Investor Update

Sep 21, 2020

Slides

Good day, and welcome to the VMS ESMO IR Event. Today's conference is being recorded. At this time, I would like to turn the conference over to Mr. Tim Power, Vice President, Investor Relations. Please go ahead, sir. Thanks, Justin, and good afternoon, everybody. Thanks for joining us today for our 2020 ESMO Investor Meeting. I I just want to make sure that you're aware that we've posted slides to bms.com that you can use to follow along with today's discussion. And obviously, we'll have time for Q and A afterwards. Joining me today for the presentation are Sumeghir Awad, our Chief Medical Officer and Head of Global Drug Development as well as Chris Berner, our Chief Commercialization Officer Giovanni Cafforio, our Board Chair and Chief Executive Officer as well as some other members of our oncology team are also here for the Q and A as well. But before we get going, I'll read our forward looking statements. During today's call, we'll make statements about the company's future plans and prospects that constitute forward looking statements. Actual results may differ materially from those indicated by these forward looking statements as a result of various important factors, including those discussed in the company's SEC filings. These forward looking statements represent our estimates as of today and should not be relied upon as representing our estimates as of any future date. We specifically disclaim any obligation to update forward looking statements even if our estimates change. With that, I'll hand it over to Giovanni. Our evicted burden to sell out. Thank you, Tim. And it is a pleasure to be able to speak with you, especially right after a very, very important meeting that has just happened, not only for the company, but also for the patients that we serve in terms of bringing new medicines for the treatment of very serious diseases. So, if you go to the next slide, Slide number 4, this today and over the last couple of days, 3 important trials with the first time data release were presented that have the potential to expand the use of Opdivo in tumor types that we are adding on overall to the overall development of Opdivo. But to start off, as you see on the left upper corner of the slide, we are pleased that our dual IO option in first line renal cell cancer continues to demonstrate durable survival after 4 years. In CheckMate 214 study with more than 50% of the patients alive after 4 years. In terms of the first time data release, Study 9ER can potentially provide an important new treatment option for patients with renal cell cancer combining Opdivo with Cabrinetix. As it relates to upper GI and ethnicities, earlier today, positive data were presented from study CheckMate 649, where we have the opportunity to be 1st in line in the first line setting for gastroesophageal cancer, a tumor with a high unmet medical need. And in CheckMate 577, Opdivo showed a benefit early stage esophageal cancer, which is now the 2nd tumor type that Opdivo has demonstrated benefit in early stage disease. Slide 5 please. Going into just a bit of detail for CheckMate 9ER. Here you can see the trial design where combination of nivolum and cabozantinib was compared to sunitinib as a treatment for patients with previously untreated advanced or metastatic renal cell cancer. Iverolumab 240 milligrams was administered along with 40 milligrams of cabo compared to 50 milligrams of Sutent. Patients included in trial encompassed all risk groups, meaning those meeting favorable, intermediate and high risk criteria. While the family endpoint was progression free survival, our key secondary endpoint in this study was overall survival along with overall response rate and safety endpoints. And you can go to Slide 6. We have most likely seen the presentation of the data day before yesterday when you saw these strong efficacy results. As a reminder, this trial met its primary endpoint of progression free survival at an interim analysis along with overall survival, which not only showed statistical significance, but also clinically meaningful improvements. As can be seen from the Kaplan Meier curves, a 49% decrease in the risk of progression is very strong. In addition, there is a clear survival benefit that is observed across all patient subgroups, including across risk status and levels of PD L1 expression. In the next slide, as we look at safety, by leveraging 40 milligram dose of cabozantinib, 9ER study delivered strong efficacy with a very encouraging tolerability profile. The discontinuation rate of 15% due to any great treatment related PAE is lower than that of other TKI I O combos on the market today. Taken together, we believe that based on the combined efficacy and safety, OPDIVO plus cabozantinib has the best in class profile relative to the other IO plus CTI therapies. And Chris will talk more about the opportunity as we work towards bringing this regimen to patients in the future. We can go to the next slide. Moving to the upper GI malignancies, we wanted to highlight another couple of trials for which we recently announced the top line data and these two trials were just presented at the Presidential Symposia, ESMO. The first one is from large development plan for Opdivo in the metastatic setting. Patients are eligible for enrollment in CheckMate 649 study shown here if they have been diagnosed with gastric, gastroesophageal junction or intratifacial adenocarcinoma and had not received prior treatment for their metastatic disease. The disease had to be HER2 negative. While this is a 3 arm study, the nivo AT arm data remains blinded until its final planned analysis and these data are expected next year. Regarding the nivo chemo arm, dual primary endpoints were PFS and OS in PD L1 CPS more than 5%, which represents about 60% of the population enrolled in the study. OARS was