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


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

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