Roche Holding AG (ROG) Earnings Call Transcript & Summary

So welcome, ladies and gentlemen, to our first virtual ASCO meeting. Before we start, maybe some organizational things, Henrik, if you could guide us through the system so that if you all know how to use it best or how to best use it, please. Henrik is our operator.

Exactly. I'm the technical operator for the ASCO '20 virtual event for today. [Operator Instructions]

Yes. Thanks a lot, Henrik. This is a new world, actually, and if I just beam myself now to Chicago, it's 10:00 there in the morning. You know that we usually do our meetings on the 6:00 in the evening. And of course, there are some meaningful differences between now and Chicago and the past. There is no dinner for you. I regret that very much. There is no red wine for us, which I also regret, I have to say. But there is also something positive actually because you don't have to run from one meeting to the next, and you will always have the feel that you have here shortened time. So at least there are some positives. But I can really tell you that I'm very much looking forward to seeing you next year in person in Chicago. So if we compare the ASCO's of maybe the past year, let's say, 2019 and 2020, I mean the total number of abstracts and presentations actually increased. I was quite surprised about it, I have to say. I mean we had last year 2,400 total ASCO presentations, abstracts. This year we have 2,600. For Roche, it's about the same number presentations, we had -- last year we had 155, this year 120 around. But also the real quality is basically the same. It's 25, 21. So it's a very similar level. But I have to say this new format of visual really doesn't make it easier, I have to say. I mean the exchange and discussion of data is much more difficult now. I don't know how you feel about it, but I really appreciated the personal meetings we had where you basically had discussions, where we could have discussions, where we had discussions with the KOLs, where we had other experts, which could exchange. At the moment, it's a bit -- an isolated thing on the one side. And I have to say, maybe while we could spend 8, maybe 10, maybe 12 hours at the ASCO side, I can guarantee you, none of us will spend 8 to 10 or whatever hours in front of the screen. So this is the other one, which is a bit more difficult. And I have to say there was also a trend in terms of dilution of important messages or important information. I mean ASCO actually really got crowded. And I have to say this new format doesn't make it much more easy. So that's our new reality. And as I said before, I sincerely hope that we are getting back to a kind of a new normal. What we have decided in view of this changed format is basically to focus a bit on some fewer data, more innovative things. We will do a short presentation than in the past. And before we go now into the presentation itself, I just wanted to thank Loren and Sabine for working on the presentation, [ Jared ] for his general support and of course, also the speakers. We have Ira Mellman with us today. He will talk about the cancer immuno cycle and anti-TIGIT. TIGIT was developed actually in his lab. So he basically is the inventor also of this new frontier, I would like to say. And this will be followed by Alan Sandler. Alan is talking about the clinical application of that and some selected data, which we are going to present at this year's ASCO. Next slide, please. Just kindly go to -- yes, exactly. So this is the journey we were on for many years now, as you know. So we have started with monotherapy only checkpoint inhibitors with Tecentriq in non-small cell lung cancer, you remember the OAK data, which actually were really good and giving good benefit for patients in later lines of lung cancer. And we have not -- recently approved the iMpower110 in monotherapy. So this was basically the first wave of monotherapy. Then we combine it with existing medications, in particular, chemotherapy, I have to say here, Ira had a brilliant idea to combine it with chemo. But unfortunately, we didn't make the full profit of it but another company. So I hope that with the TIGIT, we are in a better situation, I have to say that we are here in the lead and take full benefit of this innovation. But great data here, also hepatocellular bladder data, small cell lung cancer, triple-negative cancer. So a series of indications where we actually really were first, like in small cell lung cancer, TNB, hepatocellular and others. So we really caught up substantially. And at the moment, we are in the wave 3. So we expand to novel CITs, immune doublets, Tecentriq plus bispecifics, you will hear more about in the course of 2020 and then tira. And with this one, I would like to hand over to Ira. The floor is yours, please. Ira, you're on mute, you have to unmute yourself. Yes, okay. Very good.

