Novartis AG (NOVN) Earnings Call Transcript & Summary

Good morning and good afternoon, and welcome to the Novartis Oncology Pipeline Update Investor Call. [Operator Instructions] The conference is being recorded [Operator Instructions] With that, I would like to hand over to Mr. Samir Shah, Global Head of Investor Relations. Please go ahead, sir.

Thank you very much, and a big thank you to all of you who are listening today, a pretty busy time for you all. So good morning and good afternoon. Before we start and before I hand across to Susanne, 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 the 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. And with that, I'll hand across to Susanne Schaffert, President of our Novartis Oncology business. Susanne?

Thank you, Samir, and welcome to today's investor call on Novartis Oncology, also from my side. And good morning, good afternoon, everybody. Following AACR, ASCO and EHA, we would like to provide you an update on our oncology strategy and pipeline, which we expect to fuel our future growth. I'm joined today by the key leaders in our development and research organization, starting with Jeff Legos, Global Head of Oncology Development; Dave Feltquate, Global Head of Hematology Development; Jeff Engelman, Global Head of Oncology Research at our NIBR site; and Alice Shaw, Global Head of Translational and Clinical Oncology, also part of our NIBR organization. So let me move to Slide 4. Novartis oncology has a track record of pioneering innovative approaches. And just to name a few examples, Novartis launched the first-ever targeted therapy with Gleevec; we brought Kymriah, the first CAR-T therapy to market; and we launched the first, radioligand therapy with Lutathera, and that's only just mentioning a few examples amongst a very, very broad pipeline and portfolio. And these innovative assets have led to continuous growth and made us one of the leading companies in the market, reaching annual sales of almost $15 billion. On Slide 5, you see what makes our portfolio unique. We are the only company that is present in all 4 therapeutic modalities to treat cancer, and you see a rich portfolio in each modality. And you will have the opportunity later now to really go into all assets. So moving to Slide 6: Why we are so excited about it. I think it's very clear that research is telling us that we need to tackle cancer, not only with one of these modalities but potentially with 2 to more modalities in combination. And therefore, we believe that our unique portfolio gives us the opportunity to combine all these modalities. Here on these slides, you see that basically all of the combinations targeted NI, or radioligand and IO and all the above, you see, is possible. And I believe to have this all in-house gives us a clear competitive advantage. So moving to Slide 7. We had a very strong presence at the key conferences, ASCO, EHA and AACR, and we presented more than 170 abstracts. And just to mention a few key highlights, were an OS data update on Kisqali patients with visceral mets, then a 5-year update on Mekinist + Tafinlar in adjuvant therapy with is very impressive data. Then very exciting data from TheraP, which is an IIT, this lutetium-PSMA, our second radioligand therapy. And we presented an update on Phase I trials of MBG453, where you will hear more during this presentation. But also a 3-year update in TKI-intolerant patients with asciminib. And data from our cMET inhibitor, Tabrecta, in brain mets; as well as data from our SHP2, TNO155. So excited to hand over to Jeff Legos now to dive into our modalities and give you a further update in -- on our solid tumor franchise. So Jeff, over to you.

Sure. Thank you, Susanne. And let me start on Slide 8, and I'll focus on 2 of our key breast cancer targeted therapy medicines as well as provide you with an update on some recent ASCO data as well as progress with our life cycle management indications for these important, important assets. If we move to Slide 9. Kisqali continues to reach more patients with HR+/HER2- breast cancer. As a reminder, in both of our pivotal Phase III studies, MONALEESA-7 and MONALEESA-3, Kisqali demonstrated a consistent 30% reduction in the risk of death, and these overall survival benefits we're seeing across menopausal status, line of treatment, metastatic site of disease and independent of endocrine therapy partner. We are eagerly awaiting the overall survival results for MONALEESA-2, which is a study in endocrine-sensitive patients. The events are coming in much slower than predicted, which is great news for breast cancer patients. And we expect to have a data readout in 2021. We believe that the comprehensive overall survival evidence, plus very distinct pharmacology, is expected to continue to differentiate Kisqali within the CDK4/6 class. We're also very excited about the rapid enrollment in the NATALEE adjuvant study. Despite the COVID-19 interruptions, we continue to expect enrollment to complete this year with the data readout in 2022. If we move to Slide 10, some of the data presented at this year's ASCO reinforces the Kisqali efficacy and safety profile. In particular, the overall survival and progression-free survival benefits were seen consistently across subgroups, including patients with poor prognosis, such as those that had visceral metastases at baseline. In the Kaplan-Meier curves on the left-hand side of the slide, you will see that data from MONALEESA-3 and MONALEESA-7, which is our studies in pre- and post-menopausal patients, this is a subgroup analysis in patients specifically with liver metastases. Here, we show that these patients had a substantial 37% reduction in the risk of death in MONALEESA-3 and a 47% reduction in the risk of death in MONALEESA-7. These results are very meaningful in this poor-prognosis patient population. We also presented data at ASCO this year from our open-label Phase IIIB study. This data comes from more than 3,200 HR+/HER2- advanced breast cancer patients who received 1 or less lines of prior chemotherapy and no prior endocrine therapy. The data overall confirms the safety and efficacy of ribociclib plus letrozole in a large and diverse cohort of patients. This data closely resembles real-world clinical practice and provides further support using ribociclib plus letrozole in the first-line setting. If we move to Slide 11, we have a good amount of evidence mounting that suggests that CDK4 inhibition is more critical in the pathogenesis of HR+/HER2- breast cancer compared to CDK 6, which is much more relevant for hematopoiesis. A variety of kinase inhibition assays demonstrated internally as well as independently through external collaborations have demonstrated that ribociclib is approximately eightfold more potent against the CDK 4/6 compared to CDK 6. PK data also demonstrate that ribociclib reaches significantly higher drug concentrations at steady state compared to other CDK 4/6 inhibitors. This is very important because higher unbound free drug concentration means that more drug is available to act on tumor cells. Therefore, at clinically relevant doses and adjusting for differences in potency against CDK 4/6 as well as protein binding, Kisqali should provide greater CDK 4 inhibition. If we move to Slide 12, here is an overview of NATALEE, which is our Phase III adjuvant trial of Kisqali, which is designed to address an important unmet medical need in patients with high- and intermediate-risk breast cancer. These patients are at a high risk of relapse. We believe that NATALEE may offer benefit for these patients based on the unique properties of Kisqali, including selectivity and potency of inhibition for CDK 4 over CDK 6. Prolongation of cell cycle arrest, followed by tumor senescence and death, may be an important concept particularly in the treatment of ER-positive disease, where tumor cell dormancy and latency may be quite long. In particular, the NATALEE trial for Kisqali allows administration for 3 years to further support testing of this hypothesis. In addition, we know that Kisqali is generally effective and well tolerated across a wide range of doses, in particular, at the 600-milligram approved dose for metastatic disease. For this study, we have used 400-milligram dose, where we see very good compliance and a low rate of discontinuations due to tolerability. Sticking within our breast cancer franchise, I will move to Slide 13 and give a brief overview on Piqray. The PIK3CA mutation occurs in approximately 40% of patients with breast cancer and is well-known to be a negative prognostic factor. Piqray is the only approved precision medicine solution for these patients, and we continue to see testing rates for the mutation going up. Piqray is now approved in 13 countries worldwide, including the U.S., Canada, Switzerland and Australia. And just about 2 weeks ago, the European Union has also issued a positive opinion for patients with the PIK3CA mutation and advanced HR+ breast cancer. The new development EPIC program is well underway. And in fact, we dosed our first patient with triple-negative breast cancer in June of 2020. This will allow us to expand this treatment to other indications with a PIK3CA mutation or the PI3 kinase pathway being activated and provides an opportunity for us to reach an additional 100,000 patients. If we move to Slide 14, here is an overview of some of the recent data presented at ASCO. We know that limited data exists in patients pretreated with a CDK 4/6 inhibitor, specifically those patients with the PIK3CA mutation. Real-world evidence in this patient population suggests that median progression-free survival after progression on a CDK 4/6 inhibitor is in the range of only about 3 to 4 months. BYLieve is the first and only prospective trial evaluating alpelisib plus endocrine therapy in patients with PIK3CA mutated HR+/HER2- advanced breast cancer who were previously treated with a CDK inhibitor. The primary endpoint for this trial was met and the proportion of patients who were alive without disease progression at 6 months was just over 50%. The median PFS was 7.3 months, which is very clinically relevant in this difficult-to-treat patient population. In addition, we have also observed that since the implementation of the safety guidelines and following continuous medical education, we continue to see a significant decrease in alpelisib discontinuations overall as well as those related to hyperglycemia. The overall adverse event-related discontinuations were 20% in the BYLieve study compared to 25% with the pivotal Phase III trial in SOLAR-1, and there was fewer discontinuations due to hyperglycemia in BYLieve compared with SOLAR-1, in just over 1% compared to just over 6%. More trials are underway to address this on-target toxicity with additional treatment approaches. I would now like to turn the presentation over to my colleague, Dr. Alice Shaw, who will talk about some of our key targeted therapy pipeline assets. Alice, over to you.

