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ECCLU 2011 - C. Rothermundt - Mechanisms of action in modern RCC treatment ECCLU 2011 - C. Rothermundt - Mechanisms of action in modern RCC treatment Presentation Transcript

  • Mechanisms of Action in Modern RCC Treatment
  • Conflict of Interest Declaration
    BAYER – Advisory Board
    GLAXOSMITHKLINE – Advisory Board
    NOVARTIS – Support for this talk
  • Renal Cell Cancer – Histological Subtypes
    BHD, Birt-Hogg-Dubé; VHL, von Hippel-Lindau.
    Linehan WM, et al. Clin Cancer Res. 2007;13:671s-9s.
  • Von Hippel-Lindau (VHL) Protein Controls the Expression of the HIF- Transcription Factors
    HIF, hypoxia-inducible factor; HRE, hypoxia-responsive element; VEGF, vascular endothelial growth factor.
    Cohen HT, et al. N Engl J Med. 2005;353:2477-90.
  • VHL Loss Is Prevalent in RCC
    The majority of clear cell RCCs lack functional VHL protein1
    This loss of function may occur via VHL gene mutations or epigenetic silencing via promoter hyper-methylation1,2
    Recent studies have found VHL inactivation in RCC (via mutation or hyper-methylation) to be quite widespread
    90% of 78 patients assessed3
    91% of 205 patients assessed4
    1. Gossage L, Eisen T. Nat Rev Clin Oncol. 2010;7:277-88.
    2. Gnarra JR, et al. Nat Genet.. 1994;7:85-90.
    3. Hutson TE, et al. J Clin Oncol. 2008;26(15S):5046.
    4. Nickerson ML, et al. Clin Cancer Res. 2008;14:4726-34.
    RCC, renal cell carcinoma.
  • VHL Loss Fuels Accumulation of HIF and Uncontrolled Angiogenesis in RCC
    PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; VEGFR, VEGF receptor.
    Rini BI. Cancer. 2009;115:2306-2312.
  • Anti-VEGF Treatment
  • VEGF and VEGFR Blockade Inhibit Angiogenesis and Tumour Growth in RCC
    Rini BI. Clin Cancer Res. 2007;13:1098-106.
    Ellis LM, Hicklin DJ. Nat Rev Cancer. 2008;8:579-91.
  • Response and Duration of Response to Anti-VEGF or Anti-VEGFR Treatment
    CR, complete response; ORR, objective response rate, PD, progressive disease; PFS, progression-free survival; PR, partial response.
    1. Motzer RJ, et al. N Engl J Med. 2007;356:115-24.
    2. Escudier B, et al. Lancet. 2007;370:2103-2111.
    3. Sternberg C, et al. J Clin Oncol. 2010;28:1061-1068.
  • Adaptive resistance:VEGF-targeted agents fail to produce enduring clinical responses in most patients
    Intrinsic resistance:No predictive biomarkers available to date
    Bergers G, Hanahan D. Nat Rev Cancer. 2008;8:592-603.
    Resistance to VEGF-targeted Therapy Is a Key Clinical Issue
  • VEGFR-TKI Therapy Activates Alternate Pro­angiogenic Pathways
    Early Phase: Response to VEGF-targeted therapy
    Late Phase: Angiogenic escape of VEGF blockade
    Cancer cells
    VEGF
    Cancer cells
    VEGF
    FGF, IL-8,
    others
    No Angiogenesis
    Reactivation of Angiogenesis
    Hypoxia
    Endothelial cells
    Endothelial cells
    Inhibition of VEGF signaling transiently stops tumour growth and decreases vascularity
    Activation of other pro-angiogenic factors leads to tumour progression
    FGF, fibroblast growth factor; IL, interleukin; TKI, tyrosine kinase inhibitor.
    Figure revised from: Casanovas O, et al.
    Cancer Cell. 2005;8:299-309.
  • Anti-VEGFR2 Therapy Induces an Invasive Phenotype
    Control (end-stage)
    Anti-VEGFR2 1 week
    Anti-VEGFR2 4 weeks
    H&E
    Anti-T antigen
    Anti-CD31
    H&E, hematoxylin and eosin.
