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

Alex A. Adjei, Sumithra J. Mandrekar, Grace K. Dy, Julian R. Molina, Araba A. Adjei, David R Gandara, Katie L Allen Ziegler, Philip J. Stella, Kendrith M. Rowland, Steven E. Schild, Ralph G. Zinner

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

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/m2 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.

Original languageEnglish (US)
Pages (from-to)614-619
Number of pages6
JournalJournal of Clinical Oncology
Volume28
Issue number4
DOIs
StatePublished - Feb 1 2010

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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    Adjei, A. A., Mandrekar, S. J., Dy, G. K., Molina, J. R., Adjei, A. A., Gandara, D. R., Ziegler, K. L. A., Stella, P. J., Rowland, K. M., Schild, S. E., & Zinner, R. G. (2010). 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. Journal of Clinical Oncology, 28(4), 614-619. https://doi.org/10.1200/JCO.2009.23.6406