Current Drug Targets, 2010, 11, 61-66 61 1389-4501/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd. The Role of Pemetrexed Combined with Gemcitabine for Non-Small-Cell Lung Cancer Joanne Ngeow 1 and Chee-Keong Toh *,1 1 Department of Medical Oncology, National Cancer Centre, Singapore 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. Keywords: Gemcitabine, NSCLC, pemetrexed. INTRODUCTION Despite some advances in the treatment of advanced non- small-cell lung cancer (NSCLC), the introduction of third- generation cytotoxic agents (vinorelbine, gemcitabine, doce- taxel, irinotecan, and paclitaxel) has not achieved a break- through in improving the dismal prognosis of this disease. Patients with advanced NSCLC treated with standard chemotherapy regimes containing cisplatin or carboplatin have a median survival of about 8 months [1, 2]. Recently, several non platinum-based chemotherapy regimens have been studied in an attempt to improve the outcome as well as select for a less toxic alternative [3]. Pemetrexed, a pyrrolo [2, 3-d] pyrimidine antifolate, has shown promising activity in 2 phase III trials for NSCLC and has been rationally combined with gemcitabine to synergistically increase the activity of both agents in the treatment of NSCLC. Here, we present the data on the rationale, clinical activity as well as possible future studies on the combination of pemetrexed and gemcitabine in NSCLC. PEMETREXED, A MULTITARGETED ANTIFO- LATE, WITH A WIDE RANGE ANTITUMOR ACTIVITY Pemetrexed (Alimta®, Eli Lilly and Company, Indiana- polis,USA) is a multitargeted antifolate that can be easily administered as a 10-minute infusion every 3 weeks. The primary enzyme target is thymidylate synthase (TS), inhi- bition of which results in decreased thymidine necessary for DNA synthesis. The other enzyme targets are dihydrofolate *Address correspondence to this author at the Department of Medical Oncology, National Cancer Centre, Singapore, 11 Hospital Drive, 169610, Singapore; Tel: +65-6436 8000; Fax: +65-6227 2759; E-mail: dmotck@nccs.com.sg reductase (DHFR) and glycinamide ribonucleotide formyl- transferase (GARFT). Pemetrexed is transported into cells via the reduced folate carrier where it is rapidly metabolized intracellularly in a reaction catalyzed by folypolyglutamate synthetase (FPGS) to a pentaglutamate form, which is 60 fold more potent in its inhibition of TS. Polyglutamation also enhances the retention of pemetrexed. Pemetrexed inhibits enzymes involved in folate metabolism and thus, affects both the pyrimidine and purine pathways in DNA synthesis [4]. Pemetrexed showed promising cytotoxic activity in pre- clinical cell lines and tumor xenografts [5, 6]. Phase I studies found the most tolerable dose schedule to be once every 3 weeks [7, 8] and the recommended dose was 600 mg/m 2 every 3 weeks. Several phase II trials subsequently used doses of 500mg/m2 to 600mg/m2 every 3 weeks and have shown activity in many tumor types, including NSCLC [9- 13]. Supplementation with folic acid and vitamin B12 has been able to reduce pemetrexed induced toxicities [14]. The clinical activity of pemetrexed in NSCLC has been demonstrated in both the first and second line setting. Clarke et al. reported, in a phase II trial of chemonaive advanced NSCLC pts, a 16% response rate and median survival of 7.2 months [10]. In another phase II first-line study by Rusthoven et al., the authors reported a 23.3% response rate and a median survival of 9.2 months [9]. It was recently reported in a phase III trial by Scagliotti et al. [15], that first- line chemotherapy with pemetrexed-cisplatin was nonin- ferior to gemcitabine-cisplatin, with median survival of 10.3 months v 10.3 months (HR=0.94, 95% CI, 0.84-1.05). The pemetrexed regimen was better tolerated and had more convenient administration. In the second line setting, Hanna et al. demonstrated in a phase III trial, that single-agent pemetrexed with vitamin supplementation had less toxicity than docetaxel, with both arms having similar efficacy [16].