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Phase II Study of Pemetrexed-Gemcitabine Combination in Patients with Advanced-Stage Non-Small Cell Lung Cancer

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Phase II Study of Pemetrexed-Gemcitabine Combination in Patients with Advanced-Stage Non-Small Cell Lung Cancer Vol. 10, 5439–5446, August 15, 2004 Clinical Cancer Research 5439 Phase II Study of Pemetrexed-Gemcitabine Combination in Patients with Advanced-Stage Non-Small Cell Lung Cancer Christian Monnerat,1 Thierry Le Chevalier,1 deaths attributed to treatment. Common Toxicity Criteria Karen Kelly,2 Coleman K. Obasaju,3 grade 3/4 toxicities were neutropenia (61.7%), febrile neu- Julie Brahmer,4 Silvia Novello,1 tropenia (16.7%), fatigue (23.3%), and elevations of aspar- 3 3 tate aminotransferase (15.0%) and alanine aminotrans- Takashi Nakamura, Astra M. Liepa, ferase (20.0%). 5 2 Laurence Bozec, Paul A. Bunn, Jr, and Conclusions: This combination had good tolerance and David S. Ettinger4 achieved promising overall survival with extended 1- and 1Institut Gustave Roussy, Villejuif, France; 2The University of 2-year survival rates. This cisplatin-free regimen warrants Colorado Cancer Center, Denver, Colorado; 3Eli Lilly and Company, further evaluation in randomized trials. Indianapolis, Indiana; 4The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland; and 5Eli Lilly and Company, St. Cloud, France INTRODUCTION Pemetrexed (LY231514, Alimta; Eli Lilly and Company, ABSTRACT Indianapolis, IN) is a novel antifolate that is metabolized intra- Purpose: Cisplatin is one of the most active agents for cellularly to a pentaglutamate form. Pemetrexed inhibits three the treatment of non-small cell lung cancer (NSCLC). It is enzymes (thymidylate synthase, dihydrofolate reductase, and also known for significant toxicity, which makes it unsuit- glycinamide ribonucleotide transferase) involved in folate me- able for certain patients. Our purpose was to evaluate the tabolism and DNA synthesis (1–3). The cytotoxicity of pem- efficacy and toxicity of a promising cisplatin-free combina- etrexed is caused by inhibition of both the pyrimidine and purine tion, gemcitabine plus pemetrexed, in NSCLC. pathways. The maximum tolerated dose established in Phase I 2 Experimental Design: Chemo-naive patients with inop- studies of pemetrexed was 600 mg/m every 3 weeks (4, 5). This 2 erable NSCLC were eligible for this study. Gemcitabine dose was later reduced to 500 mg/m every 3 weeks in several (1250 mg/m2) was given intravenously on days 1 and 8, Phase II trials, particularly when used in combination with other followed by intravenous pemetrexed (500 mg/m2) on day 8. cytotoxic agents (6, 7). Folic acid and vitamin B12 supplemen- tation became a requirement for pemetrexed-based therapy early After inclusion of 13 patients, folic acid and vitamin B12 supplementation was added to lower pemetrexed-induced in this study, when analysis of safety data from multiple pem- toxicity. Quality of life was assessed with the Lung Cancer etrexed trials suggested that supplementation may decrease tox- Symptom Scale. icity (8). Single-agent pemetrexed was tested in two Phase II Results: Sixty patients enrolled; 58 were evaluable for non-small cell lung cancer (NSCLC) trials enrolling 92 chemo- response. All patients had a World Health Organization naive patients (without vitamin supplementation) by Clarke performance status of 0 or 1. Eighty-seven percent had stage et al. (9) and Rusthoven et al. (7). Response rates of 15.8% and IV disease. Nine patients had a confirmed partial response 23.3% and median survivals of 7.2 and 9.2 months were ob- [overall response rate, 15.5%; 95% confidence interval (CI), served, respectively. In these two studies, the main toxicities 7.3–27.4%]. Twenty-nine (50.0%) patients had stable dis- reported were grade 3/4 neutropenia (42% and 39%) and grade ease. Median overall survival was 10.1 months (95% CI, 3/4 skin rash (31% and 39%). 7.9–13.0 months), with a 1- and 2-year overall survival of Gemcitabine (Gemzar; Eli Lilly and Company) is a 42.6% (95% CI, 30.0–55.3%) and 18.5% (95% CI, 7.9– pyrimidine antimetabolite that is intracellularly transformed to 29.1%). Median progression-free survival was 5.0 months. difluorodeoxycytidine triphosphate. Its incorporation into DNA Median response duration was 3.3 months. There were no results in chain termination. Gemcitabine also inhibits ribonu- cleotide reductase, an enzyme required for deoxynucleoside formation and DNA synthesis (10) Gemcitabine has been widely explored in NSCLC, as a single-agent and in combina- tion. The United States Food and Drug Administration-approved Received 2/4/04; revised 4/6/04; accepted 4/13/04. dose is 1000 mg/m2 weekly for 3 weeks every 4 weeks (11, 12) Grant support: Supported by Eli Lilly and Company (Indianapolis, or 1250 mg/m2 weekly for 2 weeks every 3 weeks (13). In a IN). T. Le Chevalier, P. Bunn, and D. Ettinger have acted as consultants Phase II study of gemcitabine (1250 mg/m2) weekly for 3 of 4 of Eli Lilly and Company. The costs of publication