-
Journal of Clinical Oncology : Official... Apr 2023JCO We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680). Eligible patients with previously untreated metastatic... (Randomized Controlled Trial)
Randomized Controlled Trial
JCO We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680). Eligible patients with previously untreated metastatic nonsquamous non-small-cell lung cancer without alterations were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and investigator's choice of carboplatin/cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or unacceptable toxicity. Primary end points were overall survival (OS) and progression-free survival (PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time from random assignment to data cutoff (March 8, 2022) was 64.6 (range, 60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%. Toxicity was manageable. Among 57 patients who completed 35 cycles of pembrolizumab, objective response rate was 86.0% and 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%. Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1 expression. These data continue to support pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non-small-cell lung cancer without alterations.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Pemetrexed; Lung Neoplasms; Platinum; ErbB Receptors; Receptor Protein-Tyrosine Kinases; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36809080
DOI: 10.1200/JCO.22.01989 -
Nature Reviews. Drug Discovery May 2005In February 2004, pemetrexed disodium (Alimta; Eli Lilly), an anticancer drug that targets folate-dependent reactions that are essential for cell proliferation, became... (Review)
Review
In February 2004, pemetrexed disodium (Alimta; Eli Lilly), an anticancer drug that targets folate-dependent reactions that are essential for cell proliferation, became the first drug to be approved by the US FDA for the treatment of the rare cancer malignant pleural mesothelioma. Its accelerated approval for the second-line treatment of non-small-cell lung cancer followed in August 2004.
Topics: Antineoplastic Agents; Carbon-Nitrogen Ligases; Clinical Trials as Topic; Folic Acid Antagonists; Glutamates; Guanine; Humans; Lung Neoplasms; Mesothelioma; Pemetrexed; Tetrahydrofolate Dehydrogenase; Treatment Outcome
PubMed: 15962527
DOI: 10.1038/nrd1731 -
Journal of Clinical Oncology : Official... May 2020In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680).
METHODS
Patients were randomly assigned (2:1) to receive pemetrexed and platinum plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, then pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients with disease progression in the placebo-combination group could cross over to pembrolizumab monotherapy. Response was assessed per RECIST (version 1.1) by central review. No alpha was assigned to this updated analysis.
RESULTS
As of September 21, 2018 (median follow-up, 23.1 months), the updated median (95% CI) OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio [HR], 0.56; 95% CI, 0.45 to 0.70]). Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, respectively (HR, 0.48; 95% CI, 0.40 to 0.58). Median (95% CI) time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurred first (progression-free-survival-2; PFS-2) was 17.0 (15.1 to 19.4) months and 9.0 (7.6 to 10.4) months, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). OS and PFS benefits with pembrolizumab were observed regardless of PD-L1 expression or presence of liver/brain metastases. Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups.
CONCLUSION
First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pemetrexed; Platinum
PubMed: 32150489
DOI: 10.1200/JCO.19.03136 -
The New England Journal of Medicine Feb 2017Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown.
METHODS
In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during receipt of first-line EGFR-TKI therapy. The primary end point was investigator-assessed progression-free survival.
RESULTS
The median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the central nervous system (CNS), the median duration of progression-free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%).
CONCLUSIONS
Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced non-small-cell lung cancer (including those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy. (Funded by AstraZeneca; AURA3 ClinicalTrials.gov number, NCT02151981 .).
Topics: Acrylamides; Adult; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Pemetrexed; Piperazines; Platinum; Young Adult
PubMed: 27959700
DOI: 10.1056/NEJMoa1612674 -
Annals of Oncology : Official Journal... Jul 2021In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed-platinum) significantly improved overall... (Randomized Controlled Trial)
Randomized Controlled Trial
Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189.
BACKGROUND
In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed-platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed-platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed-platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab.
PATIENTS AND METHODS
Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m) and investigators' choice of cisplatin (75 mg/m) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed-platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS.
RESULTS
After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed-platinum continued to improve OS [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69] and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed-platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed-platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed-platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed-platinum and 66.8% of patients receiving placebo plus pemetrexed-platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off.
CONCLUSIONS
Pembrolizumab plus pemetrexed-platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed-platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous NSCLC.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Pemetrexed; Platinum; Randomized Controlled Trials as Topic
PubMed: 33894335
DOI: 10.1016/j.annonc.2021.04.008 -
Nature Reviews. Drug Discovery Oct 2004
Topics: Antineoplastic Agents; Glutamates; Guanine; Humans; Marketing; Pemetrexed; Pleural Neoplasms
PubMed: 15497247
DOI: 10.1038/nrd1528 -
Expert Opinion on Investigational Drugs Apr 2012Current therapies for recurrent ovarian cancer (OC) yield relatively modest improvements in survival. Many drugs are available but recently a renewed interest is... (Review)
Review
INTRODUCTION
Current therapies for recurrent ovarian cancer (OC) yield relatively modest improvements in survival. Many drugs are available but recently a renewed interest is addressed on antimetabolite drugs. Pemetrexed (PEM) is a multitargeted antifolate cytotoxic agent mainly used in lung cancer.
