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.
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 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.
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
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.