of this article were defrayed in part by the weeks enrolling 161 patients with advanced NSCLC, the re- payment of page charges. This article must therefore be hereby marked sponse rate was 21.8%, and median survival was 11.5 months advertisement in accordance with 18 U.S.C. Section 1734 solely to (13). Main toxicities were grade 3 neutropenia, nausea, and indicate this fact. elevations of hepatic transaminases. Requests for reprints: Thierry Le Chevalier, Department of Medicine, Institut Gustave Roussy, 39 rue Camille-Desmoulins, 94805 Villejuif Because pemetrexed and gemcitabine have both shown Cedex, France. Phone: 33-142-114322; Fax: 33-142-115219; E-mail: tle- single-agent activity against a wide range of solid tumors in- [email protected]. cluding NSCLC (7, 9, 11, 12, 14, 15), the combination of these Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2004 American Association for Cancer Research. 5440 An Outpatient Cisplatin-Free Regimen for Advanced NSCLC two agents was evaluated in vitro, and cytotoxic synergy was to 100 ml of normal saline for intravenous infusion. Gemcitab- found when gemcitabine exposure preceded that of pemetrexed ine was supplied as a lyophilized powder in 200- or 1000-mg (16). Whereas preclinical studies suggested pemetrexed on day vials. The appropriate dose was prepared with normal saline to 1 with a 90-min interval between administrations, a Phase I make a solution containing approximately 10 mg/ml for intra- study led to administration of pemetrexed on day 8 due to better venous infusion. Chemotherapy was given on a 3-week schedule hematological tolerance (16). The recommended dose was gem- and consisted of 1250 mg/m2 gemcitabine over 30 min on days citabine (1250 mg/m2) on days 1 and 8, followed by pemetrexed 1 and 8 and 500 mg/m2 pemetrexed over 10 min on day 8, (500 mg/m2) on day 8 of a 3-week cycle. The most common approximately 90 min after the gemcitabine infusion. Dose dose-limiting toxicity was neutropenia. Other toxicities included adjustments within a cycle were as follows: in case of Common nausea, fatigue, rash, and elevated hepatic transaminases (16). Toxicity Criteria Version 2.0 (18) grade 3/4 neutropenia, throm- The objective of the present Phase II study was to deter- bocytopenia, or nonhematological toxicity (except grade 3 trans- mine the antitumor activity of the pemetrexed-gemcitabine com- aminase elevation) after day 1, the day 8 doses were held until bination, a cisplatin-free outpatient regimen, in chemo-naive resolution of the toxicity, and pemetrexed and gemcitabine were patients with locally advanced or metastatic NSCLC. Secondary given at full dose in case of a grade 3 toxicity and at 50% end points were to assess toxicity of treatment, evaluate overall reduced dose in case of a grade 4 toxicity. No dose escalation and progression-free survival, and assess the impact on symp- was allowed after a dose reduction for the remainder of the toms and quality of life. study. The next cycle was not initiated until 14 days had elapsed from the administration of a delayed day 8 dose and until all toxicities resolved. Treatment could be delayed up to 35 days PATIENTS AND METHODS from the day 1 dose to allow a patient sufficient time to recover Patient Selection. Eligible patients had histological or from all toxicities. If a further cycle could not be given by day cytologic diagnosis of stage IIIB or IV NSCLC, with evidence 35, the patient was discontinued from study. For subsequent of bidimensionally measurable disease. Any clinically signifi- cycles, pemetrexed and gemcitabine doses were adjusted ac- cant effusion had to be drained and pleurodesis had to be cording to neutrophil and platelet nadir counts or maximum performed at least 2 weeks before baseline imaging. Previous nonhematological toxicity from the preceding cycle. Treatment systemic chemotherapy, as well as prior radiation therapy to was interrupted for a persistent drop of creatinine clearance target lesions, was not permitted. Other eligibility criteria in- under 45 ml/min or the appearance of a clinically significant cluded the following: age Ն 18 years; World Health Organiza- effusion. Beginning on December 10, 1999, folic acid (350– ␮ ␮ tion performance status of 0 or 1; calculated creatinine clear- 1000 g/day orally) and vitamin B12 (1000 g) i.m. every 9 ance Ն 45 ml/min (based on modified Cockcroft and Gault weeks became mandatory, starting 1 to 2 weeks before initiation method; Ref. 17); adequate hepatic function (i.e., serum biliru- of chemotherapy. Dexamethasone (4 mg or equivalent) was bin of Յ1.5 times the upper normal limit; alkaline phosphatase, given orally twice daily the day before, the day of, and the day aspartate aminotransferase, and alanine aminotransferase of after pemetrexed infusion to prevent rash. Antiemetic treatment Յ Յ 3.0 times the upper normal limit or 5.0 times the upper with a 5HT3 antagonist and dexamethasone was recommended normal limit in case of liver metastases); adequate bone marrow before each chemotherapy infusion.
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