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D. Nickens

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    P1.03 - Chemotherapy/Targeted Therapy (ID 689)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      P1.03-003 - Clinical Implications of an Analysis of Crizotinib Pharmacokinetics Co-Administered with Dexamethasone in Patients with NSCLC (ID 8004)

      09:30 - 16:00  |  Author(s): D. Nickens

      • Abstract
      • Slides

      Dexamethasone is a systemic corticosteroid often used in non-small cell lung cancer (NSCLC) patients to treat disease and treatment-related complications. It is a known weak-to-moderate cytochrome P-450 (CYP) 3A inducer that may decrease exposure of CYP3A substrate tyrosine kinase inhibitors (TKIs). Crizotinib (Xalkori®) is a selective inhibitor of anaplastic lymphoma kinase (ALK) and ROS1 and is approved for treating ALK-positive and ROS1-positive NSCLC. Crizotinib is a substrate and time-dependent inhibitor of CYP3A. Co-administration of crizotinib 250 mg BID with a strong CYP3A inducer, rifampin 600 mg QD, resulted in an 84% decrease in steady-state crizotinib exposure. In this analysis, we evaluated the effect of dexamethasone on steady-state crizotinib exposure from clinical studies in patients with ALK-positive and ROS1-positive NSCLC.

      Data were from 4 clinical studies (PROFILE 1001, 1005, 1007, and 1014) with 1669 ALK-positive and 53 ROS1-positive NSCLC patients treated with crizotinib at the recommended starting dose of 250 mg BID. For each patient, multiple steady-state trough concentrations (C~trough, ss~) of crizotinib were measured after ≥ 14 days of consecutive crizotinib 250 mg BID dosing. Within‑patient comparison of crizotinib C~trough, ss~ between crizotinib dosing alone and crizotinib co‑administered with dexamethasone consecutively for ≥ 21 days was performed using a linear mixed effects model.

      There were a total of 514 (29.8%) patients who received dexamethasone from the 4 PROFILE studies. Other less commonly used (< 10%) weak-to-moderate CYP3A inducers included: methylprednisolone, prednisone, ginkgo/ginseng and efavirenz. In this analysis, a total of 15 patients had crizotinib C~trough,ss~ for both crizotinib dosing alone and crizotinib co-administered with dexamethasone consecutively for ≥ 21 days. The adjusted geometric mean of crizotinib C~trough,ss~ following co-administration with dexamethasone was 98.2% (90% CI: 79.1%-122.0%) relative to crizotinib dosing alone, with the lower limit just below the typical bioequivalence limits of 80%-125%.

      Dexamethasone was the most commonly used CYP3A inducer across the 4 PROFILE studies. Long-term (≥ 21 days) use of dexamethasone in NSCLC patients treated with crizotinib had no statistically significant effect on crizotinib exposure and thus would not compromise treatment efficacy. Other weak-to-moderate CYP3A inducers are not expected to have an effect on crizotinib, similar to the findings with dexamethasone. The framework of this analysis can be applied when dexamethasone or other weak-to-moderate CYP3A inducers are concomitantly used with CYP3A substrate TKIs.

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