Good afternoon. My name is Jerome, and I will be your conference operator today. At this time, I would like to welcome everyone to the Merck Oncology ASCO Event Conference Call. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question and answer session.
Thank you. I would now like to turn the call over to Peter Donenbaum, Vice President, Investor Relations. Please go ahead.
Thank you, Jerome, and good afternoon, everybody. Welcome to Merck's 2020 virtual ASCO investor call. I'm joined by Doctor. Roger Perlmutter, President of Merck Research Labs Doctor. Roy Baynes, Head of Global Development and Chief Medical Officer of Merck Research Labs and Frank Clyburn, Chief Commercial Officer.
Before we begin, I would like to remind you that some of the statements that we make during today's call may be considered forward looking statements within the meaning of the Safe Harbor provisions of the U. S. Private Securities Reform Act of 1995. Such statements are made based on the current beliefs of Merck's management and are subject to significant risks and uncertainties. If our under line assumptions prove inaccurate or uncertainties materialize, actual results may differ materially from those set forth in the forward looking statements.
Our SEC filings, including Item 1A in the 2019 10 ks, identify certain risk factors and cautionary statements that could cause the company's actual results to differ materially from those projected in any of our forward looking statements made this morning. Merck undertakes no obligation to publicly update any forward looking statements. Roger will begin today's session with a slide presentation, which has been posted to our website and we'll follow that with Q and A. With that, I'd like to turn the call over to Roger.
Thank you very much, Peter. And thank you, everyone, for joining us on this virtual call. We're sorry that we can't be there together, but this is an opportunity for us to review, exciting new information that we presented at ASCO 2020 and to try and place that information in the context of our broader oncology program. So if I could advance the slide, we have first our Safe Harbor statement, which you've already heard from Peter. And if we go to the next slide, the slide is one that you're familiar with in some ways, that is that we've talked a lot about our broad oncology strategy designed to improve outcomes for patients around the world.
The first of course is that we have made KEYTRUDA a foundational treatment in cancer therapy. And we've explored combinations with KEYTRUDA, including chemotherapy and also targeted therapies that have clearly demonstrated that additional value can be brought to patients in terms of improving and extending life. We're also advancing the pipeline by bringing new strategic collaborations into the pipeline. And we've used our biomarker capabilities to identify patients who are most likely to benefit. And that includes, of course, patients who have microsatellite instability and also high tumor mutational burdens.
Next slide. So when you look at KEYTRUDA, what you can say is that it is an extraordinary drug. This is a slide that we update frequently. It simply shows waterfall plots for a whole variety of different tumor types, defined by site of origin, by histology or by genetic markers. And, what you can see on the slide is that more than 30 different types of cancer have demonstrated meaningful responses to KEYTRUDA.
Sometimes those responses are really quite extraordinary. You can see some of those in the circles. As an example, if you look at primary mediastinal B cell lymphoma, top line, second in from the right, pretty extraordinary. And right next to it, classical Hodgkin lymphoma, really, really quite dramatic. But it's also quite dramatic in the response to melanoma or
non small
cell lung cancer. As you see in those tumors all the way over on the left hand side of the top line, again, the waterfall plots where the green line is going down, each line representing an individual patient show improvement as opposed to going up in which the tumor is advancing. It's really special. And these responses, these overall responses that we see demonstrated in these kinds of waterfall plots are mirrored in outcome measures. So in the next slide, what you can see is a set of different overall survival studies, each one of which demonstrates that KEYTRUDA either as monotherapy in the top group or in combinations in the bottom group improves overall survival in a variety of different tumor types, many of which were shown all of which were shown in the overall response diagrams on the previous slide.
So that includes, of course, in melanoma, relatively responsive tumor, but also in non small cell lung cancer based on our KEYNOTE-twenty four study, in the those patients whose tumors express PD L1 at a high level, or in the KEYNOTE-forty two set in patients whose tumors express less PD L1 greater than 1%. In lung cancer, of course, the combination data KEYNOTE-one hundred and eighty nine shown in the bottom left has really become the standard of care in most jurisdictions for the way in which one treats advanced lung cancer in this population, in the non squamous population. And similarly for KEYNOTE-four zero seven in this first line squamous cell population, as most of you are aware. So it's really quite an extraordinary track record that's been driven by a large set of clinical studies now since we first registered KEYTRUDA about 6 years ago. Next slide.
