A randomized, double-blind, phase II study of two doses of pemetrexed as first-line chemotherapy for advanced breast cancer

Antonio Llombart-Cussac, Miguel Martin, Nadia Harbeck, Rodica M. Anghel, Alexandra E. Eniu, Mark W. Verrill, Patrick Neven, Jacques De Grève, Allen S. Melemed, Romnee Clark, Lorinda Simms, Christopher J. Kaiser, Doreen Ma

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24 Scopus citations


Purpose: Pemetrexed has shown varied response rates in advanced breast cancer. This randomized, double-blind, phase II study was conducted to assess the efficacy and safety of two doses of pemetrexed in a homogeneous population. A secondary objective was to identify molecular biomarkers correlating with response and toxicity. Experimental Design: Patients with newly diagnosed metastatic breast cancer or locally recurrent breast cancer received 600mg/m2 (P600 arm) or 900mg/m2 (P900 arm) of pemetrexed on day1of a 21-day cycle. All patients received folic acid and vitamin B 12 supplementation. Results: The P600 (47 patients) and P900 (45 patients) arms had response rates of 17.0% (95% confidence interval, 7.7-30.8%) and 15.6% (95% confidence interval, 6.5-29.5%) with ∼50% stable disease per arm, median progression-free survival of 4.2 and 4.1 months, and median times to tumor progression of 4.2 and 4.6 months, respectively. Both arms exhibited minimal toxicity (grade 3/4 neutropenia <20%, leukopenia <9%, and other toxicities <5%). Tumor samples from 49 patients were assessed for the expression levels of 12 pemetrexed-related genes. Folylpolyglutamate synthetase and thymidine phosphorylase correlated with efficacy. Best response rates and median time to tumor progression for high versus low thymidine phosphorylase expression were 27.6% versus 6.3% (P = 0.023) and 5.4 versus 1.9 months (P = 0.076), and for folylpolyglutamate synthetase were 37.5% versus 10.0% (P = 0.115) and 8.6 versus 3.0 months (P = 0.019), respectively. γ-Glutamyl hydrolase expression correlated with grade 3/4 toxicities: 78.6% for high versus 27.3% for low γ-glutamyl hydrolase (P = 0.024). Conclusion: The two pemetrexed doses yielded similar efficacy and safety profiles. Exploratory biomarker analysis identified efficacy and toxicity correlations and warrants further evaluation.

Original languageEnglish (US)
Pages (from-to)3652-3659
Number of pages8
JournalClinical Cancer Research
Issue number12
StatePublished - Jun 15 2007


ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Llombart-Cussac, A., Martin, M., Harbeck, N., Anghel, R. M., Eniu, A. E., Verrill, M. W., Neven, P., De Grève, J., Melemed, A. S., Clark, R., Simms, L., Kaiser, C. J., & Ma, D. (2007). A randomized, double-blind, phase II study of two doses of pemetrexed as first-line chemotherapy for advanced breast cancer. Clinical Cancer Research, 13(12), 3652-3659. https://doi.org/10.1158/1078-0432.CCR-06-2377