tested hierarchically, first in CPS greater than 5%, then in CPS greater than 1% and then in all randomized patients. On the next slide, you can see that CheckMate 649 met both its primary endpoints. Shown here are the data of overall survival, showing a 29% reduction in the risk of death in patients with CPS greater than 5% and a 20% reduction in all comers. This is the first time our PD-one inhibitor has demonstrated a survival benefit in patients with gastric cancer offering a potential new standard of care in a space where other studies have not been successful. We believe this is an important development for addressing our high unmet medical need for these patients and an opportunity for the company, which Chris will talk more about in a few moments. On the next slide, the safety data in the presentation confirms that the OPDIVO chemo regimen tested in CheckMate-six forty nine is soluble and consistent with what we have seen with prior studies of Opdivo. On the following slide, switching gears to the early stage setting. This is a slide that I shared with you back in June at our Investor Series and let me remind you of what we believe. We believe that immuno oncology can play an important role in early stage disease. From a patient perspective, this is an opportunity to medically intervene early and provide a potential for cure of the disease. We already know that checkpoint inhibitors work in adenal melanoma, where these checkpoint inhibitors are active and are benefiting patients with melanoma in the long term. This is likely because the immune system is more intact in patients with early stage disease. We've now seen Phase 3 data supporting the potential for Opdivo in early stage disease across another tumor type that is beyond melanoma with CheckMate 577 in esophageal cancer. On Slide 12, you see patients with esophageal or gastroesophageal junction cancers are in tremendous need of adjuvant options as the unmet medical need in this disease is very high. Esophageal cancer is the 7th most common cancer and 6th leading cause of cancer related deaths worldwide. For certain patients who do not achieve a pathological complete response following new adjuvant chemo radiotherapy followed by surgery, the outcomes are particularly dismal. There is a frequent recurrence of disease for many of these patients as most patients, maybe up to 70% to 75%, have a tumor that fails to achieve a pathologically complete response. These patients will generally live less than a year without disease progression, with no established adjuvant option to turn to. Patients and physicians need new treatment options that can stem disease progression and prolong life. And that's as you can see on Slide 13. In CheckMate 577, we designed a trial to address this particular patient population facing high risk of recurrence. This trial studied OPDIVA monotherapy versus placebo in patients with resected Phase II or III esophageal or gastricithelial junction cancer who received chemo radiotherapy prior to their surgery. Patients were stratified by PD-one status and histology, that is, non expressors versus expressors or a cut point of 1% for PD-one and squamous cell or adenocarcinoma histologies. Primary endpoint for the study was disease free survival, thus overall survival being the secondary endpoint. The overall survival endpoint has not yet been assessed and BMS as well as investigators remain blinded to that data. On Slide 13 are the data you saw at the Congress. I'll spend a few moments to touch on a couple of important things. The trial met its primary endpoint of disease free survival in residual and gastrointestinal junction cancer as an interim analysis. It is important to note, this is the first time a benefit has been demonstrated in this population offering a potential option for these patients for the first time. You can see the strength of the benefit overall and across all subgroups, most notably, CBL1 expression, tumor location and histology. Successful outcome in this trial further reinforces our view about the potential for Opdivo more broadly in early stage disease settings. On Slide 15, you'll see the safety profile. OPDIVO in CheckMate 570 was well tolerated with an acceptable safety profile consistent with what we know and have seen before. Overall, based on the combined efficacy and tolerability profile of this treatment, we believe that treatment rates for periadjuvant treatment could grow over time as physicians and patients recognize the promise of survival with Opdivo likely observed in adjuvant melanoma as well. On Slide 16, here is another slide we shared in June. It depicts our broad registration program now reflecting the additional trials, which have readout. We are excited to see our adjuvant program starting to bear fruit as well as realize these important near term opportunities in first line renal cell and first time gastric cancer to potentially offer Opdivo to a broader range of patients. Now beyond these opportunities, our lifecycle management program across various tumor types and stages of disease with both known and combination approaches. 