Virtual Library

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    MTE 01 - Endpoints in Clinical Trials in Advanced NSCLC (Ticketed Session) (ID 53)

    • Event: WCLC 2015
    • Type: Meet the Expert (Ticketed Session)
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/07/2015, 07:00 AM - 08:00 AM, 103
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      MTE01.01 - Endpoints in Clinical Trials in Advanced NSCLC (ID 1977)

      T. Mok

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MTE01.02 - Endpoints in Clinical Trials in Advanced NSCLC (ID 1978)

      G. Blumenthal

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MTE 12 - Therapy for Driver Mutation Positive Advanced NSCLC (Ticketed Session) (ID 64)

    • Event: WCLC 2015
    • Type: Meet the Expert (Ticketed Session)
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2015, 07:00 AM - 08:00 AM, 103
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      MTE12.01 - Therapy for Driver Mutation Positive Advanced NSCLC (ID 1997)

      L. Landi, F. Cappuzzo

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide, with a median survival that rarely exceeds 10–12 months in unselected patients with metastatic disease treated with conventional chemotherapy. In the last decade, identification of key genetic events driving tumor growth and metastatic spread led to the concept of oncogene-addiction. According to this model, the inhibition of certain molecular drivers by targeted agents could be effective in reducing tumor burden and improving patient survival. Several molecular alterations have been described in NSCLC, particularly in adenocarcinomas, especially, but not exclusively, in the never/ former smoker population. The most notable examples are the epidermal growth factor receptor (EGFR) activating mutations, mainly represented by deletion in exon 19 or the L858R substitution in exon 21, and the echinoderm microtubule protein like-4/anaplastic lymphoma kinase (EML4-ALK) translocation. Although only 12–15% of NSCLC tumors are EGFR mutated or ALK-rearrangement-positive, this translates into a considerable number of patients affected worldwide. In metastatic NSCLC, presence of EGFR activating mutations confers a more favorable prognosis and strongly predicts for sensitivity to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib or afatinib. Indeed, nine large randomized trials comparing an EGFR-TKI versus standard platinum based chemotherapy have clearly demonstrated the superiority of the target agent in prolonging progression-free survival (PFS), improving response rate (RR) along with a more favorable safety profile. Similarly, in presence of EML4-ALK translocation, the ALK inhibitor crizotinib produces higher RR and longer PFS when compared to standard chemotherapy, both in first and second line setting. Unfortunately, no patient with metastatic oncogene-addicted NSCLC can achieve a definitive cure and after a median time of 8–12 months, all patients eventually develop acquired resistance to targeted therapy. So far, several studies of tumor samples obtained at the time of treatment failure have identified different potential mechanisms responsible for acquired resistance to targeted agents. In the majority of cases resistance is the consequence of a biological event occurring in the target (target-dependent acquired resistance), whereas in other cases acquired resistance is the consequence of the activation of other pathways (target-independent acquired resistance). As for EGFR mutant NSCLCs the emergence of the secondary T790M mutation in the tyrosine kinase domain of EGFR account for up to 60% of erlotinib or gefitinib failure, investigations have focused on the potential efficacy of a new class of drugs that could irreversibly inhibit T790M clones, with reduced activity against wild-type EGFR. This new class of agents includes several new drugs under clinical development, with rociletinib and AZD9291 to-date being the most promising. A large phase I-II study evaluated the efficacy of rociletinib in patients with EGFR mutations who progressed during previous treatment with an EGFR inhibitor. In patients with centrally confirmed T790M-positive tumors, RR was approximately 60% with a median PFS that exceeded 1 year. However, also patients whose tumors were T790M-negative gained some benefits from rociletinib with a RR of 29% and median PFS of approximately 6 months. In a phase I trial conducted in patients who failed first- or second-generation EGFR-TKI, AZD9291 produced a RR of 50%. Importantly, RR was 61% in patients harboring a T790M mutation, whereas in T790M-negative cases RR was 21% with a median PFS of only 3 months. Results of ongoing trials with rociletinib and AZD9291 will better clarify the role of third generation EGFR-TKIs in the treatment algorithm of EGFR mutant NSCLC. Similarly, for the vast majority of ALK positive NSCLCs, resistance is mediated by an ALK dominant mechanism, such as mutations in the kinase domain of ALK gene or ALK fusion gene amplification. So far, a number of mutations have been identified and they seem to confer different sensitivities to second-generation ALK inhibitors. In addition, there are an increasing number of patients for which disease progression occurs only in the central nervous system (CNS), supporting the hypothesis of an inadequate CNS drug penetration. Several novel and more potent second-generation ALK inhibitors are currently under investigations in clinical trials. Among them, ceritinib and alectinib gained the FDA breakthrough therapy designation for ALK-positive NSCLC due to the encouraging results that emerged from a phase I-II trials. Beyond EGFR mutations and ALK translocation, novel biomarkers have been linked with adenocarcinoma histology, including ROS1 fusion gene, MET amplification or mutations, BRAF and HER2 mutations, for which many targeted drugs are currently under investigation. ROS1 rearrangements and MET amplification represent two additional molecular aberrations candidate as predictors for crizotinib sensitivity. Indeed, results from expansion cohorts of the PROFILE 1001 phase I suggested the potential efficacy of crizotinib in lung cancer patients with ROS1 translocation or MET amplification. Another promising target is BRAF mutation, a rare event occurring in 1% to 3% of adenocarcinoma patients, including those with a history of smoking. Recently, combination of the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib emerged as a suitable strategy in patients with BRAF mutant NSCLC. Dual BRAF/MEK axis inhibition translated into a RR of 63% with an acceptable toxicity profile. In conclusion, targeted agents are rapidly changing the natural history of NSCLC, with several new agents entering onto clinical practice. In the next few years, the major challenge will be to define the optimal sequence of targeted agents as well as their combination with novel strategies including immunotherapy.

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    MTE 23 - Standard Therapy for Advanced NSCLC in Absence of Driver Mutations (Ticketed Session) (ID 75)

    • Event: WCLC 2015
    • Type: Meet the Expert (Ticketed Session)
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2015, 07:00 AM - 08:00 AM, 103
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      MTE23.01 - Standard Therapy for Advanced NSCLC in Absence of Driver Mutations (ID 2010)

      C.J. Langer

      • Abstract
      • Presentation

      Abstract not provided

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