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MCO 2011 - Slide 20 - R.A. Stahel - Spotlight session - New drugs in oncogenic-driven malignancies (thyroid, melanoma)

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MCO 2011 - Slide 20 - R.A. Stahel - Spotlight session - New drugs in oncogenic-driven malignancies (thyroid, melanoma) MCO 2011 - Slide 20 - R.A. Stahel - Spotlight session - New drugs in oncogenic-driven malignancies (thyroid, melanoma) Presentation Transcript

  • New drugs in oncogenic-driven malignacies
    Rolf Stahel
    University Hospital
    Zürich
    Switzerland
    ESO Masterclass, Ermatingen, April 4, 2011
  • Translocation
    RAS
    PI3K
    PLC-Y
    STAT3/5
    MEK
    AKT
    PIP2
    mTOR
    ErK
    BAD
    IP3
    S6K
    Cell survival
    ALK (Anaplastic Lymphoma Kinase) pathway
    Or
    Inversion
    ALK fusion protein*
    ALK
    Tumor cellproliferation
    *Subcellular localization of the ALK fusion gene, while likely to occur inthe cytoplasm, is not confirmed.1,2
    1. Inamura K et al. J Thorac Oncol 2008;3:13–17 2. Soda M et al. Proc Natl Acad Sci U S A 2008;105:19893–19897Figure based on: Chiarle R et al. Nat Rev Cancer 2008;8(1):11–23; Mossé YP et al. Clin Cancer Res 2009;15(18):5609–5614; and Data on file. Pfizer Inc.
  • HE
  • CD5
    CD30
    HE
    CD20
    ALK
    4.jpg
  • Anaplastic T celllymphoma
    ALK-positive anaplastic large cell lymphoma represents about 6% of peripheral T-cell lymphomas
    Molecularly chararcterized by t(2;5) resulting in a fusion protein of ALK (anaplastic lymphoma kinase) and NPM (nucleophosmin)
    Good prognosis treated by CHOP chemotherapy
    Dunleavy, Clin Cancer Res 2010
  • ALK aberrations in malignancies
    Mossé, CCR 2009
  • ALK in neuroblastoma
    Identification of ALK as familial predisposition geneMosse, Nature 2008
    Somatic and germline muations of the ALK kinase receptor in neuroblastomaJanoueix-Lerosey, Nature 2008
    Activating mutations in ALK provide a therapeutic target for neuroblastomasGeorge, Nature 2008
    Alk mutations in 6.9% of 709 tumors, similar rate in favorable and unfavorable neuroblastoma: Two hotspots R1174 and F1174De Brouwer, CCR 2010
  • ALK in lung cancer
    Pao & Girard, Lancet Oncol, 2011
  • EML4–ALK is a potent “oncogenic” driver
    EML4–ALK(K589M)
    Vector EML4 ALK EML4–ALK NPM–ALK v-Ras
    3T3
    Nude
    mice
    Tumor/
    injection 0/8 0/8 0/8 8/8 0/8 8/8 2/2
    Inhibition of ALK leads to dramatic in vivo tumor regression
    Soda M et al. Nature 2007;448:561–567
    Reprinted by permission from Macmillan Publishers Ltd: Nature, © 2007
    EML4 = echinoderm microtubule-associated protein-like 4; NPM = nucleophosmin
  • Diagnosis of EML4-ALK positive NSCLC
    FISH
    PCR/Sequencing
    IHC
  • EML4
    EML4-ALK fusion by inversion (~ 70%)
    2p23-21
    3‘
    5‘
    EML4
    ALK
    ~ 12 Mb
    Curtesy Lukas Bubendorf
  • Clinical featuresofpatientswith EML4-ALK NSCLC
    Predominantly found adenocarcinoma. TTF1 pos., acinar histology, mutually exclusive with EGFR and KRAS mutationsTakeuchi, CCR 2008; Inamura, Modern Path, 2009; Takahashi, ASCO 2010; Zhang, Mol Cancer 2010
    More frequent in never or former light smokersSasaki, EJC 2010
    Predominant in younger patients
    36% (4/11) under 50 y/o (compared to 5% ALK-negative adenocarcinomas)Inamura, Modern Path, 2009
    Median age 52 yrs vs 66 and 64 for mEGFR or WT tumorsShaw, JCO 2009
  • 60
    40
    20
    0
    –20
    –40
    –60
    –80
    –100
    Progressive disease
    Stable disease
    Confirmed partial response
    Confirmed complete response
    Maximum change in tumor size (%)
    –30%
    Responses to Crizotinib for patients with ALK-positive NSCLC
    Response rate:
    • 57% (95% CI: 46, 68%)
    • 63% including 5 as yet unconfirmed
    PFS:
    • Median not yet reached (median f/u for PFS of 6.4 months)
    *
    F1174L mutation associated with resistanceSasaki, CR 2010
    Bang, ASCO 2010: Kwak, NEJM 2010
  • Targeting ALK through HSP90 inhibitors?
