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G. Esquerdo



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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
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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 - 16:30  |  Author(s): G. Esquerdo

      • 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
      Not applicable

      Results
      Not applicable

      Conclusion
      Not applicable

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    P1.24 - Poster Session 1 - Clinical Care (ID 146)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P1.24-020 - Efficacy and safety of carboplatin and pemetrexed for the first line treatment of unfit patients to receive cisplatin with nonsquamous non small cell lung cancer (ID 1563)

      09:30 - 16:30  |  Author(s): G. Esquerdo

      • Abstract

      Background
      Background: Pemetrexed activity is synergistic with both carboplatin and cisplatin in chemonaive NSCLC patients. Two phase II Pem plus carboplatin trials have confirmed the doublet’s activity in NSCLC and response rates were 31% and 24% (Scagliotti and al 2003, Zinner and al 2005). Carboplatin is a good alternative in unfit patients suggesting a balanced benefit/risk profile when combined with Pem.

      Methods
      Sixty-four patients unfit to receive cisplatin with measurable stage III-B IV NSCLC, received at least one dose of chemotherapy. Pem 500 mg/m2 over 10 min on day 1 with folic acid and vitamin B12 supplementation followed by carboplatin AUC 5 on the same day were given every 21 days for 4- 6 cycles. Primary endpoint was safety and efficacy ( progression free survival)

      Results
      Sixty four patients received at least one dose of chemotherapy. Median age was: 71.3 yrs (86−44,3), 90,6% of patients presented comorbilities , mainly cardiopathy (73,4%) . Stages IIIb: 15,6%, IV: 84,4%. Non squamous cell carcinoma: 100.% (adenocarcinoma: 92,2%, large cell carcinoma: 7.8% )Male 76,6%, female 23,4%. The median number of administered cycles was 4. Median progresion free survival and overall survival will be presented at the meeting. Grade 3/4 toxicities related to study drugs were: asthenia 6.1%, skin 3.1%, dyspnea 3.1% .Hematological grade 3/4 events were: neutropenia: 6.1%, thrombocytopenia: 1,6%, anemia: 14.1%. 10,9% of patients need dose reduction

      Conclusion
      In first line NSCLC, the combination of Pem plus carboplatin could be a valuable treatment alternative in unfit patients to recive cisplatin. Anemia is the most frequent toxicity in this combination.