PMID- 19841321 OWN - NLM STAT- MEDLINE DCOM- 20100218 LR - 20231018 IS - 1527-7755 (Electronic) IS - 0732-183X (Print) IS - 0732-183X (Linking) VI - 28 IP - 4 DP - 2010 Feb 1 TI - Phase II trial of pemetrexed plus bevacizumab for second-line therapy of patients with advanced non-small-cell lung cancer: NCCTG and SWOG study N0426. PG - 614-9 LID - 10.1200/JCO.2009.23.6406 [doi] AB - PURPOSE: To evaluate the efficacy and toxicity of pemetrexed combined with bevacizumab as second-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) and to correlate allelic variants in pemetrexed-metabolizing genes with clinical outcome. PATIENTS AND METHODS: Patients with previously treated NSCLC received pemetrexed (500 mg/m(2) intravenous) combined with bevacizumab (15 mg/kg intravenous) every 3 weeks. The primary end point, evaluated using a one-stage Fleming design for detecting a true success rate of at least 70%, was the proportion of patients who were progression free and on treatment at 3 months. Polymorphisms in genes responsible for pemetrexed transport (reduced folate carrier [SLC19A1]) and metabolism (folylpolyglutamate synthase [FPGS] and gamma-glutamyl hydrolase [GGH]) evaluated in germline DNA (blood) were correlated with treatment outcome. RESULTS: Forty-eight evaluable patients (14 females and 34 males) received a median of four cycles (range, one to 20 cycles). The most common grade 3 or 4 nonhematologic adverse events (AEs) were fatigue (13%), dyspnea (10%), and thrombosis (10%). Grade 3 or 4 hematologic AEs were neutropenia (19%) and lymphopenia (13%). Twenty-four (57%; 95% CI, 41% to 72%) of the first 42 patients met the success criteria. Median overall survival (OS) and progression-free survival (PFS) times were 8.6 and 4.0 months, respectively. The exon 6 (2522)C-->T polymorphism in SLC19A1 correlated with 3-month progression-free status (P = .01) and with PFS (P = .05). The IVS1(1307)C-->T polymorphism in GGH correlated with OS (P = .04). CONCLUSION: The study did not meet its primary end point. However, the median PFS time of 4 months is promising. Pharmacogenetic studies in larger cohorts are needed to definitively identify polymorphisms that predict for survival and toxicity of pemetrexed. FAU - Adjei, Alex A AU - Adjei AA AD - Roswell Park Cancer Institute, Buffalo, NY 14263, USA. alex.adjei@roswellpark.org FAU - Mandrekar, Sumithra J AU - Mandrekar SJ FAU - Dy, Grace K AU - Dy GK FAU - Molina, Julian R AU - Molina JR FAU - Adjei, Araba A AU - Adjei AA FAU - Gandara, David R AU - Gandara DR FAU - Ziegler, Katie L Allen AU - Ziegler KL FAU - Stella, Philip J AU - Stella PJ FAU - Rowland, Kendrith M Jr AU - Rowland KM Jr FAU - Schild, Steven E AU - Schild SE FAU - Zinner, Ralph G AU - Zinner RG LA - eng GR - U10 CA052352/CA/NCI NIH HHS/United States GR - CA-35090/CA/NCI NIH HHS/United States GR - CA-35195/CA/NCI NIH HHS/United States GR - U10 CA037404/CA/NCI NIH HHS/United States GR - CA-25224/CA/NCI NIH HHS/United States GR - N01 CA063844/CA/NCI NIH HHS/United States GR - CA-32291/CA/NCI NIH HHS/United States GR - CA-35113/CA/NCI NIH HHS/United States GR - CA-63848/CA/NCI NIH HHS/United States GR - UG1 CA233340/CA/NCI NIH HHS/United States GR - U10 CA035119/CA/NCI NIH HHS/United States GR - CA-35269/CA/NCI NIH HHS/United States GR - U10 CA025224/CA/NCI NIH HHS/United States GR - U10 CA035090/CA/NCI NIH HHS/United States GR - U10 CA035103/CA/NCI NIH HHS/United States GR - U10 CA032291/CA/NCI NIH HHS/United States GR - U10 CA035267/CA/NCI NIH HHS/United States GR - U10 CA035269/CA/NCI NIH HHS/United States GR - CA-37404/CA/NCI NIH HHS/United States GR - CA-52352/CA/NCI NIH HHS/United States GR - CA-63844/CA/NCI NIH HHS/United States GR - N01 CA035119/CA/NCI NIH HHS/United States GR - U10 CA180846/CA/NCI NIH HHS/United States GR - U10 CA063848/CA/NCI NIH HHS/United States GR - U10 CA035195/CA/NCI NIH HHS/United States GR - CA-35103/CA/NCI NIH HHS/United States GR - CA-35432/CA/NCI NIH HHS/United States GR - U10 CA035113/CA/NCI NIH HHS/United States GR - CA-35267/CA/NCI NIH HHS/United States GR - U10 CA063844/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20091019 PL - United States TA - J Clin Oncol JT - Journal of clinical oncology : official journal of the American Society of Clinical Oncology JID - 8309333 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Glutamates) RN - 0 (Membrane Transport Proteins) RN - 0 (Reduced Folate Carrier Protein) RN - 0 (SLC19A1 protein, human) RN - 04Q9AIZ7NO (Pemetrexed) RN - 2S9ZZM9Q9V (Bevacizumab) RN - 5Z93L87A1R (Guanine) RN - EC 3.2.1.- (2-O-alpha-D-glucopyranosyl-O-beta-D-galactopyranosyl-hydroxylysine glucohydrolase) RN - EC 3.2.1.- (Glucosidases) RN - EC 6.3.2.- (Peptide Synthases) RN - EC 6.3.2.17 (folylpolyglutamate synthetase) SB - IM CIN - J Clin Oncol. 2010 Mar 10;28(8):e131; author reply e132. PMID: 20100954 CIN - J Clin Oncol. 2010 Sep 20;28(27):e482-3; author reply e484. PMID: 20606096 MH - Adult MH - Aged MH - Antibodies, Monoclonal/administration & dosage MH - Antibodies, Monoclonal, Humanized MH - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use MH - Bevacizumab MH - Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/pathology MH - Female MH - Follow-Up Studies MH - Glucosidases/genetics MH - Glutamates/administration & dosage MH - Guanine/administration & dosage/analogs & derivatives MH - Humans MH - Lung Neoplasms/*drug therapy/genetics/pathology MH - Male MH - Membrane Transport Proteins/genetics MH - Middle Aged MH - Neoplasm Staging MH - Pemetrexed MH - Peptide Synthases/genetics MH - Polymorphism, Single Nucleotide/genetics MH - Prognosis MH - Reduced Folate Carrier Protein MH - Survival Rate MH - Treatment Outcome PMC - PMC2815996 COIS- Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article. EDAT- 2009/10/21 06:00 MHDA- 2010/02/19 06:00 PMCR- 2011/02/01 CRDT- 2009/10/21 06:00 PHST- 2009/10/21 06:00 [entrez] PHST- 2009/10/21 06:00 [pubmed] PHST- 2010/02/19 06:00 [medline] PHST- 2011/02/01 00:00 [pmc-release] AID - JCO.2009.23.6406 [pii] AID - 36406 [pii] AID - 10.1200/JCO.2009.23.6406 [doi] PST - ppublish SO - J Clin Oncol. 2010 Feb 1;28(4):614-9. doi: 10.1200/JCO.2009.23.6406. Epub 2009 Oct 19.