Good morning and good afternoon, and welcome to the Novartis Oncology Update. Please note that during the presentation, all participants will be on listen only mode and the conference is being recorded. After the presentation, there will be an opportunity to ask questions by pressing star and one at any time during the conference. A recording of the conference call including the Q&A session will be available on our website shortly after the call end. Should anyone need assistance during the conference call, they may signal the operator by pressing star and zero, w ith that, I would like to hand over to Mr. Samir Shah, Head of Investor Relations. Please go ahead, sir. Thank you. Good morning and good afternoon, everybody. Thank you so much for taking the time to join us today. We appreciate it. It's a really busy time, especially today with the various investor-related calls. It's my pleasure to have with us today as we go through the key highlights from ASCO, Susanne Schaffert, who's the President of Novartis Oncology. Alice Shaw, Global Head of Translational Clinical Oncology at the Novartis Institutes for BioMedical Research. Sidonie Daffner, who's the President of Radioligand Therapies, and Jeff Legos, the Global Head of Oncology Development within Novartis. Before we start, I just wanted to go through the safe harbor statement. The information presented today contains forward-looking statements that involve known and unknown risks, uncertainties, and other factors. These may cause actual results to be materially different from any future results, performance, or achievements expressed or implied by such statements. For a description of some of these factors, please refer to the company's Form 20-F and its most recent quarterly results on Form 6-K that respectively were filed with and furnished to the U.S. Securities and Exchange Commission. With that, I'll hand across to Susanne. Thank you, Samir, and also from my side, welcome to this Novartis Oncology update. Moving to slide six. Novartis is a leading company in the market, and over the past five years, we have made significant progress bringing six novel first-in-class therapies to patients, and that together with seven in-market blockbusters, have led to continuous growth for the business. We had sales of almost $15 billion last year and served 1.2 million patients with our medicines globally. For Novartis Oncology, 2021 is a truly breakthrough year in terms of delivering transformative innovation. We are planning to submit three first-in-class treatments for registration this year and also expecting two major readouts later in the year with canakinumab and tavatowimab. We have also a promising pipeline across our platforms, and you will hear more about it over the course of this call. Moving to slide eight. On slide eight, you can see what makes our portfolio. Sorry, one back. Sorry, slide seven. You can see what makes our portfolio really unique. We are the only company that is present in all four therapeutic platforms to treat cancer. We are present in targeted therapies, in radioligand therapy, in cell and gene therapy, and in immunotherapy. I believe that our portfolio gives us the unique opportunity to approach cancer with different therapeutic approaches, as well as combine all these platforms for better treatment outcomes. Moving to the next slide. This year's ASCO is very meaningful to us. We have presented more than 70 abstracts with new data across all four therapeutic platforms and presented nine oral presentations. Moving to the next slide. Let me go through each platform and share the highlights that we presented at ASCO. Let me start with targeted therapies. At ASCO, we have presented the new data on Kisqali, our CDK4/6 inhibitor that is used to treat advanced breast cancer. We have the updated MONALEESA-3 data confirming that Kisqali continues to show prolonged and consistent overall survival benefit with a median of 4.5 years. Kisqali demonstrated the longest overall survival in post-menopausal patients compared to other CDK4/6 inhibitors and is the only CDK4/6 with data in first line with fulvestrant. I believe this data further strengthens Kisqali differentiated profile and builds on Kisqali unprecedented overall survival benefit. In addition, we are going into earlier lines of breast cancer with our NATALEE study that is exploring Kisqali in the upfront setting in both intermediate and high-risk populations. These populations represent around 70% of the upfront early breast cancer patient population, and there's a clear unmet medical need. We are also excited about asciminib, a first-in-class STAMP inhibitor in 3rd line CML that we plan to submit in the U.S. and in EU in the first half of 2021. We are also planning to start a trial in 1st- line later this year. Looking ahead, we have a pipeline of combination ready molecules like our SHP2 inhibitor, a B/C-RAF inhibitor, and a KRAS G12C inhibitor that we believe can be very competitive from both a combination strategy and also from timeline perspective. Moving to the next slide on our differentiated immunotherapies platform. At ASCO, we presented data from RATIONALE-302, which evaluated tislelizumab in 2nd-line esophageal squamous cell carcinoma. As we know, a difficult to treat cancer. Efficacy and safety of tislelizumab has been comparable to already marketed PD-1 inhibitors in monotherapy and 2nd-line. These data will be used as the basis for FDA and EMA registration later this year. We aim to establish tislelizumab in key indications where PD-1s are currently marketed, but also pursue novel combinations with our portfolio. Our strategy in immuno-oncology is also focused on advancing development of canakinumab in non-small cell lung cancer and also sabatolimab, which could be the first immuno-oncology therapy for MDS. We are expecting readouts of these two assets later this year. Moving to the next slide, our cell and gene therapeutic platforms. As pioneers of cell and gene therapies, we have made strong progress in manufacturing, supply, and commercialization of this transformative one-time treatment globally. In partnership with now more than 320 qualified centers across 28 countries, we have shipped more than 5,000 doses of KYMRIAH to patients globally. We have the largest global CAR T manufacturing footprint, are exploring new targets, and are also advancing our next generation technology platform. At ASCO, we presented the data from ELARA's primary analysis of KYMRIAH in patients with relapsed or refractory follicular lymphoma that demonstrated consistent results with the interim analysis that you remember we presented at ASH 2020. These outcomes are particularly impressive given that ELARA included high-risk patients who were heavily pretreated and relapsed early. We