    Mutated proteins – such as the ALK fusion gene product – depend on HSP90 for maturation and conformational stability
    Inhibition of murine ALK-driven adeno-carcinoma by HSP90 inhibitorChen, CR 2010
    HSP90 inhibitor lowers EML-ALK levels and induces tumor regression in NSCLC modelNormant, Oncogene, 2011
    ALK Inhibitor
    HSP90 inhibitor
  • MAPK pathwayactivation in melanoma: BRAF andkit
    Arkenau, Br J Cancer 2011
  • BRAF andkitmutationsin melanoma
    60% of melanoma cell lines and cultures show oncogenic mutations of BRAFDavis, Nature 2002
    Distinct set of genetic alteration in different types of melanomaCurtin, NEJM 2003
    CSD: chronic sun-induced damage
  • PLX4032 treatmentofmelanomawithRBAF V600E mutations
    ICH at baseline and day 15 on therapy:
    Flaherty, NEJM 2010
  • PLX4032 treatmentofmelanomawith RBAFV600E mutations
    32 patient treated with in recommended phase 2 dose of 960 mg twice daily: CR 2 pts, PR 24 pts
    Estimated median progression-free survival 7 months
    Resistance mechanisms: Preclinical evidence for concomitant PTEN loss, AKT activation, cyclineD/DK5 activation, MEK mutation, …
    Flaherty, NEJM 2010; Puzanov Mol Oncol 2011,
  • Kit mutations in melanoma
    Associated with a proportion of mucosal, acral and chronically sun-damaged melanoma
    Clinical studies with imatinib and nilotinib ongoing
    Patient with metastatic melanoma of the vulva treated with imatinib
    Dummer, USZ 2009
    September 09
    June 09
  • Hedgehogpathway
    Low and de Sauvage, JCO 2010
  • Sonic hedgehogpathwaydriventumors: basal cellcarcinomaandmedulloblastoma
    Hedgehog pathway is inactive in adult tissue
    Gorlin syndrome: germ line mutation in PTCH1: numerous basal cell carcinomas and other tumors, especially medulloblastoma
    Basal cell carcinoma associated with mutations in the hedgehop signaling pathway (PCHT1 > SMO) which causes constitutive pathway signaling
    About 30% of medulloblastomas have activating mutations in PTCH1
    GDC-0449 is a selective hedgehog signalling pathway inhibitor
  • Inhibition ofhedgehogpathway in advanced basal-cellcarcinoma
    33 patients with advanced or metastatic basal cell carcinoma treated with GDC-0449, a small molecule inhibitor of SMO
    RR 54%, SD 33%, median response duration 8.8+ mths
    No DLT
    Von Hoff, NEJM 2009
  • Treatment ofmedulloblastomawithhedghogpathwayinhibitor GDC-0449
    Case report of 26 y/o man with metastatic medulloblastoma with a PTCH1 mutation treated with GDC-449. Rapid response with response duration of 3 months
    Resistance due to SMO mutationYauch, Science 2009
    2 months
    Baseline
    3 months
    Rudin, NEJM 2009
  • Phase I trialof GDC-449 in patientswithrefractory solid tumors
    Responses in 58% of 33 patientswith basal cellcarcinoma, duration 12.8+ months, 1/1 patientwithmedulloblastomaandnoneof 34 patientswith oder solid tumors (including 3 SCLC and 3 mesothelioma)
    Downregulationof GLI1 ascomparedtobaseline
    GLI1 expression
    LoRusso, CCR 2011
  • RET (REarrangedduringTransfection) receptortyrosinekinaseactivation in cancer
    Ligands: glialcellline-derivedneurotrophicfactor (GDNF) family
    Activationrequirestheformationof a multimerecomplexincludingtheligand, a GDNF-familyreceptor-α proteinbindingbindingtheligandandret
    Ret know-out mice: lack ofentericneuronsandagenesisofthekidney
    Phay, CCR 2010
  • Medullarythyroidcancer
    Araise from parafollicular or calcitonin-producingc-cells of the thyroid
    15% of thyroid malignancies
    70-80% sporadic, 20-30% familial
    Associated with paraneoplasticsyndroms related to hormone production of c-cells (diarrhea)
    Activation of TET critical in MTC tumorigenesis
    RET mutation:
    100% of hereditary MTC (autosomal dominat)
    >40% of sporadic thyroid cancer
  • Heredidary MTC-associatedsyndroms
    MEN-2A: MTC with pheochromocytoma or parathyroid hyperplasia or adenoma