Yes. The dog was making noise, so I muted, but the dog is now gone. So yes, thank you, Karl, and thank you all for being here to this virtual exercise. And hopefully, we've all learned enough to how do these things, to be -- get some utility out of it. So as Karl said, what I'd really like to concentrate on today is TIGIT. Every couple of years or so, I get the privilege of being able to talk about the mechanism of something because I think our understanding of the mechanism really goes a long way to informing why it is we're doing what we're doing and why it is we had confidence in taking a particular path. But first, I'd like to spend just 1 or 2 slides talking about some larger context and earlier-stage things just to give you some flavor of whatever is coming down the road. So this slide just really shows you how we at Genentech Roche view the world of cancer through the immunology lens, where all cancer patients, almost regardless of what indication they have fall into 1 of 3 immunological categories, which I hope you will now know, immune inflamed, immune excluded and immune desert. The inflamed group is still the group that mostly are the ones that are successfully targeted by the available and under development immunotherapies, even including TIGIT. Shown on the left, these are patients with a preexisting immune response that when we find that, that can be amplified to clinical benefit. The middle group, our immune excluded group, these are very common across all indications. And here, what happens is that the T cells that form and are trying to exhibit antitumor activity become inactivated and in many cases, even physically restrained by the stroma elements that can surround a tumor or even course through a tumor. We view this as a major opportunity for patients where we're able to actually modulate this stromal barrier because it -- as 60%, 70% or more colorectal cancer patients fall into this category and even, 40% to 50% of non-small cell lung cancer patients do. And first instance, the existence of the stromal barrier may be responsible for why the response rates in non-small cell are as they are. And finally, the immune deserts are in those patients, again, throughout indications that have showed no obvious sign of immune response. So that's the overall landscape. And next slide just shows you that we are trying to take a systematic analysis of the reasons why each of these 3 different immune profiles or immune phenotypes exist and develop agents that will modulate the activities and the restraining factors associated with each of these immune barriers. In some cases, there will be only one major barrier, in which case then those patients can be expected to respond to monotherapy. And we believe this is -- explains why it is. There is a subset of patients that respond very well to Tecentriq and other PD-1, PDL-1 blockers. But we're coming to the realization that, that is insufficient and that on occasion and in fact, probably keenly moving forward, patients will have to get more than one block or modulator. And this is obviously the reason for having progressed into TIGIT, although, both Tecentriq and TIGIT or tira are looking at the immune inflamed group. Next slide, this shows -- can you hit it again, maybe the -- yes, there is. Next slide just shows that it's even a little bit more broad than that. If you think about how all this works conceptually. The immunomodulators, such as the PD-1 blockers and TIGIT, work on advancing endogenous immunity. In other words, trying to persuade a patient's immune system to do a better job than it's already doing. Vaccines, personalized vaccines, as you probably know, we're involved in with our partner BioNTech in Germany also do this. Again, trying to persuade the immune system to do what it has not been doing successfully on its own. But there are also elements of synthetic immunity. And I think leading the pack here are the CAR type therapies. And in our case, our focus on immune cell engagers, this is the bispecific programs that we will not be speaking very much about today. And finally, cell therapies. And indeed, we have made the plunge for those of you who are wondering why we have not done so in the past and indeed, are starting to get quite interested in cellular therapy. And this is shown on the next slide, where we're taking 2 rather forward-looking approaches to the problem of how to get into both cell therapy as well as vaccine therapies, about which you may know a little. The idea is that we feel to have the maximum benefit for patients is that we have to figure out a way to develop drugs that are matched not only to individual patient groups, but actually to individual patients because by targeting the mutational profile precisely associated with each individual patient that requires that to make a new drug for each patient. And we've, I think, proved that we can do this, again, with BioNTech in the setting of personalized vaccines, there will be some data presented on this at AACR, which was supposed to precede ASCO, but now we'll be following ASCO next month. So I won't be able to tell you anything about what those data look like. But more recently, within the last year or so, we've entered into a collaboration with Adaptive Biotechnologies in Seattle to -- on the strength of having convinced ourselves that it is possible to make patient-by-patient drugs. We've gone into a targeted cellulose therapies using individual T cell receptors that are specific for mutations that are found specifically in each individual patient. Workflow for that is just summarized on the next slide, just to give you an idea of how this works. You can either look for an easy and off-the-shelf approach, whereby you target those neoantigens or mutations that are commonly distributed among patient groups or identify individual neoantigens associated with an individual patient, go into libraries of T cell receptors, which is what we do with Adaptive, pull out the T-cell receptors that are specific to one or another of the desired mutations and those -- and then take those T cell receptors and engineer them in using CRISPR technology into either autologous or allogeneic T cells, which then can be readministered back into the patient. These are very early days. But I think there's a lot of advantages actually associated with cellular therapies in solid tumors if you can target them selectively with a great deal of precision to the tumors and thereby, leave alone the normal tissues in the patient. So that's about what I'd say with respect to context. Let's now turn to TIGIT, and why TIGIT, in the next slide. As you know and as we've all known, there are -- is a whole panoply of negative and positive placebotory molecules associated with T cells that both advance and restrict the ability of T cells to do their jobs in cancer. And many of them are paired. So for example, CTLA-4, of course, shown here on the top, will regulate the important costimulatory molecule CD28. One that's very close to that conceptually, of course, is TIGIT where this molecule is a negative regulator that in first approximation controls another important costimulatory molecule called CD226. When TIGIT was first discovered actually by Jane Grogan some years ago at Genentech, it was not really knowing that there was that relationship, but with time, we understood that to be the case. And as a result, because of the similarity to the CTLA-4 CD28 situation, we decided to pursue it. As shown on the next slide, you see how we believe TIGIT controls CD226, this occurs in 2 ways. One is that they both compete for the same ligand, which is again, similar to the effect of CTLA-4 on CD28. TIGIT and CD226, both like to bind to PVR or CD155. And since TIGIT binds with a higher affinity than CD226, it is expressed, it outcompetes CD226 where it's activating ligand. And the hypothesis was it if you would block the interaction of TIGIT with PVR or other ligands, you would allow those ligands to now