The development program for KEYTRUDA though continues and in many ways is simply expanding. We have in excess of 1200 ongoing clinical trials, of which about 90 are registrational, and about something over 100 are trials in earlier settings, adjuvant and neoadjuvant. We'll have a little bit more to say about that in a few minutes. And the vast majority at this point are combination trials. I've said in many of our earnings calls that we're pretty much done with our monotherapy studies, but we're gaining more and more traction in combination studies.
And that, of course, will lead to more and more registration programs with combinations. Next slide. So at ASCO 2020, we had the opportunity to update the broader oncology community, including more than 40,000 people who attended that in double inverted comments, the meeting via virtual mechanisms. It included a lot of new Phase III data, which we'll look at, for KEYTRUDA in triple negative breast cancer in the MSI high colorectal cancer setting and in classical Hodgkin lymphoma, as well as some Phase II data for KEYTRUDA in Stage III non small cell lung cancer, which we believe will expand the field substantially. We won't discuss it in detail here, but happy to respond to questions about the KEYNOTE-seven ninety nine program.
We also had the opportunity to update long term survival data. And the good news there is that the treatment effects of KEYTRUDA are very durable, both in monotherapy and combination therapy settings. And we also had the opportunity to talk about some novel mechanisms, some of which we'll mention here as well. Next slide. So to begin, KEYNOTE-three fifty five was or is a study in patients with triple negative breast cancer.
We had the opportunity, which we top lined a little while ago, to talk about the progression free survival data, one endpoint of the study, the overall survival endpoint was not examined at this interim analysis. But what you can see here is that, if you compare KEYTRUDA plus chemo versus chemo alone, for certain patients with triple negative breast cancer, the outcome in terms of progression free survival is really quite impressive. And we have the strong view that, that will ultimately translate into overall survival benefit. But of course, we have to demonstrate that. I should say that this trial complements very much the KEYNOTE-five twenty two study, which we had the opportunity to present at ESMO last year, and which demonstrated in that particular case in the neoadjuvant setting that administration of KEYTRUDA in combination with traditional chemotherapy and triple negative breast cancer improved the pathologic complete response rate.
And that study continues for, to obtain event free survival data. So those two studies in a way are mutually reinforcing with respect to triple negative breast cancer along with prior studies that we have in that setting. Next slide. So we also had the opportunity to show the data from KEYNOTE-one hundred and seventy seven. And as was pointed out by the discussant, who reviewed the presentation after it was given at ASCO, this really does represent a new standard of care in first line MSI high colorectal cancer patients.
As you can see, a 307 patients who are randomized either to receive KEYTRUDA monotherapy or to receive traditional therapy investigators choice in the setting of individuals who present with MSI high colorectal cancer in the first line. And the results are quite dramatic. KEYTRUDA monotherapy in terms of progression free survival is far superior and that trial as well as continuing for overall survival. So, we hope to have the opportunity to see that soon, but it really is important to look at the 24 month PFS rate with 48%, nearly half, who have not progressed receiving KEYTRUDA as compared to around 20% with traditional therapy. So really quite an impressive result.
And the next slide shows you the results from the KEYNOTE-two zero four study, just a heads to head study comparing antibody drug conjugate shown here as BV, which is commonly used, Seattle Genetics product commonly used in the late line treatment relapsed refractory classic Hodgkin's lymphoma, as compared with KEYTRUDA monotherapy. And here you can see that in this second line plus setting that KEYTRUDA monotherapy is clearly superior because, as I mentioned, class Hodgkin lymphoma is really a very responsive tumor and is very responsive even after having non responsive to multiple product therapies. So quite a good result in terms of progression free survival on the trial hearing and also continues for overall survival. Next slide. So in addition to these new Phase III data that we had a chance to present, we also had a chance to present data relevant to the durability of the treatment effect of KEYTRUDA and administered in non small cell lung cancer, renal cell carcinoma or melanoma.