    Paez-Ribes M, et al. Cancer Cell. 2009;15:220-31.
  • VEGFR Inhibition Triggers Upregulation of FGF and Other Angiogenic Factors
    In a mouse model of pancreatic islet carcinogenesis (RIP-Tag2):
    Resistance to VEGFR2 antibody was accompanied by up-regulation of mRNA expression for several pro-angiogenic factors, including FGF1, FGF2, FGF7, and Ang-1, in tumour and/or stromal cells
    2.5
    2.0
    1.5
    Fold Change in Expressionin VEGFR2-blocked vs Control
    1.0
    0.5
    0
    FGF1
    FGF2
    FGF7
    VEGF
    EphA2
    FGFR1
    FGFR2
    VEGFR1
    VEGFR2
    Angiop.1
    Angiop.2
    EphrinA1
    Casanovas O, et al. Cancer Cell. 2005;8:299-309.
  • Additional Possible Mechanisms of Resistance to VEGFR-TKI Therapy
    Hypoxia HIF1-a circulating VEGF and PDGF 
    Placental growth factor (PlGF)
    Inter-molecular crosstalk between FLT1 and FLK1
    Up-regulation of the expression of VEGF-A, FGF2, PDGFB, MMPs
    Up-regulation of pro-angiogenic stromal cells
    Tumour-associated fibroblasts (TAFs)
    Bone marrow-derived cells
    Vascular progenitors and pro-angiogenic monocytic cells, TIE2+ monocytes, VEGFR-1+ hemangiocytes, CD11b+ myeloid cells
    Inadequate target inhibition
    Azam F, et al. Eur J Cancer. 2010;46:1323-1332
  • Increased Secretion of IL-8 Linked to Sunitinib Resistance in RCC
    786-O Xenograft
    IL-8 Level in Plasma From786-O Xenograft Mice (Day 68)
    0.8
    *
    3.0
    Sensitive
    Resistant
    2.5
    0.6
    2.0
    (n = 15)
    0.4
    1.5
    Tumor Growth Ratio
    IL-8(pg/mL/mm3 tumor)
    1.0
    0.2
    (n = 3)**
    0.5
    0
    0
    33
    36
    67
    40
    43
    46
    48
    50
    53
    55
    57
    60
    62
    64
    Control
    Sensitive
    Resisitant
    Time After Tumor Inoculation (d)
    Huang D, Ding Y, Zhou M, et al. Cancer Res. 2010;70:1063-1071.
  • IL-8 Expression Is Increased in Patients With Intrinsic Resistance to Sunitinib
    IL-8 scoring
    Negative
    Weakly positive
    Strongly positive
    Sunitinib sensitive
    Sunitinib refractory
    Huang D, Ding Y, Zhou M, et al. Cancer Res. 2010;70:1063-1071.
  • Re-challenge With Anti-VEGF Treatment
    Sunitinib in bevacizumab-refractory patients1
    Axitinib in sorafenib-refractory patients2
    Sunitinib re-challenge after previous treatment with sunitinib3
    1. Rini BI, et al. J Clin Oncol. 2008;26:3743-3748.
    2. Rini BI, et al. J Clin Oncol. 2009;27:4462-4468.
    3. Zama IN, et al. Cancer. 2010;116:5400-5406.
  • Summary: VEGF Inhibitors
    Loss of functional VHL and over-expression of HIF drive uncontrolled angiogenesis in RCC
    VEGF-targeted agents inhibit angiogenesis and have become the standard-of-care first-line treatment in mRCC
    Durable responses to VEGF-targeted agents are rare, and resistance can arise via multiple mechanisms
  • mTOR Inhibition
  • mTOR Inhibition Blocks HIF-1 Production and Slows Tumour Growth in RCC
    Everolimus
    Temsirolimus
    mTOR, mammalian target of rapamycin.
    Rini BI. J Clin Oncol. 2009;27:3225-34.
