 What is the hottest new small molecule in RCC? And we have asked Emilio Calvo from IDIT to answer this question. Please. Thank you very much, John. Yes, in the next 15 minutes, I will be talking on this topic what is the potentially best new molecule in kidney cancer. I will be talking not only on small molecules, but also on monoclonal antibodies. And I will be excluding on purpose the targeted team of therapeutic agents because this has been already reviewed yesterday by McDermott. So as you know, we have currently therapeutic agents that target multiple alternative pathways that are involved in kidney cancer. And these are currently under investigation. And this is because in spite of the fact that all the drugs are ideal for all the patients according to our prior colleagues, the approved treatments are not curative. The median overall survival remains optimal. And the patients, at the end of the day, progress of the disease. Also, drug resistance is a major challenge for the available agents that are BGF-targeted drugs or end-to-end inhibitors. And in addition, we have a lot of off-target effects that can occur with the BGF-targeted therapies and make it difficult for the patients to have these drugs because of clinically relevant toxicities. So the way that we are developing the novel agents in kidney cancers can be grouped in two different approaches. On one hand, we have the potential of trying to develop more selective BGF-RTKIs mid-to-drugs, trying to get less toxic agents and potentially more active. And here we have the paradigm of the BGF-RTK that have not been approved. But it is interesting to comment on that to explore that concept. And then we have drugs that are approaching or targeting different targets in the search of more activity. And the targets that are being more intensively exploring kidney cancer are CMET, Type 2, ALK-1, end-to-end inhibitors, and PI-3K-AKT end-to-end inhibitors. And for my talk, I will be grouping this into two different groups. The novel pure anti-angiogenic agents like the ones that are here on red, T-Bosani, again, just to explore the mid-to-BFRTKI failure paradigm, the CMET inhibitors, like Kavosantinib or Furetinib, then the Type 2 inhibitor regrafinib, and also the ALK-1 end-to-end inhibitor. And then I will talk also on the other group of agents that are novel PI-3K-AKT end-to-end inhibitors. So let's get started with the T-Bosani paradigm. As you know, this is probably the most potent T-K-A-I-B-F-R-TKI that we have currently compared to the ones that are available from a commercial point of view. And there was a randomized pi-botal phase three trial, the T-B-1, comparing head-to-head infest-line therapy, T-Bosani versus Saurafenib, more than 500 patients, and those progression on Saurafenib were allowed to receive T-Bosani in a separate protocol. This is a positive trial regarding the main primary and point progression-free survival. You can see that with T-Bosani, the PFS was the longest one that we have had in a randomized phase three trial, almost 13 months. It was statistically superior to the PFS of Saurafenib, named MAHMS, and also we compare with the other two phase three pi-botal trials for Suneet and Sampasopan if they are approved in phase-line therapy. It seems to be superior or at least comparable or not inferior to them. The issue was with the overall survival was not the primary and point, and you can see that the overall survival percentage after one year was similar for T-Bosani and Saurafenib, about 80%, and similar also for the other two drugs that are approved, Suneet and Sampasopanib. It is interesting to comment that only 15% of the patients on T-Bosani received second-line therapy and for Saurafenib are almost two-thirds of the patients were having second-line therapy with T-Bosani, so that might explain also this lack of difference in the secondary endpoint. But which is very interesting from our perspective is the very good tolerance profile that was shown for T-Bosani with only 10, 15% of patients requiring dose reduction, less than 20% of patients requiring dose interaction, which makes this drug a very easy drug to administer and also for potential combinational therapy. But at the end of the day, the regulatory agencies, the FDA, didn't approve this drug because it is already a very saturated field with four more TKIs already approved and because of some problems in the design, the overall survival results, crossovers, et cetera. At the end of the day, this is reflecting the need of not going for the similar mid-to-BJFR TKI drugs or empty or similar drugs and try to be more creative trying to get new, really novel agents to the market. So as an introduction for the novel angiogenic targets, you can see that there are many different angiogenic, pro-angiogenic factors that affect the angiogenesis process at different parts. The BGF, for example, is very important for endothelial cell activation, survival, proliferation of migration, but there are some other pro-angiogenic factors important for base membrane integration to formation, branching, and sprouting and also for maturation of the network of vessels like ALQ1, endogene, PDGF, S1P, or angiopoietins. And these are the targets of the drugs that are being explored currently in kidney cancer. Also important to understand is the concept of the second angiogenic switch that we have with kidney cancer that in comparison with the primary angiogenic switch that is dependent on the bone hippo endowed primary alteration. The second one is acquire resistance to angiogenesis inhibitors and tumor evolution with vascular embolization and produces and is driven by some other pro-angiogenic factors like hepatocyte growth factor and the semen receptor, assuming growth factor, et cetera, that can be also target for our new agents that are coming for kidney cancer patients. Some of the drugs are having the tibocyanic problem that are very similar to the ones that are already approved like Nintenanib, Linifanib, Sedidanib, I will not talk too much about them, but I think that this is already quite difficult for the pharma companies to get these type of drugs approved by the regulatory agents because of the saturation of the market. And then I will talk with further extension about the CMET, which is one target that is probably more advanced right now in kidney cancer regarding novel agents. The CMET is an important receptor tyrosine kinase that is binded by the hepatocyte growth factor, which is its natural ligand, and by doing so it activates different signaling pathways like the RAS, RAD, macanase, the FEC1, the PI3K, EKT, MTOR, and by doing that it is activating cell proliferation, cell invasion, epithelial mesenchymal