2 of these opportunities in particular are in combination with new mechanisms like rilatilumab and bempeg, which I will discuss briefly on the next slide. Now, the journey in immuno oncology doesn't end with life cycle management of Opdivo and years ago. We have 2 next generation IO mechanisms under late stage development. Bempeg, our IL-two partnered with Nektar and relapsedimab, our anti LAG-three. We are studying how bempeg can be combined with Opdivo, first in melanoma and then in several of the other indications that you can see on the slide. As it relates to rolaflinab, we are now testing this medicine in a randomized Phase twothree trial looking at what added benefit rilatinab might demonstrate on top of Opdivo. Both these agents have the opportunity to provide additional therapeutic options for patients through next generation immuno oncology innovation. On the next slide, I just want to remind you of the mechanism of action that we are pursuing in immuno oncology with our LAG-three inhibitor, rilaplimab. The hypothesis behind this agent is that LAG-three expression is associated with T cell exhaustion and that could be leading to a form of primary or possibly secondary resistance to PD L1 blockade or PD L1 blockade. Now, blocking LAG-three expression using the elaplimab could allow for T cell activation in instances where T cell exhaustion is causing that lack of response. Therefore, in addition to providing us with potentially registrational data from the ongoing first time study melanoma, this trial will provide us with data to probably inform potential lifecycle management plans for future development of relapimumab. And in the next slide before I wrap up, I just wanted to summarize. We are excited about the data shared at ASMO and for the ability to build on our presence in first line renal cell space as well as expanding on the IO opportunities in the upper GI tumors. Opdivo and Opdivo based therapies continue to offer life expanding options for patients facing serious cancers with unmet need and we look forward to additional readouts from our robust program that you saw earlier across both metastatic and early stage settings. We continue to invest in innovative next generation mechanisms and await pivotal data from our late stage IO pipeline with rilapimab and Bentay. I will now turn it over to Chris to take you through the commercial perspective. Thank you. Thanks, Amit, and good afternoon. I want to pick up where Amit left off and talk a bit about how we think about the data presented at ESMO from a commercial standpoint and how it fits into the broader IO growth narrative for the company. Starting on Slide 21, as we've discussed previously, we've built a very in a dozen tumor types, and the majority of which BMS IO is in a dozen tumor types and the majority of which BMS IO is now standard of care. This book of business provides a strong foundation for continued growth in 2021 and beyond. And an important component of that growth was obviously the launch of first line lung cancer in the U. S. Earlier this summer. Those launches continue to proceed well, and I'm happy to discuss that further in Q and A if you like. We also last week received a positive CHMP opinion for Opdivo plus Yervoy combined with 2 cycles of chemotherapy, and we look forward to launching that regimen in Europe in the coming months. At ESMO this year, we saw data across 2 other tumor types that will also be important contributors to near term growth. So let me spend a few minutes providing a commercial perspective on these. I'll start with renal cell carcinoma on Slide 22. RCC accounts for roughly 1 quarter of Opdivo sales in the U. S. With Opdivo plus Yervoy, garnering approximately 35% share in the first line segment. As you can see on the left hand side of chart, the vast majority of this use is in patients with intermediate and poor performance status, which is our labeled indication. We've maintained this very strong position in first line renal in spite of significant competitive pressures here, in large part because of the impressive long term benefit of DUAL I O therapy. This long term benefit was reinforced with the 4 year survival data presented over the weekend, which you see on the right hand side of this slide with over 50% of patients alive at 48 months and a relatively stable hazard ratio compared to the last data update at ASCO GU. Moving on to the next slide, Slide 23. It's into this context that we anticipate introducing the 9 9R combination. Over the last number of months, we've had the chance to discuss with key customers the highlights of the data Sanathust went through and which were shared at this conference. The consistent feedback we hear is that the OPDIVO plus cabo as evidenced by the impressive OS and PFS benefit that compares very well against existing therapies and a very manageable safety profile. Given this profile, we see multiple opportunities to build upon our existing position in this market by displacing existing single agent TKI use, which you'll note from the previous slide still accounts for approximately 20% of current frontline use. We also see the opportunity to extend the benefit of Opdivo based therapy into the favorable risk patients with this regimen, which as I mentioned is currently off label for us. And finally, we see the opportunity to compete effectively in patients receiving currently available I O plus TKI options. Importantly, once approved, we'll be the only company to offer multiple IO based options to renal cell cancer patients, both dual IO and what we believe is the most compelling IO plus TKI option. Moving on to gastric cancer on Slide 24. We are very excited with the opportunity to bring Iotherapy to first line gastric patients. As noted on this slide, gastric cancers, including gastroesophageal junction cancer and esophageal cancer, are among the top 10 deadliest cancers worldwide. They are also cancers where we have seen limited advancements in over a decade, resulting in a substantial need for therapies that improve survival in the metastatic setting and, as we'll discuss on the next slide, prevent recurrence in locally advanced disease. With the CheckMate649 data Simon just reviewed, we are very excited with the potential to be the 1st and only IL regimen demonstrating the superior survival benefit versus chemotherapy in non HER2 positive disease across upper GI tumors. From a commercial standpoint, I'd highlight a few things about the opportunity here. First, the early feedback from physicians with whom we've shared these data has been very promising. Specifically, they note the compelling survival benefit that offers the potential to improve on current standard double chemotherapy in these upper GI tumors. The fact that clinical benefit was shown across PD L1 expression models is also viewed as important, as is the fact that these benefits were accompanied by a generally manageable safety profile. 