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Haura EB , Ricart AD , Larson TG , Stella PJ , Bazhenova L , Miller VA , Cohen RB , Eisenberg PD , Selaru P , Wilner KD , Gadgeel SM
A Phase II Study of PD-0325901, an Oral MEK Inhibitor, in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer
Clinical Cancer Research. 2010 Apr;16(8) :2450-2457
PMID: ISI:000278595900024   
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Purpose: To evaluate the efficacy of mitogen-activated protein kinase/extracellular signal-related kinase kinase inhibitor PD-0325901 in advanced non-small cell lung cancer patients who had experienced treatment failure after, or were refractory to, standard systemic therapy. Experimental Design: This open-label, phase II study initially evaluated 15 mg PD-0325901 twice daily administered intermittently (3 weeks on/1 week off; schedule A). As this schedule was not well tolerated, a second schedule was introduced as follows: 5 days on/2 days off for 3 weeks, followed by 1 week off (schedule B). The primary end point was objective response. Results: All patients had received prior systemic therapy (median of two regimens, including epidermal growth factor receptor inhibitors in 26%). Of 13 patients treated on schedule A, three discontinued due to adverse events (blurred vision, fatigue, and hallucinations, respectively). Twenty-one patients received schedule B. Main toxicities included diarrhea, fatigue, rash, vomiting, nausea, and reversible visual disturbances. Hematologic toxicity consisted mainly of mild-to-moderate anemia, without neutropenia. Chemistry abnormalities were rare. Mean (coefficient of variation) PD-0325901 trough plasma concentrations were 100 ng/mL (52%) and 173 ng/mL (73%) for schedules A and B, respectively, above the minimum target concentration established in preclinical studies (16.5 ng/mL). There were no objective responses. Seven patients had stable disease. Median (95% confidence interval) progression-free survival was 1.8 months (1.5-1.9) and overall survival was 7.8 months (4.5-13.9). Conclusions: PD-0325901 did not meet its primary efficacy end point. Future studies should focus on PD-0325901 schedule, rational combination strategies, and enrichment of patient selection based on mode of action. Clin Cancer Res; 16(8); 2450-7. (C) 2010 AACR.
Haura, Eric B. Ricart, Alejandro D. Larson, Timothy G. Stella, Philip J. Bazhenova, Lyudmila Miller, Vincent A. Cohen, Roger B. Eisenberg, Peter D. Selaru, Paulina Wilner, Keith D. Gadgeel, Shirish M. Pfizer, Inc. ; Bristol Myers Squibb R. B. Cohen, commercial research grant, Pfizer (paid to Fox Chase Cancer Center for the trial itself). P. D. Eisenberg, commercial research grant, Pfizer. A. D. Ricart, P. Selaru, and K. D. Wilner, employment, Pfizer. P. Selaru, K. D. Wilner, stockholders, Pfizer. E. Haura, commercial research grant, Bristol Myers Squibb; filed patent for biomarkers of dasatinib. The other authors have disclosed no potential conflicts of interest. Medical writing support was provided by Christine Arris at ACUMED (Tytherington, UK) and was funded by Pfizer, Inc. The study was funded by Pfizer, Inc. 29 Amer assoc cancer research; 615 chestnut st, 17th floor, philadelphia, pa 19106-4404 usa 608ow