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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.

ABSTRACT: 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 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.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).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.

SUBMITTER: Adjei AA

PROVIDER: S-EPMC2815996 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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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.

Adjei Alex A AA Mandrekar Sumithra J SJ Dy Grace K GK Molina Julian R JR Adjei Araba A AA Gandara David R DR Ziegler Katie L Allen KL Stella Philip J PJ Rowland Kendrith M KM Schild Steven E SE Zinner Ralph G RG

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20091019 4

<h4>Purpose</h4>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.<h4>Patients and methods</h4>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 Fle ...[more]

PMID: 19841321

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Project description:BackgroundPatients with advanced biliary tract cancer who progress on first-line therapy have limited treatment options. The TreeTopp study assessed varlitinib, a reversible small molecule pan-human epidermal growth factor receptor inhibitor, plus capecitabine in previously treated advanced biliary tract cancer.Patients and methodsThis global, double-blind, randomized, placebo-controlled phase II study enrolled patients with confirmed unresectable or metastatic biliary tract cancer and disease progression after one prior line of gemcitabine-containing chemotherapy. Patients received oral varlitinib 300 mg or placebo twice daily (b.i.d.) for 21 days, plus oral capecitabine 1000 mg/m2 b.i.d. on days 1-14, in 21-day treatment cycles. Co-primary endpoints were objective response rate and progression-free survival (PFS) according to RECIST v1.1 by Independent Central Review.ResultsIn total, 127 patients received varlitinib plus capecitabine (n = 64) or placebo plus capecitabine (n = 63). The objective response rate was 9.4% with varlitinib plus capecitabine versus 4.8% with capecitabine alone (odds ratio 2.28; P = 0.42). Median PFS was 2.83 versus 2.79 months [hazard ratio (HR), 0.90; 95% confidence interval (CI), 0.60-1.37; P = 0.63] and overall survival was 7.8 versus 7.5 months (HR, 1.11; 95% CI, 0.69-1.79; P = 0.66), respectively. In a subgroup analysis, the addition of varlitinib appeared to provide a PFS benefit in female patients (median, 4.1 versus 2.8 months; HR, 0.59; 95% CI, 0.28-1.23) and those with gallbladder cancer (median, 2.9 versus 1.6 months; HR, 0.55; 95% CI, 0.26-1.19). Grade ≥3 treatment-emergent adverse events were reported in 65.6% of patients receiving varlitinib plus capecitabine versus 58.7% of those receiving capecitabine alone.ConclusionsIn patients with advanced biliary tract cancer, second-line treatment with varlitinib plus capecitabine was well tolerated but did not improve efficacy versus capecitabine alone. A PFS benefit was suggested in female patients and those with gallbladder cancer.

Project description:BackgroundPatients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. We assessed the efficacy and tolerability of pemetrexed and cisplatin combination therapy in patients with refractory bone and soft tissue sarcoma (STS).Patients and methodsPatients were included in this multicenter, phase II study (ClinicalTrials.gov identifier NCT03809637) if they progressed after receiving one or more chemotherapy regimens containing an anthracycline and/or ifosfamide. Pemetrexed was first administered intravenously, followed by cisplatin, over a cycle of 21 days, for a maximum of six cycles. The primary endpoint was a progression-free rate (PFR) at 3 months (3-month PFR).ResultsFrom January 2017 to September 2019, we enrolled 37 patients; of these, 73% had previously undergone three or more rounds of chemotherapy. Five patients (13.5%) exhibited objective responses, including two patients (2/6, 33.3%) with malignant peripheral nerve sheath tumors, one patient (1/4, 25%) with synovial sarcoma, one patient (1/4, 25%) with undifferentiated pleomorphic sarcoma, and one patient (1/4, 25%) with angiosarcoma. The median progression-free survival was 2.6 months, and the 3-month PFR was 45.9% (n = 17). None of the four patients with osteosarcoma exhibited objective responses or were progression free at 3 months. The most frequent treatment-related grade 3-4 toxicities included neutropenia (16.2%), anemia (13.5%), thrombocytopenia (13.5%), and fatigue (8.1%). Among 26 patients (70.3%) available for immunohistochemical assessments, patients in the low-excision repair cross-complementation group 1 (ERCC1) and low-thymidylate synthase expression groups showed a tendency for longer overall survival.ConclusionsCombination therapy with pemetrexed and cisplatin was associated with clinically meaningful and sustained responses among patients with advanced and refractory STS. The combination therapy met its predefined primary study endpoint.

Dataset Information

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.

Publications

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.

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