2nd, I would also note that while this is a new tumor for IO, this is a customer set we know well and which has experience with IO and Opdivo based regimens in other tumors. Bottom line, we're very excited about the opportunity we have in the diabetes data. Moving on to Slide 25, The 577 data give us the opportunity to move IOT therapy into early stage esophageal cancer. As we have discussed within the context of our adjuvant melanoma experience, we know that when we are able to introduce effective bio therapies in early stage disease, we have the opportunity to not only treat the set of patients being treated with existing therapies, but also expand the pool of patients available for treatment. In fact, in melanoma, we saw greater than twofold increase in treatment rates. In early stage esophageal cancer, as Summit noted, there is a significant unmet need for patients. Only about 45% of stage IIIII patients today receive neoadjuvant chemotherapy plus radiotherapy, and the treatment rate post CRT and resection is extremely low. Moreover, among those who undergo Finally, while neoadjuvant and perioperative chemotherapy is Finally, while neoadjuvant and perioperative chemotherapy is used in a number of patients, there are still no systemic adjuvant therapies available for patients and outcomes remain poor. Based on the 577 data presented at ESMO, we believe we have the opportunity to drive adoption of adjuvant Opdivo across upper GI tumors post CRT and surgery. As Summit highlighted, the study demonstrated a highly significant and meaningful increase in disease free survival. That benefit was seen across subgroups. And importantly, given this is early stage disease, the benefit was accompanied by a well tolerated safety profile. Obviously, it's still early days and we'll continue to engage customers now that the full data set has been presented. But we think OPDIVO has an important role to play for Stage twothree patients with esophageal and gastroesophageal junction cancers. Next slide, please. Let me close here on Slide 26. As we've discussed previously, we have a strong base of business today across multiple tumors globally. We are happy with the early experience we're having in first line lung cancer with our U. S. Launches and look forward to the launch of the 9LA regimen in Europe in the coming months. And we're very pleased with last week's positive CHMP opinion supporting that launch. At this conference, we've heard about data in 2 additional tumors that would be near to medium term catalyst for IO growth. In renal cell carcinoma, the updated 214 data for our givopos yervoy continue to emphasize the longer term durable survival benefit seen with dual IO therapy. Data from CheckMate 9ER allow us to build upon this leadership position by providing what we believe is the best in class IOTKI option for patients, and we see meaningful opportunities where we can grow our business with this regimen. CheckMate649 and CheckMate 577 provide us the opportunity to establish IO and Opdivo specifically as an important treatment option for patients with upper GI tumors in both frontline metastatic setting as well as early stage disease. Collectively, the data presented here are part of a robust set of lifecycle options for our existing IO agents as well as the potential we have with next generation assets including relapamib and venpad. And with that, I'll turn it back over to Tim to moderate the Q and A. Thanks very much, Chris. And as a reminder, as well as Chris and Sumit, we have Giovanni Cafforio, our Board Chair and Chief Executive Officer on the line for Q and A as well as some of the folks from our oncology team as well. So with that, Justin, if you don't mind, can we go to the first question, please? Thank Our first question comes from Chris Schott with JPMorgan. Great. Thanks so much for the questions and congrats on the data here. I just had 2. Maybe first on adjuvant esophageal. Can you just talk about the penetration rates you seen with Opdivo and combos in adjuvant melanoma? And should we think about that as a decent analogy when we think about what you can achieve in this esophageal setting and if there's any similarities or differences that you'd highlight there? And maybe just also get an update in terms of where you stand in terms of the frontline non small cell cancer launch in the U. S. Type of share that you're seeing. I think with the 2Q results, you talked about some very encouraging trends. And can we just maybe just get an update of how that's progressed over the last, I guess, 1.5 months or so since that last update? Thanks so much. Sure. Thanks for the question, Chris. As you know, the penetration we've seen in adjuvant melanoma is roughly around 40%. That was a tumor where treatment rates were very low when we launched IO into that setting. We've grown those treatment rates upwards of 80% today. I think there are some fundamental differences as you look into esophageal cancer. First, this is a setting in which you've seen very little systemic use of any agents for patients in the adjuvant setting. This is an area where it's not really one disease, it's actually multiple diseases. So as you may know, 577 is a study that covered esophageal adenone and squamous cancers as well as gastroesophageal junction cancers. So I don't think you can really compare in terms of the underlying dynamics of melanoma to what we see in this particular space. What I will say is comparable though with the level of benefit that we're seeing with IO therapies. We're very excited with the