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G. Mugundu

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    ORAL 33 - ALK (ID 145)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL33.07 - Clinical Activity and Safety of the ALK/ROS1 TK Inhibitor PF-06463922 in Advanced NSCLC (ID 295)

      16:45 - 18:15  |  Author(s): G. Mugundu

      • Abstract
      • Presentation
      • Slides

      Overcoming acquired resistance in ALK+ and ROS1+ non-small-cell lung cancer (NSCLC) patients (pts) is key to optimizing therapy. PF-06463922 is a selective, brain-penetrant tyrosine kinase inhibitor (TKI) with demonstrated clinical activity against de novo fusions as well as resistance mutations, including ALK G1202R, that arise during treatment with other TKIs.

      In this ongoing phase I study, eligible pts had ALK+ or ROS1+ NSCLC, with or without brain metastases, and were treatment naïve or had disease progression after at least 1 prior TKIs. Pts with central nervous system (CNS) metastases, including untreated asymptomatic metastases, were eligible. Tumor tissue (archival sample or de novo biopsy) was required for enrollment. A modified continual reassessment method was used to estimate the maximum tolerated dose (MTD) and select a recommended phase II dose (RP2D). Once- (QD) or twice-daily (BID) dosing in 21-day cycles was explored. Secondary objectives included efficacy, safety, tolerability, pharmacokinetics (PK), effect on cognitive function, patient-reported outcomes, potential to induce/inhibit CYP3A4, biomarkers of drug response and resistance, and intracranial antitumor activity.

      25 ALK+ pts (20 with CNS metastases, 23 previously treated with at least 1 ALK TKIs) and 5 ROS1+ pts (3 with CNS metastases, 3 previously treated with crizotinib) have been enrolled across 7 QD dose levels and 2 BID dose levels. Of 21 patients evaluable for intracranial response, 16 had stable disease or confirmed complete/partial response. The most common treatment-related adverse events (AEs) were hypercholesterolemia, peripheral neuropathy, and peripheral edema, occurring in 47%, 27% and 23% of pts, respectively. Peripheral neuropathy was reversible following treatment delay or dose reduction. The most common grade 3 and higher treatment-related AE was hypercholesterolemia, occurring in 10% of pts, which was well managed with statins. One DLT was reported for a pt at 200 mg QD, who received less than 16 of the 21 planned doses of study drug due to grade 2 CNS effects. To date, 20 pts remain on treatment. Preliminary PK analyses suggest that exposure increased linearly from 10 to 75 mg QD, with a terminal half-life of 20-28 hrs. At doses beyond 75 mg QD, the increase in exposure appeared to be non-proportional. PF-06463922 is considered a moderate inducer of CYP3A4.

      PF-06463922 is a potent ALK/ROS1 TKI that has demonstrated clinical activity in ALK+ and ROS1+ NSCLC pts, most of whom had CNS metastases and had received at least 1 prior TKI. The RP2D has not yet been established.

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