Presentación del tema: "Papel de los nuevos Tki: AXITINIB"— Transcripción de la presentación:
1Papel de los nuevos Tki: AXITINIB Dr. Javier Puente VázquezServicio Oncología MédicaHospital Universitario Clínico San Carlos
2The challenge of treatment in mRCC Benefits of tyrosine kinase inhibitors (TKIs) are well established; however, there are limitationsThere are few complete responsesInitial partial responses are followed by progressionIn other cases there is no objective benefitDrug resistance remains an ongoing obstacle to successful treatment of mRCCLimits the success of therapy and reduces survival ratesMotzer RJ, et al. J Clin Oncol 2009; Rini B, et al. J Clin Oncol 2010; Escudier B, et al. J Clin Oncol 2010; Escudier B, et al. N Engl J Med 2007; Hudes G, N Engl J Med 2007
3Patterns of tumor progression on VEGF or VEGFR inhibitors Primary refractoryEarly progressorsLate progressorsGroup CChange in Tumor Measurements (%)Change in Tumor Measurements (%)Change in Tumor Measurements (%)Group AGroup B
4Targeted therapy in mRCC: mechanisms of resistance Group AGroup B-CTTP > 6 months. TKI´s sensitiveTTP < 6 months. TKI´s resistanceCont. VEGFr inhibitors ?Switch to mTOR inhibitors ?
5Inhibiting VEGF Receptors 1, 2, 3 Axitinib is an Oral, Potent, and Highly Selective Inhibitor of VEGF Receptors 1, 2, 3Small molecule indazole derivativeOrally administered: 5 mg BID5 mg Film Coated TabletAxitinibHNSCOMeAxitinib is an oral, potent, and highly selective inhibitor of VEGF receptors 1, 2, 3, and is in clinical development for a variety of tumour types. The chemical structure of axitinib was specifically designed to attach very tightly to an important binding site on the VEGF family of receptors and it does not bind firmly to other cell surface receptors. Because it only binds to the three VEGF receptors, it is referred to as a selective inhibitor.When a cell surface receptor is activated by its ligand, the receptor requires energy to initiate the intracellular message to the nucleus. An important intracellular energy supply is in the chemical form of adenosine triphospate bonds know as ATP. So, when a ligand binds to the receptor, ATP must also bind to the receptor to provide a source of energy. Axitinib, and other tyrosine kinase inhibitors, also bind at the ATP binding site on the receptor and thus can block ATP binding and generation of the intracellular message. Axitinib has a very high affinity for the ATP binding site and therefore is one of the most potent inhibitors of the VEGF family of receptors. The advantage of high potency is that axitinib may be able to inhibit the receptor when less potent drugs are not effective.BID = twice dailyHu-Lowe DD, et al. Clin Cancer Res. 2008;14:7272–7283.
6Disrupting Tumour Progression Axitinib comprehensively disrupts tumour progression by inhibiting the VEGF receptor signalling system.Metastatic Tumour Colonisation via LymphangiogenesisTumour Growth viaVascular Angiogenesis Tumour Cell ProliferationTumour Spread viaPIGFVEGF BVEGF AVEGF DVEGF CVEGFR 1VEGFR 2VEGFR 3AxitinibAs we discussed, axitinib is a potent and selective inhibitor of the VEGF family of receptors. By blocking VEGFR-1 and 2, axitinib can decrease tumour growth by blocking tumour cell proliferation and angiogenesis.Furthermore, by blocking VEGFR-3, axitinib can block lymphangiogenesis and thus decrease the possibility of metastasis.Ellis LM, Hicklin DJ. Nat Rev Cancer. 2008;8:579–591.
7Axitinib is a Selective Inhibitor of VEGF Receptors 1, 2, 3 RTKCellular IC50 (nM)VEGFR-10.1*VEGFR-20.2VEGFR-30.1–0.3PDGFR-α5.0PDGFR-β1.6KIT1.7CSF-1R73FGFR-1231FLT3>1000RETSelective InhibitorLow IC50 indicates higher affinity.Axitinib inhibits VEGF receptors 1, 2, and 3 at picomolar concentrations, suggesting potent and highly selective activity against these receptors.This slide depicts the biological activity of axitinib against a number of tyrosine kinase receptors. The biological activity is measured as the concentration of a drug that inhibits 50% of the activity of a receptor; this is called the inhibitory concentration 50 or IC50.Notice that the IC50 for axitinib is 10 times lower for the VEGF family of receptors than for other tyrosine kinase receptors. Also, notice that axitinib can block other receptors but not at the concentrations of the drug that are attained in the body. These data are the basis for the statement that axitinib is a selective inhibitor of the VEGF family of receptors.Hu-Lowe DD, et al. Clin Can Res. 2008;14:7272–7283.