And you can see on the left hand side, a final analysis, pre specified final analysis for KEYNOTE-one hundred and eighty nine demonstrating the extraordinary window that's opened up between individuals receiving KEYTRUDA in combination with chemotherapy as opposed to chemotherapy alone. And it really is quite remarkable and something that we hear about frequently from our colleagues who are practicing thoracic metrology that they are just seeing more and more patients surviving for a longer period of time. You can see at 24 months, the overall survival is around nearly 46% for a key treatment plus chemotherapy combination. And the hazard ratio for this comparison at that point is 0.56. So it's really quite an impressive result for what would otherwise be continued considered to be a completely refractory disease.
KEYTRUDA in combination with chemotherapy has really changed even dramatically. Similarly, if you look at renal cell carcinoma, the updated analysis from KEYNOTE-four 26, which is a combination of KEYTRUDA plus axitinib, continue to demonstrate really impressive activity versus sunitinib in this case. And you can see overall survival numbers at 24 months, 74% in renal cell carcinoma, which is certainly a very impressive number. The last one I'd like to point out though is KEYNOTE-fifty four, which in this case we had the opportunity to look at 3 year follow-up data from AORTC for adjuvant treatment of melanoma with KEYTRUDA. And you can see, I mean, look at those curves, the KEYTRUDA curve at the top, the green curve separates early from the placebo in adjuvant setting.
These are individuals who have undergone a definitive resection of malignant melanoma, but are at high risk of deference. So this is a respected high risk stage 3 melanoma. And when you look at those individuals, what you can see is that at 3 years, the recurrence of free, 8% alive and recurrence free is nearly 64%, which is quite remarkable compared to the 44% from those who just underwent surgical reception. The hazard ratio for that comparison again 0.56. So there is no doubt that this 3 meter follow-up KEYTRUDA as monotherapy in an adjuvant setting is providing substantial value to patients with malignant melanoma.
These adjuvant and neoadjuvant studies are continuing, next slide, and we are interested in a variety of them. But we're also interested in new mechanisms and one of those is MK6482. We have the opportunity to show data from 6,000 482 in the von Hippel Lindau setting. And von Hippel Lindau disease is a disease that results from typically an inherited mutation in the BHL protein, which results in the relative persistence of a transcriptional mediator called KIF-two alpha. K-six thousand four hundred and eighty two is a KIF-two alpha inhibitor.
And if you look in von Hippel Lindau disease and look at patients who have clear cell renal cell carcinoma, which is extremely frequent complication of undepalLindau, the most prominent complication, although there are many other tumors, say the one that was dealt with most frequently. The overall response rate in the setting of 6,482, which is the first time this has been examined in a small study in because these target lesions, these tumors really are driven by the stabilization of HIF-two alpha as a result of the lack of the DHL protein. And so 6,482 can be very effective, we believe in that setting. And a Phase III trial is underway studying 6,482 versus several liners in patients with advanced second line renal cell carcinoma who've progressed following currently accepted standard of care therapy. Next slide.
So looking at across all of those things, I think it's important to emphasize, as I was just saying that we're doing a lot of work in the adjuvant immuno as we've said, we've already talked about KEYNOTE-fifty four, which was approved a couple of years ago. And I've already mentioned our triple negative breast cancer neoadjuvant adjuvant study, KEYNOTE-five twenty two. But there are a variety of other important studies in continuous glu cell carcinoma, in head and neck cancer, non small cell lung cancer and melanoma that will be rolling out over the next several years. And we're optimistic given the strong performance of KEYTRUDA in all of these tumor types and the fact that in general KEYTRUDA performs better in earlier things to these that we will see meaningful improvements in patients' responses and in fact in reference free survival, perhaps even in overall survival in some settings. So we're quite enthusiastic about that.
Next slide. But KEYTRUDA, of course, in addition to being used with chemotherapy, can also be used in combination with 2 other molecules that we are pursuing, Lynparza and LENVIA. For Lynparza, of course, Lynparza as monotherapy is already an extremely important drug. It's been demonstrated to have activity and maintenance of treatment response in ovarian cancer, in breast cancer, in pancreatic cancer. And I think you all saw that in addition to the U.
S. Approval, we had a recommendation of a positive review from the CHMP. They adopted a positive opinion of the based on the POLA-one data for the use of the EPARSA in that extremely rare patients with RAVA-one or 2 mutations to pancreatic cancer, but still an important concept. And of course, the PROPOUND data in prostate cancer, which is extremely important. But going forward, a lot of combination studies will be pursued in each one of these things.
