Multitargeted antifolate LY231514 as first-line chemotherapy for patients with advanced non-small-cell lung cancer: A phase II study. National Cancer Institute of Canada Clinical Trials Group.
ABSTRACT To evaluate the efficacy and safety of the multitargeted antifolate LY231514 (MTA) in patients receiving initial chemotherapy for unresectable, advanced non-small-cell lung cancer (NSCLC).
Patients with measurable, advanced NSCLC who had not received previous chemotherapy for advanced disease were considered for this study. Eligible patients who gave written informed consent initially received MTA 600 mg/m(2) intravenously (IV) for 10 minutes every 3 weeks. After three patients received treatment at this dose, the dose was reduced to 500 mg/m(2) IV at the same infusion time and frequency because of toxicity seen in this study and another Canadian MTA trial in colorectal cancer. Patients received up to four cycles after complete or partial remission or six cycles after stable disease was documented.
Thirty-three patients were accrued onto the study. All were assessable for toxicity, and 30 patients were assessable for response. All but one patient had an Eastern Cooperative Oncology Group performance status score of 0 or 1, 18 patients (55%) had adenocarcinoma, and nine patients (27%) had squamous cell carcinoma. Twenty-five patients (76%) had stage IV disease, and the remainder had stage IIIB disease at trial entry. Seven patients experienced a confirmed partial response and no complete responses were seen; thus, the overall response rate was 23.3% (95% confidence interval, 9.9% to 42.3%). The median duration of response was 3.1 months (range, 2. 3 to 13.5 months) after a median follow-up period of 7.9 months. Four (67%) of six patients with stage IIIB disease and three (12.5%) of 24 with stage IV disease responded to treatment. Four patients (13.3%) experienced febrile neutropenia and 13 (39%) experienced grade 3 or 4 neutropenia, whereas only one patient (3%) developed grade 4 thrombocytopenia. Nonhematologic toxicity was generally mild or moderate, but 39% of patients developed a grade 3 skin rash. Most other toxicities comprised grade 1 or 2 stomatitis, diarrhea, lethargy, and anorexia. Ten patients stopped protocol therapy because of toxicity.
MTA seems to have clinically meaningful activity as a single agent against advanced NSCLC. Toxicity is generally mild and tolerable. Further study of this agent in combination with cisplatin and other active drugs is warranted in this disease.
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ABSTRACT: Pemetrexed is a multitargeted antifolate that inhibits at least three folate dependent enzymes involved in DNA synthesis. Gemcitabine is a broadly active pyrimidine nucleoside antimetabolite that is incorporated into DNA and causes chain termination. Both pemetrexed and gemcitabine, as single agents, have shown antitumor activity in a wide range of solid tumors, including non-small-cell lung cancer (NSCLC). Based on preclinical in vitro and in vivo synergism of the combination of pemetrexed and gemcitabine, the 2 drugs were studied in several phase I and II trials in patients with advanced NSCLC. The published studies found response rates between 13 to 31%, with overall survival times similar to established standard chemotherapy regimens. The grade 3 or 4 toxicities with this combination are mainly haematologic, dermatologic and transaminitis. In this paper, we review the pemetrexed-gemcitabine combination in the treatment of NSCLC patients with regards to the rationale, clinical activity as well as the future directions for this new 2-drug combination.Current drug targets 09/2009; 11(1):61-6. · 3.93 Impact Factor
Article: The role of pemetrexed in second-line chemotherapy for advanced non-small cell lung cancer.[show abstract] [hide abstract]
ABSTRACT: Despite improvements in first-line therapy for advanced NSCLC all patients with metastatic disease will progress at some point. Patients with favorable prognostic factors such as good performance status, non-squamous histology, stable weight, and perhaps female gender are more likely to receive second-line chemotherapy. Currently the United States FDA recognizes three single agents (docetaxel, erlotinib, and pemetrexed) as established for providing a benefit in patients who have experienced progression after first-line therapy. This review focus on the role of PEM in the treatment of advanced NSCLC in patients who have experienced disease progression during or after first-line therapy. The multi-targeted antifolate pemetrexed is equivalent to docetaxel for second-line therapy and with less toxicity.Current drug targets 09/2009; 11(1):58-60. · 3.93 Impact Factor
Article: The role of pemetrexed in advanced non small-cell lung cancer: special focus on pharmacology and mechanism of action.[show abstract] [hide abstract]
ABSTRACT: Pemetrexed is a newer antifolate drug that has been approved as first-line treatment for patients with advanced non-squamous, non-small cell lung cancer (NSCLC) in combination with cisplatin, and as single agent for relapsed or chemotherapy refractory NSCLC after platinum-containing chemotherapy, at a dose of 500 mg/m(2). Pemetrexed undergoes intracellular activation by poly-gamma-glutamylation, that is essential for its antiproliferative activity. Polyglutamate derivatives mainly inhibit three key enzymes of intracellular folate metabolism, i.e. thymidylates synthase (TYMS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), with TYMS being the most relevant target. Pemetrexed undergoes rapid renal elimination as unchanged parent compound, with a terminal half-life of between two to five hours. In later clinical development, the usefulness of supplementation with folic acid and vitamin B(12) became evident, to control pemetrexed-related toxicity. The results from the phase III upfront registration study, a retrospective observational data, and a recent maintenance study of pemetrexed in NSCLC suggest histological subtype to be the most important predictive marker for clinical outcome in patients receiving pemetrexed, Pemetrexed is active in patients with non-squamous cell NSCLC while no benefit is seen in patients with squamous-cell histology, possibly as a result of different expression of intratumoral TYMS. These are important steps towards individualisation of anticancer treatment in patients with advanced NSCLC.Current drug targets 09/2009; 11(1):37-47. · 3.93 Impact Factor