Thanks, Jeff, and good morning. So I'll be discussing another set of targeted therapy stories, starting on Slide 15, all of which center around this key concept of oncogene dependency as a key therapeutic vulnerability in human cancers. As you heard from Susanne, Novartis has a long and rich history in this field, having developed Gleevec, the first TKI in CML; followed by Tasigna, a second-generation ABL TKI for resistant disease; and most recently, asciminib. Asciminib is distinct from previous ABL TKIs in that it's an allosteric inhibitor. It doesn't bind to the ATP binding site where other TKIs bind and where resistance mutations often develop, but instead, it binds in a myristoyl pocket and actually restores inhibition of BCR-ABL. The Phase I data showing clinical activity in heavily pretreated resistant CML was published last December in The New England Journal, so here, I'm just highlighting the latest data we presented on asciminib at EHA last week. And here, the focus was on a subgroup of patients in a Phase I study who were previously PKI-intolerant. And these patients really do well on asciminib with 75% still on treatment and in MMR after a median follow-up of over 3 years. Asciminib was really well tolerated with only 6% of patients discontinuing due to AEs. So currently, asciminib is in a pivotal Phase III study in third-line CML with data readout expected in the second half of this year. But I'd like to turn now for the next 10 minutes to oncogene dependency in solid tumors with a focus on the central role of RAS/MAP kinase signaling. So on Slide 16, the left panel is a simplified schematic highlighting RTK signaling to RAS and its canonical downstream effector pathways. At Novartis, we have an incredible toolbox of small molecules targeting essentially every step of the RAS/MAP kinase pathway. From the top, this includes TKIs targeting RTKs; our SHP2 inhibitor, TNO155; our B/C RAF inhibitor, LXH254; our MEK inhibitor, trametinib; our ERK inhibitor, LTT 462; and finally, our CDK 4/6 inhibitor, Kisqali. We also have our own KRAS G12C inhibitor, JDT 443, which is currently in IND-enabling studies. So why focus on RTK/RAS/MAP kinase signaling? As shown in the middle panel, the last decade has shown us that solid tumors, particularly lung adenocarcinomas, but also melanomas and GISTs and others, can be driven by a variety of genetic alterations leading to activation of this pathway. And importantly, we've seen that small molecules targeting this pathway can be incredibly effective. Shown in the right panel is one example with Zykadia, the first of the next-generation ALK inhibitors for ALK-positive lung cancer, where you can see that median overall survival in chemo-treated patients receiving Zykadia as their first ALK TKI is over 51 months. So as we see early on with -- so as we saw early on with Gleevec for CML, targeted therapies really have the potential to completely transform the course of disease in oncogene-driven cancers. So let's start with 2 validated targets for which we have standard of care targeted therapies. The first is MET, which is activated by exon-14 skipping mutations in 3% to 4% of non-small cell lung cancer patients. And to summarize in Slide 17, Tabrecta, or capmatinib, was just approved by the FDA last month for MET exon-14 patients, along with a companion diagnostic from Foundation Medicine. NCCN guidelines are updated almost immediately to list Tabrecta as the preferred option for lung cancer patients with MET exon-14 skipping regardless of line. Given the pandemic, we've made the first-ever wave-based launch, which leverages our digital capabilities to ensure patient access. And we're anticipating capmatinib's next approval in Japan. Now on the right-hand side of this slide is a high-level summary of ongoing efforts to maximize the potential of Tabrecta. We're planning a confirmatory Phase III study of Tabrecta as well as further exploration of Tabrecta in specific settings, such as brain mets. But what I'm most excited about is Tabrecta-based combinations because these may allow us to potentially expand beyond the MET exon-14 subset. So I'll come back to Tabrecta combinations in just a minute. But first, on Slide 18, I wanted to remind you of the key clinical data supporting Tabrecta's approval and its differentiation from other MET TKIs. This data comes from the GEOMETRY mono-1 study, which was a large study with multiple different cohorts of patients with MET exon-14 mutations or differing levels of MET amplifications. And the waterfall plots here shows Tabrecta's activity in previously treated and treatment-naive MET exon-14 patients. And I think what's particularly notable is how active the drug is as first-line therapy with a response rate of 68%, disease control rate of 96% and median PSF (sic) [ PFS ] of over 12 months. In the second-line setting and beyond, Tabrecta is also highly active. And at ASCO a few weeks ago, we presented additional data from GEOMETRY focusing on second-line patients, this is cohort 6, where the response rate was 48% and disease control rate, 90%, which is consistent with what we've reported previously. Tabrecta is also very active in the CNS. And at the virtual AACR meeting this year, we presented an analysis of MET exon-14 patients who had brain metastases at baseline and received Tabrecta. There are 13 patients in this analysis, and intracranial responses were achieved in 54%, including 31% with complete resolutions. Finally, we've also looked at Tabrecta's activity in patients with high-level MET gene amplification, defined as a gene copy number of 10 or higher. And at ASCO this year, we reported a response rate of 29% in previously treated patients and 40% in treatment-naive patients with high level MET amp. These findings support further studies of Tabrecta in MET-amplified cancers, including possibly as a combination partner in EGFR-mutant patients who become resistant to EGFR TKIs due to MET amplification. So other Tabrecta combinations are also under investigation, including combinations with PD-1 inhibitors in first-line non-small cell lung cancer, and the left panel on Slide 19 summarizes the preclinical rationale for these combinations, which really centers on the immunosuppressive role MET and its ligands, HGF, may play in the tumor microenvironment, and the preclinical demonstration that capmatinib in combination with PD-1 inhibitors can enhance tumor response in models irrespective of MET status. So we're currently testing the combination of Tabrecta with PD-1 inhibitors in 2 distinct settings. The first is Tabrecta combined with KEYTRUDA in first-line PD-L1-high metastatic non-small cell lung cancer. And as a reminder, high PD-L1 is seen in about 20%, 25% of non-small cell lung cancers. This is a global randomized Phase II study with KEYTRUDA as a comparator. And FPSE was in January this year. The second study is Tabrecta combined with our PD-1 inhibitor, spartalizumab, in first-line non-small cell lung cancer with MET exon-14 skipping mutations. This is also a global randomized Phase II study, but with Tabrecta as a comparator since the patients all have MET exon-14. FPSE is planned for next month, and the hope is that spartalizumab could further improve on Tabrecta's efficacy in the first-line setting. So now let's move to Slide 20 and the second validated target, BRAF mutation, for which we have standard of care, dabrafenib+trametinib, or Taf/Mek, for BRAF V600 mutant melanoma and non-small cell lung cancer. As shown on the left, Taf/Mek has shown strong growth the last 5 years, with recent growth driven by launches in BRAF in lung cancer and also in receptive BRAF-mutant melanoma. At ASCO this year, we actually presented updated data for COMBI-AD, which was a Phase III randomized trial, comparing 1 year of adjuvant Taf/Mek with placebo in patients with receptive Stage 3 BRAF-mutant melanoma. After a median follow-up of 5 years, patients who received Taf/Mek continued to show a significant improvement in relapse-free survival, at 52% compared to 36%, hazard ratio 0.51. And these findings confirm that 1 year of adjuvant Taf/Mek does confer a long-term survival benefit in patients with receptive BRAF-mutant melanoma. What about metastatic BRAF-mutant melanoma? Again, at ASCO, we presented what we hope may build on the current standard of care and become another growth opportunity, and that's the addition of PD-1 inhibitor to Taf/Mek. So on Slide 21, you can see that preclinical studies suggests that, in addition to targeting BRAF-mutant tumor cells, MAP kinase inhibition may alter the tumor microenvironment and augment the antitumor immune response. Early clinical trials of combined PD-1 inhibitors and BRAF MEK inhibitors also suggest added benefit of the combination. So COMBI-I is a 3-part Phase III trial evaluating spartalizumab plus Taf/Mek in previously untreated metastatic BRAF-mutant melanoma. And shown here are the updated efficacy data from Part 1, which was the safety run-in; as well as Part 2, the biomarker cohort. There were 36 patients total from Parts 1 and 2, all of whom received the triplet of spartalizumab, Taf and Mek. And at a median follow-up now of just over 24 months, the confirmed response was 78% and with notably a CR rate of 44%. Responses have been durable with median duration of response not reached and a 24-month PFS rate of 41%. In addition, the triplet appear tolerable in terms of safety, with adverse events consistent with the known safety profiles of each drug. Overall, I would say the results are encouraging, but of course we're all waiting for the randomized Part III of COMBI-I, which will directly test sparta/Taf/Mek versus Taf/Mek, with readout expected later this year. Now moving to Slide 22. One limitation of Tafinlar and other approved BRAF inhibitors is that they inhibit only mutant BRAF V600 monomers and they're not active against RAF dimers; BRAF nonV600-mutant signal those dimers; and in addition, activated RAF associates with RAF, forming BRAF and CRAF homodimers and heterodimers. So this knowledge has spurred the development of newer RAF inhibitors, such as our LXH254, which is a potent and selective BRAF and CRAF inhibitor, which can block both dimeric and monomeric BRAF and CRAF kinases. In our first-in-human Phase I trial, LXH was well tolerated as a single agent, but there was limited antitumor activity in patients with KRAS-mutant and BRAF-mutant cancers. However, shown here, preclinical studies have shown really robust activity with LXH-based vertical combinations in cell lines and animal models, including LXH combined with MEK, ERK and CDK 4/6 inhibitors. So now we're really focusing on developing these LXH combinations in the clinic. And these combinations are being tested in BRAF-mutant melanomas and NRAS-mutant melanomas, which together make up about 70% of all melanomas. And we're also testing these combinations in non-small cell lung cancers harboring BRAF V600 as well as nonV600 mutations which are found in about 4% of cases. So hopefully, based on these studies, we'll be able to extend the reach of our MAP kinase portfolio to additional patient populations in need. So the next slide, Slide 23, highlights what is probably the greatest challenge in the field of targeted therapies, which is the development of resistance. Even the most sensitive oncogene-addicted solid tumors will eventually develop mechanisms of resistance, which then lead to clinical relapse. And as our targeted therapies have gotten more potent and more selective, we're seeing less secondary mutations in the target kinase and a lot more bypass or off-target mechanisms that, in many cases, lead to MAP kinase reactivation. As an example, in EGFR mutant lung cancer treated with first-line Tagrisso, only 5% to 10% of relapsing cases have a secondary EGFR mutation, while the remaining 90%-plus have a multitude of different EGFR-independent mechanisms of resistance. Now SHP2 is a tyrosine phosphatase that serves as a critical node in the RAS/MAP kinase pathway by mediating GTP loading of RAS, downstream of many different RTKs, and recent work from a number of groups has identified SHP2 as a potential target to address acquired and adaptive resistance. For example, in shRNA screen and ALK TKI resistant cell line models, we found that SHP2 was the most common hit with down-regulation of SHP2 resensitizing resistant cancers to ALK inhibition. More recently, several groups have examined adaptive resistance to KRAS G12C inhibitors in preclinical models and found that SHP2 plays a critical role in RTK-mediated RAS/MAP kinase pathway reactivation, which underlies adaptive resistance to G12C inhibition and likely underlies early relapses on G12C inhibitors. So Slide 24 is a very high-level summary of our SHP2 inhibitor, TNO155, which we presented at AACR this year. TNO is a small-molecule allosteric inhibitor of SHP2 with an IC50 of 11 nanomolar. And as shown here, TNO has ideal drug-like properties, including high solubility, high permeability and no CYP450 inhibition, which may also make it an ideal combination partner. In preclinical studies, TNO has demonstrated efficacy as a single agent and in combination with various RTK/RAS/MAP kinase inhibitors. And I should note that TNO was the first SHP2 inhibitor in the clinic and is currently in Phase I single agent and combination studies, as shown on the next slide. And so here, Slide 25, are the 3 ongoing studies of TNO155 in the clinic and some of the preclinical data supporting these combination strategies. The first-in-human study, 2101 is testing TNO single agent in advanced solid tumors; and we'll also test TNO combination with our third-generation EGFR TKI, nazartinib, in EGFR-mutant patients who become resistant to Tagrisso. We've also opened a second TNO study, B1, focusing on 2 specific TNO combinations: TNO with spartalizumab and TNO with Kisqali. The TNO/spartalizumab combination is pretty interesting, given the emerging data showing that SHP2 plays a role in PD-1 signaling in immune cells, and that SHP2 blockade may promote antitumor immunity. And finally, where I think one of the greatest opportunities may lie, in combination with KRAS G12C inhibitors. And there's now extensive preclinical data showing that combined G12C and SHP2 inhibitors leads to greater RAS/MAP kinase suppression and improved efficacy. So in collaboration with Mirati, we started testing the combination of TNO with their G12C inhibitor, MRTX849, in advanced G12C-mutant solid tumors, and really with the hope of more robustly inhibiting G12C as well as blocking adaptive resistance, which should translate to improved responses in the clinic. Okay. So with that, I'm going to turn it over to Jeff to review our immunotherapies. Jeff?