got orphan drug designation from FDA and are planning to file for this indication later this year. Moving to the next slide. Now, last but not least, our radioligand therapy platform. Since the acquisition of Triple A in 2018, we have built a strong global expertise in commercializing radioligand therapies as the only big pharmaceutical company. With LUTATHERA and neuroendocrine tumors, we are working together with 400 centers treating more than 9,000 patients since launch. At ASCO, we have shared the data from NETTER-1, which is the final analysis that has shown that LUTATHERA significantly reduced the risk of progression of this by 82% and demonstrated a clinically meaningful trend towards prolongation of OS by almost 12 months. These data support LUTATHERA's position as a valuable precision medicine option for advanced neuroendocrine tumors. On the broader radioligand development side, we are advancing four clinical programs and around 11 preclinical and discovery programs to identify the next wave of radioligand therapies. We are very excited to share how we are building our leadership on radioligand therapies, and I think there's nobody better to cover that than Sidonie. Sidonie, over to you. Thank you so much. in cancer care. Why do we think RLT? It's the eye-opening. You treat what you see. It's a new level of visualization for physicians. On the slide you see on the left-hand side with the same target here, PSMA, you can perform precision imaging via PET scan to visualize tumors, offer additional insights on disease burden, diagnose or provide benchmarks for outcome. On the right-hand side, you can treat with the same target and a radioactive payload, here with lutetium- 177. The radiation is directly and specifically delivered to tumor cells only. This is precision medicine at its best. We go to slide 15. We are the pioneers in this space with a significant lead in the three key areas. First, our manufacturing capabilities, second, our commercial expertise, and third, our R&D approach. These three key pillars are the key fundamentals of our RLT platform. On slide 16, I show that we have established a high quality and on-demand manufacturing footprint with the ability to deliver RLT in two weeks after order receipt. We have broken down for you this complex process in single steps to showcase this very efficient model that is vertically integrated from raw material to patient administration. Time is of great essence given the short shelf life of the product. Our efficiency of this model was clearly shown during the pandemic, where we didn't miss a single dose, and we can be very proud of this team. As we look ahead, most importantly, for our future launches, we continue to invest by building a new site in Indianapolis while expanding our existing sites. On slide 17, I come to the second big piece. We are the only player in RLT with a globally commercialized product. We learned a lot and gained a lot momentum with Lutathera. In partnership with more than 400 centers, we were able to treat more than 9,000 patients since launch. Based on these key learnings, we structured our customer-facing teams in a demand and a delivery team with deep expertise in nuclear medicine and oncology respectively. We are not stopping here and working hard to strengthen this new commercial model ahead of our future launches. We leverage our extended footprint to drive proper referrals from community centers, where two-thirds of our patients sit today to RLT centers. On slide 18, you see that we are facing a kind of complex patient journey and approach in mCRPC. Launching PSMA will require a multidisciplinary approach. The primary decision-makers in prostate cancer vary by disease state. You have the urologist, you have the med onc, the rad onc, the nuclear medicine physician. Therefore, doubling down in medical education is key across all the decision-makers to educate the value of RLT and the requirements for adoption in their routine practice. On slide 19, you can see that this approach will be supported by the expansion of our disease awareness campaign on PSMA and phenotypic precision medicine across all physician groups. It's important to note that stratifying patients for a specific targeted therapy is a well-supported treatment approach by medical oncologists. PSMA is overexpressed in more than 80% of men with prostate cancer and can be detected via non-invasive PET scanning. The FDA has approved recently two PSMA imaging agents. On slide 20, you can see our long-term approach, because we know and anticipating earlier lines of launches, we have to work together with our customers to increase capacity and extend our RLT infrastructure. Short term, we will be able to launch PSMA in existing sites by encouraging increased infusion hours, increased infusion days, and increased infusion chairs, leveraging the best practice from our highly productive centers. Long term, we aim to double the contracted RLT sites ahead of our pretaxane launch. We will target community practices that currently have optimized alpha hot labs to expand to better leveraging the existing infrastructure and account expertise, which will be also a quick win. To execute this approach, we need a strong cross-functional team, commercial, medical, value and access, and also our development teams to execute on this strategy. Our customers are already excited to embark into this journey together with us, which the quotes on the right-hand side of the slide show. We go to slide 21. We are the pioneers, we strongly intend to maintain our leadership position, expanding our pipeline. We will continue to invest into new technologies and assets, we have shown this in the most recent months. We have in-licensed a library of FAP-targeting agents. We invest into Actinium Pharmaceuticals for the development of alpha-based RLTs. We are collaborating with Artios Pharma to discover novel combinations of DNA damage response inhibitors. We are leveraging the RLT-specific R&D advantages that exist and our expertise in-house, and we are well-positioned to accelerate our path to market. On slide 22, you can also see that we are growing our RLT pipeline, and this has great potential also to address a range of other solid tumors. Besides the life cycle management for PSMA, in the first part of the slide, we are investing in targets in different stages of development. We have shown that we have the expertise to run these programs in RLT, and we are super confident that we maintain our leadership in the development area as well. To summarize, we have generated a unique skill set and experience in manufacturing, commercial, and R&D, and built a sustainable platform. New entrants to the field will need to establish access to raw materials and end-to-end manufacturing