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Journal of Thoracic Oncology : Official... Oct 2020Sintilimab, an anti-programmed death 1 antibody, plus pemetrexed and platinum had revealed promising efficacy for nonsquamous NSCLC in a phase 1b study. We conducted a... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11).
INTRODUCTION
Sintilimab, an anti-programmed death 1 antibody, plus pemetrexed and platinum had revealed promising efficacy for nonsquamous NSCLC in a phase 1b study. We conducted a randomized, double-blind, phase 3 study to compare the efficacy and safety of sintilimab with placebo, both in combination with such chemotherapy (ClinicalTrials.gov: NCT03607539).
METHODS
A total of 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC without sensitizing EGFR or anaplastic lymphoma kinase genomic aberration were randomized (2:1 ratio) to receive either sintilimab 200 mg or placebo plus pemetrexed and platinum once every 3 weeks for four cycles, followed by sintilimab or placebo plus pemetrexed therapy. Crossover or treatment beyond disease progression was allowed. The primary end point was progression-free survival (PFS) as judged by an independent radiographic review committee.
RESULTS
As of November 15, 2019, the median follow-up was 8.9 months. The median PFS was significantly longer in the sintilimab-combination group than that in the placebo-combination group (8.9 versus 5.0 mo; hazard ratio, 0.482, 95% confidence interval [CI]: 0.362-0.643; p < 0.00001). The confirmed objective response rate was 51.9% (95% CI: 45.7%-58.0%) in the sintilimab-combination group and 29.8% (95% CI: 22.1%-38.4%) in placebo-combination group. The incidence of grade 3 or higher adverse events was 61.7% in sintilimab-combination group and 58.8% in placebo-combination group.
CONCLUSIONS
In Chinese patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC, the addition of sintilimab to chemotherapy with pemetrexed and platinum resulted in considerably longer PFS than with chemotherapy alone with manageable safety profiles.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Humans; Lung Neoplasms; Pemetrexed; Platinum
PubMed: 32781263
DOI: 10.1016/j.jtho.2020.07.014 -
Recent Patents on Anti-cancer Drug... 2021Pemetrexed is a folate analogue metabolic inhibitor for mammalian cells. Pemetrexed is toxic to several cancer cells by interfering with their new biosynthesis of... (Review)
Review
BACKGROUND
Pemetrexed is a folate analogue metabolic inhibitor for mammalian cells. Pemetrexed is toxic to several cancer cells by interfering with their new biosynthesis of nucleotides, thus causing cell apoptosis. Presently, Pemetrexed is given to patients with Non-Small Cell Lung Cancer (NSCLC).
OBJECTIVE
This review focuses on the recent patents of Pemetrexed. This assessment includes patents grouped in segments like crystalline form patent, composition related patents, product patents, as well as a method of treatment. The aim of this review is to simplify inventors with existing patents in a single place.
METHODS
Data were searched from several available databases, including paid databases which include Orbit® and SciFinder®. Free databases include Worldwide Espacenet® (EPO), Patentscope® (WIPO), InPASS (Indian patent database) and Google Patents.
RESULTS
Some new polymorph and composition-related inventions of Pemetrexed have been recently patented as its orange-book listed patents will soon expire in May 2022. Further, because of the problem of oxidation through the development and continuing storage of Pemetrexed composition, several excipients are experimented with within these patents to stabilize the same. Nevertheless, there is a need for further development of an improved composition of Pemetrexed with improved characteristics.
CONCLUSION
Wide research has been conducted on different processes for preparing Pemetrexed and formulation thereof. Such type of active research may clear the track for the generic companies in the United States, producing the formulation at low prices and providing universal health care at economical prices.
Topics: Adenocarcinoma of Lung; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Folic Acid Antagonists; Humans; Lung Neoplasms; Patents as Topic; Pemetrexed
PubMed: 33494684
DOI: 10.2174/1574892816666210120113256 -
Journal of Thoracic Oncology : Official... May 2023In CameL phase 3 study (ClinicalTrials.gov: NCT03134872), addition of camrelizumab to first-line chemotherapy significantly improved the progression-free survival in... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
In CameL phase 3 study (ClinicalTrials.gov: NCT03134872), addition of camrelizumab to first-line chemotherapy significantly improved the progression-free survival in patients with stages IIIB to IV nonsquamous NSCLC. Here, we present outcomes after a minimum follow-up of 43.9 months since last patient randomization.