Thank you, Alice. So if we can move to Slide 26. We're going to spend a few minutes talking about some of the progress on our immunotherapy pipeline. Specifically, we're going to speak about canakinumab, which is our IL-1 beta antibody. In addition, although we won't speak to it directly, as you've heard throughout the presentation so far, we are actively developing our own PD-1, spartalizumab, in combination with Taf/Mek and with Tabrecta, and we will continue to use spartalizumab to allow us to develop these types of combinations that we think will have a huge impact on patient outcomes. We will also speak about MBG453, our anti-TIM-3 antibody that's being pursued in MDS and AML. And just to note, we are also developing another IL-1 beta antibody, VPM087, in renal cell carcinoma in colorectal cancer. And our NIS 793 is our TGF-beta antibody that's being explored in several tumors. So I wanted to spend a moment talking about canakinumab on Slide 27, please, and just to reiterate the concept of pro-tumor inflammation. And this is very different from the types of inflammation we think about for treating cancer. Over the past several years, with the advent and implementation of anti-PD-1 antibodies, we've seen how inflammation -- the induction of inflammation or T cell activation can eliminate tumor cells. And that is a different type of inflammation here, where we're actually saying that inflation is bad, the inflammation promotes the cancer. And unlike with PD-1, where we're activating T cells for an adaptive immune recognition of the cancer cells, this play with IL-1 beta is out of the inflammasome. And the inflammasome is not made for adaptive immune responses. It is a very primitive immune response to foreign entities, including particulates and other exposures that lead to inflammation. And several studies have shown that this type of inflammation can be very important for inducing cancer, inducing metastases and invasiveness. And so we're targeting this inflammation, this inflammation by the inflammasome in myeloid cells, where the production of IL-1 beta and IL-18 is inducing more myeloid infiltration, exacerbating this immune infiltration by myeloid cells, which inhibits the ability of the T cells to recognize the cancer and kill it. So in our study -- Slide 28, please. In our CANTOS study, which was looking at using the IL-1 beta antibody to block the progression of cardiovascular disease due to the hypothesis, the activation of the inflammasome was exacerbating cardiovascular disease. In this setting, they also did an analysis -- we also did an analysis, looking at the development of cancer. And what was striking is what's shown here on Slide 28, and was published in The Lancet a few years ago, was we saw a dose-dependent decrease in the risk of developing lung cancer and a dose-dependent increase -- or a dose-dependent decrease in lung cancer mortality. So these were striking results that we saw. It made a lot of sense because most of these lung cancers occurred in patients who were smokers or former smokers, where we would expect a lot of inflammation through this pathway. And the effect on lung cancer was just astonishing and dose-dependent. And this led us to pursuing this hypothesis in a prospective manner that led to the launch of 4 different studies looking at targeting IL-1 beta to treat cancer. And the first study, which most approximates the CANTOS study, which is to take patients after they've had complete resection of their tumor and they've gotten their post-resection chemotherapy, to randomize patients to receive canakinumab or placebo to see if canakinumab will prevent or delay significantly the development of recurrence, where about 40% of our patients have been enrolled, and we're planning that filing for 2023. We also have the first-line lung cancer CANOPY-1 study. And in this study, we're adding -- IL-1 beta antibody, Alaris, we're adding that to chemo plus pembro, which is a standard first-line regimen, and we're seeing if the addition of this IL-1 beta antibody improved outcomes in those patients. We expect an interim analysis at the end of this year and filing in 2021 if the study is positive. And in the third trial is the CANOPY-2 study, which is looking at this in the second-line therapy that would add canakinumab to docetaxel to see if it's better than docetaxel alone. Again, we're expecting that to read out next year. And finally, in the neoadjuvant study, which is really a study that is going to help us understand the biology of what canakinumab is doing, we're looking at the use of canakinumab, canakinumab plus pembro or pembro alone in a neoadjuvant study to understand the biological [ sys-quality ] of targeting those pathways. On Slide 30, you can see the actual details of the CANOPY-A study design. This is a study, again, for patients in the adjuvant setting, which we feel is a bit closer to the setting in the CANTOS study, where we were treating patients that didn't even known to have cancer, just had a high risk of cancer. And finally, in Slide 31, I wanted to mention that at Novartis, we're very focused on developing the next generation of inhibitors for this pathway. The inflammasome pathway has been implicated in many diseases, including Parkinson's disease, multiple sclerosis, Alzheimer's disease and cancer. And so we have several different small molecule programs as well as antibody programs, where we're looking to use inhibition of this pathway to treat many diseases, and in particular, using it to treat cancer. And we're very excited about trying to identify patients at high risk of developing cancer to see if we can start using this class of medicines for cancer prevention. And with that, I'm going to hand this over to Dave Feltquate, who will speak about MBG453, our TIM-3 antibody, in hematology.