So it gives us the opportunity to see whether as we believe based on our early studies, intruded in combination with human partners that can be used effectively to further improve patient outcomes. Next slide. For the LENVIMA program and LENVIMA also is approved monotherapy, for example, in fibro cancer and hepatocellular carcinoma. But here we have a large number of combinations, including some approved combinations. So for example, in the 2nd line endometrial cancer setting, where the combination of KEYTRUDA and LENVIVA shown in KEYNOTE-one hundred and six study was extremely effective.
And we also have data that is emerging in renal cell carcinoma, in hepatocellular carcinoma and in a variety of other tumor types. And so we expect that we'll have a chance to see those going forward. So, if I could now go to the next slide, and I understand that, maybe the auto understood. I'll try to speak a little bit more clearly. But this slide simply shows that in our oncology pipeline, we have a set of investigational immunotherapeutic candidates, more than 20 in fact, which includes many that you've heard of, a large number of which are now in Phase II studies designed to demonstrate that they have activity, particularly that they have activity when used in combination with KEYTRUDA.
And I should emphasize here, as I have on earnings calls, that to date, despite the fact that we have studied many, many different mechanisms, including immune agonists, including those things that inhibit negative regulators as KEYTRUDA itself does, but also LAG-three antibodies, CTLA-four, TIGIT and the ILT-four agonist. Personalized cancer vaccines, which we have a number, and things that act on the tumor microenvironment. There is nothing that has the broad spectrum and dramatic efficacy of KEYTRUDA by itself. We've not seen anything that has that sort of activity. We are, however, seeing signals in the combinations that make us actually feel quite optimistic that some of these combinations are going to prove to be important and will become future standards of care in many tumor types.
And we continue to pursue those for these different molecules that are mentioned here. And we'll have a chance to update you on those at future meetings, including of course future ASCO and WCR meetings. The next slide mentions that, while we have generated a lot of these different molecules ourselves, we also have had the HIF-two alpha inhibitor that we acquired from Peloton, which is currently in Phase 3 in renal cell carcinoma and for which data were obtained in the setting of Von Hippel Lindau syndrome, which are really very impressive. We are quite optimistic that this HIF-two alpha inhibitor, the first molecule of its kind, will prove to be effective in this setting and is potentially useful in other settings as well. We also had the opportunity to obtain through the acquisition of ArQule, a non covalent BTK inhibitor that has impressive properties and that is currently in Phase 2 in chronic lymphocytic leukemia, but in principle can be used to address the whole spectrum of B cell malignancies that a BTK inhibitor can generally be used for and should be quite active, in fact, has been shown to be active, in individuals whose tumors have sustained a mutation of BTK that such that they are no longer susceptible to the cystine acting covalent inhibitors.
But we've also had opportunity to gain new oncolytic viruses, for example, from our acquisition Viralytics, and to have collaborations, for example, with Tyoelastex for the development of KRAS, various different KRAS inhibitors, which in fact target the entire RAS pathway, including both GDP and GTP bound and other forms besides KRAS. So those are things at the preclinical stage, but it gives you a sense that we have a broad commitment to oncology mechanisms and a quite broad opportunity to further develop KEYTRUDA in combination with many new molecules. Next slide. So over the next 5 years, you have a sense of what we will be delivering because you can see the new studies that are going to appear. And more importantly, you see already the data that we have published and the data that we have registered, which provides a substrate for really meaningful revenue growth, margin expansion and hence accelerated bottom line growth, which we can talk about Frank can talk about a little bit later.
Beyond 5 years, the pipeline is extremely rich. And as I've said, we're optimistic that many new molecules used with KEYTRUDA in combination and some as single agents that will be important. And then over 10 years, of course, well, that's out at the horizon of what can be predicted. But I have to say that the expertise that we've developed in fundamental biology, in understanding malignant cells and in understanding the tumor micro environment bodes very well for improved therapies for many years to come. And with that, I will close the slide presentation.
I thank you for your attention and we look forward to your questions.
Great. Thank you so much, Roger. Jerome, we're ready to put together the queue for Q and A. I request that questioners limit themselves to 1 or 2 perhaps so that we can get through as many questions as possible.