METHODS
Eligible patients were randomized 1:1 to 4 to 6 cycles of camrelizumab plus carboplatin and pemetrexed or chemotherapy alone every 3 weeks, followed by maintenance camrelizumab plus pemetrexed or pemetrexed only (n = 205 and 207, respectively). Total camrelizumab exposure was up to 2 years.
RESULTS
As of January 31, 2022, camrelizumab plus chemotherapy exhibited substantially improved overall survival over chemotherapy alone (median, 27.1 versus 19.8 mo; hazard ratio = 0.72 [95% confidence interval: 0.57-0.92]). In the chemotherapy-alone group, 95 patients (45.9%) crossed over to camrelizumab monotherapy. After adjustment for crossover, the survival benefit with camrelizumab plus chemotherapy was more pronounced (adjusted hazard ratio = 0.55 [95% confidence interval: 0.42-0.71]). In camrelizumab plus chemotherapy group, 33 patients completed 2 years of camrelizumab. Objective response rate was 97.0%, with ongoing responses in 17 of the 32 responses (53.1%), and 93.9% (31 of 33) of the patients were alive at data cutoff. Safety profiles were consistent with the previous report, and no obvious evidence of cumulative toxicity was found with long exposure to camrelizumab.
CONCLUSIONS
Camrelizumab plus carboplatin and pemetrexed provides long-term survival benefit over chemotherapy, with manageable toxicity and remarkable and durable response in patients receiving 2 years of camrelizumab, further supporting camrelizumab combination as first-line treatment for advanced nonsquamous NSCLC.
Topics: Humans; Animals; Pemetrexed; Carboplatin; Camelus; Lung Neoplasms; Follow-Up Studies; Carcinoma, Non-Small-Cell Lung; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36646210
DOI: 10.1016/j.jtho.2022.12.017 -
Journal of Thoracic Oncology : Official... Jan 2021In cohort G of KEYNOTE-021 (NCT02039674), first-line pembrolizumab plus pemetrexed-carboplatin significantly improved the objective response rate and progression-free... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
In cohort G of KEYNOTE-021 (NCT02039674), first-line pembrolizumab plus pemetrexed-carboplatin significantly improved the objective response rate and progression-free survival versus chemotherapy alone with manageable toxicity in advanced nonsquamous NSCLC. We report the long-term outcomes from this study.
METHODS
Patients with previously untreated advanced nonsquamous NSCLC without sensitizing EGFR or ALK alterations were randomly assigned 1:1 to receive open-label pemetrexed 500 mg/m plus carboplatin at area under the concentration-time curve of 5 mg/mL/min (four cycles) with or without pembrolizumab 200 mg (up to 2 years), with optional pemetrexed maintenance, each administered every 3 weeks. Eligible patients could crossover from the chemotherapy arm to pembrolizumab monotherapy after progression. Responses were assessed per the Response Evaluation Criteria in Solid Tumors version 1.1.
RESULTS
After the median time of 49.4 months from randomization to data cutoff, objective response rate (58% versus 33%) and progression-free survival (median: 24.5 versus 9.9 mo; hazard ratio: 0.54; 95% confidence interval: 0.35‒0.83) remained improved with pembrolizumab combination (n = 60) versus chemotherapy (n = 63), regardless of programmed death ligand 1 status. Median overall survival was 34.5 versus 21.1 months (hazard ratio: 0.71; 95% confidence interval: 0.45‒1.12), despite a 70% crossover rate from chemotherapy alone to anti‒programmed death (ligand) 1 therapy. Among the 12 patients who completed 2 years of pembrolizumab, 92% were alive at data cutoff; the estimated 3-year duration of response rate was 100%. Grade 3 to 5 treatment-related adverse events occurred in 39% of patients receiving pembrolizumab combination and 31% receiving chemotherapy.