AREAS COVERED
This review summarizes the available evidence on the use of PEM in the treatment of OC. This article consists of material obtained via Medline, PubMed and EMBASE literature searches, up to November 2011. Currently available published data on mechanism of action, pharmacokinetics, safety and efficacy of PEM in the treatment of recurrent OC are described.
EXPERT OPINION
Eight trials evaluated the use of PEM in OC patients. Studies using PEM in combination with carboplatin in platinum-sensitive OC suggested that the response rate is similar to other combination therapies. However, based on the absence of randomized trials comparing this doublet with currently used combination treatments, it is difficult to draw conclusions on the efficacy of PEM regimens in these patients. In platinum-resistant OC patients, two studies suggested that PEM alone might have equivalent activity to other single-agent treatment. Further pharmacogenomic and clinical data are warranted to better define the role of PEM in the treatment of recurrent OC.
Topics: Antimetabolites, Antineoplastic; Clinical Trials as Topic; Female; Glutamates; Guanine; Humans; Ovarian Neoplasms; Pemetrexed; Randomized Controlled Trials as Topic
PubMed: 22324304
DOI: 10.1517/13543784.2012.661714 -
Drugs of Today (Barcelona, Spain : 1998) Sep 2008Pemetrexed disodium is a multitargeted antifolate cytotoxic chemotherapy agent approved by the U.S. Food and Drug Administration (FDA) initially for the treatment of... (Review)
Review
Pemetrexed disodium is a multitargeted antifolate cytotoxic chemotherapy agent approved by the U.S. Food and Drug Administration (FDA) initially for the treatment of malignant pleural mesothelioma, and in August 2004 for second-line treatment of non-small cell lung cancer (NSCLC). In September 2008, the FDA also approved pemetrexed and cisplatin as first-line therapy for NSCLC. Pemetrexed is also no longer recommended for treatment of NSCLC with squamous cell carcinoma histology. Pemetrexed is currently being tested in clinical trials as part of second-line combination, first-line, adjuvant and maintenance therapies.
Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Combined Modality Therapy; Glutamates; Guanine; Humans; Lung Neoplasms; Pemetrexed; Practice Guidelines as Topic
PubMed: 19137122
DOI: 10.1358/dot.2008.44.9.1250412 -
The Lancet. Oncology May 2001Pemetrexed disodium is a potent new antifolate which inhibits many folate-dependent reactions that are essential for cell proliferation. Its primary target is... (Review)
Review
Pemetrexed disodium is a potent new antifolate which inhibits many folate-dependent reactions that are essential for cell proliferation. Its primary target is thymidylate synthase but it also inhibits folate-dependent enzymes involved in purine synthesis. Cells that are resistant to antifolates are generally less resistant to pemetrexed, irrespective of the mechanism of resistance. Pemetrexed has shown good activity in preclinical models with human tumour cells and xenografts. In the majority of clinical trials of pemetrexed, the dose-limiting toxic effect is neutropenia; other side-effects are mostly gastrointestinal. Preclinical studies indicate that the toxic effects of pemetrexed can be reduced by dietary folate, resulting in an improved therapeutic index. Low folate status is also associated with higher levels of toxicity in patients. As a single agent pemetrexed has shown good activity against non-small-cell lung cancer, squamous-cell carcinoma of head and neck, colon cancer, and breast cancer, and it appears to be particularly active in combination with cisplatin against non-small-cell lung cancer and mesothelioma. Phase II and III studies are underway.
Topics: Antineoplastic Agents; Cell Cycle; Clinical Trials as Topic; Drug Resistance, Neoplasm; Folic Acid Antagonists; Glutamates; Guanine; Humans; Neoplasms; Pemetrexed
PubMed: 11905785
DOI: 10.1016/s1470-2045(00)00325-9 -
The Oncologist 2001Pemetrexed disodium (ALIMTA), "pemetrexed") is a novel, multi-targeted antifolate that has demonstrated promising clinical activity in a wide variety of solid tumors,... (Review)
Review
Pemetrexed disodium (ALIMTA), "pemetrexed") is a novel, multi-targeted antifolate that has demonstrated promising clinical activity in a wide variety of solid tumors, including non-small cell lung, breast, mesothelioma, colorectal, pancreatic, gastric, bladder, cervix, and head and neck. Pemetrexed inhibits multiple folate-dependent enzymes involved in both purine and pyrimidine synthesis including thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide ribonucleotide formyltransferase. As a single agent, pemetrexed exhibits a moderate toxicity profile at a dose of 500 mg/m(2) by 10-minute infusion once every 21 days with myelosuppression being the dose-limiting toxicity. Folic acid added to the diet in preclinical studies reduced toxicities while maintaining antitumor activity. Based on this observation and clinical toxicities, folic acid and vitamin B(12) dietary supplementation has been recently introduced into all ongoing trials. Studies combining pemetrexed with other active chemotherapeutic agents demonstrate that these combination therapies may become important treatment regimens in a variety of cancer types. Currently, pemetrexed phase III trials are ongoing in mesothelioma and non-small cell lung cancer with future trials planned to explore this unique multitargeted antifolate.
Topics: Clinical Trials as Topic; Folic Acid Antagonists; Glutamates; Guanine; Humans; Neoplasms; Pemetrexed; Thymidylate Synthase
PubMed: 11524555
DOI: 10.1634/theoncologist.6-4-363