Your first question comes from the line of Umer Raffat with Evercore ISI. You may now ask your question. Umer, you may now ask your question. Your line is now open.
Let's go to the next question please Jerome.
Your next question comes from the line of Steve Scala with Cowen. You may now ask your question.
Thank you. Roger, many novel I O targets have disappointed, but TIGIT appears more promising. TIGIT antibody effector function has been cited by at least Roche as an important factor for efficacy. So Merck's molecule has an intact IgG1 effector function, but it still appears to underperform the Roche molecule. What other factors could explain the efficacy difference?
So that's the first question. And second, Frank, if Roche anti TIGIT Phase 3 data replicates Phase 2, then how do you see Merck's competitive position changing in lung cancer? Thank you.
Roger?
Steve, thanks for that. So first of all, we have seen the data from Roche for their molecule. And what you can see is that the combination with atezolizumab in their study seemed to generate some improvement. It's a little hard to of course, you can't these cross study comparisons are extremely difficult to do. The data which were obtained using our 22C3 antibody to define a TPS population, don't look that remarkable.
That may be because of tezolizumab as monotherapy doesn't really provide that much benefit, as compared to what we see with KEYTRUDA. I mean, if you compare the KEYTRUDA KEYTRUDA-twenty four results, for example, which are pretty impressive. We don't know how much headroom there is beyond what KEYTRUDA-twenty four does. We are looking at our molecule, our TIGID molecule. And we think that there is some evidence for meaningful headroom there.
What we've shown is that though we haven't had the opportunity to present our data in detail, what we've shown is that the combination of the 2 looks pretty intriguing. But what we really need to see are data that compare KEYTRUDA alone with KEYTRUDA plus TIGIT in a very rigorous fashion and those data are coming along. So when we have a chance to look at those, we'll be able to say. I don't see any reason to believe that our molecule would be any different from the Roche molecule, have initial. It all comes down to the data.
I'm struck by the fact that I would say that at this point, KEYTRUDA has demonstrated over and over and over again, a remarkable spectrum of activity. And that could be because KEYTRUDA, for example, is superior to other anti PD-1s for reasons that we can't establish exactly pre clinically, or it could be because of aspects of clinical trial design. And so without really seeing that kind of information and having it come out broadly in a lot of studies, pretty difficult to make a comparison. Frank?
Yes, Roger. Thank you. And to just follow-up on Roger's point, I think the data we are saying from Roche from CityScape in non small cell lung cancer was scientifically interesting. But I think we'll have to wait and see how the data continues to materialize. But I would want to make sure that we reinforce how confident we are in our leadership position in non small cell lung cancer with our overall survival data.
And as Roger highlighted, from our Phase III trials across monotherapy and combination, regardless of PD L1 expression, we believe the bar is extremely high. Right now, we're seeing in the marketplace over 8 out of every 10 eligible patient that does not have a genomic marker of ALK or EGFR is being treated with KEYTRUDA. And in the high population PDL-one hundred and fifty and above. The keynote on 20,024 is a very strong monotherapy regimen, probably about 60% of the patients in the U. S.
Are being treated monotherapy. The rest are on a combination with chemotherapy. So we feel extremely confident in our current position as we've mentioned previously in non small cell lung cancer. Great.
Next question please, Jerome.
Your next question comes from the line of Umer Raffat with Evercore ISI. You may now ask your question.
Hi, thanks so much for taking my question. Sorry, I'm learning how to use the mute button here. I guess, two questions, if I may. The first one really has to do with your thoughts perhaps on effector function and if you think in the context of TIGIT that will be a big deal or not. And I think the and especially as we saw, obviously, some of the preclinical data from Roche suggesting it could be very relevant.
And I know there have been question marks whether or not it is relevant based on human experience? And the second one is, would it or would it not make sense for Merck to have a randomized trial in lung initiated and caught up on timelines right away? Because I think there's been question marks over whether it makes sense to be doing that down the road when competitors have made further progress. And finally, if you could just catch us up on Peloton, it looked like the early responses were quite interesting between confirmed and unconfirmed and what the development track would look like. Thank you so much.
Roger?