    Morgensztern D, McLeod HL. Anticancer Drugs. 2005;16:797-803.
  • mTOR Blockade Affords Broad Inhibition of Tumour Vasculature
    In a mouse model of melanoma (B16/BL6):
    Everolimus reduces VEGF in tumour and plasma, while the VEGFR-TKI vatalanib (PTK787) only reduces plasma VEGF
    Everolimus has a more profound effect on mature blood vessels (by SMA staining of smooth muscle cells)
    SMA, smooth muscle antibody.
    Lane HA, et al. Clin Cancer Res. 2009;15:1612-22.
  • Temsirolimus Improves OS in Patients With Poor Prognosis mRCC
    n = 626; all histologies
    1.00
    Temsirolimus: median OS 10.9 months
    Interferon: median OS 7.3 months
    0.75
    Temsirolimus
    0.50
    Probability of Survival
    Combination
    Interferon
    0.25
    0.00
    0
    5
    10
    15
    20
    25
    30
    Months
    mRCC, metastatic RCC; OS, overall survival.
    Hudes G, et al. N Engl J Med. 2007;356:2271-81.
  • Everolimus Shows Clinical Efficacy in VEGFR-TKI-refractory mRCC
    n = 416, clear cell histology
    100
    Everolimus: median PFS 4.90 months
    Placebo: median PFS 1.87 months
    80
    HR: 0.33
    (95% CI: 0.25, 0.43)
    Log rank P < .001
    60
    Probability, %
    40
    20
    0
    0
    2
    4
    6
    8
    10
    12
    14
    Time, months
    CI, confidence interval; HR, hazard ratio.
    Motzer RJ et al. Cancer. 2010;116:4256-65.
  • PI3K/Akt Activation May Drive Resistance to mTORC1 inhibitors
    Everolimus
    Temsirolimus
    Figure adapted from:
    Rini BI, Atkins MB. Lancet Oncol. 2009;10:992-1000.
  • Novel Strategies for Targeting PI3K/Akt/mTOR Signaling in RCC are emerging
    Dual PI3K/mTOR inhibitor BEZ235
    786-O
    2500
    NVP-BEZ235
    BEZ235
    Rapamycin
    2000
    V
    ehicle
    1500
    Volume (mm3)
    1000
    500
    0
    0
    1
    3
    5
    7
    9
    11
    13
    15
    17
    19
    21
    Days
    BEZ235 treatment resulted in growth arrest, compared to slight tumor regression with rapamycin
    Figure adapted from: Rini BI, Atkins MB. Lancet Oncol. 2009;10:992-1000.
    Cho DC, et al. Clin Cancer Res. 2010;16:3628-38.
  • mTOR Inhibition Activates MEK/ERK SignalingMEK and EGFR inhibitors may overcome mTOR resistance
    Wang X, et al. Cancer Biol Ther. 2008;7:1952-8.
  • Summary: mTOR Inhibitors
    Inhibition of mTOR overcomes resistance to VEGF-targeted agents in mRCC
    Temsirolimus is the standard of care in patients with poor prognosis mRCC and everolimus is the standard of care in patients with mRCC who have failed initial VEGFR-TKI therapy
    mTORC2 complex is neither inhibited by temsirolimus nore everolimus
    mTORC1 inhibition may cause compensatory activation of PI3K and AKT
  • Other Investigational Targets in RCC
  • FGFR/FGF Signaling Is Dysregulated in Cancer
    Dysregulated expression of FGFs or FGFRs due to genetic or epigenetic changes1
    FGF signaling plays a prominent role in angiogenesis1
    Highly vascularised tumours, e.g. RCC, often contain high levels of FGFs and FGFRs after treatment with VEGF pathway inhibitors2
    FGFR, FGF receptor.