CONCLUSIONS
First-line pembrolizumab plus pemetrexed-carboplatin continued to show improved response and survival versus chemotherapy alone in advanced nonsquamous NSCLC, with durable clinical benefit in patients who completed 2 years of therapy. No new safety signals were observed with longer follow-up.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Humans; Lung Neoplasms; Pemetrexed
PubMed: 33069888
DOI: 10.1016/j.jtho.2020.09.015 -
Journal of Translational Medicine Aug 2023Resistance to pemetrexed (PEM), a rare chemotherapeutic agent that can efficiently cross the blood-brain barrier, limits the therapeutic efficacy for patients with lung...
BACKGROUND
Resistance to pemetrexed (PEM), a rare chemotherapeutic agent that can efficiently cross the blood-brain barrier, limits the therapeutic efficacy for patients with lung cancer brain metastasis (BM). Aldo-keto reductase family 1 B10 (AKR1B10) was recently found to be elevated in lung cancer BM. The link between AKR1B10 and BM-acquired PEM is unknown.
METHODS
PEM drug-sensitivity was assessed in the preclinical BM model of PC9 lung adenocarcinoma cells and the BM cells with or without AKR1B10 interference in vitro and in vivo. Metabolic reprogramming of BM attributed to AKR1B10 was identified by chromatography-mass spectrometry (GC-MS) metabolomics, and the mechanism of how AKR1B10 mediates PEM chemoresistance via a way of modified metabolism was revealed by RNA sequencing as well as further molecular biology experimental approaches.
RESULTS
The lung cancer brain metastatic subpopulation cells (PC9-BrM3) exhibited significant resistance to PEM and silencing AKR1B10 in PC9-BrM3 increased the PEM sensitivity in vitro and in vivo. Metabolic profiling revealed that AKR1B10 prominently facilitated the Warburg metabolism characterized by the overproduction of lactate. Glycolysis regulated by AKR1B10 is vital for the resistance to PEM. In mechanism, AKR1B10 promoted glycolysis by regulating the expression of lactate dehydrogenase (LDHA) and the increased lactate, acts as a precursor that stimulates histone lactylation (H4K12la), activated the transcription of CCNB1 and accelerated the DNA replication and cell cycle.
CONCLUSIONS
Our finding demonstrates that AKR1B10/glycolysis/H4K12la/CCNB1 promotes acquired PEM chemoresistance in lung cancer BM, providing novel strategies to sensitize PEM response in the treatment of lung cancer patients suffering from BM.
Topics: Humans; Adenocarcinoma of Lung; Aldo-Keto Reductases; Brain Neoplasms; Lung Neoplasms; Pemetrexed; Drug Resistance, Neoplasm
PubMed: 37587486
DOI: 10.1186/s12967-023-04403-0 -
American Journal of Therapeutics
Topics: Humans; Pemetrexed; Exanthema; Lung Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 32039988
DOI: 10.1097/MJT.0000000000001146 -
Journal of Clinical Oncology : Official... Apr 2023
Topics: Humans; Cisplatin; Pemetrexed; Mesothelioma, Malignant; Mesothelioma; Pleural Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Lung Neoplasms
PubMed: 37068376
DOI: 10.1200/JCO.22.02720 -
Journal of Clinical Oncology : Official... May 2023
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Pemetrexed; Cisplatin; Lung Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome
PubMed: 37146425
DOI: 10.1200/JCO.22.02804 -
Journal of Clinical Oncology : Official... Oct 2023The Atezo-Brain study evaluated atezolizumab combined with chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) with untreated brain metastases, a...
Phase II Trial of Atezolizumab Combined With Carboplatin and Pemetrexed for Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer With Untreated Brain Metastases (Atezo-Brain, GECP17/05).
PURPOSE
The Atezo-Brain study evaluated atezolizumab combined with chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) with untreated brain metastases, a population traditionally excluded from trials.