Right. So, first of all, with respect to effector function, what I would say is that we don't have any information that's germane here. We as has been mentioned, of course, we have an intact IgG1 in terms of the TIGIT molecule. And we're seeing results. There's no doubt that our TIGIT molecule has activity.
I can't tell you what others would look like and we just have to continue to pursue the studies. And we do intend to move that thing forward as the data emerge. I think one of the things that we've demonstrated is that patient selection is really extremely important and understanding what you're doing is very important. And so we're I wouldn't say that we're in any way lagging behind on this. I think when our data come forward, I think you'll be pleased with the way we've prosecuted that program.
And then with respect to the Peloton molecule, the results look terrific and we are engaged in fact in registration enabling studies in the renal cell carcinoma setting, as I mentioned. So the question, of course, beyond I really believe based on what we've seen thus far in early studies in DHL that we'll see activity there. I think the question is, will we see an activity in other tumor types? And Roy, maybe you'd like to say a few words about this.
Thanks, Roger. Yes. So firstly, on the VHL side of the discussion, remember this is a multisystem disease and the most problematic is the development of malignancies including kidney, pancreas, pheochromocytoma. And interestingly, the natural history of this disease is one of recurrence. So typically patients will undergo surgical resection of a tumor only to have another one pop up.
And these patients are destined to have lifelong surgeries. Now importantly, what this drug has shown early on is that disease control is extremely high. So while the response rate now is approximating 30%, we're quite early in the course of this. And what we've seen our responses continue to accrue over time. And I don't believe there's I think there might be one patient that has actually progressed during this time.
The vast majority have had disease control. It's also important to recognize that many other manifestations of the disease are also controlled such as for example pancreatic neoplasms, various cystic lesions, hemangioblastomas of the involving the brain and the eye. So this does look as though it's going to be a fundamentally important treatment for this disease. Now this is a good area to focus on because clearly deranged VHL and HIF-two alpha biology is a hallmark of renal cell cancer and particularly in the advanced setting. And so we have, as you've already seen, had some salvage data to establish proof of concept.
And we have, as Roger mentioned, Phase 3 studies in the relapse setting comparing the HIF2alpha molecule to everolimus. We are also moving into additional lines of treatment. These are under design at the moment. And then as Roger mentioned, we are also looking at other solid tumors where indeed VHL biology and HIF-two alpha biology seems to be an important axis. So more to come.
Thank you. Next question please, Jerome.
Your next question comes from the line of Andrew Baum with Citi. You may now ask your question.
Thank you. A couple of questions for Roger. First on TIGIT, biologically, and I appreciate that you're running the trials, but biologically, would you expect DIGIT to be additive to efficacy with a chemo PD-one combination in non small cell to PD L1 low tumors, number 1? And then the second question is in reference to your keynote 6 and 8 Phase 3 non small cell lung cancer trials. As you seek to use PARP inhibitor maintenance therapy in first line lung to extend your franchise, There's been some papers suggesting that Bylulik loss is relatively rare in the non small cell lung indication.
Does that diminish your confidence in a positive outcome for this trial compared to some other tumor types where this seems to be more common? Many thanks.
Thank you, Andrew. Roger?
Yes. Thanks, Andrew. So the first question is, okay, so an anti ticket antibody, where would it work? And it appears to be a separate inhibitory input to T cells and NK cells. The question is, how important is that inhibitory input?
And what is the population in which that inhibitory input is important? So the poliovirus receptor interacting with TIGIT does what exactly. And that's an important thing to understand. But ultimately, I don't think we can we get much without going into the clinical setting. And that's the, of course, the setting we're exploring and we're doing a lot of studies in which we measure the activity of the molecules.
But I mean, ultimately, it depends on accruing data in those places. So not much I can add to that. And then with respect to the key link program and PARP inhibitor, what we've learned is that there are many potential contributors to the activity of PARP inhibitors that include, of course, BRCA1, BRCA2, but also a whole variety of other mutations. So the question is what sort of the burden of those mutations on mismatch repair in tumor populations and keep in mind, of course, that the tumor itself may be heterogeneous. To the extent that tumor cells are actually die as a result of this treatment, Tumor cell death is pro inflammatory and that could turn out to be quite positive, in the setting of KEYTRUDA administration where of course KEYTRUDA works better in tumors that are more inflamed.