8Axitinib is More Potent Than Most VEGF Receptor Kinase Inhibitors 1,0001001010.10.01VEGFR-1VEGFR-2VEGFR-3Less potentPotency: IC50 (nM)More potentThis graph depicts the IC50 for a number of tyrosine kinase inhibitors–known as TKIs–against the VEGF family of receptors. Notice that only two TKIs have IC50 less than 1 and axitinib is in this category.These data are the basis for the statement that axitinib is a potent inhibitor of the VEGF family of receptors.AV-951AxitinibCediranibMotesanib AMG-706SunitinibABT-869PazopanibSorafenibVatalanib PTK787VandetanibFigure modified using data from: Chow LQM, Eckhardt SG. J Clin Oncol. 2007;25:884–896; Eskens FALM, et al. Proceedings of the 99th Annual Meeting of the American Association for Cancer Research Abstract LB-201; and Hu-Lowe DD, et al. Clin Cancer Res 2008;14:
9Decreasing VEGFR-2 in Animal Models Axitinib Decreases VEGFR-2 in Animal ModelsAxitinib 7 daysBlockade of VEGFR-2 may lead to a decrease in MVD and blood flow.Significant reductions in intensity of VEGFR-2 and VEGFR-3 of RIP-Tag2† tumour vessels after 7 days of axitinib treatmentVehicleAxitinib 7 daysAfter establishing the potency and selectivity of cancer drugs against a receptor in test tubes, the next stage of testing is generally to determine if the drug will block the activity of the receptor in an animal model of cancer. In this study, a RIP-Tag2 model of spontaneous pancreatic tumours was used. In the model, because of a genetic deficit in pancreatic cells, the cells will convert to small tumours without investigator manipulation.In this animal model, inhibition of VEGF signaling can reduce the number of VEGFR-2 receptors found on the cell surface of certain types of blood vessels. Thus, axitinib was given to animals and VEGFR-2 expression was measured 7 days later and compared to pretreatment receptor expression. In this experiment, VEGF-2 expression was measured by attaching a fluorescence tag to a molecule that would bind to the VEGFR-2 receptor.As depicted in the top figure, the amount of fluorescence was dramatically reduced after axitinib treatment for 7 days which supports the ability of axitinib to inhibit VEGF signalling in animals. Also notice that the number of fluorescent peaks was decreased after axitinib treatment, which demonstrates that the actual number of blood vessels was also decreased.The microvessel density (MVD) is a measure of the number of small blood vessels in a certain amount of tissue and is positively correlated the amount of blood flow to that tissue. In this case, axitinib decreased MVD and therefore blood flow.The lower figure is comparing the activity of axitinib on the fluorescent intensity of a number of receptors including VEGFR-2 and 3. Again, these data confirm that the predominant action of axitinib is selective blockade of VEGF receptors.*Different from corresponding vehicle (P< 0.05)†The RIP-Tag2 animal model is of pancreatic islet cell cancer.MVD = microvessel densityInai T, McDonald D. J Am Pathol. 2004;165:35–52. Olsson AK, et al. Molec Cell Biol. 2006;7:359–371.
10Reduces Tumour Blood Vessels Axitinib Reduces the Number of Tumour Blood VesselsAxitinib reduced MVD and normalised tumour vasculature in 7 daysWithdrawal resulted in regrowth of vessels.CD31UntreatedAxitinib 7 daysWithdrawal 2 daysWithdrawal 7 daysIn other animal experiments, actual endothelial cells were stained red so one could visualise the outline of blood vessels in a tissue. In these studies, axitinib was given to the animals to test if it could reduce the number of blood vessels or MVD. Indeed, after 7 days of axitinib, there was a marked reduction in the number of blood vessels in this tumour tissue. The second part of the experiment tested if the administration of axitinib was stopped, would the tissue return to an untreated appearance.As can be seen in panels C and D, after axitinib was taken away, new blood vessels began to grow and after 7 days, the tissue had returned to pre-axitinib appearance. This constitutes strong evidence that axitinib can dramatically reduce microvessel density in animal models of cancer.RIP-Tag2Mancuso MR, et al. J Clin Invest. 2006;116:2610–2621.