METHODS
This single-arm phase II clinical trial enrolled patients with advanced nonsquamous NSCLC with untreated brain metastases without neurologic symptoms or asymptomatic with medical treatment. Dexamethasone was allowed up to 4 mg once daily. Atezolizumab plus carboplatin and pemetrexed was given for four to six cycles followed by atezolizumab plus pemetrexed until progression for a maximum of 2 years. The primary end points were to determine the progression-free survival (PFS) rate at 12 weeks and the incidence of grade ≥3 adverse events during the first 9 weeks. Intracranial outcomes were assessed using response assessment in neuro-oncology brain metastases criteria.
RESULTS
Forty patients were enrolled and 22 (55%) were receiving corticosteroids at baseline. The overall 12-week PFS rate was 62.2% (95% credibility interval [CrI], 47.1 to 76.2). The rate of grade 3/4 adverse events during the first 9 weeks was 27.5%. Most neurologic events were grade 1 and 2 but five patients (12.5%) experienced grade 3-4 neurologic events. With a median follow-up of 31 months, intracranial median PFS was 6.9 months and response rate was 42.7% (95% CrI, 28.1 to 57.9). Systemic median PFS was 8.9 months and response rate was 45% (95% CrI, 28.1 to 57.9). The median overall survival (OS) was 11.8 months (95% CI, 7.6 to 16.9) and the 2-year OS rate was 27.5% (95% CI, 16.6 to 45.5).
CONCLUSION
Atezolizumab plus carboplatin and pemetrexed demonstrates activity in patients with advanced nonsquamous NSCLC with untreated brain metastases with an acceptable safety profile.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Carboplatin; Pemetrexed; Lung Neoplasms; Brain Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Brain
PubMed: 37603816
DOI: 10.1200/JCO.22.02561 -
The New England Journal of Medicine Nov 2023Amivantamab has been approved for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor () exon 20 insertions... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Amivantamab has been approved for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor () exon 20 insertions who have had disease progression during or after platinum-based chemotherapy. Phase 1 data showed the safety and antitumor activity of amivantamab plus carboplatin-pemetrexed (chemotherapy). Additional data on this combination therapy are needed.
METHODS
In this phase 3, international, randomized trial, we assigned in a 1:1 ratio patients with advanced NSCLC with exon 20 insertions who had not received previous systemic therapy to receive intravenous amivantamab plus chemotherapy (amivantamab-chemotherapy) or chemotherapy alone. The primary outcome was progression-free survival according to blinded independent central review. Patients in the chemotherapy group who had disease progression were allowed to cross over to receive amivantamab monotherapy.
RESULTS
A total of 308 patients underwent randomization (153 to receive amivantamab-chemotherapy and 155 to receive chemotherapy alone). Progression-free survival was significantly longer in the amivantamab-chemotherapy group than in the chemotherapy group (median, 11.4 months and 6.7 months, respectively; hazard ratio for disease progression or death, 0.40; 95% confidence interval [CI], 0.30 to 0.53; P<0.001). At 18 months, progression-free survival was reported in 31% of the patients in the amivantamab-chemotherapy group and in 3% in the chemotherapy group; a complete or partial response at data cutoff was reported in 73% and 47%, respectively (rate ratio, 1.50; 95% CI, 1.32 to 1.68; P<0.001). In the interim overall survival analysis (33% maturity), the hazard ratio for death for amivantamab-chemotherapy as compared with chemotherapy was 0.67 (95% CI, 0.42 to 1.09; P = 0.11). The predominant adverse events associated with amivantamab-chemotherapy were reversible hematologic and EGFR-related toxic effects; 7% of patients discontinued amivantamab owing to adverse reactions.
CONCLUSIONS
The use of amivantamab-chemotherapy resulted in superior efficacy as compared with chemotherapy alone as first-line treatment of patients with advanced NSCLC with exon 20 insertions. (Funded by Janssen Research and Development; PAPILLON ClinicalTrials.gov number, NCT04538664.).
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Disease Progression; ErbB Receptors; Exons; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Carboplatin; Pemetrexed; Antineoplastic Agents, Immunological
PubMed: 37870976
DOI: 10.1056/NEJMoa2306441