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J. Soria



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    MO07 - NSCLC - Targeted Therapies II (ID 114)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO07.05 - DISCUSSANT (ID 3952)

      16:15 - 17:45  |  Author(s): J. Soria

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS27 - Mechanisms of Acquired Resistance to Targeted Therapy (ID 44)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Medical Oncology
    • Presentations: 1
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      MS27.4 - Trial Design as it Applies to Resistance (ID 592)

      10:30 - 12:00  |  Author(s): J. Soria

      • Abstract
      • Presentation
      • Slides

      Abstract
      Lung cancer therapy in the metastatic setting is invariably characterized by the emergence of resistance. This applies both to conventional chemotherapy and molecular targeted agents. This presentation will focus on the biological background and subsequent trial designs as it applies to resistance regarding molecular targeted agents (MTA). In the clinical setting when a patient develops progressive disease while exposed to a MTA some key basic considerations should be taken into account before considering acquired biological resistance. Compliance of the patient to the prescribed therapy is an obvious one. Indeed chronic exposure to tyrosine kinase inhibitors (TKI) exposes the patient to chronic toxicities. Some of these toxicities can become intolerable for the patient, thus leading to patient-driven therapeutic breaks that are frequently not specified to the clinician. This is notably true for week-end breaks as well holiday breaks. Honest dialogue with the patient is necessary to identify compliance issues and pharmacological (PK) dosage in the blood of the relevant TKI is an approach to be discussed. Further pharmacokinetic interactions represent a real issue with TKI: many TKI are metabolized by the liver and can have CYP liabilities (ie erlotinib, gefitinib are susbtrated of CYP3A4). Inter-individual PK variability due to genotypic background (polymorphisms in genes encoding drug metabolizing enzymes), inflammatory and nutritional status, may result in suboptimal drug concentrations and decreased efficacy. Significant decrease in drug exposure over time have also been described for and may result in secondary progression despite preserved sensitivity to these agents, with a potential role for subsequent dose escalation. From a biological perspective, 3 main mechanisms have been described to explain resistance to TKI: a) mutation/amplification in the target (ie T790M for EGFR or ALK L1196M), bypass mechanism (ie Met amplification, PI3K mutation, HER 3 activation,) and growth survival/apoptosis resistance (ie loss of BIM, SCLC, EMT). Stronger kinase inhibitors and use of combinations appear as potential solutions to deal with these resistance mechanisms. Some of the potential designs to address acquired resistance include: a) upfront combinations, b) use of third generation inhibitors or mutant-specific inhibitors, c) rolling trials (ie the use of sequential TKI therapies), c) alternating therapeutic approaches (TKI followed by chemotherapy or TKI followed by immunotherapy).

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