11Decreasing Tumour Blood Flow Axitinib Decreases Tumour Blood FlowAxitinib rapidly decreases tumour blood vessel patency, blood flow, and vessel number within 24 hours of exposure.Vehicle Axitinib 1 DayReduction of FlowReduction of Angiogenic VesselsOverlayThis experiment tested the effect of axitinib on blood vessel number, diameter, or patency and flow. In the top panels (A and B), a green dye was injected into the blood vessels of animals just prior to sacrifice; if a vessel was patent or open, the green dye would fill up the vessels indicating flow.It is obvious that one day of axitinib therapy markedly reduced the amount of green dye in the tumour tissue, demonstrating reductions in blood flow. In panels C and D, endothelial cells are stained red so blood vessels could be visualised. Again, one day of axitinib therapy reduced the number of blood vessels in the tumour tissue.Finally, the two techniques of measuring blood flow and blood vessels were simultaneously evaluated in panels E and F. In panel F, after axitinib treatment, it can be seen that many blood vessels do stain red but appear not to have any green stain in them indicating that they were empty vessels. This result can be interpreted that the vessels had collapsed upon themselves and lost patency.The overall message is that axitinib can inhibit VEGF receptors in animal models of cancer and this leads to decreased blood vessel numbers, blood vessel patency, and blood flow.Inai T, McDonald D. J Am Pathol. 2004;165:35–52
12Axitinib Blocks Vascular Sprouting in Animal Models UntreatedVascular sprouting is one of the initial processes associated with angiogenesis.Axitinib 7 daysAxitinib effectively blocks vascular sprouting.As we discussed previously, vascular sprouting is a principle mechanism by which angiogenesis occurs and is under the control of the VEGF family of receptors. In the RIP-Tag2 animal model of spontaneous pancreatic cancer, vascular sprouting occurs as tumours grow and can be visualised through electron microscopes.In the top panel, untreated animals exhibit numerous sprouts on tumour blood vessels undergoing angiogenesis.In the bottom panel, one sees the results of axitinib treatment. Axitinib was administered to the animals for 7 days and the amount of vascular sprouting is drastically reduced. This study confirms that axitinib can inhibit the VEGF family of receptors and the result is inhibition of sprouting and angiogenesis.Tammela T, et al. Nature. 2008;454:656–660; Inai T, McDonald D. J Am Pathol. 2004;165:35–52.
13Axitinib Reduces Tumour Growth Reduction in Vascular PermeabilityAxitinib decreased vascular permeability after 7 days.7 days post-treatmentBaseline0.0100.1000.0500.0250.075KPS (mL/100 g/min)Control 1Axitinib 1Axitinib 2Control 2Color maps of Kps values in the central tumour sliceTumour volume is a true measure of tumour growth and is dependent upon a number of variables such as tumour cell proliferation, angiogenesis, and vascular permeability; all of these variables are partially regulated by the VEGF family of receptors.Vascular permeability is important because it helps to determine how much oxygen and nutrients enter the tumour tissue from the blood stream and how many waste products leave the tissue and are carried away by the blood stream. In this animal study, the effects of axitinib on both vascular permeability and tumour volume were evaluated.In the panel, which shows slices of tumours, the intensity of the red and yellow colors correlate with increased vascular permeability. As you can see, the intensity of the colours is reduced after the animals are treated with axitinib.MRI = magnetic resonance imaging; Kps = tumour endothelial transfer coefficient Wilmes LJ, et al. Magn Reson Imaging. 2007;25:319–327.
14Axitinib Reduces Tumour Growth Reduction in Tumour VolumeAxitinib reduced tumour volume in mice.Mean volume change after 7 days–200–100100200300400(mm3)ControlAxitinib+ 213 mm3- 160 mm3MRI enhanced tumour measurements showed significant decreases in tumour volume for the axitinib vs. control group.Tumour volume is a true measure of tumour growth and is dependent upon a number of variables such as tumour cell proliferation, angiogenesis, and vascular permeability; all of these variables are partially regulated by the VEGF family of receptors.The tumour in axitinib-treated animals actually decreased in volume after 7 days of treatment instead of increasing volume through growth.This is another confirmation that axitinib can inhibit VEGF signaling in animals, leading to decreased vascular permeability and tumour volume.MRI = magnetic resonance imaging; Kps = tumour endothelial transfer coefficient Wilmes LJ, et al. Magn Reson Imaging. 2007;25:319–327.
29Reflexiones ASPECTOS POSITIVOS ASPECTOS ???? Estudio Fase III randomizado.Estudio PURO de 2ª línea.Mediana PFS: 6.7 mesesTR: 19%Tolerancia similar TkiBaja tasa de discontinuación45% de los pacientes no recibieron sunitinib.En pre-Sunit, PFS: 4.8 meses¿Porqué tanta discrepancia entre IRC e investigadores?¿Porqué dar la opción de incrementar la dosis?
30Conclusiones- Axitinib es un nuevo inhibidor de tirosina quinasa de alto poder inhibitorio sobre VEGFR 1, 2 y En el contexto de la segunda línea, y en comparación con sorafenib, prolonga la SLP de forma significativa. - Axitinib presenta un perfil de tolerabilidad semejante a otros Tki (hipertensión, hipotiroidismo) pero, en comparación con sorafenib, presenta menos SMP, rash y alopecia. - Axitinib se postula como una alterantiva terapéutica en el contexto de la segunda línea del CCRm.