So all of this is a bit of hand waving. We just have to do the studies and see. But I'm optimistic actually that we'll see responses in that combination. And indeed, we have had both preclinical and clinical data that suggests that that's true. Roy, am I missing something?
Roger, I think you've got it right. And just to remember that we have multiple other signal detection projects ongoing looking at other doublets and other triplets. So this is a very active field and we are quite compelled by the PIP data and we're confident enough to move that forward into Phase 3.
Next question please, Jerome.
Your next question comes from the line of Navin Jacob with UBS. You may now ask your question.
Great. Thanks for taking my question. Two questions for Roger and Roy, 1 on TIGIT and 1 on HIFALPA. On the TIGIT, if Roche's TIGIT was to show low monotherapy efficacy at AACR2, say low single digits for example, but yet we're seeing good data in combination with PD L1 and over the 50% PD L1 expressors. That would suggest synergy in a way that was expected by other mechanisms, but never realized such as IDO or IL-two.
And because of the weakness of those Latitude that looked
weak
on a monotherapy basis. And so, that looked weak on a monotherapy basis? And so would that with the Roche TIGIT data showing low monotherapy efficacy, would that change the way you approach your development programs for IO products, even if they show low monotherapy efficacy? And then a follow-up question on HIFALA.
Roger? Okay. So you want to do that seriatim? Okay. So first of all, what I would say about the general question of what does it take before you want to advance a molecule.
What we have tried to do with a very large set now is signal trends signal detection studies in which we introduce new molecules into clinical trials, both as a monotherapy with a monotherapy arm and a combination arm. If a monotherapy arm is flat negative, we just don't see any responses. That makes it a much higher bar to think about advancing combination studies. And again, these are small numbers of patients, but if you do 20 or 30 in monotherapy in a particular tumor type and see nothing, It makes you feel like, well, that's probably not a large treatment effect. But I would say the molecules that we are advancing at this point have really pretty weak monotherapy activity.
And nevertheless, we're optimistic based on what we're seeing in chemotherapy sorry, in combination therapy that could prove to be important. So I think we've already adapted basically because of what the data tell us, we've adapted to the idea that we're unlikely to see a molecule that has the sort of activity that a PD-one antagonist, certainly KEYTRUDA has. But on the other hand, we can still potentially gain some benefit. There's still some headroom, in terms of certainly response rate and we hope overall survival with some of these other molecules. And we have a few actually that are demonstrating that kind of activity in the combination studies.
We just now have to actually rigorously show the contribution of each component. So now on to HIFO and Alpha, I guess.
How do you think about potential synergistic effect with VEGF TKI? And then also, are you concerned at all about potential down regulation that HIFALA could cause tumor microenvironment offsetting any efficacy with KEYTRUDA? And where are you looking for potential combinations in the broader RCC earlier lines of therapy as part of your development plan?
Maybe Roy, you want to respond to that question specifically about HIF-two alpha. I would say that it's early days here. We have a relatively small amount of data from monotherapy with 6,482. So we don't really know, but maybe Roy you have a few comments.
Sure. So I think in the frontline treatment of renal cell cancer, I think we would all agree that the results of I O, VEGF combinations, particularly the KEYTRUDA plus axitinib combination is pretty impressive. And again, how much headroom you will have there is not terribly clear, but it still merits pursuit. And so, yes, absolutely, we're thinking quite diligently about what where we might fit HIF2 alpha into that mix. Probably more important will be in the at least initially in the salvage situation where patients have failed an IO and an VEGF modulator.
And that's sort of where we're pursuing things fairly actively right now. And again, this could be in combination with other agents that the patient might not have seen or frankly in combination with agents they might have seen. And so there is an emerging program there, which is again going to be fairly broad. And certainly, frontline is in the mix, but the headroom may be quite limited just given the efficacy
upfront, that'd be helpful, please. Next question please, Jerome.
All right. Your next question comes from the line of Dana Graybosch with SVB Leerink. You may ask your question.
Great. Thank you for the question. 2 from me. One, we've noticed you recently posted many new umbrella studies and you've added 1 or 2 cohorts. I think some of these have TIGIT or you're STING.