be available for binding by CD226, and indeed, that is what seems to happen. Next slide, please. So that was the theory. So but why TIGIT? Why do that and knock all of the others? And so here, I want to take a brief diversion back into the background theory as to why all of this is thought to work in the first place. So where we all started, and in fact, that includes ourselves, was with a very simple concept, which was that there are things called exhausted T cells, which are prevalent in tumors, which is still true to this day. And that exhaustion process is driven by PD-L1 on tumor cell binding to the negative regulator PD-1 on the T cell driving the exhaustion process. And by blocking the interaction between PD-1 and PD-L1, you would somehow reverse that, rejuvenate the T cells and they would come back to life and begin to eliminate tumor cells. With our commitment to trying to understand how this works, basically, we and now others in the field are finding is that this is -- may be true, but it's a significant oversimplification of how the process works. Next slide shows, I think, an updated view of something that's not mutually exclusive with the reversal of exhaustion idea, but which we think now in many patients and in many animal model systems is the prevalent mechanism. And this has to do with -- rather than reversing exhaustion, preventing it or limiting its effects in the first place. And so what you're looking at here is a dendritic cell, which is simulating a naive T cell to become an antitumor T cell. And what we find is that when you treat with an antibody that blocks the interaction with PD-1, with PD-L1 is this -- the population that derives exactly from the newly primed T cells called the stem-like T cells, we call them stem-like memory T cells, expands. So that's the one and the most important and most dramatic event that occurs following PD-1, PD-L1 therapies, the expansion of this T stem cell memory like compartment. So as a result, you can generate more memory T cells, those can generate more effector T cells and also avoid the normal progression that would otherwise have been taken to the exhausted compartment. So this changes things entirely because much of this probably happens not in the tumor, but in the lymph node. Second -- next slide we'll just show you again in a different way why we think this works. So on the top panel, what you're looking at is what we believe happens in a patient that is -- actually who has mounted an immune response to their tumor. There is kind of an equilibrium that exists between the growth of the tumor and the number of stem cells that can generate T cells that are capable of dealing with the tumor. And eventually, of course, the tumor wins out. By using a PD-1 blockade, shown in the bottom panel, you increase the number of these stem cells -- the stem progenitor cells, and as a consequence, allow the immune system to generate, almost in a geometric fashion, more T cells that now are available to attack the tumor and eliminate it. So when works, we believe now that this is a critically important component of that. So why TIGIT? Let's start it on the next slide, and I apologize, this is a piece of hardcore science for those of you who don't know what this is. But what you're looking at here are cytometer -- flow cytometer tracings that show you one very critically important thing, which is that this stem cell memory compartment, in fact, has, as you would expect, an expression of PD-1, but the only other negative regulator that it expresses in addition to PD-1 is TIGIT, okay? So that -- if we come to the idea that the stem cell memory compartment is actually key for mediating responses to PD-1, PD-L1 blockade, and TIGIT is also there as a second negative regulator, we reason that it might also be a good idea to block TIGIT so that it can actually add to the ability of PD-1 blockade to -- it manifest a clinical result. Next slide just shows how this works, again, using a T cell lineage diagram. If the T stem cell memory compartment is the target, you then wind up generating more cells that are capable of progressing to cytotoxic effector T cells. And if the ability of that stem cell memory compartment to proliferate is restricted both by PD-1 and by TIGIT, which is what we now believe, then blocking both of those markers, in fact, will have additional activity and the initial clinical results that you're -- we're now recently aware of, in fact, I think, are consistent with that therapeutic hypothesis. Now the last issue I want to turn to is summarized on the next slide, which is that TIGIT also does a little bit more than that. And that may turn out also to be a key feature, and this was unexpected, which is that we find from mouse studies as well as from biomarker studies that TIGIT also somehow seems to activate or redefine how the myeloid cell compartment works. These are both macrophages and dendritic cells that are involved here. And since we believe that all of these activities associated with expansion of the stem cell memory compartment occurs as a consequence of an interaction between the T cell and the myeloid cell is perhaps not surprising that there may be an effect directly on the myeloid cell as well. And as shown here, possibly on Tregs that are also very high in TIGIT. Now the way we think this works still is a bit mysterious, but we think, though, it has a lot to do with the availability of an intact Fc domain on the anti-TIGIT antibody. And we'll give you an idea of how that looks and how dramatic that can be in some systems on the next slide. Where you're looking at on the left, anti-TIGIT monotherapy, which doesn't really do very much, but does seem to do a little bit if you're using an anti-TIGIT, shown in the second panel from the left that has an intact Fc domain associated with it. In combination with anti-PD-1 or anti-PD-L1, the advantage of having an intact Fc domain -- again, these are all mouse experiments, but the advantage of having an intact Fc domain turns out to be really quite dramatic. So although you don't absolutely need it for at least some activity, providing it, obviously, provides you with a very larger amount of activity. And it's really based on data such as these that we decided when we went into the clinic, we're -- even though we didn't completely understand why this was the case we felt that the Fc domain was contributing and as a consequence, moved our antibody in. We know that there are various molecules from our competitors, some of which have intact Fc domains, some of which do not and perhaps we'll see from human data over the next couple of years, whether or not this aspect of the hypothesis also holds to be true. So the final slide, actually skip to -- we're going to skip on to end here. I just really wanted to leave you with a pictorial illustration of the revised thinking that I think we all have to now take more seriously, which is that there's a continuous communication between what's going on in the tumor and what's going on in lymphoid organs, such as lymph nodes that are draining the tumor bed, such that a lot of the molecules that we're using for immunomodulation, in addition to or perhaps even instead of working only in the tumor may be working within the lymph node or the compartment. And as a consequence, by their ability to generate more and better and more active T cells at the site of their formation in lymph nodes and then have those T cells migrate through the blood back into the tumor, one, we really find where the core or the heart of all of the activity we are coming to associate with this particular class of checkpoint inhibitors. So again, this changes a concept, and it may not ipso facto change the clinical result. But what it does do is change your understanding and change where it is you're going to be looking for your next targets in order to further improve on what we can do already. So that's all. I thank you for listening, assuming you are still listening.