data that we've seen with 577. Remember, this has the opportunity to be the 1st IO to market in the early stages of the dual setting. The data here are very compelling, doubling of DFS with a manageable safety profile. And based on that, we think we have the opportunity to significantly improve on the outcomes for patients, which as Simon noted, the majority of patients, in fact about 3 quarter of patients who undergo CRT and resection do not actually get a pathological CR and that puts in very bad outcomes for those patients. And so we're excited about the opportunity that we have here. I would just be a little bit reluctant to do a simplistic on look at what our penetration rates were in melanoma applied and here these are different diseases. With respect to first one, do you want me to sorry, with respect to first one, do you want me to yes, Let me make a few comments and then we have the Head of our U. S. Business, Adam Lekalski, on and he can jump on as necessary. What I would say is we continue to be very happy with the performance of the launch. As I mentioned in the second quarter call, we're seeing penetration rates in the high percentage of the high prescribing physicians. We space where the community physicians are very important. And so we've been targeting those physicians who have experience in the community setting with Opdivo and Yervoy and other tumors. Again, that's an area where we see very good engagement. And we're particularly excited because as we noted on the Q2 call, we are not seeing physicians pigeonhole the use of Opdivo and Yervoy in lung cancer into a specific patient type. We're actually seeing use really across a broad swath of patients. The majority of the use is in the PD L1 to 49 segment. We are seeing some use above 50% PD L1 expression. We're starting to see a pickup in the PD L1 negative and non expressors. That's the regimen that is covered or that's the space that's covered by the 9LA regimen. So overall, very happy with what we're seeing in first line lung. Adam, anything to add there? I think you said it well. We're very encouraged by the uptake. It's still early. We're approximately 3 months post approval. We knew entering the market is going to be an entrenched market with KEYTRUDA and KEYTRUDA plus LINZA. But as Chris mentioned, our share in just over 3 months is now in the mid to high single digits and we're seeing continued growth and we're seeing use across all PD L1 expression as well as in squamous and in non squamous. What we're hearing back from our physicians is our profile for both 227 and 49LA. The profile is differentiated. The durability, the 3 year landmark survival and chemo free messages are all resonating. And we've shown that we're increasing awareness, particularly in 9LA, because because 9LA launched after CheckMate 227, and we're seeing uptake now with that regimen largely in the negative. Team has done a very nice job with remote engagement. We have been almost exclusively virtually engaging our customers and we have penetrated our highest value customers over 60%. We're focusing on our O plus wide prescribers as early adopters and we've been ahead of our competition in share of voice. Lastly, I'll mention, you probably have seen we launched a national direct to consumer campaign last week to help educate patients and hopefully drive patients in to ask and have a dialogue with their physicians around Opdivo and Yervoy and the durability and chemo free option for long term survival. Our next question comes from Seamus Fernandez with Guggenheim. Thanks so much for the question. So just wanted to get a quick sense. When we look at the tolerability of the 9ER regimen, frankly, this looks better tolerated than any other TKI regimen. It looks better tolerated than Opdivo plus Yervoy. Why wouldn't this be your sort of a leading option, particularly given the robust PFS? Obviously, that was the message from the discussion. And then separately, just wanted to get a better sense in the gastric cancer setting. Would you guys help us understand where the most likely first line gastric cancer opportunity you believe is? Is this really an area globally where you expect use in gastric cancer plus chemo to be in the 5% plus patient population, 1% plus PD L1 positive Or is it your expectation that the benefit is actually across the entire patient population? I know it's statistically valid in the overall population, but just wondering how you expect treatment to evolve globally given the results we've done over the weekend? Thanks. Sure. Thanks, Seamus. I'll take that and then Samu, you can obviously add on as you need to. So with respect to first line renal cell, I mean, I think that you characterized the way we see 214 and 9ER pretty well. I mean, I think that, in fact, the discussion summarizes it as well. We think we have the best in class I OTKI regimen with Opdivo plus cabozantinib. And I think the data that we've seen with Q14, both from an efficacy and safety standpoint, continues to impress with the long term durability of that. In terms of how this ultimately will be used, we actually think that there's an analog to the way that physicians have begun to think about these regimens in first line with what we saw in second line. When we launched IO in second line, what we saw is physicians were choosing to use TKI for those more aggressive patients, patients where you needed to get an immediate response. And for those patients where you could allow IO time to work, they would opt for IO therapy. That's begun to be the approach that physicians are using as they think about 214 in the existing IO option. So we're very happy now to be the only company to have multiple IO approaches to offer in this space. We think we've got a best in class IOTKI with Opdivo Cabo, not only from an efficacy standpoint, but also a very good safety profile. Again, as