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Gene Profiling in Clinical Oncology - Slide 3 - O. Gautschi - Do we know how to chose the best maintenance treatment?

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  • 1. Do we know how to choose the
    best maintenance treatment?
    oliver.gautschi@onkologie.ch
  • 2. Firstline therapy (metastatic disease)
    Continuation maintenance
    Switch maintenance
    Secondline therapy (at progression)
    2
    Definitions
  • 3. Delay tumor progression
    Prolong survival
    Optimal tolerance
    No cumulative toxicity
    Maintain life quality
    3
    Aims and Expectations
  • 4. Meta-analysis: PFS Soon JCO 2009
  • 5. Meta-analysis: OS Soon JCO 2009
  • 6. Continuation chemotherapy
    is not standard-of-careBelani ASCO 2010
  • 7. Continuation of Bevacizumab ?Sandler NEJM 2006; Reck JCO 2009
    E4599: cont. 53%
    AVAiL : cont. 41-42%
  • 8. Switch to Pemetrexed: JMENCiuleanu ASCO 2008, Lancet Oncol 2010
    Gem / Platin
    Pac / Platin
    Doc / Platin
    No PD
    PS 0,1
  • 9. JMEN: HistologyBelani ASCO 2009, Ciuleanu Lancet 2009
  • 10. JMEN : initial ResponseCiuleanu, Lancet 2009
    OS for non-squamous:
    HR
    CR/PR
    0.81
    0.61
    SD
    1.2
    1.0
    0.8
    0.6
    0.4
    Favours pemetrexed
    Favours placebo
  • 11. JMEN : ToxicityCiuleanu, Lancet 2009
    Relevant grade 2 toxicities
    Fatigue
    Nausea 20 %
    Anorexie
  • 12. Switch to Erlotinib: SATURNCappuzzo ASCO 2009 / Lancet Oncol 2010
  • 13. SATURN: OSCappuzzo, Lancet Oncol 2010
  • 14. SATURN: SubgroupsCappuzzo, Lancet Oncol 2010
  • 15. Response to Firstline TherapyCappuzzo, Lancet Oncol 2010
  • 16. SATURN: EGFR MutationBrugger, ASCO 2009
    EGFR mutation
    EGFR wild type
    HR=0.10 (0.04–0.25)
    HR=0.78 (0.63–0.96)
    1.0
    0.8
    0.6
    0.4
    0.2
    0
    1.0
    0.8
    0.6
    0.4
    0.2
    0
    Log-rank p<0.0001
    Log-rank p=0.0185
    PFS probability
    0 8 16 24 32 40 48 56 64 72 80 88 96
    0 8 16 24 32 40 48 56 64 72 80 88 96
    Time (weeks)
    Time (weeks)
  • 17.
  • 18. What did we learn from these
    registration trials ?
    Maintainance therapy is an approved option
    Histology is predictive for pemetrexed
    EGFR mutations are predictive for erlotinib
    but it is still not proven if maintenance offers a true survival advantage over secondline therapy with the same drug given at the right time
  • 19. Ongoing Phase III Trials
  • 20. Large Cell
    Small Cell
    Squamous
    Adeno
    M. Gugger, Bern University
  • 21. Predictive Markers for ChemotherapyGandara, Curr Opin Oncol 2010
    Histology is a predictive factor for
    pemetrexed, gemcitabine and bevacizumab.
    Are molecular markers better ? Candidates:
    TTF1, ERCC1, TS, BRCA1, gene signatures
  • 22.
  • 23. TS and Drug ResistanceOzasa, Cancer Sci 2010
    23
  • 24. SAKK19/09 (BIOPRO)Multicenter phase II trial
  • 25. EGFR T790M Kobayashi, NEJM 2005
    25
  • 26.
  • 27.
  • 28. Case 1: EGFR mutation
    15 MAR 2010
    18 MAR 2011
    Erlotinib
    28
  • 29. EGFR-TKI and Line of TherapyMok ESMO 2010, Rosell NEJM 2009
  • 30. Case 2: ALK Translocation
    Crizotinib
    19 FEB 2011
    17 MAR 2011
  • 31. ALK-FISHJ. Diebold, Pathology Luzern
    HE: Adenocarcinoma with signet ring cells
    ALK FISH (break apart probe): positive (patient)
    IHC: TTF1 +
    ALK FISH (break apart probe): negative control
  • 32. ALK Inhibitor Crizotinib Kwak, NEJM 2010
    pretreated = 94%
  • 33. ETOP
    LUNGSCAPE
  • 34. Sequential TestingHorn, JCO 2009
  • 35. Parallel TestingKim AACR 2010+11
  • 36. Circulating DNAJCO 2004/Cancer Lett 2007
    mKRAS
    wtKRAS
  • 37. Mok, IPASS 2010
  • 38. Emerging markers: FGFR Weiss, Science Translat Med 2010
  • 39. Perspectives Gandara 2010
  • 40. Enroll patients in clinical trials
    If not possible, consider switch maintenance if SD, good PS or symptomatic
    Pemetrexed if non-SQ and not pretreated
    Erlotinib if SQ or previous pemetrexed or oral drug preferred
    Test for EGFR and ALK
    Recommendations
  • 41. Disclosure Slide
    Chair of investigator-initiated clinical trials supported by Roche, Eli Lilly, AMGEN, Bayer
    Advisory role for AstraZeneca
    No stocks
    No employment