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• 10583

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  P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 10641

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    P1.06-058 - The PHALCIS Trial (PHarmacogenomic ALimta CISplatin): A clinical trial in progress by The Spanish Lung Cancer Group (ID 3425)

    09:30 - 09:30  |  Author(s): J.A. Macias
    • Abstract

    Background
    The inherent molecular heterogeneity prevents the efforts to improve outcomes for patients with non-small cell lung cancer (NSCLC). Platinum doublets are the standard option for the treatment of advanced NSCLC, but none of the platinum-based combinations used offer a significant advantage over the others. Pemetrexed is an antifolate antimetabolite that inhibits several key folate-dependent enzymes, mainly thymidylate synthase (TS). A phase III trial conducted in the first-line setting of advanced NSCLC demonstrated that survival was statistically superior for cisplatin plus pemetrexed in patients with adenocarcinoma (12.6 versus 10.9 months; HR 0.84, P = 0.03), and large-cell carcinoma (10.4 versus 6.7 months; HR 0.67; P = 0.0 3 compared with cisplatin plus gemcitabine (1). Preclinical data have indicated that overexpression of TS correlates with reduced sensitivity to pemetrexed (2). Baseline expression of the TS gene is superior in squamous cell carcinoma compared with adenocarcinoma (P < 0.0001) (3). BRCA1 is a component of multiple DNA repair pathways and functions as a molecular determinant of response to a range of cytotoxic chemotherapeutics agents. The analysis of BRCA expression levels in patients who had received neoadjuvant gemcitabine/cisplatin chemotherapy found that patients with low levels of BRCA1 had longer survival (P = 0.01) compared to those with high expression levels (4). RAP80 is an interacting protein that form complexes with BRCA1 and could modulate the effect of BRCA1. In patients with non-squamous lung carcinoma, survival was influenced by RAP80 expression (5). Taking into account this background, the Spanish Lung Cancer Group has started a phase IIA study of pemetrexed plus cisplatin as first line treatment for advanced/metastatic non-squamous lung carcinoma. The availability of tissue samples for analysis of expression of BRCA1, RAP80 and thymidylate synthase is mandatory. The primary objective is response rate adjusted for different expression levels of BRCA1, RAP80 and TS. Secondary objectives are OS, TTP and toxicity profile of the combination and its relationship with the biomarkers. The expected total number of patients accrued will be 90. Forty-nine patients have been included up to now. References Scagliotti GV, Parikh P, Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients with advanced-stage non–small-cell lung cancer. J Clin Oncol 2008. Sigmond J, Backus HH, Wouters D, et al. Induction of resistance to the multitarged antifolate pemetrexed in WiDr human colon cancer cells is associated with thymidylate synthase overexpression. Biochem Pharmacol 2003. Ceppi P, Volante M, Saviozzi S, et al. Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer 2006. Taron M, Rosell R, Felip E, et al. BRCA1 mRNA expression levels as an indicator of chemoresistance in lung cancer. Hum Mol Genet 2004. Rosell R, Perez-Roca L, Sanchez JJ, et al. Customized treatment in non-small cell lung cancer based on EGFR mutations and BRCA1 expression. PLoS ONE 2009.

    Methods
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    Results
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    Conclusion
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