process and capabilities. Proprietary insights regarding isotope and stable RLT formulations are key. We will leverage our global commercial footprint with expertise in nuclear medicine and oncology, and Lu- PSMA-617 patent protected until 2034. I hand over to my colleague, Jeff, to talk about the exciting VISION data. Thank you, Sidonie. We were very excited to present the potentially practice-changing VISION Phase III clinical trial data this past Sunday during the plenary session of ASCO. I'd like to spend the next few minutes just providing some additional context around the clinical relevance of this result and spend some time highlighting the key results coming out of that Phase III clinical trial. In terms of the disease, prostate cancer is one of the most commonly diagnosed cancers, and in particular, the second most commonly diagnosed cancer in males. The main goal of treatment in earlier lines of earlier stages of disease is to reduce testosterone levels, and that can be accomplished through surgical castration or biochemical castration. At the time that these patients stop responding to castration-related therapies, approximately 80% or more of these patients have seen their disease metastasize to other parts of the body beyond the lymph nodes, and/or initial prostate cancer cells. Although there are treatments available for patients such as androgen axis inhibitors and/or taxane-based therapies, we do acknowledge and recognize that there is still a high unmet medical need and opportunities to do better, and approximately only 30% of patients who become castrate resistant are actually surviving for five years. At the time that patients have exhausted these therapies, such as taxane-based chemotherapy or the novel androgen axis inhibitors, these patients are often seeing their disease progress quite quickly, on average in about four months, and their median overall survival is limited to about 10 months. Slide 26, please. This just shows an example as to when patients see their disease progressing, they have less and less treatment options available. If we particularly focus on patients in third or fourth line, what you could see from this bar chart here is approximately 2/3 of patients in the 3rd-line setting are actually not receiving therapy to date, either because they die before they actually get to that point, their disease progresses or is progressing at a rate that makes them ineligible for therapy, or the available standards of care actually are used in only a palliative setting. Therefore, this represents a high unmet medical need, and this is the patient population that we studied in the VISION trial that I'll come onto in subsequent slides. Next slide, please. I wanted to share a little bit more about both the technology as well as the target for the VISION trial. In particular, PSMA is a membrane-bound enzyme that's highly expressed in prostate cancer across a variety of sites and stages of disease. The expression in normal tissue is highly restricted, making PSMA a very attractive target for both PET imaging as well as radioligand therapy. Lu-PSMA-617 is a small molecule that targets the PSMA receptor with very high affinity and delivers a payload of beta particle emitting lutetium-177 through receptor-mediated endocytosis. It's delivering it specifically to the cancer cell and minimizing radiation to the surrounding normal tissue or neighboring cells. Next slide. In terms of the VISION overall study design, I'll start on the left-hand side, focusing on the eligible patient population. These are patients that have been previously treated with at least one, or potentially more than one androgen receptor pathway inhibitors, and they will have received at least one but no more than two taxane-based regimens. Patients, as per protocol, are permitted to receive standard of care before randomization and after randomization, as long as those standards of care did not include chemotherapy, immunotherapy, radium-223, or investigational drugs, because none of these agents have been tested in combination with lutetium PSMA 617. In addition, one of the key eligibility criterias was for patients to have a PSMA positive PET scan prior to study entry and randomization with gallium PSMA 11. In particular, patients had to have at least one gallium positive PET lesion, meaning that the gallium uptake in the tumor had to be greater than that in the liver. Secondly, there could be no lesions that were PSMA negative. In terms of study design, 831 patients were randomized 2:1 to receive standard of care therapy plus or minus lutetium PSMA-617. These patients were given at least four cycles of therapy, and they were eligible to receive an additional two cycles of therapy if they were deriving benefit. The overall primary endpoints included both radiographic progression-free survival and overall survival. These were alternate primary endpoints, which means that we could declare a positive trial on the basis of either or both endpoints, and alpha was allocated accordingly to maintain the traditional alpha spend of 0.025 in terms of a type one, type two error. In terms of key secondary endpoints, we had included several secondary endpoints, including time to first symptomatic skeletal event, overall response rate, disease control rate, as well as treatment emergent adverse events. Next slide. In terms of the patient population, both demographics as well as baseline disease characteristics were well-balanced across treatment arms, and this represented the patient population intended to be studied. Next slide. Here are the key results in terms of the primary endpoint. Starting on the left was the overall survival results. As you can see from the Kaplan-Meier curve, these curves separate early, and that separation is maintained throughout the entire duration of follow-up. This resulted in a hazard ratio of 0.62 or 38% reduction in the risk of death. The experimental arm of lutetium PSMA-617 also significantly demonstrated a clinically meaningful improvement in median overall survival, as shown here, by an improvement of four months, with medians of 15.3 versus 11.3 months in the control arm. On the right-hand side of the slide, you see that lutetium PSMA-617 also significantly reduced the risk of radiographic disease progression or death by 60%, which translates into a hazard ratio of 0.40, you can see the curves separate early and here is reflected more than five-month improvement in median radiographic progression-free survival. Next slide. We also demonstrated an improvement in all key secondary endpoints, including an overall response rate of 29.8% versus 1.7%. These include all patients evaluated by RECIST 1.1. If you look at patients that only had measurable disease at baseline, the overall response rate