Thank you. Over to Alan.

Yes. Thanks, Karl. Thanks, Ira, and thanks, everyone, for taking some time of your day to join us here and listen to our discussion. So I'll start off. As you see here, a little bit of lung cancer with CITYSCAPE and update on ALEX, the tumor agnostics and then close with a discussion -- a brief discussion of IMbrave150. Next slide, please. So CITYSCAPE is a randomized Phase II study that looked at the combination of tiragolumab with Tecentriq in diagnostically selected non-small cell lung cancer. And comparison was with Tecentriq, and it was a placebo-controlled trial, as you see here. It was for EGFR/ALK wild-type patients, and again, a 1% cutoff using 22C3. There was also no crossover in this study. And you see the coprimary endpoints of response and PFS. Shown you in the table below the stratification factors -- 4 of the stratification factors and show that they're equally balanced between the 2 arms there. So the next slide. So here are the results of the initial primary analysis with a nearly 6-month median follow-up that you're familiar with. Looking at the overall response rate, which was nearly doubled from 16% to 31% with the combination of tiragolumab and Tecentriq. And then also the PFS, which is shown here, improvement in the median from roughly 3.5 to 5.5 months. But more importantly, as medians are merely a single point on a curve, I think the more important is looking at the hazard ratio, which was 0.57 here, so a 43% reduction in the risk of an event for these patients, either progression or death. So in fact, tiragolumab and Tecentriq met both coprimary endpoints in the ITT population, again defined at 1% positivity. Next slide. So now this is the updated analysis now with nearly 11 months of median follow-up. And what I'm showing you here is the ITT population with respect to response rate. And you see that the response rate has actually improved a bit in both arms with additional follow-up allowing for some of the unconfirmed responses to become confirmed with additional follow-up. So 37% -- or the combination and 21% for Tecentriq. I am now also showing you the exploratory analysis for the response rates with respect to the breakdown by PD-L1 expression. So the greater than 50% group had the -- drove most of the difference in response rate with a 66% response rate for the combination and 24% for Tecentriq monotherapy as opposed to the 1% to 49%, where the response rates were quite similar. So again, here, you see the consistent and clinically meaningful response rate data driven by, again, the TPS greater than 50%. Next slide. Now this is the same updated analysis now looking at progression-free survival. Looking at ITT on the left with medians from about 3.9 to 5.6 months. But again, importantly, the hazard ratio of 0.58. And then looking at the TPS greater than 50% population that shows the median of 4.1 months for monotherapy and a median that has not yet been reached with the combination arm. And again, importantly, a hazard ratio of 0.3, which is certainly quite remarkable in this setting. So again, consistent and clinically meaningful progression-free survival with the longer follow-up, driven primarily by the higher PD-L1 population. Next slide, please. So next 2 slides I have shown the adverse events. This is all-cause adverse events shown here in a tornado plot, which, in essence, show that the combination of tiragolumab and Tecentriq is very well tolerated and similar rates of all Grade and 3 plus AEs when compared to Tecentriq alone. Before going to the next slide, there, I will call out the Grade 3-4 for increase in lipase shown here. An important point here is that is essentially a biochemical test not -- that did not really manifest itself clinically, and we can talk about that more with the next slide. That shows the immune-mediated adverse events. Again shown here, looking at pancreatitis, which is essentially the reflection of that elevated lipase, which is predominantly a laboratory abnormality that was seen and not something that was manifested significantly clinically. Next slide. So to conclude for CITYSCAPE, tiragolumab and Tecentriq showed clinically meaningful improvement in response in PFS in the ITT population when compared to Tecentriq and placebo alone. And with longer follow-up, the treatment benefit remained consistent and a greater magnitude of improvement that was seen, however, in the greater-than-50% subgroup for PD-L1 by TPS. The combination of tiragolumab and Tecentriq was well tolerated, and the safety profile was similar to Tecentriq alone. The immune-mediated adverse events were more frequent with the combination, but were primarily Grade 1 to 2 mostly IRR and rash and were quite manageable. The observed activity and safety of tiragolumab and Tecentriq is to be confirmed in an ongoing Phase III study known as SKYSCRAPER-01 in first-line PD-L 1 patients with TPS greater or equal to 50%. Next slide. The slide shows the clinical development program as it stands now and an -- is an active evolution, as you can imagine. We have the Phase I studies in solid tumors, which, interestingly enough, you haven't seen that data yet again because of the COVID pandemic, it was to be presented at AACR, but when AACR on the virtual meeting split into 2 presentations, it's in the second one. So that you'll see at the next AACR presentation. Suffice it to say that there was evidence to move forward with CITYSCAPE. As you see also, we're looking at a broad range of different malignancies, both in terms of Phase III studies. And also utilizing our novel platform MORPHEUS for GI malignancies, pancreatic cancer and urothelial carcinoma as well. And I've mentioned that there are, in fact, 2 Phase III studies that are ongoing, the SKYSCRAPER-01 with the PD-L1, TPs greater than 50% population and also in combination with chemotherapy and Tecentriq in extensive small cell. Additional studies will be forthcoming. Let's move to the next slide where we'll -- we have an update for you on ALEX. Great. So this is an update of Alecensa in frontline ALK positive non-small cell lung cancer, the randomized study comparing Alecensa to crizotinib in this setting. And this has a median follow-up now of 4 years in the Alecensa arm. And you see that the 5-year overall survival rate for this ITT population is now 62.5%. And looking at the median, you see a median of nearly 5 years with crizotinib, however, the median for the Alecensa arm has not yet been reached. And again, importantly, that hazard ratio is 0.67, so we're looking at a 33% reduction in the risk of death. And this analysis also looking on the right, looks at the landmark analysis over multiple years. I'll emphasize the fifth year where, again, 45.5% for crizotinib alive at 5 years versus 62.5% with Alecensa. So truly remarkable performance in this ALK positive patient population. Great. So now we'll talk about Rozlytrek. I have 2 slides to discuss this. And I think the first thing that I'd like to call out is, actually today, we received a positive CHMP opinion for Rozlytrek in NTRK fusion-positive solid tumors, so a tumor-agnostic indication as well as ROS1 positive advanced non-small cell lung cancer in patients 12 years of age and older. Now this slide is an update of a slide I think we might have shown at ESMO last year, if I remember correctly, and it's looking at response rate in pediatric solid tumors. An overall response rate in fusion-positive tumors is 76%. And I do want to call out this particular slide that you do see a few progressions on the left in gray. Most of those are in patients who did not have fusions. This study initially included patients without fusions as well. So that -- I just want to call that out. Otherwise, you see responses across the board in multiple malignancies. Also with NTRK, ALK and ROS1 fusions. The median DOR has not yet been reached at this point. And the safety profile has been consistent with what's been seen previously. Lastly, actually, I apologize. But going back, I did want to point out the efficacy, again, both in systemically and in CNS malignancies as well. Thanks. Now we can go to the next one. So this slide is Rozlytrek in adult patients defined by NTRK fusion-positive solid tumors. This is again, an updated analysis that's shown, you see the waterfall plot here, which, again, illustrates predominant response or improvement, I should say, in virtually all patients, translating into a response rate of 63.5%, that's certainly clinically meaningful with a median PFS of 11.2 months and the median overall survival of 23.9 months. When you break that down by efficacy with the presence or absence of CNS metastases at baseline, you see the response rates are again quite similar in the -- around 63%. The specific intracranial efficacy in patients with CNS metastases at baseline shows a response rate of 50%. So clear-cut evidence of its -- of Rozyltrek's impact in the CNS. And there is -- the disease control, again, is durable with a duration of response of nearly 13 months, and this is updated from the prior presentation of 10.4 months. And the last thing that I'll call out is the multiple different disease subtites -- subtypes, I'm sorry, that are listed in that upper right-hand corner that I won't go over details that you can -- that you'll be able to see. Okay. Next slide. So this is a slide that for those of you who have been with us on other calls and meetings, this is a slide that shows our broad non-small cell lung cancer portfolio. It also illustrates the potential that we have for chemo-free combinations as well and has now been updated with studies involving tiragolumab as well. I won't go into this in much detail other than the fact, as Karl had pointed out, I think, in his slide that we've taken an approach of looking at monotherapy, both initially in advanced disease and then moving monotherapy into earlier disease, which you see in the top, the neoadjuvant or adjuvant approach, which I'll have a slide on that in a couple of moments that we'll talk about. And then also, of course, in combination, Tecentriq, multiple combinations. And on the far left, shows that we also have programs in the noncancer immunotherapy space, looking at targeted agents across the board with ALK, EGFR, ROS1 and NTRK. Next. And we're ready to close here with an update if you will or an additional drill down on some of the data, I should say, from IMbrave150, our Phase III study of Tecentriq and Avastin in frontline HCC, which now, of course, represents a new standard of care in the unresectable HCC population. So the primary analysis is shown there, again, showing the hazard ratio of 0.58 with a median OS not reached for the combination and also improvements in the progression-free survival on the far right, again, with a hazard ratio of 0.59, and improvements in the median PFS from 4.3 to 6.8 months. And believe that Tecentriq and Avastin may well become a practice-changing treatment for patients with unresectable HCC without prior treatment. So the next slide shows a subset of those patients that looks at those patients who were able to achieve a complete response. And you're all aware that achieving a complete response in a paracellular carcinoma is fairly remarkable and it's not seen terribly often, as you can imagine. And if you look that here and the IRF RECIST, you see that it is 18 patients who achieved that, a 6% response rate versus -- 6% complete response rate versus 0 with sorafenib. And what's been shown is these are independent prognostic factors or the HCC etiology as well. And these patients, of course, tend to do quite well and potentially better than those patients not achieving a complete response. Next slide. And I think this might be my last slide. This is the overview of our cancer immunotherapy adjuvant program that we thought we would share with you. Again, the importance of -- and drug development one-off and tends to start with end-stage disease initially for proof of concept. And then, of course, looking to move earlier into patients with resectable disease who have the potential to impact and increase the cure rate in these patient populations. And so you see that we have a wide range of randomized Phase III studies ongoing in various diseases, looking at the adjuvant setting. One, I'm going to call out for you is the ALINA study, Alecensa in the adjuvant ALK positive patient population. Given the results that we've all seen regarding osimertinib for EGFR positive patients and the dramatic results seen there, this certainly would provide additional confidence for us with this particular study as well. I think this may be it. Yes. So thank you, again, very much for your time today.

Yes. Thanks a lot. Maybe, Henrik, you can explain again how the people can ask questions. So we have already many of them, I have to say, which is good news. I have here 10 on the Q&A, which I will read. We also have some on the chat. But maybe, Henrik, if you could kindly remind the people on how to place questions.

[Operator Instructions]

Okay. So we do have a bit of a timing issue as well because I can see that there are now 20 callers, which are -- which do have questions and I have 10 on the line. I tried to do my best now to manage and group the question somehow. So the first one is from Steve Scala. He asked about the fact that the competitors' TIGIT's have not generated nearly as compelling data as you have despite similar molecules. So this, I guess, is a question to both of you, Alan and Ira. What is the reason for you standing out than the others? Now I think I already gave a good explanation with the Fc, but maybe we go explain this one...

