for a single change of the intracanal medicament and 85% for two or more. In 13% of the studies concerning artificial apical plug, the procedure included a single visit. Calcium hydroxide was left in the root canal for 3-12 months in 59% of the long term apexification studies, for 12-24 in 42% and for 24 months or more in 10%.
CONCLUSION
Both techniques can lead to favourable clinical outcomes. There is a tendency for the artificial apical barrier apexification over the years, which usually includes the use of intracanal medicament for a short time.
Topics: Aluminum Compounds; Apexification; Biocompatible Materials; Calcium Compounds; Calcium Hydroxide; Drug Combinations; Humans; Oxides; Pemetrexed; Root Canal Filling Materials; Silicates
PubMed: 29380612
DOI: 10.23804/ejpd.2017.18.04.03