increased to about 45% in the lutetium PSMA-617 arm. Another important and key secondary endpoint was the time to first symptomatic skeletal event. We know very well that patients with advanced prostate cancer are at risk for fractures, for spinal cord compression, and for palliative-related chemotherapy or other related therapies to the bone because of significant related pain. Here we also show a hazard ratio of 0.5 or a 50% reduction in the time to first symptomatic skeletal event, an improvement in that median time of approximately five months. Next slide. In terms of overall safety, we did observe that there was an increase in overall treatment emergent adverse events, both in all grades as well as high grades. In particular, if we look at high-grade bone marrow suppression, here we see that anywhere from 5%-13% of patients are experiencing high-grade cytopenias. We also noticed that there was an increase in high-grade fatigue and urinary tract infections in the Lu-PSMA-617 arm compared to the standard of care only arm. There was also a higher rate of treatment discontinuations that were related to treatment emergent adverse events. As you see on the left-hand side, that was approximately 12% in patients in the Lu-PSMA arm versus 8% in the standard of care arm. Next slide. In summary, the combination of Lu-PSMA with standard of care resulted in a 38% reduction in the risk of death and a 60% reduction in the risk of radiographic disease progression or death compared to standard of care alone. To put these results into context, I know the ASCO discussant mentioned that a four-month improvement in overall survival was consistent with previous phase III data for other therapies in patients with prostate cancer. It is very difficult, if not impossible, to make indirect cross-trial comparisons to studies that were done historically in different patient populations, different lines of therapy, as well as with different control or comparator arms. In particular, the results of this trial are quite clinically meaningful because these patients often have no alternative and are receiving standard of care therapies that often include only palliative-related therapies, rather than true treatment-related therapies. In terms of the four-month median improvement in survival, that actually translates into about a 40% reduction in risk, quite clinically significant and should not be compared to trials that were done in very different populations in the past. I'm very proud that we continue to have dialogue with health authorities around the world. Regulatory submissions in the U.S. and the E.U. are on track for the second half of 2021. Based on these clinically impressive and relevant results, these data support further investigating Lu-PSMA into earlier lines of therapy and potentially earlier stages of disease. If we go to the next slide. Here is an overview of the current development plans and the areas that we are currently exploring to go into earlier stages. The current trial focuses on patients with metastatic castrate prostate resistance cancer in the third and fourth line after receiving one and no more than two taxane-based chemotherapies. In terms of the upcoming clinical trials that we are currently planning and executing, we have two additional phase III trials called PSMAfore. This is in the pre-taxane, so prior to docetaxel or cabazitaxel chemotherapy, and this study start is imminent. We also have a phase III study that has already started enrolling patients in metastatic hormone-sensitive prostate cancer, and that trial is a global phase III trial, and both are available on clinicaltrials.gov. Based on this data, we are also considering other combination-based therapies in the castrate-resistant prostate cancer patient population, as well as exploring the potential to move this into earlier stages of disease. With that, I will turn it over to Dr. Alice Shaw, who will take us through some of our other combination-based and targeted therapy approaches. Alice, over to you. Thanks, Jeff. Good morning, good afternoon. Starting at slide number 36, we're going to shift now from RLT to targeted therapies in our early pipeline with a focus on our first-in-class allosteric SHP2 inhibitor TNO155 and targeting the MAP kinase pathway. Just as a reminder, SHP2 is a tyrosine phosphatase that links upstream activated RTKs such as EGFR and FGFR to the RAS MAP kinase pathway and specifically mediates GTP loading of RAS downstream of RTKs. As shown here on the right, SHP2 has also been shown to function downstream of PD-1 signaling in T-cells, leading to suppression of T-cell mediated immune responses. There are multiple and diverse roles for SHP2 in the tumor itself and in the tumor microenvironment, suggesting many opportunities for a SHP2 inhibitor such as TNO. Next slide. In this slide, this is number 37, I summarized one of the major areas of interest in targeting SHP2, which is in the setting of drug resistance. As you can see on the left, we know that resistance in oncogenic cancers can be mediated by many different resistance mechanisms, the majority of which involve activation of alternative kinases or so-called bypass mechanisms, and these lead to MAP kinase reactivation. Many of these bypass paths are dependent on SHP2, co-targeting the oncogenic driver and SHP2 could be broadly effective in overcoming resistance. In support of this, a number of preclinical studies, and I've shown two here on the right, have shown that TKI/SHP2 inhibitor combinations are highly active in resistant PDX models and notably more active than the SHP2 inhibitor alone. Next slide. Another key combination shown here, this is slide number 38, and this is the combination of G12C and SHP2 inhibitors. Now many studies have demonstrated really strong preclinical synergy between G12C and SHP2 inhibitors in G12C-driven cancers. As an example, on the right are internal data showing, in general, greater anti-tumor activity with a combination of G12C and SHP2 inhibitors compared to either single agent. The mechanistic basis for the synergy is summarized here on the left and includes the ability of SHP2 inhibitors to enrich the GDP-bound form of G12C, and that's the target of currently available G12C inhibitors, and also SHP2 inhibitor-mediated suppression of feedback activation of RAS MAP kinase in the setting of G12C inhibition. Two distinct mechanisms that drive a true synergistic interaction between G12C and SHP2 inhibitors. Next slide. Slide number 39 depicts the study design and patient population enrolled in our phase I, first-in-human study of TNO155. As you can see, we tested multiple dose levels and schedules, and this was really done with the goal of optimizing dose and schedule in order to enable TNO-based combinations. To