Author of

• 11745

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  P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Medical Oncology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11756

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    P2.11-011 - A Phase Ib study of high-dose intermittent (HDI) afatinib in EGFR T790M mutation-positive non-small cell lung cancer patients with acquired resistance to reversible EGFR TKIs (ID 1127)

    09:30 - 09:30  |  Author(s): E. Dowling
    • Abstract

    Background
    Afatinib, an irreversible ErbB Family Blocker, displayed nanomolar inhibitory activity in proliferation assays using lung adenocarcinoma cell lines expressing mutant EGFR[L858R/T790M] (NCI-H1975 EC~50~ 92 nM).[1] In NSCLC patients with prior erlotinib/gefitinib failure and one/two previous lines of chemotherapy, 50mg afatinib once daily produced confirmed objective responses in 7% of patients and a median PFS of 3.3 months.[2] Preclinical models suggested that administering afatinib using a high-dose intermittent (HDI) schedule, leading to higher maximal plasma concentrations, may provide an alternative means to block T790M-harbouring cells effectively. It may also potentially reduce wild-type EGFR-mediated adverse events noted with continuous dosing of EGFR TKIs. In this ongoing open-label study, the maximum tolerated dose (MTD), safety and pharmacokinetics (PKs) of HDI afatinib are being assessed in Part A in patients with advanced solid tumours. The MTD of HDI afatinib will be evaluated in Part B in patients with T790M-mutated advanced NSCLC following prior EGFR TKI therapy. Preliminary results from Part A are presented.

    Methods
    In Part A, patients with metastatic/unresectable solid tumours and adequate organ function were administered 90–200mg afatinib on Days 1–3 every 14 days in each 28-day cycle using a 3+3 dose-escalation design. Doses are escalated until MTD (primary endpoint), defined as the dose at which less than two of up to six patients develop dose-limiting toxicities (DLTs) in Cycle 1. PK sampling was conducted on Days 1–3, 8, 15–17, 29, 43 and 57, with C~max~ of afatinib on Day 3 of Cycle 1 being the secondary endpoint. In Part B, the MTD cohort will be expanded to specifically include EGFR TKI-pretreated advanced NSCLC patients with T790M mutations. Exploration of baseline and on-therapy plasma levels of detectable T790M is planned.

    Results
    To date, 16 patients have been recruited in Part A (90mg n=6; 120mg n=3; 150mg n=4; 200mg n=3; male/female n=8/8; median age 65 years; never smokers/ex-smokers n=10/6; primary tumour site lung n=9; known T790M mutation n=7). The most common drug-related adverse events (DRAEs) were diarrhoea, rash, dermatitis acneiform and nausea. DRAEs of Grade ≥3 were seen in one patient at 90mg (Grade 3 worsening cellulitis [Cycle 1; DLT] and urosepsis [Cycle 2]) and one patient at 150mg (Grade 3 dehydration, hypokalaemia, hypophosphataemia, diarrhoea [Cycle 2]). Preliminary response data on evaluable T790M-mutated NSCLC patients will be presented as available. Preliminary PK analyses suggest 150mg afatinib once daily for 3 days is sufficient to achieve total plasma C~max~ concentrations at or above the predicted IC~50~ value for T790M. Afatinib trough plasma concentrations will also be presented.

    Conclusion
    HDI afatinib elicited a manageable safety profile up to 200mg on Days 1–3 every 14 days. Total plasma C~max~ concentrations at or above the predicted efficacious threshold for T790M inhibition were already achieved in the 150mg cohort. Treatment in the 200mg cohort is ongoing. Additional cohorts may be included to explore shorter drug-free dosing periods. 1. Solca F, et al. JPET 2012;343:342–50. 2. Miller V, et al. Lancet Oncol 2012;13:528–38.