Thanks, Jeff, and good morning, good afternoon to everyone. I'm glad to speak to you today. So let me talk a little bit about MBG453. This is another IO therapeutic that is designed to do actually 2 interesting things. It recognizes TIM-3. TIM-3 is an interesting checkpoint molecule. It's not only expressed on activated and exhausted T cells and monocytes and macrophages, but it's also expressed on myeloid leukemic stem cells but not on normal bone marrow stem cells. In preclinical studies, anti-TIM-3 is active against myeloid malignancies with evidence of 2 distinct mechanisms of action. One, it blocks the inhibiting activity of signaling through TIM-3 on T cells, so allowing reawakening of exhausted cells, these T cells to be active; but also has a direct effect on leukemic stem cells that are -- that express TIM-3. So in both these ways, it seems to be exerting activity. Now we looked at the activity of MBG453 in a large Phase I study, evaluating it as a single agent and in combination with several agents, both in high-risk MDS patients as well as patients with AML. And we observed promising clinical activity in both of those subgroups of patients, specifically those that were treated with a combination of hypomethylating agents, either decitabine; or later, we also explore the combination with azacitidine. Updated data from the study was just presented a few days ago at EHA. And as shown on the next slide, Slide 33, the overall activity in terms of objective response rate was approximately 60% of both the patients receiving the combination with decitabine or the combination with azacitidine. Notably, most of those responses, approximately 50%, were complete responses, and they were durable with respect to the duration of follow-up for this study. There were some patients who actually went on to get a transplant. From a safety perspective, this was very well tolerated. In fact, the safety profile is very similar to just the hypomethylating agents alone, signifying that not only is this a combination of good activity, but MBG453 as a component is something that may be suitable to even provide other agents on top of. Now if you go to Slide 34, based on these data, we created the STIMULUS program. And it's composed of a number of different studies. Starting off with high-risk MDS, we have STIMULUS-MDS-1. This is an ongoing randomized Phase II study comparing the combination of MBG453 with azacitidine versus azacitidine alone in high-risk MDS patients. The endpoints are complete response and event-free survival. This study is ongoing, and we expect enrollment to complete in the second half of this year. Our companion study is STIMULUS-MDS-2. This is a Phase III study, so this will be a confirmatory study. Also randomized, same design, combining with azacitidine versus azacitiinde. But here, the endpoint is survival. And we expect this study to begin later in the second half of this year. In AML, we have a study called STIMULUS-AML-1. This is a study -- it's a Phase II study evaluating a triplet, MBG plus azacitidine plus venetoclax. And this is what's very interesting about MBG453. Because of the safety profile, it's very well tolerated, and so we're able to build more complex regimens, which we think will be important in AML. Lastly, we also continue to explore other combinations with MBG453, not only in MDS and AML, but also in myelofibrosis. So if we go to Slide 35, I'm going to move on now and talk about one of the other therapeutic modalities: Cell therapy. And we'll go on to Slide 36. There's 2 components of what I really want to tell you. I'm going to tell you about Kymriah, but I'm also going to tell you about where we're moving towards the future. So in terms of Kymriah, as you all know, this was the first approved CAR-T cell therapy. It's also the first therapy with approval in 2 indications. And we continue to make progress in expanding the availability of this treatment to patients. And we're doing that in a number of ways. So number one, manufacturing. We've been able to make continuous progress in terms of the quality of the product. At this point, 90% of bottled products are available to patients. We've also augmented our capacity. So our global footprint is 7 sites. Currently, we have 3 sites that are able to produce commercial product, and we expect 2 more to be opened by the end of the year. One of the sites that is open for commercial production is the Morris Plains site. And we had earlier this year, the FDA give us the go-ahead to expand the capacity at that site. So all of these illustrate our ability to further increase the supply for patients. We've also continued to make gains in regulatory approvals globally and negotiating access and reimbursement in these countries where we're getting approval. So at this point, 25 countries have approval for Kymriah. And over 240 qualified centers are now able to provide this to patients. So what does this all mean? Well, this -- we translate this into doubling of sales compared to the previous year. So we're seeing a continuous upward trajectory by providing more supply. The other things that are happening is an expansion of data. So we continue to bring in real-world data through our registries. This continues to show comparable efficacy from the original pivotal trials, but more importantly, the safety we're demonstrating on -- in these registries showing better tolerated, specifically lower rates of CRS and lower rates of CNS toxicity. And this is due to both the increased ability to prevent, to recognize and manage the toxicities that do develop in patients. We're also continuing to expand the development of Kymriah. There are a number of studies ongoing, the 2 most important are the BELINDA study, which is in patients with relapsed diffuse large B-cell lymphoma; and the ELARA study, which is in patients with relapsed refractory follicular lymphoma. It's notable about the ELARA study, is that earlier this year, the FDA granted RMAT status based on outstanding preliminary data from this study. We'll move on to Slide 37. So the other thing I want to tell you about cell therapy is where we're going. So I think everyone knows the key challenges with version 1.0 of CAR-T cell therapy across the field is needing to improve manufacturing. So it's important that we innovate new ways to make improvements to simplify the process, to make it more reliable and to augment the turnaround time to improve benefits for patients. Our approach to this is something called activated rapid manufacturing, or otherwise known as ARM. And this is a platform by which we're basing all of our next therapies on, and this will allow us to make these meaningful improvements in manufacturing. The first asset that is in the platform is something called YTB323. This is a CAR-T therapy targeting CD19. It's actually the same vector that we're using for Kymriah, but it's on this platform. There is a Phase I study ongoing now to learn about the activity of this agent. And then we have other agents that are being built now that are targeting BCMA individually or in combination with other -- with CD19 as well as looking at CD22. And we continue to revise and update what other targets we will develop, again, on this exciting platform. Now I'm going to hand this back to Jeff, who's going to discuss our radioligand therapeutics.