date, 125 patients have been treated in dose escalation, all with advanced solid tumors, mostly colorectal cancer and GIST, but some non-small cell lung cancer and head and neck cancer, as you can see in the table. I should also note that we had very few patients in this first-in-human study, about 5%, with potentially sensitive G12C mutant tumors. Next slide. Here on slide number 40, as predicted by preclinical studies, TNO demonstrated favorable PK in patients with dose proportional exposure, as you can see on the left. In addition, TNO has been shown not to induce or inhibit major metabolic enzymes, making drug-drug interactions unlikely and further supporting combinability. There's also clear evidence of PD or target engagement based on PHEX6 suppression in on-treatment versus pre-treatment biopsies, as you can see here on the right. Next slide. Shown here on slide number 41 is the safety profile of TNO155. Overall, TNO was generally well-tolerated, with most AEs grade one or two in severity and many of the common AEs similar to what's seen with other RTK and MAP kinase pathway inhibitors. Decreased ejection fraction is also an expected on-target toxicity, and we saw it in about 10% of patients. Again, mostly mild in severity, reversible, and really detected because of the frequent monitoring mandated by the protocol. Next slide. Here on slide number 42, the waterfall plot summarizes the best overall response across all valuable patients in dose escalation. Not surprisingly, with single-agent TNO in a predominantly CRC and GIST population and across all different dose levels, we saw limited clinical activity with stable disease as the best response. However, I should note that there were several prolonged stable diseases in non-CRC patients, including a GIST patient whose disease has remained stable for almost three years. Next slide. Next steps with the study will be to expand the indications predicted to be sensitive to single-agent SHP2 inhibition based on preclinical data. Really our main focus, now that we've thoroughly examined PK, PD, and safety across different doses and schedules, is to establish the activity of TNO in combination with other agents. The various TNO combinations that we're developing are shown here. This is slide number 43. All of these are supported by preclinical studies. Most of these have actually already entered the clinic. As you can see, we're testing combinations of TNO with EGFR and ALK TKIs, triplet combinations of TNO with RAF/MEK and RAF/ERK inhibitors with BRAF V600 mutant CRC, TNO combined with our checkpoint inhibitors sabatolimab or our CDK4/6 inhibitor ribociclib in a variety of different cancers. Finally, TNO in combination with our G12C inhibitors, both our own JDQ443, as well as Mirati's adagrasib in G12C-driven cancers. Next slide. Here on slide number 44, I've included one case report that was shared last fall by Mirati and really highlights the potentially marked activity of TNO combined with G12C inhibitors. This is a patient with G12C mutant lung cancer who had failed sotorasib previously after responding, as well as a combination of Revolution Medicines' SHP2 inhibitor combined with the MEK inhibitor cobimetinib. This patient went on to receive the combination of adagrasib and TNO155 and experienced a very dramatic clinical and radiologic response, as you can see here on the right. This is just one patient, but I think between the known preclinical synergy between G12C and SHP2 inhibitors and now this emerging clinical data, we are very excited about combining TNO with G12C inhibitors to maximize the activity and the clinical benefit of G12C inhibition. Next slide. Here, this is my last slide, number 45. You can see our current MAP kinase pipeline. This includes small molecules targeting essentially every step of the pathway, starting with KRAS, then SHP2, BRAF and CRAF, MEK and ERK, and a few other downstream MAP kinase targets that I haven't shown here. We know that targeting single nodes in this pathway may not adequately suppress the pathway. These molecules are really enabling us to explore many different MAP kinase combinations, even beyond the TNO combinations that I've already mentioned. Two examples worth highlighting include combinations with our BRAF/CRAF dimer inhibitor, LXH254, for NRAS mutant melanoma, BRAF mutant melanoma, and other RAF-driven cancers. Also combinations with our G12C inhibitor, JDQ443, which is currently in phase I testing. I think there's lots more to come in terms of TNO combinations and also other MAP kinase combinations. Back to you, Susanne. Thank you, Alice. Maybe just to briefly summarize our key takeaways. Novartis is a global leader in oncology, and we have a strong track record in pioneering innovation. This year, quality that we presented. We are the only company with depth and expertise in four therapeutic platforms, which we believe will be critical for the future of cancer care. The VISION trial, as presented by Jeff Legos, further solidifies our leadership in the radioligand space, and we are excited to see that radioligand therapy can dramatically improve patient outcomes, not only in a rare disease like neuroendocrine tumors but also for prostate cancer, one of the most prevalent cancers in men. We believe we are well-positioned with our portfolio to tackle the remaining unmet needs in cancer, including through combination across our platforms. With that, I would hand over to Samir to kick off the Q&A. Thank you very much, Susanne, and thank you to all the presenters. We've got quite a lot of questions online at the moment, so ideally for the people who are asking the question, one question, or if you must ask two short questions, please. Operator, if we could have the first question, please. Of course. Just as a reminder, to ask a question, you will need to press star one on your telephone and wait for your name to be announced. To withdraw your question, please press the pound or hash key. Once again, that is star one if you wish to ask a question. Your first question comes from Graham Parry from Bank of America. Please go ahead. Your line is open. Great. Thanks for taking my question. Firstly, could you just help us understand what your expectations are around launch trajectory on Lu- PSMA- 617, just given the need to get the radioligand therapy centers set up? Do you have enough at the moment to support what you think is needed to be the late line of therapy, or do you feel that the launch trajectory could be inhibited by the need to get further centers lined up? Secondly, could you help us understand the differentiation of your LAG-3 and your KRAS Inhibitors versus Bristol's LAG-3 and Gilead's LEMTRADA, or the Mirati KRAS for that matter. How do you see it's differentiated, and how does that affect