    1. Korc M, Friesel RE. Curr Cancer Drug Targets. 2009;9:639-51.
    2. Presta M, et al. Cytokine Growth Factor Rev. 2005;16:159-78.
  • Dovitinib (TKI258) Inhibits FGFR and Other TKIs
    Inhibits the tyrosine kinase activity1 of
    FGFR, VEGFR
    PDGFR, c-KIT, FLT-3, CSF1R
    Nanomolar IC50 values1
    Exhibits direct anti-tumour and anti-angiogenic activity2
    Oral dosing2
    Clinical trials ongoing in renal, breast, and urothelial cell cancers and in multiple myeloma
    IC50, half maximal inhibitory concentration.
    Lopes de Menezes DE, et al. Clin Cancer Res. 2005;11:5281-91.
    Renhowe PA, et al. J Med Chem. 2009;52:278-92.
  • Targeting HGF/c-Met Signaling in Papillary RCC
    Hereditary and sporadic papillary RCCs show activating mutations in the c-Met receptor tyrosine kinase
    HGF/c-Met signaling is also implicated in angiogenesis
    Several c-Met inhibitors are now in clinical trials, including:
    Foretinib
    ARQ 197
    HGF, hepatocyte growth factor.
    Maulik G, et al. Cytokine Growth Factor Rev. 2002;13:41-59.
    Figure adapted from Sekulic A et al. Mayo Clin Proc. 2008;83:825-46.
  • c-Met as a Target in Clear Cell RCC
    Analysis of c-Met protein expression in 317 RCC tumour specimens
    c-Met is expressed in all RCCs, including those of clear cell histology
    Expression is highest in tumours with papillary and sarcomatoid histology
    High c-Met expression correlates with higher tumour grade (P = .0019) and clinical stage (P = .0208)
    High c-Met expression is an independent predictor of poor OS (P = .017) in RCC, including the clear cell subtype
    Gibney G, et al. J Clin Oncol. 2011;29(7 suppl):360.
  • CTLA-4 and PD-1 Blockade May Prolong T-cell Activation in Multiple Tumour Types
    Ipilimumab, an anti-CTLA-4 monoclonal antibody, was recently approved by the US Food and Drug Administration for use in patients with metastatic melanoma2
    1. Kandalaft LE, et al. J Clin Oncol 29:925-933.
    2. “Ipilimumab”, http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm248478.htm.
  • Anti-CTLA-4 mAbs Show Preliminary Efficacy in mRCC
    Phase I dose-escalation study of tremelimumab in combination with sunitinib in mRCC1
    21 patients enrolled; 9 achieved a PR
    Phase II trial of ipilimumab monotherapy in patients with mRCC2
    61 patients enrolled; 6 achieved a PR
    33% of patients experienced grade 3/4 autoimmune-mediated toxicity
    Significant association between autoimmune events and anti-tumour activity
    30% response rate in 20 patients with autoimmune toxicity
    0% response rate in 41 patients with no autoimmune toxicity
    P = .0007
    1. Rini BI, et al. Cancer. 2011;117:758-67.
    2. Yang JC, et al. J Immunother. 2007;30:825-30.
  • MDX-1106, a Fully Human Anti-PD-1 mAb, Affords Tumour Regression in a Patient With mRCC
    1 patient with mRCC in a phase I dose-escalation trial of MDX-1106 in patients with refractory solid tumours
    Previously treated with sunitinib, sorafenib, and an experimental histone deacetylase inhibitor
    PR for 16+ months
    Regression of Metastases in Mediastinal Lymph Nodes by Contrast-enhanced CT Scan in a Patient With mRCC After Repeat Dosing With MDX-1106 at 10 mg/kg.
    CT, computed tomography.
    Brahmer JR, et al. J Clin Oncol. 2010;28:3167-75.
  • Conclusions
    Novel therapeutic targets currently under investigation may provide treatment options for patients who progress after VEGF-targeted treatment and mTOR inhibitors
    Predictive markers are needed for treatment selection
    Definition of resistance by RECIST criteria has limitations
    Functional imaging needs validation and has to become widely available
    Dose escalation, drug combinations, dual pathway inhibition and sequencing of treatments are therapeutic strategies
    RECIST, Response Evaluation Criteria In Solid Tumors.