    MEN-2A:MTC with pheochromocytoma and associated clinical abnormalities (mucosal neuromas, intestinal ganglioneuromtosis, delayed puberty, marfanoid habitus, skeletal abnormalities, corneal nerve thickening
    FMCT:Familial disease with no evidence for pheochromocytom or parathyroid adenoma
  • Vandetanibformedullarythyroidcarcinoma
    Oral TKI targeting VEGFR, EGFR und RET
    30 patients, RR 20% (mean durstions 311+ days), additional SDR at 24 weeks 53%
    Wells, JCO 2009
  • Vandetanibvsplacebo in medullarythyroidcancer
    Wells, ASCO 2010
  • Motesanib in locallyadvancedormetastatichereditaryMTC
    Oral TKI targeting VEGFR, PDGF, Kit and RET
    Phase II study
    Response in 2% of 91 patients, stable disease (>24 weeks) in 81%
    Decrease in calcitonin 83%
    Schlumberger, JCO 2009
  • Targetedtherapyformetastaticdifferentiatedthyroidcancer
    Most frequent - mutually exclusive - mutations: in papillary thyroid cancer
    BRAF 45%, almost all V600E
    RAS 15%
    RET-translocations 20%
    Most frequent mutations in follicular thyroid cancer:
    RAS 45%
    PAX8-PPARϒ rearrangement 35%
    Mutation in PI3K/Akt pathway 10%
    O’Neill, Oncologist, 2010
  • Sorafenibin thyroidcancer
    Sorafenib: TKI against VEGFR2, PDGF, BRAF,
    Medullary thyroid cancer:16 pts, 1 objective response, 14 stable disease
    Differentiated thyroid cancer:Ongoing randomized phase III study versus placebo with cross over
    Lam, JCO 2010
  • Pazopanib in radioiodine-refractorymetastaticdifferentiatedthyroidcancer
    Oral TKI targeting VEGFRs, PDGFR and kit
    Responses in 49% of 39 patients
    1-year PFS 47%
    Bible, Lancet Oncol 2010
  • MET in lung cancer
    Pao & Girard, Lancet Oncol, 2011
  • Why targeting MET and HGF in NSCLC:Met amplification and EGFR resistance
    NSCLC cell lines with met amplification depend on MET for growth and survivalLutterbach, CR 2007
    Increased MET copy number(4%) associated with worse prognosis in resected NSCLC. Cappuzzo, JCO 2009
    MET amplification and resistance to EGFR TKIs:
    Combination of gefitinib andMET inhibitor Engleman, Science 2007; Spigel, ESMO 2010
    Erlotinib+ MetMAb
    Control
  • How to target MET
    Anti-HGF Ab
    • AMG102
    • SCH900105
    Anti-c-METAb
    • METMAb
    Selective
    c-MET inhibitors
    • Tivantinib (ARQ 197)
    • JNJ-38877605
    • PF04217903
    Non-selective
    c-MET inhibitors
    • PF02341066
    • Cabozantinib (XL184)
    • Foretinib (GSK1363089)
    • MK-2461
    • MP470
    • MGCD265
    Curtesy Alex Adjei
  • MetMab


    HGF
    HGF
    In Vivo
    EGFR WT NSCLC XenograftNSCLC
    MetMAb
    Erlotinib+ MetMAb
    Control
    Met
    Met
    Growth, Migration, Survival
    No Activity
    Spigel, ESMO 2010
  • Development of Met IHC as a Diagnostic
    • Intensity of Met staining on tumor cells scored on 0–3+ scale
    1+
    2+
    3+
    • Estimated that ~50% of patients would have ‘Met High’ tumors
    • Met by IHC was assessed after randomization
    ‘Met High’ was defined prior to unblinding as:
    ≥50% tumor cells with a staining intensity of 2+ or 3+
    • Tissue was obtained from 100% of patients.
    • 95% of patients had adequate tissue for evaluation of Met by IHC.
    • 54% patients had ‘Met High’ NSCLC.
    Spigel, ESMO 2010
    38
  • 39
    Anti-MetMonovalent Antibody: PFS Subgroup Analyses in ITT
    Spigel, ESMO 2010
  • Selective oral MET inhibitor ARQ 197 (tavantinib)
    Tivantinib (ARQ 197) targets inactive kinase conformations
    Phase II trial comparing erlotinib plus ARQ 197 to erlotinib plus placebo in second lineSchiller, ASCO 2010
    Tivantinib
    c-MET
    Key motifs
  • Phase II trial of erlotinib plus ARQ 197 vs erlotinib plus placebo in second line: Histologic and molecular subgroups
    Schiller, ASCO 2010
  • Cabozantinib (XL184) multikinase inhibitor
    ATP competitive, reversible
  • Cabozantinib (XL184): Promising activity in previously treated NSCLC patients
    Best Radiologic Time Point Response of Patients with >1 Post-baseline Tumor Assessment
    Interim RDT data presented at 2010 EORTC-NCI-AACR Symposium