your combo strategy with Mirati KRAS going forward with your shift too? Thank you. Fantastic. Thank you, Graham. For the first question, I'll hand it across to Sidonie and then I'll get Alice to address the question with respect to the differentiation of the LAG-3 and KRAS. Sidonie, on the launch trajectory, please. Thank you. Capacity is pretty important for a successful launch. Indeed, into the existing LUTATHERA treatment centers because it's late line and a smaller population. Long term, we will work to expand the capacity as lined out in my short presentation. In this infusion days, infusion hours, and also infusion chairs. We will share the best practice because as usual, you have highly productive centers and less productive centers. Sharing this best practice will be key as well. We will double the existing centers. We have time until the pre-taxane study reads out. We want to double these centers and set up new centers, communities, practices that currently have optimized themselves with Alpha Hot Labs to expand for better for lutetium-177 to leverage these already existing accounts with Hot Labs have to treat patients with Lu-PSMA-617. For sure, we will provide them the best practice education on process and site expansion to ensure that these sites are ready for their first infusion. Thank you. Alice, the question on the differentiation of the LAG-3 versus the KRAS. Yeah, I'm going to come back to you, Susanne, because maybe it was difficult to hear you, Sidonie. Maybe Susanne wants to come back on that point. Susanne? Sure. No, I hope everybody could hear. I think, Sidonie was clear that we have enough capacity for now. We expect that we can cover all the patients in first line, and then we have plans to double a number of centers and reserve capacity, and we should be well ready before the earlier trial, selective pre-taxane trial will read out. I think with that, over to Alice now. Sure. I'll start with the KRAS and then go to LAG-3. With our KRAS G12C inhibitor, JDQ443, this is a potent and selective, irreversible G12C inhibitor, specifically KRAS, similar to other G12C inhibitors such as sotorasib and adagrasib. I mentioned that JDQ443 is currently in a first-in-human study right now. I would say it's difficult to make comparisons. Of course, there could be potential for differentiation in terms of safety, even in terms of efficacy. Actually where I think our differentiation really will come with JDQ443 is our ability to combine our G12C inhibitor with many other assets in our portfolio, which I highlighted during my talk. TNO155 is one obvious combination partner, and as I mentioned, we are focusing on the JDQ TNO combination, and that will be in our first-in-human study. There are actually many other combinations of G12C inhibitors, with other potential MAP kinase pathway inhibitors that could be highly active in the setting of G12C driven cancer. That's where I believe we may have true differentiation is in terms of our JDQ-based combinations. In terms of LAG-3, we do have a LAG-3 antibody, which is LAG525, and we actually have studied LAG525 as a single agent as well as in combination with our PD-1 inhibitor, spartalizumab, in advanced solid tumors. Presented the data from the phase I/II study, where we showed that there was very little single-agent activity with LAG525. We did see potential activity of our LAG-3 inhibitor with spartalizumab, and we explored a number of different expansions in our phase II study, in both IO naive as well as IO pretreated patients. I would say in general, we did see some potential signs of added benefit with LAG525, and this has in fact supported further evaluations of LAG525 in late development. Maybe with that I'll ask Jeff if he wants to comment. No, thank you, Alice. Graham, thanks for the question. We currently have an ongoing study following up on some of those early signals that Alice mentioned in different patient populations and different subsets of patients based on biomarker selection criteria. I think in terms of differentiation, our differentiation would be in the development approach via combinations. If I just spend a minute on the benefit of the tislelizumab licensing deal that we had done recently, this gives us the ability to have data from up to 15 registration-directed trials, where five of those have already reported out positively and a number of other trials still yet to report out. In addition, the development plan for tislelizumab is quite broad, with probably now more than 100 studies ongoing or soon to be started for tislelizumab, which will give us insight into other cancers and help us identify where the potential addition of a LAG-3 inhibitor or this distinct checkpoint receptor combination will potentially benefit patients going forward. We are currently assessing all of the data that has merged at ASCO, and that we have it in our hands to define the next steps. Great. Thank you very much, Alice and Jeff. Operator, we're ready for the next question, please. Thank you. Your next question comes from Mark Purcell from Morgan Stanley. Yeah, thank you for taking my question. In terms of Lu- PSMA- 617 moving into early lines of therapy, can you help us understand your confidence in making that shift? The challenges superficially appear to be the route of administration and the need for specialist infusion centers, it's not clear from the presentation which of the AEs was most problematic when it came to the 12% instance of discontinuation. Helping us understand that would be great. It appears that you're basically targeting lymph nodes and bone and organs, in terms of binding to all PSMA-expressing cancer cells. What's the importance of this sort of broader targeting when it comes to the move into early lines of therapy? Thank you. Great. Thank you very much, Mark. Both the questions will be for Jeff. They're related. Both relate to the early lines of therapy, and it's to do with going into how much to specialist centers, the route of administration, the AEs, and also targeting for the early lines of therapy as a secondary question. Jeff? Thanks for the question, Mark. In terms of earlier lines of therapy, both our confidence as well as the rationale to do so. You may have remembered a phase II randomized trial that was done by the Australian-New Zealand Cooperative Group as a head-to-head study against cabazitaxel, showing a clear benefit in terms of reduction in PSA levels versus taxane-based chemotherapy. In that trial, in particular, we saw both clear efficacy signal as well as very manageable safety, and there was no treatment or drug-related fatalities in that particular population. As we go into earlier lines of therapy, there is also strong hypotheses that androgen deprivation or inhibiting the androgen-related