Thank you, Dave. So I'll just spend a few minutes covering our fourth modality here on radioligand therapy. This is a unique opportunity that allows us to use a common molecule as a backbone and either label it with a radiotracer to identify the target of interest or subsequently replace that radiotracer with a radio-labeled isotope, such as lutetium, which then can become a therapeutic agent. I'll first start with Lutathera. This molecule remains on track for blockbuster status in the coming years, even in its current orphan indication of GEP-NET, which is gastroenteropancreatic neuroendocrine tumors. And if you recall, this was the first radioligand therapy that demonstrated a substantial and very clinically meaningful improvement in progression-free survival with a hazard ratio of 0.21. We are currently tracking the overall survival events, and we expect that data from that original trial called NETTER-1 to be available in 2021. At this year's ASCO, we had presented real-world safety data from the U.S. expanded access program, and this was also included in the ASCO highlights and demonstrated that Lutathera continues to have a very well-tolerated safety profile in a range of different patients with advanced neuroendocrine tumors and was consistent with the data from the Phase III NETTER-1 study. In addition, we've also established a NETTER-2 trial, which moves us into first-line neuroendocrine disease in patients with grade 2 and grade 3 neuroendocrine tumors. Looking forward, our next wave of innovation in the radioligand therapy modality will come from broader indications, such as metastatic castrate-resistant prostate cancer as well as the exploration of new targets, including the investigation of use in earlier lines of therapy in prostate cancer, looking at different radio isotopes like alpha emitters as well as exploring additional targets that could take us into multiple other solid tumors. If we move to Slide 40 and speaking about the future direction of radioligand therapy, there was quite a lot of attention and energy at ASCO around the TheraP study. This was an independent investigator-initiated trial. It was sponsored by the Australia and New Zealand Urogenital and Prostate Cancer Trials Working Group. TheraP is the first randomized study comparing investigational PSMA-617 therapy against cabazitaxel when used as a second taxane following progression after docetaxel in patients with metastatic castrate-resistant prostate cancer. The primary endpoint for this trial was PSA response, which was defined as a reduction in PSA levels by greater than 50%. And there was also the inclusion of secondary endpoints with respect to PSA, progression-free survival, overall survival as well as traditional PFS and OS as per RESIST and traditional survival. 200 patients were randomized 1:1 to receive either PSMA-617 or cabazitaxel. If we go to Slide 41, the TheraP principal investigator, Dr. Michael Hofman did report that PSMA-617 resulted in a 29% absolute greater PSA response rate compared to cabazitaxel in this setting, and nearly 2/3 of patients treated with PSMA-617 had reductions in their PSA levels greater than 50%. He also reported that this therapy resulted in relatively few Grade 3 and Grade 4 adverse events. Radiographic progression-free survival and overall survival data are still pending. But these results further highlight the potential clinical activity for PSMA-617. If we move to Slide 42, this leads us to our own Phase III VISION study evaluating PSMA-617 in patients with metastatic castrate-resistant prostate cancer. And this trial continues to go well, and we are expecting a data readout later in 2020. Key aspects around the VISION trial include: Patients must have progressive metastatic castrate-resistant prostate cancer; have received at least 1 prior therapy of novel androgen access drug as well; as at least 1, but not more than 2, lines of taxane-based chemotherapy, which they may have also received one of these in an adjuvant setting. There are 3 main differences in this VISION trial compared to the TheraP trial that was presented on the previous slide. First is the comparator arm. This includes best-available therapy or best standard of care. Secondly, is the patient population. The TheraP patients were eligible for cabazitaxel and had only 1 prior taxane-based treatments, while VISION patients had 1 or 2 prior taxanes or were not candidates for cabazitaxel. And then lastly, the primary endpoint for the VISION trial include both radiographic progression-free survival as well as overall survival. We are eagerly awaiting these results in the second half of this year. And in addition to that, we are also in the process of setting up additional life cycle management indications. As we look across the prostate cancer landscape, there is a clear opportunity in the metastatic stage of disease, particularly in the initial target patient population for 617 based on the VISION study, where these patients have limited to no treatment options, and in third to fourth line prostate cancer, therapy is often palliative only. If we think about what the literature shows, there's approximately 10% to 20% of men with prostate cancer who become castrate-resistance within approximately 5 years of follow-up; and over 80% of men with castrate-resistant prostate cancer disease that have metastasized. These patients have a significant unmet medical need and a 5-year survival rate of approximately only 30%. Our next step is to explore PSMA-617 radioligand therapy in earlier areas of unmet medical need, such as the pre-taxane setting, as well as in metastatic hormone-sensitive patients. And as you could see from the figure above, the patient numbers go up incrementally as you move into earlier lines of therapy. I'd now like to turn the call back over to the operator and then open it up to a Q&A. Operator?

[Operator Instructions] And the first question comes from the line of Graham Parry.

So a couple on canakinumab. So firstly, could you help us understand what the stopping criteria for both efficacy and safety in the CANOPY-1 progression-free survival interim analysis in Q4? What quantum of PFS benefit needs to be seen in order to stop there rather than continue to the overall survival? And is there a safety element to that, too, given the fatal infection risk seen with the drug in CANTOS? Secondly, have you had these discussions with regulators as to the fileability of that PFS data and whether they would be happy with that without any OS data given the risk again of infection risk on that product? And then thirdly, what was the reason in that study for not selecting patients by characteristics seen in CANTOS? So high CRP, high smoking or former smoking status, for example. And were patients stratified by CRP level and smoking status and any other biomarkers still allow you to identify subpopulations in that study that might be fileable even if the overall data is not successful?

Thank you, Graham. And I think that's a question for Jeff Legos. Jeff, go ahead.

Yes. Thank you, Susanne. And, Graham, thank you very much for the question. Maybe I'll start with safety. So prior to the start of the randomized Phase III portion of the study, we had also included a safety run-in of about 30 patients. And we were able to demonstrate that the safety was highly consistent with what was observed or what you would expect based on platinum and pembro alone and/or the addition of canakinumab. So we were very comfortable moving into the Phase III randomized portion. Secondly, safety has continued to be monitored throughout the entire trial through an independent data management committee or data monitoring committee, and the consistent guidance would be to continue the trial as planned with no modifications. Thirdly, the interim analysis that is expected or upcoming later this year is not a futility analysis. It is an efficacy analysis, and it is designed with stopping criteria that is clinically meaningful and highly significant. In terms of the overall trial design itself, we have included multiple primary endpoints. So both progression-free survival and overall survival are independent endpoints as part of this trial. And again, we have designed it in a way to demonstrate a statistically significant and clinically meaningful benefit. In terms of your last question regarding CRP, we know that CRP continues to increase as the disease metastasizes and worsens throughout the course of metastatic disease. In this particular trial, data from the safety run-in have demonstrated that the median CRP levels are greater than 10, so approximately 15, in just the safety run-in portion of the trial itself. And this is consistent with a retrospective analysis from a previous trial. So these are -- as Dr. Engelman had mentioned, these are higher than what we have seen in the CANTOS patient population, and we did not stratify based on CRP levels at baseline. CRP is an independent and core prognostic factor. And we believe the addition of canakinumab, hopefully, will actually help restore CRP levels to normal and allow pembrolizumab and platinum chemotherapy to work even better than just those therapies alone.