Yes. Thanks. Yes, certainly, an interesting question. I can't really comment much on competitor molecules or competitor studies. I'd like to think that it may well be related to just how good tiragolumab is and using some of the background that Ira gave with respect to the science behind it. And I don't know if Ira if you want to I emphasize -- reemphasize anything in particular for that?

I mean the Fc domain may explain part of it, but clearly, some of the competitor molecules at least do have Fc domains. I think this just really speaks to the incredible value associated with running a randomized trial rather than trying to use historical or cross-trial comparisons.

Okay. It's a fact that it works. That's a fact, yes. Absolutely. So maybe we can try a question over the phone. Andrew, so I see if I can allow to talk. Please, Andrew. Andrew Baum.

Can you hear me?

Yes. We can hear you, yes.

So 3 questions, please. Firstly, could you talk to the performance of the control arm in trial, which is obviously for some, a subject of consternation? Second, my assumption when I initially saw the data was this reflected the demographics associated with poor performance or an older patient group who wanted to enroll and trial where they weren't going to be randomized to a chemotherapy containing arm, and therefore, it would explain why the performance of these patients -- it was -- is less favorable than what you saw in historic trials. If that is the case then how are you going to stop that replicating itself in the ongoing Phase III trial, which is designed in exactly the same way, so should we expect the same type of baseline performance in the Phase III? Are you taking measures to avoid that or anything you could add there? And then my final question is, obviously, the big commercial opportunity is combining with chemo in non-small cell lung cancer across the board, PDL-1 high, PD-L1 low, and you're obviously going to have an improved regimen as does your competitors. I note that you were running Phase I trial -- basket trial within that to explore the combination. But yet you went straight into Phase III with a chemo combination in small cell. So what's holding you back here in non-small cell? Is it a function of trying to characterize the chemo backbone? Is there some other issues? And would you go against KEYTRUDA as the control arm?

Yes. Before we -- before you answer -- and then the same question actually came from Sam Faze from Bloomberg, just to complete the picture. So there have been some more questions, in particular, on the control arm. So I give it over to you Alan.

Okay. Great. Thanks. I'll -- I jotted the notes, so I think I've got all 3 of your questions. So the first relates to the control arm and the thoughts behind that. And I think I'll give you a couple of thoughts. Initially and importantly, this is a randomized Phase II study. So again, the randomization takes into account what may have happened with 2 various populations in both arms. I think in addition, though, for the control arm, it's a small study as well, although randomized, and differences in numbers of patients on one side or another can account for differences in the response rate. With the follow-up study, the response rates are getting closer to 28% versus 38%-ish. And I think that also, we now have, of course, a randomized Phase III study IMpower110, that certainly showed the value of Tecentriq in this selected patient population and of course, approval by the FDA in that setting. So the purpose of a randomized Phase II is to prove the hypothesis that, in this case, the addition of tiragolumab added to Tecentriq, we think it did that and are confident in moving forward in the Phase III study. The second part of the question related to the demographics. And could that, a, have contributed to the control arm performing differently. And what are we -- what our expectations for the Phase III study. It is possible that with an approved agent in the -- 2 approved agents in this setting that patients may -- there may be certain selections by investigators as to who you put on the clinical trial, but that's the beauty of the randomized study. And I think that regardless of how that how that performs with the control arm or whatnot. If we see similar results in CITYSCAPE, in our randomized Phase III study, I think we'll be quite pleased with that outcome. We are not taking any specific plans in terms of how to modify who enters on the study. It of course will be a global study and -- so that will be perhaps a bit broader than that CITYSCAPE study as well. And the last question relates to the chemotherapy combinations. And yes, we're moving ahead rapidly in small cell lung cancer and we also have plans to continue to study the combination with chemotherapy in non-small cell lung cancer as well as we feel that, that may well be an important aspect in building upon checkpoint inhibition in non-small cell lung cancer, potentially broadening its effect beyond that of the 50% or higher. I addressed the questions?

Yes. I guess I was looking for some sense of time lines for opening the Phase III in combination with chemo because you went straight into a Phase III in small cell in combination with chemo without having any previous patients in Phase I. So how -- I note that you are now -- added an arm, a cohort to your Phase I basket trial with chemo combination in non-small cell, what time lines are we looking at before you initiate a Phase III trial in combination with chemo and Tecentriq? And will you use KEYTRUDA in the control arm?

Yes. I think that what I'll state and then Heather, who is our Lifecycle Leader for tiragolumab, I'll offer her to comment more specifically. But in general, this is a combination that we're, of course, quite interested in and have plans to continue this study. Not certain we'll be providing the specifics regarding time line, but I'll ask Heather if she'd like to add further or -- and/or Sushil Patel franchise head.

Thanks, Alan. I would just reiterate what you've already stated that we're very interested in this chemo combination space in non-small cell lung cancer. And I think you can expect to see more news coming in due course. Thanks.

Thanks, Heather.

Thank you, Andrew, for the question. I have one, which I read to you now. So from -- it's from Tim Anderson from Wolfe Research. He was -- says that what stands out in CITYSCAPE results is the PD-L1 low expressors. There's a big benefit in the high expressers. So he was wondering if there is any biologic explanation for this. And what would you expect to see in other tumor types where you apply TIGIT?

So I think by the use of the word biologic explanation, that allows me to tag Ira Mellman for his thoughts on the biologics.

Okay.

All right. Thank you for the extra 15 seconds. I think 2 things we were -- first, the numbers are small. So any result may appear more binary than analog in terms of how it reads out at this stage. So larger studies will indicate that, I think, more clearly. But second, remember, the -- what's used as the diagnostic here is PD-L1 expression, which basically has one degree of separation away from TIGIT. And that's one feature. The second feature is that if, in fact, the diagnostics that we all use are from a biological point of view, all flawed because you're looking only at what's happening in the tumor and not what's happening where the quite possible site of action is of these agents, i.e., in the lymph nodes, then we always -- we may be missing the finder points of gradation at times. So I think by combining those 2 features, may provide some sort of an explanation at this point. But again, we'll know a lot more as the patient numbers increase.

Yes. Thank you. There was a similar question from [ Diane Graybosch ] also on the biomarker and the biological explanation. I just wanted to make that point that you covered this aspect. So maybe we can -- Richard Vosser from JPMorgan. If you have your question here via the phone, please?

Can you hear me?

Yes. Perfect. Yes.