pathways also influences PSMA expression. This may provide a unique opportunity to demonstrate even greater clinical efficacy in these patient populations, either alone as a combination with standard of care therapy. In terms of the safety, we do know that cytopenias and bone marrow suppression is an important side effect to be cognizant of. In particular, even within the VISION trial, we noted that these side effects were often manageable and reversible, and it's something that oncologists are very familiar dealing with through supportive care measures such as growth factors. This is something that we will continue to monitor and to manage in the earlier lines of disease as we study those as well. Operator, next question, please. If I could just insist people try and keep to one main question if possible. Thank you. Thank you. Your next question comes from Emmanuel Papadakis from Deutsche Bank. Please go ahead. Your line is open. Thanks for taking the question. Maybe take one on the Lu-PSMA competitive outlet. POINT Biopharma announced a few days ago they're initiating their relatively equivalent trials, PSMAfore. Do you see any points of clinical differentiation there? Do you have any IP barriers to provide some competitive protection, or you would expect to share the market equally with a bigger Thank you. On that particular question, we won't comment on competitor and their design of studies, et cetera. In terms of how we stand versus competition, perhaps I'll ask Susanne if she wants to say anything on that particular point. Susanne? Yeah, Emmanuel, you ask about IP protection. Let me say the following. To manufacture a radioligand therapy includes many complex steps. As you can imagine, there is many of these processes that are proprietary and usually also that's know-how that's not very broadly known. It's known to only a very limited group of people. In terms of patent protection, we feel we have a robust portfolio of patents on Lu-PSMA. We have basic patent protection under 2034, and there is also a potential extension in the U.S. and EU. We feel we are very well protected. As I said, it's not as trivial to just produce these radioligand therapies at scale, and therefore we still feel we are in a good competitive situation. Thank you very much, Susanne. Operator, we are ready for the next question, please. Thank you. Your next question comes from Simon Baker from Redburn. Please go ahead. Your line is open. Thanks. Thanks for my question. I am going back to Lu-PSMA-617 and the plenary presentation. Just two things that cropped up in the discussion. Firstly, from the discussant, the suggestion that PSMA screening was unnecessary given it's so widely expressed. Just wonder what your thoughts are on the potential for an all-comers indication at some stage. Then secondly, the presenter discussed the importance of the relationship between nuclear medicine and medical oncology in the trial and problems where that relationship is not strong. I just wondered if that's a real-world problem that you see a lot and the learnings that you can take from this study to the broader radioligand therapy market. Thanks so much. Great. With the first question on the likely label and do you need to do PSMA screening or not, I'll give it to Jeff. The second question in terms of nuclear medicine specialists and the medical oncologist and what their relationship's like, we'll give to Sidonie. With the first question, please, Jeff. No, thanks, Simon. I think it's a very relevant question, and I think this one in particular because PSMA expression is often found in more than 80% of prostate cancer patients, it begs the question as to how important that screening becomes. It is not just about selecting whether or not a patient is eligible for therapy, but it is also understanding the heterogeneity of their disease. Coming back to the point of treating what you can see, the advantage of using PSMA PET screening is the ability to see which lesions are PET positive, and the value of radioligand-based therapy is you're switching out that gallium-based tracer for lutetium, so that you're ultimately using the same PSMA target as both a diagnostic as well as a therapeutic. This affords us to better understand the heterogeneity of the disease, and it will also help us to better understand the lesions and why they are responding or maybe not responding after a period of time. It will provide unique insights into the therapeutic, both monitoring as well as selection of patients going forward. At a platform level, I think the screening becomes even more important as we think about future targets that may not be expressed as high as 80%. I do think there is value in not only screening for these patients who have prostate cancer, but also for the platform and our pipeline of assets to come. Maybe I'll turn it over on the next question regarding the interdependency on the nuclear medicines and the medical oncologists. Sidonie? Thank you, Jeff. The multidisciplinary approach and really discussing the patients and having the patients treated in strong alignment between the disciplines that are involved is super important, not only for PSMA but also moving forward with our pipeline products because we will have other disciplines as well. The patient journey is a complex one, and as said, you have the urologist, you have the medical oncologist, the radiation oncologist, and the nuclear medicine physician. I think it was Mike Morris who said some dropouts were related to not proper handling of this relationship. It's our task to bring them together and educate across all these decision-makers the value of RLT and then the requirements, how they set up the process together to support this approach. Thank you very much, Sidonie. Thank you. Next question, please, operator. Thank you. Your next question comes from Florent Cespedes from Société Générale. Please go ahead. Your line is open. Good afternoon. Thank you very much for taking my question. A leading one on slide 22, maybe for Sidonie. Could you share with us why you have, in prostate cancer, five radioligand projects? Do you believe that some will be better tolerated or some could show better efficacy? If you could elaborate on this, it would be great. Thank you. Okay. I think you're referring to the pipeline slide, Florent, in which case it's probably better if it's Jeff who actually talks about the pipeline, if that's okay. Happy to, Florent. In terms of why there is multiple agents listed on that slide, we do have a unique opportunity here where we can look at different PSMA targets in terms of both their dosimetry as well as their distribution. As Sidonie mentioned in one of her slides, it also gives us an opportunity to look at different isotopes based on either dose or distribution. I