And the next question comes from the line of Andrew Baum from Citi.

A couple of questions on Lu-PSMA. Could you talk to the potential concerns about renal toxicity, particularly as you move upstream with potentially more administrations, more doses? Second, I'm curious on PALACE because, obviously, this is critical to the outcome of NATALEE. I wasn't sure whether you're pointing to hoping for greater adherence or whether you were basing your hopes on the differential activity on CDK 4/6. It would seem that there seems to be an early treatment effect, which may have meant the PALACE didn't transpire. I was just curious whether you agree. And then finally, what's notable -- notably missing from your portfolio is bispecifics, your representative of most of the other modalities. Could you just update us in your interest in that particular class of antibody, and whether you have some that are going to be migrating themselves into the clinical and near future?

Thank you, Andrew. So I don't know. Jeff Legos, I think on lutetium PSMA, renal toxicity, and then also PALACE and NATALEE, I think. And then maybe bispecifics, that I would say Alice and Jeff could comment.

Sure. Sure. Thank you, Susanne. And, Andrew, nice to hear your voice again, and thank you very much for the question. So in terms of the PSMA-617 program thus far, almost all patients have completed their 6-cycle doses of PSMA-617. And we have not observed any major concerns with adverse events, especially those related to the kidney in the ongoing VISION trial. As we continue to move upstream with respect to the future studies that I mentioned during my presentation, we expect those -- the duration of therapy to continue to be around 6 cycles of therapy. With respect to the PALACE trial, the second question, regarding the announcements recently released by Pfizer, we obviously haven't seen the data so cannot comment or speculate on their reasons. But I do want to reiterate the point that you made in the question, and it's likely a combination of both, right? We do believe that there are some unique differences for Kisqali compared to some of the other CDK 4/6 inhibitors. Firstly, we are the only one that has clinical evidence to demonstrate not 1, but 2 successful trials, demonstrating improvements in overall survival; secondly, coming back to the unique pharmacology, specifically the increased selectivity of Kisqali against CDK 4 compared to CDK 6. And then with respect to the overall study designed for NATALEE, maybe a few key points. So firstly, we believe that we have a very homogeneous patient population with respect to following the AJCC guidelines, specifically using Ki-67 index as a marker to ensure that stage 2 patients are adequately included based on their risk for relapse. Secondly, in terms of our dosing duration, so we, in the NATALEE trial patients continue to receive therapy for up to 3 years. And then lastly, with respect to the overall dose that was actually used, which was 400 milligrams compared to the approved dose of 600 milligrams, we have shown that this is a very efficacious dose. And thus far, on the trial, we have a very low discontinuation rate, giving us further confidence that compliance and adherence, at least to date, is going quite well. So thank you. And maybe with respect to the bispecifics...

And maybe Jeff Engelman? Exactly. Yes. Jeff Engelman, you want to comment on the bispecifics?

Sure, absolutely. Andrew, thank you for the question. Yes, we do have a significant interest in bispecifics, and we didn't highlight it during this discussion mainly for space limitations. Currently, we have 2 bispecifics in the clinic. As you may recall, 3 or 4 years ago, we made a deal with Xencor, a collaboration. We're using the Xencor format. We have a CD 123 bispecific in the clinic in collaboration with Xencor, and we have a BCMA bispecific that just entered Phase I. We continue to be very interested in this therapeutic modality. We have significant research and drug discovery efforts, but we have not yet publicly disclosed our next-generation of therapeutics. So I'm going to just have to leave it at that for now. But thank you for the question.

And the next question comes from Steve Scala from Cowen.

Regarding the NATALEE trial, the estimated primary completion on ClinicalTrials.gov is 2025. Slide 9 says data in 2022. So what gives you the confidence that the interim look will be positive? Is this a reflection of how events are accumulating? So that's question number one. Question number two is, can you clarify the timing around the CANOPY trials? At the time of the December analyst meeting, the trials were 50% enrolled. Now they're fully enrolled. So 400 patients were added in the last 6 months. CANOPY-1 has a readout of 18 months, primary completion of 18 months. CANOPY-2 has 26 months. So can you explain how it's even possible to file in 2021 except in the presence of a successful interim? And then lastly, Pfizer is working on a CDK2/4/6. I'm wondering if you could tell us what your view is of interacting with CDK2.

So, Jeff Legos, I think NATALEE and CANOPY, you want to comment there?

Yes. Thank you, Susanne. And, Steve, thanks for the question. With respect to NATALEE, when we have presented to you at R&D Day in December of last year, our 2022 data readout, you are correct, was based on an interim analysis. Since that date, we continue to be extraordinarily pleased with how rapid the enrollment has gone. We are more than 75% accrued to the trial to date, and enrollment has gone well, and we are reopen in most territories that were affected and are interrupted during COVID-19. In addition to that, we have a pretty good handle on the overall patient population enrolled. And based on the expected prognosis as to when we would see our events, we are actually now planning for not just the interim analysis, but the actual first relapse-free survival analysis to occur in 2022. With respect to the CANOPY trials, so CANOPY-1 was fully enrolled as of January this year. So it is now June. And we, on average, were enrolling anywhere between 80 and 100 patients per month, and the overall Phase III enrollment for that trial in the randomized Phase III portion was just over 6.5 to 7 months. So it has gone exceedingly fast. The trial initially opened the randomized portion in June of 2019. And based on our current events projection, we are expecting an interim analysis this year and then additional OS and PFS analyses in the first half of 2021, obviously, depending on the number of events. CANOPY-2 is different that we -- the primary endpoint for CANOPY-2 is overall survival. That trial had completed its Phase III enrollment in March of this year. We have not reached our event goal, but we are expecting our events to be projected in 2021. And if positive, that would enable us an additional opportunity to file CANOPY in 2021 as well. Maybe with respect to your question regarding the CDK2/4/6 inhibitor, I'll turn it over to Jeff Engelman. Jeff?

Thanks, Jeff, and thank you for the question. Without commenting specifically on Pfizer's program, I think it's a very interesting point about targeting CDK2. There are several preclinical studies suggesting that CDK2 hyperactivation may be a way that cancer cells can get around CDK 4/6 inhibition and using CDK2 to promote reentry into the cell cycle. I think what we still need to figure out as a field is, what is the best therapeutic approach to targeting CDK2? Will it be, as you've mentioned, a drug that can hit 2, 4 and 6? Is it a selective 2 inhibitor that you combine with a selective 4 inhibitor or so on and so forth to maintain a therapeutic index? But the biology is extremely interesting. I think it's an area of intense research and drug discovery by -- I would assume by many companies. I hope that answers your question.

The next question comes from the line of Matthew Weston from Crédit Suisse.

Two questions, please. The first is on Piqray. The data on Slide 23 in your deck shows that about 7% of patients after first-line Tagrisso in EGFR mutant lung relapsed with a PIK3CA mutation. So I wondered if you have plans to take Piqray into lung cancer in that second-line post-Tagrisso setting, particularly now it looks like it's moving into adjuvant. And then secondly, on capmatinib, you flagged the idea of capmatinib in cMET mutant patients, again, in the EGFR mutant setting. I just wondered if you could update us as to where the trials are. I recall you had a combination study with EGF816, but also that you stepped back from EGF816 in monotherapy a number of years ago. So if you could just update us in that strategy of capmatinib post EGFR, I'd be very grateful.

I think, Alice, as you are our lung cancer specialist, maybe you want to have a go on the 2 questions.

