Phase I-IIa study of BMS-690514, an EGFR, HER-2 and -4 and VEGFR-1 to -3 oral tyrosine kinase inhibitor, in patients with advanced or metastatic solid tumours

Jean Charles Soria, José Baselga, Nasser Hanna, Scott A. Laurie, Rastislav Bahleda, Enriqueta Felip, Emiliano Calvo, Jean Pierre Armand, Frances A. Shepherd, Christopher T. Harbison, David Berman, Jong Soon Park, Steven Zhang, Blisse Vakkalagadda, John F. Kurland, Ashutosh K. Pathak, Roy S. Herbst

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    18 Citations (Scopus)

    Résumé

    Purpose: BMS-690514 is a potent, reversible oral inhibitor of epidermal growth factor receptor (EGFR/HER-1), HER-2 and -4, and vascular endothelial growth factor receptors (VEGFRs)-1 to -3 offering targeted inhibition of tumour growth and vascularisation in a single agent. This phase I-IIa study was designed to identify the maximum tolerated dose (MTD) and assess safety, antitumour activity, pharmacokinetics and pharmacodynamics of BMS-690514. Patients and methods: In phase I, patients with advanced solid tumours received escalating doses of once-daily BMS-690514. In phase IIa, erlotinib-naïve (cohort A) or erlotinib-resistant (cohort B) patients with advanced non-small-cell lung cancer (NSCLC) received BMS-690514 once-daily at the MTD. Results: In phase I (n = 28), the MTD was determined to be 200 mg daily. BMS-690514 was rapidly absorbed and highly metabolised after repeated oral administration with minimum drug accumulation. In phase IIa (n = 62), the most frequent treatment-related adverse events were diarrhoea and acneiform rash. Adverse events that led to >1 discontinuation were diarrhoea (n = 4; 4%) and rash (n = 2; 2%). Disease control (≥4 months) and objective response rates, respectively, were 43.3% and 3.3% (cohort A) and 22.6% and 3.2% (cohort B). Six of 21 (29%) NSCLC patients with wild-type EGFR achieved disease control versus seven of 10 (70%) patients with EGFR mutations (including T790M). At MTD, BMS-690514 modulated pharmacodynamic biomarkers associated with inhibition of VEGFR- and EGFR-signalling pathways. Conclusion: This phase I-IIa study suggests that BMS-690514 has manageable safety profile and antitumour activity in patients with NSCLC at 200 mg/d, including those with EGFR mutations conferring resistance to erlotinib.

    langue originaleAnglais
    Pages (de - à)1815-1824
    Nombre de pages10
    journalEuropean Journal of Cancer
    Volume49
    Numéro de publication8
    Les DOIs
    étatPublié - 1 mai 2013

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