Marvelous. So just one question, just thinking about that maybe lower efficacy in the 1% to 49% as well. The discussion was talking about other biomarkers, I think DNAM-1 and maybe PVR as well that you've talked about in the presentation. So is there any data showing the correlation of TIGIT response with those biomarkers? And could that have any reason or explanation for the lower efficacy in the low responders or the lower PD-L1 expressors? Second question, just on pleural effusion. I think that had an increase in Grade 3 toxicity as well. And again, the discussion talked about it being an on-target effect, but how can that be maybe potentially managed? Is that a concern at all here? I mean, obviously, there's potentially good efficacy. And then maybe one question just a little bit off east from TIGIT, talking about bladder cancer. And just maybe you could help us put into context the rather tricky Bavencio data from your competitors with the very different regimen that they're trialing at a switch maintenance regimen versus chemo combo. How are physicians going to sort between those, given the difficulty of looking between the regimens? Just your thoughts there would be very useful.

Thank you. So I'll start. I'm going to give Ira heads up on the biomarker question, but I'll start with the pleural effusion. I think clinically, I don't believe that it was terribly significant in terms of anything that one would be concerned about regarding a particular toxicity that might cause someone to not utilize this agent. It's also of interest to know that, of course, sometimes cancer patients -- lung cancer patients will progress with a pleural effusion. The typical way that it can be treated of course is you actually can remove the pleural effusion if it's symptomatic. I don't believe that many of those patients suffered to that degree with the pleural effusions. And I'll ask Heather if she has any more that she wishes to add to that. But that's the general thought with the pleural effusion, that it was a small minority of those patients and not something that we're worried about moving forward. And I'm seeing from Heather that I got that answer correct. So I'm going to move -- give -- I'm going to give Ira a little more time, and I'll take your bladder cancer question. And yes, that is an interesting question that's been around with other diseases, non-small cell lung cancer, for example, with pemetrexed back in the early days as switch maintenance. And I think in general and as a former medical oncologist, I guess I'm always a medical oncologist, but former practicing medical oncologist. But sometimes for some, it's easier to utilize the combination where you just -- you're not necessarily thinking about which patient to utilize, and you can do something upfront that you have a regimen for a patient that you see in your office, and that's the combination. Others may wish to utilize chemotherapy as a means to distinguish those patients that might do well. So almost like a biomarker, I guess, in a setting like that. It does make for a very challenging ability to cross-trial comparison, and it's very difficult to compare the data because you're looking at different types of patients. And the old saying that good patients do better than bad patients, those patients who are responding, of course, do better than those that don't. And those initial studies with all-comer patients with combination include all of those patients. So I -- you're spot on that this is going to be something that the clinicians will have to kind of put this together to try and decide how they make their decisions, but they're both very viable opportunities for patients, which is always good. And now I think Ira is ready. I see him in the green room, and so I'm going to pass the baton.

I think with respect to looking at PBR, all I can say is that the reason PD-L1 works as a biomarker is that it -- when assessed in tumors is that it reflects the presence or absence with the degree of an ongoing anticancer T cell response. PBR, on the other hand, is constitutively expressed by a wide variety of cells, both in and out of the immune system. And at least our initial impression is that it's not linked to the presence of an ongoing response, which means that although it's an important component, obviously, in triggering the TIGIT pathway, it may not really be predictive of what's happening or what you could expect to happen with TIGIT blockade. And again, as I said before, using PD-L1 is kind of step removed from the actual precise mechanism of TIGIT. So we would very much like to have another biomarker that we could use. And certainly, we're looking very, very hard for that. But at the moment, just assessing the degree to which a preexisting response exists and using that as a way to select patients or stratify patients. PD-L1 seems to be still the best we can do.

Thank you. Thanks for the question, Richard. We had actually similar questions from [ Kushal Patel. ] I just wanted to close the loop here. Maybe one remark from my side. I mean if you do these cross-trial comparisons, I mean, it may be also worthwhile to look which patients have been included, so in particular, in the bladder data. So if the patients were already -- and still responding or stable after chemotherapy and what the combination was and what was included and excluded from those, so we have definitely included everything some other trials have excluded the nonresponders. So it's really and you need to look at the specific patient population studied. Otherwise, it's virtually impossible to do a cross-trial comparison in particular here. There was one question which I'll just read now from Michael Leuchten from UBS. He was more -- asking about the general question about the combinations going forward mechanistically. So what is the plan here for the TIGIT going forward with chemo, without chemo, what is the philosophy of combinations? So a more general question on the next steps.

Sure. So I'll start with that. I think that, number one, it's -- the primary emphasis is going to be in combination with Tecentriq as the backbone, both to build upon this -- the efficacy already established with Tecentriq and the fact that both preclinical and clinical data that show that, that combination provides additional benefit. We've already discussed the concept of chemotherapy that we believe that adding chemotherapy also has both preclinical rationale and clinical rationale that we've seen with other checkpoint inhibitors such as Tecentriq in this particular setting. We will also be looking and probably be -- not probably, but of course, be led by Ira, as he provides us with information as to what other cancer immunotherapy agents should be added to the cocktail, either in addition to or in lieu of perhaps chemotherapy. So we will, as always, be following the science in building upon our combination approach.

Thank you. Maybe we can go to the phone. Simon Baker would be the next one. So I allow to talk. Simon, it's your...

I hope you can hear me. Two questions, if I may, please. Firstly, I wonder if you have now or intend to publish later any more stratification of PD-L1 expression levels. At the moment, we have 1% to 49% and 50% and above. I just wonder if you have any more detail on exactly where the tipping point is. And secondly, you talked about chemo combinations with TIGIT, Tecentriq. But I saw there was a paper published in June last year on animal studies looking at the PD-L1 TIGIT combination with fractionated radiotherapy. I was wondering what your thoughts were as that -- on that as a potential combination approach?

Okay. Great. So the -- with your -- with respect to your first question regarding PD-L1 levels, we are, of course, looking at various biomarker approaches and in terms of the exploratory analysis that we have, and we'll be looking into that to see what we may or may not be able to find. I don't believe that specific question that we may necessarily be able to address since the cutoffs were, basically, you had 2 bins with which those patients fit in. And although one could supposedly potentially retrofit that looking back again, I think that the 2 bins that we have are essentially where they're going to be as opposed to additional cutoffs. So that's not necessarily likely to be able to do that. The other question I will start and let Ira clean up and correct me if necessary. But I think the issue is there has been that concept of radiation therapy being used that changes sort of the PD-L1 ml/u that may allow for maybe improved efficacy post radiation therapy. And that's -- those are some of the thoughts that are going around and certainly, things that we are looking at exploring potentially. As far as the preclinical avenue of that, I'll let Ira address it specifically.

Well, I don't really have that much to say about that. It's just part of ongoing investigations. The radiation therapy when Alan brings up is, I think, a super interesting one, though. Although probably the best way from an immunological perspective to do that is make use of these new low-dose radiation protocols that are themselves not inherently cytotoxic but rather are sufficiency induced DNA damage under conditions where so-called STING pathway can be activated in tumors, which then increases the degree to which their immunogenic. I think it was in the group of inflamed tumors, doing things with cytokines and cytokine delivery may be a good path to go. In some cases, using Avastin may also be a very, very promising path. Beyond that, what we're looking towards in the laboratory is getting out of the inflamed group, particularly into the excluded group of tumors, where we think if we can address the stromal barrier issue, everything that we are doing in the inflamed group will be now applicable to that group as well.