Yes. I'll start with the -- maybe the second question first around capmatinib and the role of capmatinib in blocking met amplification as a driver of resistance. As you were saying, Matthew, we certainly know that met amplification is seen probably in about 10% to 15% of EGFR patients, who are failing TKIs -- first, second and third-generation EGFR TKIs, including Tagrisso. And so, certainly, capmatinib -- met is a very interesting target. And we already have data from both preclinical studies, but, more importantly, from the clinic showing that combinations of EGFR and [ MEK ] inhibitors can overcome met-driven resistance. And so we have looked at capmatinib in this setting in combination with gefitinib, but, also, I think what you were getting at is possibly a combination of capmatinib with a third-generation inhibitor, such as either ours, EGF816, which is nazartinib, or with the standard-of-care third-generation EGFR inhibitor, which is Tagrisso or osimertinib. And we're considering both of those as options for combinations with capmatinib. In terms of Piqray, I may actually ask Jeff Engelman to comment on this, if that's okay, Jeff, to comment on the PIK3CA mutations that emerge in some patients, who are failing on EGFR TKIs in the role of Piqray.

Yes. Thank you, Alice, and thanks for the question. It's a great question. I don't know -- there were studies that were combining EGFR inhibitors and PI3 kinase inhibitors back a long time ago. I don't know if it's been ever looked at with a specific p110 alpha selective inhibitor in combination with EGFR inhibitors and cancers that progress specifically with that resistance pattern. I don't know if we have strong data to suggest that this will resensitize substantially. But it's a good question. And just to be honest, it's not something that we've prioritized. We think about overcoming resistance being more common through SHP2 or met amplification, but I appreciate you raising this awareness. Maybe we'll think about it some more.

And the next question comes from the line of Peter Welford from Jefferies.

I actually have adding 2 left. So firstly, just with regards to going back to the CANOPY studies of canakinumab. Curious, you said CANOPY-2, the final analysis is 2021. Just to understand, was there an interim analysis? And did this pass? And can you perhaps comment as well on any findings that the DMC have had so far in the CANOPY-2 study? And I guess also in CANOPY-A, can you just outline the sort of the timing we should think about enrollment for that study? I think you gave some patient numbers in terms of CANOPY-1. Can you give us some idea of sort of run rate of CANOPY-A as well? And then just I think then, this is something Susanne, I think, made in the opening remarks. I think she said, apologies if I got this wrong, JDQ443, which, I think, was a KRAS inhibitor. Can you just outline, I guess, how that potentially differs to the -- and to the KRAS G12C inhibitors that are already in the clinic, and how we should think about that potentially moving forward in Novartis?

Thank you, Peter. So I think Jeff Legos again for CANOPY, and then Alice or Engelman.

Yes. Thank you, Susanne. And, Peter, thanks for the question. So if we think about CANOPY-2, right, this is a combination of canakinumab plus docetaxel in second or third line non-small cell lung cancer, where patients most likely have failed immunotherapy plus or minus chemotherapy. The prognosis of these patients is incredibly poor, with progression-free survivals on docetaxel being very short on the order of just a few months and even overall survival being on the order of 8 months. As you recall, the clinical trial design was very efficient with just about 226 patients or so for the target enrollment. So we had not included an interim analysis for overall survival, and the study was designed and powered to demonstrate a statistically significant and clinically meaningful effect against overall survival as the primary endpoint. In terms of the findings of the DMC, there was nothing remarkable. And with each interim or with each independent monitoring committee meeting, they had just provided advice to us to continue the trial without modification. With respect to CANOPY-A, the adjuvant trial, this trial is much larger in size. It's approximately 1,500 patients. Secondly, we know, from the industry as a whole, it has been more challenging to enroll to the adjuvant trials. And in fact, some of the other trials ongoing from some of the other companies have also been delayed. So we do expect this trial to continue its enrollment throughout 2020 and in 2021 and expect enrollment to be complete in 2022. And maybe I'll turn it over to Jeff Engelman or Alice to comment on JDQ.

Sure. This is Alice. So, yes, I think we all recognize that KRAS G12C represents a huge opportunity, particularly in non-small cell lung cancer and CRC. And as I mentioned, we now have our own G12C inhibitor, JDQ. JDQ is also a covalent -- potent covalent inhibitor of KRAS G12C, currently in late-stage of GLP tox, and we're hoping that we'll be able to enter the clinic early next year. But I think what you're getting at with your question is that, of course, there are many G12C inhibitors already in the clinic. And for example, AMG is several years ahead of us. And so, certainly, it's a valid question in terms of how we plan to develop in this very competitive space. I mean, I think it's, for me, all kind of gets back to what we know about G12C-driven lung cancers. And I highlighted some of the data in my slides, where we know that G12C positive lung cancers are going to be really prone to developing adaptive resistance or adaptive feedback reactivation. And so it's very likely that G12C inhibitors as monotherapy will not be sort of a transformative therapy like EGFR inhibitors or ALK inhibitors that we would hope for, and then, instead, will almost certainly need G12C combinations. And so, certainly, given our sort of extensive portfolio in the MAP Kinase space, I think we're positioned really well to be able to interrogate these combinations and very rapidly in the clinic. So I hope that answers your question.

The next question comes from the line of Simon Baker from Redburn.

Two questions. Firstly, going back to Slide 37, you talked about the activated rapid manufacturing approach for cell therapy. I wonder if you could give us some idea of the quantum between that and the existing Kymriah process in terms of time and cost. And then secondly, a broader question on radioligands. We've seen plenty of radio-labeled PD-1, PD-L1 antibodies for diagnostic purposes using iodine and zirconium. I was wondering if you've thought about using a more therapeutic isotope coupled with a PD antibody, given the interesting concomitant radio immunotherapy.

Well, maybe Dave, so would you want to start with why PD and manufacturing of cell therapies.

Sure. Glad to do so. Thanks for the question, Simon. Yes. So I can tell you really in general terms what we're trying to do with activated rapid manufacturing. As you know, it's quite complex in terms of the process to manufacture Kymriah and all of the first-generation compounds. A lot of this work is done by Ken. It's cumbersome, and it's prone to, in some cases, error as we're able to do this. So the activated rapid manufacturing process is designed basically to try to move closer and closer to a closed system and to make this more reliable and to really speed this process up. I'm not able to disclose to you what the time horizons we're looking at, but it's done in a way to make this, what I would describe, as much more clinically meaningful for patients. So that we decrease the ability or the necessity to use transition therapies as they're waiting for cell therapies. Because this is moving towards a closed system, where there are less human involvement, it actually lowers the costs in terms of overall, everything that needs to go into the production of this.

Thank you, Dave. And maybe Jeff Engelman on radioligand and the potential of combining with PD antibodies.

Sure. Can I just ask the questioner to restate the question just for clarity as to what specific aspect of that combo?

Yes. So it was a broad question on, instead of using diagnostic isotopes connected to PD antibodies, which we've seen before, for diagnostic purposes about using a more therapeutic isotope, so you would have concomitant radio immunotherapy, as is being investigated in a number of trials, particularly in lung cancer at the moment.

Yes. So thank you for the question. It's an interesting idea. We're certainly looking at combining radioligand therapy with systemic anti-PD-1 therapies that are not radio-labeled to PD1, just a radio-labeled therapy like Lutathera or the PSMA-617 and then combining that with an anti-PD-1. And I think that's our first foray into this area. Obviously, it builds on some historical work suggesting that radiation may stimulate an immune response to cancer through the death of all of the cancer cells. And can we add to that by giving PD-1 and really augmenting this immune response following radiation damage? I will say from my reading, the data on external beam radiation with PD-1, actually, I think, has been a little bit disappointing over the past few years. And I think one of the advantages to this approach will be that we don't have to zap a whole field. But since it's the radioligand therapy, it goes specifically to the cancer cells. And zapping the whole field may also impair the ability of the body's immune system to react to the cancer because we've kind of fried the whole area. So using this with RLT is of great interest. Now whether we should put the radioactive isotope on the PD-1 antibody itself, that's something we haven't explored as of yet. I think one of the potential things to consider is all of the radioactivity that would go through every body -- every part of your body that was expressing PD-1 or PD-L1. As we know, the expression of these PD-1 and PD-L1 is quite promiscuous throughout the body. So I'm not sure we would localize the radiation to the tumor as effectively with that approach, but that's something that we have not investigated thoroughly to be able to answer your question with specific data.

