Efficacy and Safety of Two Doses of Pemetrexed Supplemented with Folic Acid and Vitamin B12 in Previously Treated Patients with Non-Small Cell Lung Cancer.

Purpose: The objective of this study was to evaluate the efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in pretreated Japanese patients with advanced non-small cell lung cancer (NSCLC). Experimental Design: Patients with an Eastern Cooperative Oncology Group performance status 0 to 2, stage III or IV, and who received previously one or two chemotherapy regimens were randomized to receive 500 mg/m pemetrexed (P500) or 1,000 mg/m pemetrexed (P1000) on day1every 3 weeks.The primary endpoint was response rate. Results: Of the 216 patients evaluable for efficacy (108 in each arm), response rates were 18.5% (90% confidence interval, 12.6-25.8%) and 14.8% (90% confidence interval, 9.5-21.6%), median survival times were 16.0 and 12.6 months, 1-year survival rates were 59.2% and 53.7%, and median progression-free survival were 3.0 and 2.5 months for the P500 and P1000, respectively. Cox multiple regression analysis indicated that pemetrexed dose was not a significant prognostic factor. Drug-related toxicity was generally tolerable for both doses; however, the safety profile of P500 showedgenerally milder toxicity.Main adverse drug reactions of severity grade 3 or 4 were neutrophil count decreased (20.2%) and alanine aminotransferase (glutamine pyruvic transaminase) increased (15.8%) in P500 and neutrophil count decreased (24.3%),WBC count decreased (20.7%), and lymphocyte count decreased (18.0%) in P1000. One drug-related death from interstitial lung disease occurred in the P500. Conclusion: P500 and P1000 are similarly active with promising efficacy and acceptable safety outcomes in pretreated patients with NSCLC. These results support the use of P500 as a secondand third-line treatment of NSCLC. Pemetrexed (LY231514; Alimta), a multitargeted antifolate, has shown antitumor activity as a single agent or in combination with other anticancer agents (1, 2). Pemetrexed at doses of 500 or 600 mg/m has been evaluated in various clinical settings in a broad range of tumors including lung (non-small cell and mesothelioma), colorectal, gastric, pancreatic, head and neck, bladder, cervical, and breast cancers (3–13). In a randomized phase III trial that compared 3-week regimens of single-agent 500 mg/m pemetrexed versus 75 mg/m docetaxel in pretreated patients with non-small cell lung cancer (NSCLC), respective response rates (9.1% versus 8.8%) and median survival times (MST; 8.3 versus 7.9 months) did not differ between pemetrexed and docetaxel. However, fewer hematologic adverse effects, such as grade 3 or 4 neutropenia, febrile neutropenia, and neutropenic fever, were observed in patients treated with pemetrexed (3). Myelosuppression is the predominant dose-limiting toxicity of pemetrexed as reported in phase I studies (14–16). A multivariate analysis identified the correlation between poor folate status (as indicated by elevated plasma homocysteine levels) and increased toxicity to pemetrexed, which led to the requirement that patients in all pemetrexed studies receive folic acid and vitamin B12 supplementation (2, 17). This has been shown to decrease toxicity to pemetrexed without compromising efficacy (18). Without supplementation, the maximum tolerated dose of pemetrexed, given every 3 weeks, has been shown to be 600 mg/m in heavily pretreated patients (14); however, with supplementation, higher pemetrexed doses have been given without limiting side effects. In a Japanese phase I Cancer Therapy: Clinical Authors’Affiliations: Department of Internal Medicine, National Cancer Center Hospital,Tokyo, Japan; National Kyushu Cancer Center, Fukuoka, Japan; Kinki University School of Medicine, Osakasayama, Japan; National Cancer Center Hospital East, Kashiwa, Japan; Shizuoka Cancer Center Hospital, Shizuoka, Japan; Eli Lilly and Company, Oncology PlatformTeam, Indianapolis, Indiana; and Eli LillyJapan K.K., Lilly Research LaboratoriesJapan, Kobe, Japan Received12/11/07; revised 3/6/08; accepted 3/19/08. Grant support: Eli Lilly and Company (study code: H3E-JE-NS01). The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Note:The results of this study have been reported at American Society of Clinical Oncology,World Conference on Lung Cancer, and European Cancer Conference in 2007. Requests for reprints:Yuichiro Ohe, Department of Internal Medicine, National Cancer Center Hospital, 5-1-1Tsukiji, Chuo-ku,Tokyo 104-0045, Japan. Phone: 81-3-3542-2511; Fax: 81-3-3542-7006; E-mail: yohe@ncc.go.jp. F2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-5143 www.aacrjournals.org Clin Cancer Res 2008;14(13) July1, 2008 4206 Research. on May 22, 2017. © 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from study of pemetrexed that included folic acid and vitamin B12 supplementation, the maximum tolerated dose of pemetrexed was 1,200 mg/m and recommended dose was 1,000 mg/m given every 3 weeks (19). Pemetrexed pharmacokinetics in Japanese patients was not overtly different from those observed in Caucasian patients. In view of these data, we conducted a randomized, phase II study that confirmed the efficacy and safety of a standard dose of pemetrexed (500 mg/m; P500) with that of a higher dose (1,000 mg/m; P1000), including folic acid and vitamin B12 supplementation, in previously treated NSCLC patients. The primary endpoint was evaluation of response rate. Secondary endpoints were assessments of response duration, progression-free survival (PFS), 1-year survival rate, MST, quality of life (QoL), and adverse events. Materials andMethods Patient selection. Men and women, between 20 and 75 years old, with a life expectancy of at least 12 weeks and histologically and/or cytologically confirmed advanced NSCLC were eligible for the study. In addition, all patients met the following inclusion criteria: stage III or IV disease, at least one target lesion, one or two prior chemotherapeutic regimens, an Eastern Cooperative Oncology Group performance status (PS) of 0 to 2, adequate bone marrow function (neutrophils z2,000/mm, platelets z100,000/mm, and hemoglobin z9.0 g/dL), hepatic function [total bilirubin within 1.5 times the upper normal limit, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) within 2.5 times the upper normal limit, and serum albumin z2.5 g/dL], renal function (serum creatinine V1.2 mg/dL and creatinine clearance z45 mL/min), and pulmonary function (functional oxygen saturation z92%). Patients were excluded from the study for radiographic signs of interstitial pneumonitis or pulmonary fibrosis, serious or uncontrolled concomitant systemic disorders, active infections, the need for chronic administration of systemic corticosteroids, active double cancer and/or brain metastases, treatment with third-space fluid collections within 2 weeks of signing the informed consent or the need of such treatment, grade 3 or 4 toxicity, peripheral sensory neuropathy, previous pemetrexed therapy, unable or unwilling to take folic acid or vitamin B12 supplementation, or pregnant or breast-feeding. This study was conducted in compliance with the guidelines of good clinical practice and the principles of the Declaration of Helsinki, and it was approved by the local institutional review boards. All patients gave written informed consent before study entry. Study design and sample size. This open-label multicenter study had response rate as the primary objective, and 244 patients were enrolled and 226 were allocated to either 500 mg/m (P500) or 1,000 mg/m