Yes. Thank you. There was a question on the stratification of the trial, I have to say. And so there was -- wondering if there was any kind of an imbalance in the trial, 40% patients with squamous, non-squamous, so if there is any -- if there was any imbalance and how these data compared to real life -- to real world data?

Yes. I'm looking at that -- I was looking at that question, too. I'm not so sure if it was related to the imbalance or whether or not the squames might have contributed to a lower response rate because there was not imbalance based on that stratification factor. So just to clarify. Yes, it's interesting. And this is something that happens that we've talked about and hinted that sometimes the demographics from study to study differ. 40% squames is probably something that might be a bit higher than one might otherwise expect in a study, might have expected something more 20% to 25% or so. And whether that may have contributed or not is not necessarily clear. We see efficacy for the combination in both groups, although as the question here points out, sometimes squames tend to do a little less well than non-squames historically.

Thank you. Yes, a similar question here -- actually was here from Luisa Hector. Just to complete the picture that everybody feels, let's say, reflected in the questions. Maybe we take the next question from the line, Emmanuel Papadakis. Allowed to talk. So I have to press the -- so now it works. Emmanuel, please.

Emmanuel from Barclays. Maybe just a follow-up, IRA. I mean even take into account your comments around the limitations of using tumor biopsy-based PD-1 biomarking. It doesn't sound from your mechanistic introduction like TIGIT will fundamentally bring much to the equation in the PD-L1 patient population. So is there any mechanistic reason why you would expect any meaningful additive or a synergistic efficacy with chemo in that setting like PD-1 low lung population assuming that is where you're going to start a Phase III trial, too?

Thank you for the question, Emmanuel. Ira, I guess this is one for you.

Yes. I've mentioned -- good question, Emmanuel. I'd say it's one that really has to be tested in the clinic, and it really gets to 2 unknowns, which is what is the mechanism whereby chemo, when it does combine with checkpoint inhibitors, how does it do it. Does it do it simply by an additive mechanism? Or is there some level of synergy by increasing the amount of endogenous immunity to the tumor increase the later? Then you might even expect that there would be a good possibility that adding TIGIT to PD-L1 would increase response rates and would increase benefit in that way.

Yes. Thank you. Maybe we take the next question. Does that answer your question, Emmanuel?

Yes, kind of. Ira is not really telling us whether he thinks that's likely to be the case.

You're asking if I think it's likely to be the case?

Yes. Do you believe that we'll likely to see any synergy based on the evidence you have seen? Biologic evidence, is that working as...

My guess, based on what I've seen so far and just factoring back is that the effects may be additive. So you'll derive independent effects from chemo and from the checkpoint inhibitors. And so in other words, you would could quite well amplify at least somewhat the effect of chemo on patients -- the benefit of chemo combos in patients who indeed have a PD-L1 low because they may be just below the threshold that you need to see a response. And by ramping it up a little bit, you may now reveal some activity in the low group.

There was one question for Sush on the Alecensa Adivant trial readout, when is the next interim?

That's -- so the current planning is 2022 for the interim, but these are event-driven, and so we'll continue to monitor that and provide updates.

Okay. Thank you. So there is one telephone number where there is no name behind. It starts with a 44 U.K. 78430. So we give it a try. We do allow to talk, and let's see who is behind the number and which questions we get.

Karl, it's Sachin here. Yes. I didn't realize I was hiding myself, but anyways we're here now.

Yes. It's a new world, Sachin, it's a new world. Yes, please go ahead.

A few questions, please. First, if you could just give us some color on timing of data beyond AACR? And in particular, when you plan to give us some of the data on solid tumors beyond lung? Second and related, is it fair to think that lung is a tumor where you're seeing the best response rates, given that's the one you've progressed to Phase III first? And then thirdly, I guess, just mechanistically back to some questions on TIGIT that have already happened. Should we expect any monotherapy activity with TIGIT, and is the lack of it any concern as and when we see that data? Those are my questions on TIGIT. And then just one on adjuvant. You flagged ALINA [indiscernible], just update us on Tecentriq adjuvant in lung. Do we still expect that entry by year-end?

All right. Well, we got a little bit. I'm going to -- let's see, we'll tee up Heather for the timing for the TIGIT studies, which was your first question, I'll give her a couple of moments to prepare. With respect to the monotherapy question, we will have that Phase I data that will be both Phase Ia and b data that will be upcoming at AACR, as I mentioned. With respect to concern as to whether or not there is single-agent data, I think can best be answered by CITYSCAPE. And looking at the dramatic improvement in response rate seen in the combination versus Tecentriq, which provides in that randomized setting considerable confidence that, that combination does provide -- that TIGIT certainly provides a lot of that effort in that combination. So I'll leave with that. With lung for TIGIT, I don't know that lung is necessarily going to be the best. I think there is opportunities in a broad range of the malignancies. And again, the Ib data will probably be helpful for you there. We do anticipate activity across a broad range of malignancies, much like with Tecentriq as a checkpoint inhibitor as well. Let's see, maybe, Heather, do you want to talk about timing for TIGIT?

Yes. Thank you, Alan. So it is our intention to look at upcoming congresses to share the updated data on CITYSCAPE once we have the last. The timing is to be determined there as well as for the additional disease cohorts in our Phase Ib data set. We're looking at sometime next year to share that data. I just want to comment that, as you've noted, we are still actively enrolling in our Phase Ib. So when that data becomes available and mature, we will certainly share it.

Thanks, Heather. And I'll -- I think there was one other question regarding adjuvant for Tecentriq, and I'll have Sush on standby. But for that, again, those are event-driven, and we're anticipating data coming up within the next year, give or take. But I look at Sush, if he's shaking, he said, yes, or let him provide some color...

No, that's correct, Alan. Obviously, with the ongoing COVID situation, there may be some slight delays, so we're working through that.

Thank you very much. There is one question here for Ira from [ Ed Bitman. ] There is a mechanism, now I hope that I said it correctly, PVRIG, that some say is important to combine with anti-TIGIT, what is your view?

No. We're well aware of those data. And it is possible. It's a question, though, since you basically activating the same system as to whether or not doubling down on the same signaling pathway is going to result in that much more benefit. But we are evaluating that because I think it's an interesting succession.

Yes. So we take one -- next question over the phone from Tim Anderson. Oh, let's see if it works. Tim, the floor is yours.

Yes. Can you hear me?

Yes, we can hear you.