transition, cell survival, and this signaling through CMET is activated sometimes in a constitutive way, but sometimes it's also activated by tumor hypoxia and very important acquired resistance to BF targeted agents. And we have two drugs that have been developed, Cabo-Santinib and Phuratinib, that needed CMET in addition to BFR2. Cabo-Santinib is probably the one that is most advanced nowadays. The first data of activity, we obtained them from a phase one drug interaction study that was presented by Dr. Ciori, with 25 patients with heavily treated advanced kidney cancer, with Cabo-Santinib 140 milligrams daily, you can see that the disease control rate at four months was very good, 70%, with different percentages of tumor regression from four to 60% and a very interesting PFS of 15 months. It was well tolerated, being the most severe side effects hypophosphatemia, hyponatomia, and phytic, in less than 30, 20% of patients. And here it is more easily seen the dynamic changes in tumor sizes for the 25 patients that were participating, most of them were having some degree of decrease of the tumor, in spite of being heavily protruded. On this basis, there are two randomized trials with Cabo-Santinib, one is the Alliance Calculative Phase II study in first line therapy, comparing to Sunitinib, the primary point is progression of free survival, 150 patients, and the data probably the result will have it at some point this year. And then there is a Pivotal Phase III study of Cabo-Santinib, 50 milligrams versus a better Lungsten milligrams, in progression to be a F-R-T-K-I first or second line therapy. But interestingly here in the two randomized trials is that the dose of Cabo-Santinib is less than 50% of the recommended dose in the phase one trials or the dose that is actually approved for thyroid medullary cancer. And this might be a challenge in order to demonstrate superiority of this drug because it is optimally dosed. Foretinib is also a drug that is inhibiting C-Met and BGFR too potently, but also in less potency type II. It is mainly developed for papillatic kidney cancer which depends on C-Met in many times. And this phase II trial with 75 patients was showing an overall response rate of 15% with disease stabilization of 88%. The tolerance was not that good with 30, 40% of patients with Sibir fatigue, nausea, vomiting, diarrhea, hypertension and 8-10 patients with pulmonary embolism. BFS, 10 months, and again the dynamic changes in tumor size 75% or less of the patients were having some degree of decrease and independently of patients of metaboration germline mutations or in the absence as well. The next one is the graphenib which is a multiple kinase inhibitor, BGFR, BGFR, fibroblast, gofato receptor but also in a very potent way, type II. There is a phase II for kidney cancer that was presented by Tom Asen with the graphenib, 160 millions per day. The primary endpoint was response rate, 50 patients were participating and only 10% of the patients were having disease progression, 40% were having objective partial response. The toxicity was also a little bit hard for the patients, 70% of them were having any type of grade III or IV toxicity, one third of them were having Sibir or life-threatening harmful to skin reaction, fatigue of any degree in half of the patients, the same for diarrhea, allopecia, mucositis, mainly grade I or II but it was hard. Especially there were two patients out of the 50 participating ones with grade IV cardiac ischemic events and two toxic dead. So this drug is not easy to administer which is something that we don't see with colorectal cancer, for example. And finally, the inhibitors of activating like NH1 or endocrine receptors, as you can see here, these receptors are members of the transforming growth factor beta superfamily. They are expressed on activated endothelial cells and very interestingly, the ALQ1 receptor loss produces the hereditary telangiotasia syndrome because it is affecting the maturation part of the angiogenesis, the network of new vessels, mature vessels. From a preclinical standpoint, it has been demonstrated as soon as it is synergistic with the protein fusion of ALQ constant fraction. And the drugs that we have in the clinic are several. We have the protein fusion protein of ALQ1 from gene intake and also from aceleron that binds and neutralizes the ligand of a bone MP9 and 10 which is a TGS beta ligand. Also we have a monoclonal antibody acting here against the ALQ receptor. And we have also another monoclonal antibody against the endocrine receptor for a tracon biopharmaceutical company. All of them are having good tolerance and the angiogenic activity. And in kidney cancer, the ones that are having some preliminary evidence of activity and clinical data are the one from aceleron, the Lantersep and a tracon 105 in phase one two mainly. Finally, the last type of drugs, the novel PSCK-AKT mTOR inhibitors, which is a very important pathway in kidney cancer as you already know. And the way to try to improve these RAPLOX is through a better inhibition of the mTOR inhibitors of different parts of the pathway PSCK or AKT and sometimes dual inhibition of these different parts. These are non-alosteric inhibitors. They directly block the ATP binding sites in the PSCK mTOR pathway. And you can see here the ones that are in the clinic, the specific inhibitor of mTOR complex one and two, the inhibitors of PSCK sometimes pump PSCK in ATP competitive way from Novartis, VKM, 220 and Bill, 719. Alosteric inhibitor of AKT from Merck, which has been suspended in kidney cancer because of toxicity. Then we have the ones that are more advanced dual PSCK and mTOR kinase inhibitor for gene intake and from Novartis. And finally, the periphozin one, which is in the clinical arena from 10 years ago, which is a PSCK-AKT dual inhibitor and there are some data in phase two studies. The ones from all these mTOR PSCK-AKT drugs that are a little bit more advanced is the pump PSCK mTOR inhibitor from gene intake. There is a randomized phase two trial with 80 patients comparing that with everolimus. And to conclude, BIFR inhibitors and mTOR inhibitors are still the backbone of kidney cancer, but they are probably at their very best plateau as single agents. So we need to get new targets and new drugs and very importantly, we have to base this in understanding and overcoming the resistance to these drugs. We can group them as novel pure anti-angiogenics or novel PI-3K-AKT mTOR inhibitors that are acting not only on endothelial cells but also in tumor cells. And from all these ones, the CMET-BFR2 inhibitor Cabo-Santinif is the most advanced ones between the novel drugs, again, excluding the T-cell modulators. Thank you very much.