I mentioned yesterday, good opportunity for us to over the weekend, a good opportunity for those patients who need a very quick response. But then for those patients where you're looking for a long term benefit, 214 provides an option there. And so happy to be able to have both of these regimens available for renal cell patients. And I think that's roughly how we're going to see that segment out. With respect to how we think about gastric and first line, I think that the 649 data has clearly demonstrated an improvement across all patient segments. The data is particularly strong, as you know, in CPS greater than 5%. What's on label is ultimately going to be a regulatory discussion. We'll have to see how those discussions play out both in the U. S. And ex U. S. What I would say is that given this is a space where we've not seen much in the way of innovation in over a decade, given the significant unmet need here. I think you're likely to see physician interest certainly in the U. S. To be in a very broad patient population. As you get outside of the U. S, given HCA dynamics, we may see a different set of dynamics play out there. But again, we're going to have to wait and see how the regulatory discussions go and it certainly are believed that the benefit here is across the entire population. Our next question comes from Steve Scala with Cowen. A few questions. First, Asian markets that you've noted are key to the GI indications. What are the timelines for filing in Japan and China? And can you remind us of the Bristol Myers Squibb Asian footprint in terms of sales force? Secondly, Bristol has a digit, but it gets little attention. Now that a second company has shown positive results, is your view changing? And then thirdly, if you will allow me, Bristol recently said that the liso cel plants had not been inspected yet. Can you tell us if the dates have been set to inspect each plant? Thank you. Sonak, do you want to start? Sure. Maybe we can start with, Phil, in the order that you asked. First of all, in the Asian market, it's a filing timeline around the data for gastrointestinal tumors that we've just studied in the upper GI because obviously very important data and we see the data applicable from these global studies, both in the adjuvant setting as well as in the first time setting. So, we have a global registration strategy always that we work through and since the trials have enrolled from across the globe, we will be discussing these. We cannot today tell you exactly the timeline because there are lots of pre submission meetings that we have to carry out with health authorities. But as the timelines become more finalized, we would certainly communicate those that we are working towards those aspects of filing. From a strategic perspective, certainly, we are looking obviously at the data that was presented recently at ASMO from other companies. We have our own digit, as we have said before, which is in Phase I right now. We are continuing to evaluate that. It's not that we changed our strategy. We just have to wait for the Phase 1 data to read out from both the safety perspective, dose perspective and any hint of activity perspective and then we will be able to third The third question you asked was about Lifesocel. And as we have recently communicated, both myself as well as Giovanni and others, we have spoken publicly, But we continue to work with the FDA in terms of assessing when the inspections will be. The plants have not yet been inspected. Just a reminder, we do have a day 2 30 designation. A reminder that we have a PDFA date in November. As soon as the FDA will inform us, we certainly take that into account. But right now, we don't have a date for inspection at the time. So, they have not been inspected yet. Thank you. And just very quickly on the presence in Asian markets, we have a presence in all of the key Asian markets. And certainly, as you know, gastric is an important potential opportunity in these markets. Our next question comes from Geoff Meacham with Bank of America. Hey, guys. Thanks so much for the question and congrats on all the updates that I snuck. For Chris on 9ER, I just want to understand the commercial positioning of nivoipi versus nivo cabo. Just what are the puts and takes for IO, IO versus IO TKI share in renal? And then for Samet, data for 649 was strong, but looking at the tail of the curve, it's not really close to what you see in other Iosensitive tumors in terms of long term OS benefit. You think gastric is just a difficult indication that's less immunogenic or IO doublets or triplets needed in your view to improve OS further? Thank you. Maybe I'll start and then I'll turn it over to Samit. I think with respect to the puts and takes for 9ER, as I said earlier, I think that as we look at where 214 and 9ER will be positioned, I think you're likely to continue to see physicians look to IOTKI options for those patients who need a more immediate response or have a more aggressive disease, and then they'll opt for 214 potentially for those patients with less aggressive disease where they have more time for I O therapy to work. The other thing I would note is that 9ER, because it included patients across performance status, gives us the opportunity to promote in the favorable patient population, which as I mentioned in the presentation, we don't have the ability to do in 214. So that's something that is somewhat unique to 9ER and is an important opportunity for us. And with that, I'll maybe turn it over to Simon. Thank you, Chris. And for 649, we do look, there are 2 things to note over here. 1, as you very well pointed out, very difficult and it's a very challenging tumor type to treat. And the fact that we've been able to isolate these types are making a difference in the overall outcome, both from a progression free survival and overall survival benefit