do think these are important parameters for us going forward. We do have ongoing phase I studies looking at the different PSMA ligands, with different isotopes, whether it's lutetium-based and/or actinium-based. Some of those, I can't see the pipeline slide in front of me at the moment, they may also include the diagnostic component as well, either the gallium-68 or the potential to have a fluorine-based PET imaging tracer as well. That's why you may also see a longer list for prostate cancer. Thank you very much, Jeff. Thank you very much. Thank you. Operator, next question, please. Thank you. Your next question comes from Seamus Fernandez from Guggenheim Partners. Please go ahead, your line is open. Oh, great. Thanks very much for the question. I just have one question. I wanted to get a better sense of the cardiac profile of TNO155, and it appeared as though there was some cardiac toxicity. Is that something that's directly related to the mechanism of action, or do you believe that this is some off-target toxicity? Added to that, we know that there are some KRAS agents that have some cardiac signals, QTc prolongation as well. Just wanted to get a better understanding of the combinability of TNO155, given some of those early profile signals and, again, your views there. Thanks so much. Great. Thank you, Seamus. So it's a question for Alice. TNO, specifically cardiac adverse events, is it MOA-related, off target, and implications for combos? Thank you for that question. We did highlight this toxicity from our TNO155 phase I study in the ASCO presentation, I briefly mentioned it, but just to provide some more detail, a decreased ejection fraction was seen in about 10% of our patients. We do believe based on preclinical data that this is an on-target toxicity. As I noted, what's important is that this decrease in ejection fraction was typically mild and also reversible. I should say that because we were attuned to this being an on-target toxicity, we actually did monitor for cardiac contractility very frequently in our protocol, we were able to detect even these mild, asymptomatic decreases in ejection fraction. So far, I think we haven't seen any issues regarding QTc prolongation, really it's around this potential impact on cardiac contractility. Only in 10% of patients, easily monitored and reversible. I think that this is quite comparable to data that we've seen with other MAP kinase pathway inhibitors, including MEK inhibitors. Of course, we are very aggressively advancing our combinations and believe that even in the setting of combinations, because we understand this cardiac toxicity so well, we will be able to manage it. Great. Thank you. Operator, next question, please. Thank you. The next question comes from Wimal Kapadia from Bernstein. Please go ahead, your line is open. Great. Thank you very much for taking my question. Wimal Kapadia from Bernstein. Can I just come back to Lu-PSMA-617, please? I appreciate you flagged the caveat across trial comparisons, but if I have a look at previous CABA data, particularly the CARD trial, I look at VISION and I think about TheraP, how are you thinking about the efficacy and safety profile of the product versus caba in this setting? How will Novartis really be discussing this profile with physicians? Do you actually believe you have a better profile for the treatment in the post taxane setting? Thank you. Thank you very much, Wimal. Back to Jeff for contextualizing the data. I think it's a good question, and maybe just as a reminder in terms of patient population. These are patients that had to either have already received two prior lines of taxane-based chemotherapy, such as docetaxel and cabazitaxel, or they had to be deemed ineligible to receive any further lines of chemotherapy. Making a comparison around efficacy related to cabazitaxel would not be fair because that would not be a treatment alternative for these patients. As you rightly alluded to, the TheraP trial continues to be ongoing, and we will await additional data from that particular trial in terms of the head-to-head data versus cabazitaxel. Then, as we talked about earlier, we have two upcoming trials that are in the pre-taxane setting against the appropriate comparators prior to patients being eligible or receiving taxane-based chemotherapy. Thank you very much, Jeff. Now for our final question, please. Operator. Thank you. Your final question comes from Matthew Weston from Credit Suisse. Please go ahead, your line is open. Thank you very much. A quick follow-up, if I can, on one of the PI's comments in the presentation during the plenary. He specifically said that approval would require a change in the approval of the PSMA PET so that it can now be used for the selection of patients rather than tracking patients' tumors. Is that something that you anticipate and something that you believe will be done prior to Lu-PSMA being approved? Just if I can sneak a final one in, can you let us know whether the Endocyte manufacturing facility has been FDA approved or there is a risk that that adds further delay at the approval end in due course? Thank you. Great. Thank you very much, Matthew. Jeff, do you want to take both the questions, the first one with respect to the PSMA and what's required in terms of selection of the test? I don't know whether you can comment anything else with respect to the manufacturing facility from anybody. I can take the first one, and then I may defer to Sidonie or Susanne on the second part of the question. Okay. In terms of the FDA expectations, there are already gallium-based PSMA tests that are actually approved for use. I think what is unique here is that we are using the PSMA-11 gallium-based test as a mechanism to select patients, which would therefore then constitute a companion diagnostic or a specific regulatory pathway for that. We have been in discussion with the FDA regarding the requirements for our upcoming drug submission, and we would include the PSMA diagnostic as part of that upcoming submission to the health authorities accordingly. Thank you. Susanne, on the sites? I think we can ask Sidonie, taking it. Okay, Sidonie. Manufacturing, Sidonie? Yes. We plan to produce in Millburn, which is FDA-approved, and we can also produce in Europe, in Ivrea, which also has FDA approval. We have flexibility. Great. Thank you. Just to comment on that, these are both AAA sites, so we already prepared the tech transfer after we acquired Endocyte. That's why the production for FDA will be done from established AAA sites that are FDA approved. Fantastic. Thank you all very much. A special thanks to everybody outside of Novartis because I appreciate, or we all appreciate it's a super busy day for all of you. Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.