Yes. Okay. Great. Actually, Ira, I want to go back and press you again on the first question I asked, which is in low expressors and lung, there really wasn't any activity or it was very marginal based on CITYSCAPE with the doublet. So do you expect that just with doublet therapy alone with nothing else added in that in other tumor types or maybe even in the Phase III broader non-small cell lung trial, you might see better activity and low expressors that 1% to 49% cohort than what you saw in CITYSCAPE? So were the CITYSCAPE findings anomalous potentially? And then the second question is, when you describe this concept of stem cell like T cells, I'm wondering how well accepted this is as the underlying biology for how anti-PD-1 therapies are working. I do see some academic labs publishing on this, so maybe it's well accepted at this point. Or is this something that will be debated?

To head with that first. I mean as with anything that falls into the category of assumptions and conventional wisdom, it's hard to move people off of a basic consumption. So I would say amongst people whom are actively working in this area, either in academia or in industry, we now all pretty much accept that this is a component of the activity, whether or not it is the only complement responsible for activity is another question entirely. I'm not even sure I sign on to that. But I do take very seriously for a variety of reasons, both data from ourselves as well as data from outside that this is clearly an important component. But again, to change wider perceptions, those are lagging behind. This looks like trying to turn around battleship after it's steaming ahead at full speed. As to the first question you asked, I mean, it's obviously a very important one, but I'm not quite sure how to have a prediction as to whether we think that lung cancer is an outlier and that we'll see only responses in the PD-L1 high group and nothing in the low group. I'd like to see more patients even with simply that experiment in lung cancer before really rendering a verdict on it. And again, getting back to the issue of whether there's going to be a graded response that there will be a correlation as we've seen in the past between the amount of PD-L1 and the amount of clinical response. And all I want to say is, although we're optimistic to think that adding TIGIT should track pretty much along with the response characteristics as a function of PD-L1 expression, I just do want to reemphasize that PD-L1 expression is for the one step removed from the actual mechanism of action of TIGIT than it is for the mechanism of action of PD-1 blockers. So it's entirely possible that this will be how it is, but we're certainly not making an assumption regarding one idea or the other at this point.

Thank you. There was one question from Matthew Weston, again -- also again, on the time lines, adjuvant readout for Tecentriq lung. Q1 we said it's most likely in 2021. This update, we said end of the year. So the reason is that it's really flipping around between end of the year, beginning of next year, it's really a bit of event-driven. And we ask the teams where the recruitment is going over, the case is better to say in these cases -- in this case, are going and could go, let's say, either way. And either this year or latest early next year, somewhere around this time frame. We have a question from [ Will Hamlin ], please.

Sorry, that was a mistake. I was asking a question, sorry. I don't know why...

Okay. Perfect. No worries. And then you have one last, I think there's an echo in the line. If maybe we can take that off. Muted so -- good thing is here, I have the full control. It's like a pilot. I feel like a pilot, you can press the things here, and it's all going according to my fashion. That's not happening very often, I have to say, but I don't complain about it. We have so far one last question from Mark Purcell. The others have more or less been addressed, but maybe it's a good closing here. He was asking about, could you provide your latest perspective on effector pathways, CIT approaches, which could be used in combination with Tecentriq and TIGIT, plus/minus chemo? Please could you profile your upcoming data on the personalized vaccine approaches and the potential to boost responses with TIGIT and Tecentriq? Ira, this is one for you.

Did that come in on the chat?

It is on the chat, yes. It's at the lower end of the questions.

Yes.

You see it's the third one.

I was responding to another question online so I missed the first part of that. So can you read it again? Or I'll...

Yes, sure, no. Please could you provide you latest -- oh, you can -- people can see if I read the questions correctly, that's also a good. Perspective and effective pathway, CIT approaches, which could be used in combination with Tecentriq and TIGIT plus/minus chemo? And please, could you profile upcoming data on the personalized vaccine approach and the potential to boost response with Tecentriq and TIGIT?

Well, I understand the second half of the question. So the first data from our studies, we've maybe treated 150 patients or so with the personalized vaccine will come out next month at ASCO, not ASCO, AACR. And what we will show is that indeed the -- that 2 things are possible. One is that it is, in fact, possible with a usable turnaround time to generate vaccines or generate drugs for individual patients. So getting through the workflow on that was no small task, and now we have a lot of confidence going forward. Second is that we were able to generate quite nice and robust T cell responses, as you'll see. And the question that will emerge from that is, how do we then optimize those responses to maximize the clinical benefit that we're seeing as well. So these are still very early days in this process. And as to the first part of the question, I can't say I quite understood what was being asked.

That was the -- I think you addressed it already. I mean it's basically on the overall approach, let's say, what is combinable in that area, the CIT approaches could be used in combination with Tecentriq and TIGIT in more general terms, chemo combo. We've got also other questions, let's say, if you can potentially open -- maybe it's going into -- in this direction. If you can potentially open new markets by just putting a chemo on, is it then also for PD-L1 lows? Or do you go for PD-L1 highs? I mean, what is the strategy going forward in more general terms?

Well, I think at this point, the strategy is going to be determined in the clinic more by Alan and Heather and the Tecentriq teams because there are series that you can generate in animal models that really are not easily translatable to human cancer patients, particularly when it comes to broad acting combinations, such as chemotherapy together with one or another checkpoint inhibitor. Best I can say is what I said already before, which is we're looking towards, for example, not only vaccine combinations, which I think would combine extremely well, but also, we've moved a couple of different interesting new, and we hope are going to be well tolerated, cytokines, T cell-directed cytokines into the clinic. Those things also would be expected to combine extremely well with checkpoint inhibitors and specifically with the PD-1 TIGIT combination. Beyond that, I think the market I'm really looking to open up or the opportunity I'm really looking to open up, again, gets back to this issue of the 3 immune phenotype. And I think the next one that is really ramped up for the taking is this excluded group, if we can come up with a way of safely and effectively removing stromal barrier.

Last question is for [ Kushal Patel ], do you believe that there is a difference in combination if you combine a PD-1 or a PD-L1 with the TIGIT?

We have no reason to think that there would be a difference there. And the other thing I can [indiscernible] is with respect to the Fc interactions, we have looked carefully at whether or not a Tecentriq with an intact Fc domain without an intact Fc domain is equivalent and to the best of our abilities, preclinically, we find that they're identical.

Okay. Thanks a lot. So we are coming to an end for the first ASCO virtual meeting. I hope it went well. If you could do a favor those who participated that you just drop me a mail, if that format worked for you. So we really want to learn and hope it worked so that you could see what's ongoing, that it was transparent that you could hear us, that the format was good. And that would help us very much. And with this one, I just wanted to thank our speakers again, Alan, Sush, Heather, Ira. Thanks a lot for your interest in Roche, and I wish everybody a nice weekend, and all the best. Thank you. Bye-bye.

Bye, everybody.

Bye-bye. Bye-bye, everybody.