that is addition to these patients and their outcomes. We need to do more, both from longer term follow-up to see what the pay will ultimately evolve into. We still need to build that data further up. And you're absolutely right. I think new therapies will need to investigate if they can add more from that perspective to elevate the tails occur further than what we currently see. So, more biomarker work needs to be done, isolate the effects beyond the CPS-one, five and all comer. What else can we do to really make a difference to the lives of these patients? It is a challenging tumor. We do see that the Asian patients in general like in Japan, they do better because they have more surveillance programs, smaller tumor types that are treated much earlier, as you also heard during the ESMO presentation. Maybe some of those things will need to be taken into account as well in the future as we continue to build towards improving overall outcomes for gastric and upper gastrointestinal tumors. Thanks so much. Just if we can get to the next question please. Thank you. Our next question will come from Tim Anderson with Wolfe Research. Thank you. Discussments of the 577 adjuvant data criticized the use of DFS as a primary endpoint. But in early stage cancer, I've been under the impression that that's an appropriate reasonably well accepted measurement. And I'm hoping you can comment on whether you think that was an unfounded criticism. But related to that, in Europe at least, could it be that you don't secure widespread reimbursement until you have less results in hand, especially because there was no benefit seen in patient reported outcomes? And when do you think you might have less results? I'll start and I'll pass it on to Chris. You're absolutely right. We do believe that if you look at any tumor type, RFS, BFS, whether it be melanoma, breast cancer, colorectal cancer and many of the other tumor types, the approval of drugs have been based on disease free survival or elapse free survival endpoints. And these are settings that there is a lot of guidelines that have been provided by regulators. So, we don't believe that from a regulatory point of view, there is any question about use of DFS as a primary endpoint for approval to the endpoints. As you know, overall survival is a secondary endpoint and patients are being followed for that. It remains blinded because we don't have enough events yet in this study to really make a good analytical output in terms of the results that will be meaningful. So, we will continue to work with the D and C or data monitoring committee to understand that when we will have the data. And then at that time, we will be able to share that with the regulatory agencies and beyond that. From a reimbursement perspective, how difficult it will be? Maybe, Chris, you want to comment on that? Sure. The only thing I would just add on the DFS point is that not only is there clear precedent, but we've obviously shared these data globally and there's very strong interest on the part of customers around the benefit that we've seen on DFS. And I think uniformly across geography, customers view that as a meaningful improvement. As you note, in some markets, there may be a requirement for overall survival, though I would say that given the timing of HTA assessments in European markets, we may actually have OS data by then. Obviously, that's going to be dependent upon the data. But as you well know, these typically are sequenced. And so we may have some OS data as we get into European markets given the timing. The only thing I would the only other thing I would add is that patient reported outcomes really will not impact reimbursement in a meaningful way. Thank you. Any questions? Can we move to the next question please? Absolutely. That will come from Terence Flynn with Goldman Sachs. Hi. Thanks for hosting the call and thanks for taking the question. I was just wondering as you think about the CheckMate 8 16 study in lung that's going to re out later this year. Just wondering if you can remind us what magnitude of improvement you're hoping to show here and if you'd be able to file for approval on a PCR endpoint or if you'd also have to wait for EFS data in that setting? Thank you. I can start off over there. So maybe the second question first. As we it's something that we will need to discuss with the cell lung cancer as a PCI as an endpoint. So, something that we will need to discuss with the regulatory agencies and it will obviously probably depend on the magnitude of the data once the DMC shares that with us. And if the DMC will share with us the data, then we can certainly engage the regulatory authorities in those discussions. But that is yet to be seen. And we are waiting to hear from the DMC once they are available and ready for analysis. In terms of the magnitude that we're looking for, these are competitors. So, it depends on what the placebo arm will show and then, of course, what the treatment arm will show. So, I can't give you the magnitude that we're looking for to find success. Those are statistical assumptions that we've placed in the protocol and when the DMC refills data, then we'll be able to get better guidance. Great. Just can we go to the next one, please? Our next question will come from Dane Leone with Raymond James. Thank you for taking the questions and congratulations on all the updates across your programs at ESMO this year. A lot of progress and great for Nivo. The question I'll limit myself to is just on CheckMate649. As you're anticipating the regulatory discussions on this study for approval. How do you think the narrative will go around the point of maybe having an enriched patient population for the CPS for N5. That did come up in the discussion session today. How are you thinking about your approach to how you would want the indication to be written on