Thank you, Jeff. And we are quite late in time, and there are several questions in the queue. So I would suggest if you could limit maybe your questions to one, then we would be maybe able to get all through.

And the next question comes from the line of Laura Sutcliffe from UBS.

I'll stick to one. Just on canakinumab, and I'm sorry if I missed this, obviously, the CANOPY trials have combination with pembro. Pembro is approved in its standard of care, but do you see any opportunity later on to in-house the entire combination by using spartalizumab instead?

Thank you, Laura. Jeff Legos?

Yes. Thanks, Susanne, and thank you, Laura, for the question. Absolutely. We have already generated safety data with canakinumab, spartalizumab and chemotherapy, so that we know that it is a safe combination. So it does give us the option to evaluate that combination in future studies, yes.

And the next question comes from the line of Mark Purcell from Morgan Stanley.

It's Mark Purcell, Morgan Stanley. Going back to the sort of therapy platform, can you help us understand any progress or any initiatives you have on the autologous side of CARs? And then in terms of the arm platform, can you add other modalities such as NK cells onto that platform?

Thank you, Mark. So, Dave Feltquate, could you take that one?

Yes. I think first, I think Jeff Engelman might be able to address the second. Can we just repeat the first? Because I want to make sure I specifically get what you were talking about with autologous. Were you talking about autologous or allogeneic?

Sorry. In terms of both platforms, I just wondered what progress you're making across both. And then the second question was just whether you could use NK cells in your discrete consent in terms of the closest to manufacturing?

Sure. So I'll take the first one. Yes, we definitely continue to make good progress. Our primary focus is on autologous using the activated rapid manufacturing platform. And Jeff, again, will talk a bit more about that, but we continue to look for additional targets as well as means of adding additional biologic functions to help the lives of these T cells. And so that they're more active and live longer. In terms of allo, we also continue to work preclinically in collaborations to understand more about this technology. I'll hand it off to Jeff with respect to the second question.

Sure, Dave. Thanks, and thanks for the question. We have significant focus on how to improve the autologous transplant -- I mean, not transplant, the autologous CAR-T cells, which were the basis for Kymriah and are the basis for this more rapid manufacturing program, the arm program that Dave spoke of. We are very interested in the allo approach, obviously, the ease of the off the shelf. And we're watching this data emerge very carefully to see if we think that there is going to be significant activity and durability from that approach. Those questions still remain, but this obviously would be a very exciting outcome. We are confident that we would be able to modify our approaches or our evolving approach to accommodate other types of cells, including NK cells and other cells. Of course, there would be modest tweaks and modest technology development to get it working perfectly for those systems, but the actual manufacturing infrastructure that we're developing, we think, would be applicable to the other cell types as well.

The next question comes from Seamus Fernandez from Guggenheim.

So just a couple of quick questions. On the PSMA, I think in the [ arms up ] study, there was an imbalance in depths 11 versus 5 in the 2 separate arms. Can you just explain or help us understand that imbalance? I know that the tolerability did look better, but I think that was -- that would be helpful to just have an explanation around that. And then as we look at the TIM-3 opportunity, can you just help us understand Novartis' interest in combining the TIM-3 with other antibodies, and if it makes sense rationally to combine with other targets like CD47?

Thank you, Seamus. So maybe, first, Jeff Legos and then Dave on TIM-3.

Yes. Seamus, thanks for the question. I assume you are talking about the therapy data that was presented at ASCO in terms of the imbalance, correct?

Yes. Sorry, I referred to the wrong study.

No. No. I just wanted to make sure I clarify it. Right. So this, obviously, since it's an investigator-initiated, sponsored trial, it's difficult for us to comment on their results. Maybe that's something we could check with them and come back to you on a response. I don't want to comment on their study.

And then, Dave, on TIM-3 in combination, what combinations do you see? I think, Seamus, you asked about CD47 specifically.

Yes. You know what? It's really interesting when you think about what's happening in both MDS and in AML. There are a number of interesting combinations with azacitidine. And when you think about all the different approaches, they all utilize different mechanisms. Ultimately, it makes sense. We would want to combine therapies with different mechanisms of actions that are nonoverlapping. Historically, in doing that, you tend to create the most active regimen. One of the challenges in doing so, though, is the limits to combine all these mechanisms. So oftentimes, you increase toxicity and you have limits for what we can do. So with that in mind, MBG is very interesting, right? So though its mechanism is distinct from some of the other approaches that are taking place in these disease settings, you mentioned venetoclax, CD47, like this is distinct. It's also so well tolerated that, unlike some of these other compounds, where we're seeing increased toxicity, it may jeopardize the ability to do multiple kinds of combinations of those as a phase. I think with MBG, we're going to have a lot more success. So one of the combinations are looking at as a triplet with azacitidine, MBG, and venetoclax. And we're starting to evaluate others. We've mentioned within our pipeline HDM201 and things like this. But it's the idea is trying to take rational combinations and put them together to create the most activity.

The next question comes from Emmanuel Papadakis from Barclays.

Several have asked, but if I restrict myself to one, maybe just give us your thoughts on the potential impact of a forthcoming CD19 mass launch in the NHL sector. It would seem clear that is going to be a potentially material competitor for CD19-directed CAR-T therapy, but would be interested to hear your thoughts as to whether you think that's a risk, and, if not, why not?

Yes. Thank you, Emmanuel. Maybe I take this question. I hope I understood it well. It's about CD19 impact on Kymriah and CAR-T that how -- I hope I understood the question correctly.

Yes.

Yes. Yes. Actually, I think we saw this also now during COVID is that Kymriah and CAR-T therapies are really very, very meaningful treatment for patients with lymphoma and in pediatric ALL. And we even saw during COVID that physicians are continuing these treatments despite it's quite a cumbersome process and despite it might block some hospital space. And I think the reason is that really results are remarkable in a onetime treatment, and they are very, very durable. So that's why we believe that CAR-T therapies will have still a very, very strong position. I mean where I probably potentially see CD19 coming in is more in the community centers because, of course, we have to be clear that not every patient can be treated in specialized centers. And while, for example, on our side, we have really significantly expanded centers, there will always be patients, especially the ones that are considered unfit, that cannot travel and could not go to specialized hospitals. And that's how we would expect the market to be divided. Maybe one last question, operator, and then I'm afraid we have to close it because we already have run late.

And the last question comes from the line of Kerry Holford from Berenberg.

Just one left for me on canakinumab. Clearly, considerable investment continues, and now we're looking at the lung cancer setting, where it looks very interesting, but in the context of this and the time it's taken to get here, can you remind us of the IP protection you have for this drug? Is there anything more you can do here to perhaps extend that?

Yes. Thank you, Kerry. Let me take that. So the IP is until 2024. And you're right, obviously, that it takes a while develop. But on the other side, I mean, we also have a quite good understanding of the biosimilars market. And given that Ilaris is in a very rare indication, we don't expect biosimilars to come in quickly because there has to be a certain sales for a biosimilar to develop. So we feel we have enough time still to explore the potential, but then maybe also you saw on the slides that we're already working on the next generation. So we have canakinumab in -- as another IL-1 better in development. And then we have also a broad development program on the inflammasome, as Jeff Engelman has pointed out. So we have a backup plan, but we believe that we still can leverage canakinumab and really benefit from that. So maybe we said -- let me close here. I hope we could get you a good overview of our very intense and very broad pipeline. As I said, we feel that we are very well positioned being the only company that is present in all the 4 treatment modalities. And you, I think, heard from this wonderful team in development and research that, I think, we have a very broad pipeline under each of these modalities. So I think I can just only ask you to stay tuned for the major readout that we have in the second half of this year. So we have asciminib coming up. We have lutetium PSMA, and we have the triplet melanoma for Mekinist, Tafinlar and spartalizumab. So we will keep you updated. Thank you for your interest, and have all a good rest of the day. Thank you, everybody. And turning back to the operator. _

And that does conclude our conference for today. Thank you for participating. You may all disconnect. Speakers, please stand by.