the updated label and think about all patients versus having that segmented scoring? Thank you. Thank you for the question. So, from the study perspective, it was an all commerce study. We did not enrich any of the patient populations. Of course, when we look at the data now, we see that approximately 60% of the patients did fall in the category of about 5% and that was certainly one of the primary endpoints. And then, of course, there was a hierarchical testing as you also heard. So, we do believe that the overall benefit has been observed not only in patients with tPS greater than 5, but also overall survival benefit also been shown in all comer population. So, those are the discussions we will have to have with the regulatory agencies. Over on, we'll see that the regulatory agencies ultimately will come to a conclusion with. But our interpretation of the data is the benefit is seen in all comers. And when we look at overall response rate, overall survival, all patients are benefiting. So, that's what our position will be going into the discussions with regulatory agencies, both with the FDA and the European side. Okay, great. Could we go to the next one please, Justin? Our next question comes from Matt Hitz with William Blair. Good afternoon. Thanks for having me and definitely the Osmo update. Just one question. You guys interestingly bring up relaunumab quite a bit today's presentation. If not, I haven't really talked about much, but we initially look at refractory PD-one melanoma population. But my question is really not, you're not so much at the melanoma trial, but how much of the success of that trial is going to be required to move the 6 dose combinations of Opdivo and rilatilimab forward into additional development? I believe that's kind of the lifecycle management program you mentioned as well. Thank you for the question. So, rivatinibab certainly is an important immune checkpoint inhibitor that is being investigated. And as I said earlier, melanoma is the venue that we are first investigating. And certainly, the 6 dose combination that you have talked about is important. And now as we look at the additional indications, as we look at the data emergence and we look at the overall development plan going forward, it will play an important role, certainly from a commercial perspective. Chris or Adam might want to comment on that. From a development perspective, defining those pathways of how to combine the 2 drugs, give them together, add the doses that we will be able to take forward, not in one indication, but multitude of indications because the applicability could be quite wide. We have to certainly test that out. We are looking forward to the readout in the early part of next year for the first study and the right in the life cycle management plan going forward. I don't know, Chris, if you or Adam want to comment on commercial aspects? I think you've covered it mainly. I mean, I think there's obviously we've had some tremendous success with our existing therapies in melanoma. The bar is high, but there's always room for potential improvement, not only in efficacy, but continue to improve on safety. And we'll have to wait and see how the data pan out, but we're excited about the possibility of adding rolatlumab in this setting. Thanks, Chris, and thanks Matt for the question. Just I think we've got time for one last question. That question will come from Navin Jacob with UBS. Hi, this is John Lim on for Navin Jacob. Congratulations on the data. Looking at the CheckMate 649 data, we noticed that the overall survival hazard ratio confidence interval for gastric was a bit tighter and didn't cross 1 versus those intervals for GEJ or AAC primary tumors. How should we think about this and what could this mean? Do we know very well where the primary is? Is there any confusion? I have a couple of words. I'm sorry. Can you repeat the question, Tim or Chris? Yes. So we were looking at CheckMate 649, and we noticed that the hazard ratio that that doesn't cross 1. But then for GEJC or EAC primary, those confidence intervals are a bit wider. And we were just wondering how what we should make of this? Sure, sure. Perhaps you in the overall population, if you think about it, you've got an overall benefit. Now, when we start to cut the data further and further, if you look at the forest plot, you've seen that in the gastric cancer population, you've got a sample size of 667. So, you get to see a little bit more power to be able to do that analysis and get a hazard ratio of 0.66. Now, for doing the GED junction as well as the schizophrenia of the carcinoma, we've got 170 patients and 118 patients respectively. But overall hazard ratio still remains beneficial at 0.84 and 0.78 respectively. And if you look at the overall median, it's 142.2 months for GV junction cancer, for example, and 11.2 months. But it's again, one has to really keep in mind, what we start when we start to drill down in the data and the sample size gets smaller and smaller, it's hard to keep the intervals as tight as you would see with a larger population. But I think the more important point is, when you look at all the endpoints in this study, when you look at PFS, when you look at ROIs, when you look at overall response rate, duration response, are you able to keep the trends in the right place beyond the primary and secondary endpoints? That's, I think, going to be very, very important and that's what it depicts in general. That's our take from the data. Great. Well, thanks, Simon, and thanks, everybody, for your time today. Obviously, it's a great meeting for the company, for our patients. And if you've got follow-up questions, you know where to find us afterwards. So thanks again. Thank you. Thank you. Thanks, everyone. And that does conclude today's conference. We do thank you for your participation. Have a wonderful day.