I wonder if you can speak to your approach of those trials, if you're going to include single agent KEYTRUDA randomization arms in that. And the second question is, I know ahead of some more data coming in frontline RCC, I wonder if you can speak to differences you see in the TKIs between axitinib, lambatatinib and cabozantinib, in particular in relation to cancer immunity? And also if you can give an update on when we could expect data from the CLEAR trial?
Great. Thank you. Roger?
Yes. I'll just provide a brief introduction, but this again is something that I think Roy can comment on and provide more detail. Part of what we try and do through these umbrella studies is really help to define the patient populations with some precision in terms of where to pursue registration enabling studies. The goal of the umbrella studies sometimes is the definitive identification of contribution of components, but more often we're looking at signals. And so I'll let Roy speak about that more.
And of course, with respect to the first line RCC, all we can do is look at the numbers absent head to head comparisons, pretty hard to tell. But clearly, we've shown already the combination of KEYTRUDA plus axitinib. And as Roy has mentioned, the data are really very impressive and we saw some of those data also in the presentation. But of course, this very similar data set, we believe will accrue, who knows, maybe stronger with lenvatinib based on our Phase II data, extremely strong data for the combination renal cell carcinoma. So we believe that each one of the small molecule inhibitors of protein tyrosine kinases has its own set of strengths and weaknesses and it will be important to look at each data set as a standalone.
But Roy, maybe you can add something about umbrella strategy or renal cell.
Sure. Yes, as you can imagine with our very strong pipeline as well as a number of the assets that Roger has referred to that we have brought in, we do need to have an efficient signal detection mechanism. And as Roger has mentioned, some of these can actually pave the way to accelerated approvals if indeed big effect sizes are seen. So you referenced a number of umbrellas and essentially the idea here is to have for the major tumor types umbrellas that we can explore signal detection fairly readily and in a flexible way where we can actually add arms as needed. You had a question about controls.
Yes, we do gather parallel controls in a somewhat analogous way to iSpire, not quite Bayesian, but that type of idea. In terms of the different TKIs, I think Roger has answered that perfectly. It's sort of impressive when you look at KEYTRUDA monotherapy in RCC, how active the drug is. Certainly, when you add TKI to it and as in the case of axitinib, clearly we've demonstrated remarkable efficacy. We've already shown Phase 2 data in combination with lenvatinib, which is quite dramatic.
And we had data at ASCO, as you know, in the PD-one experience population also that was really quite impressive. So we do think that both as a frontline treatment and potentially a salvage treatments, TKIs plus KEYTRUDA will have a role to play.
Thank you. Next question please, Jerome.
Your next question comes from the line of Tim Anderson with Wolfe Research. You may now ask your question.
Thank you. I pressed you on the potential risk that the PD-1s don't in the advent setting in contrast to their consistent activity in metastatic disease based on the idea that underlying value may be different tumor disease versus metastatic. And you have a bit of a mixed track record positive results in melanoma, we don't have trial in blood. You've been adamant that this is a mix. You've said ones will work even better in the earlier.
So I'd like to get your perspective on this in light of iurantaline adjuvant. I know that's a different tumor type. It's a different class of drug, but it does lend support to the idea that early stages of the advanced patients might act differently. This question is stanfevergenerate and keep talking about their PD-one and it's having co activity to KEYTRUDA in lung. An important difference in their trial excluded smokers.
And I'd like to get your kind of what sort of steps that might make it interpreting?
Tim, you were breaking up quite a bit when you asked the question. So I'm not sure if Roger was able to understand the question or not. I know the first one related to the difference in PD-one versus adjuvant versus metastatic. Roger, could you understand the question?
Well, I think the question, Tim, if I'm not mistaken, had to do with isn't the tumor environment different in metastatic versus the early stage? And what gives me confidence that the statement I've made repeatedly that KEYTRUDA appears to work better earlier on, when from your perspective, I think that you felt the data were a little mixed. Is that right?
Yes. I'm just wondering if there's risk in asthma, especially in light of Ibrance failing, you've given that different mechanism that lends support to the idea that maybe early stage tumor disease is going to look and attribute that as static disease?
Yes. So I don't think of course, I and as you said, I mean, you can't really reason from Ibrance and their observation to KEYTRUDA, the mechanisms are so different, signal transduction inhibitor, that to a first approximation is cell autonomous as opposed to KEYTRUDA, which is acting in the entire tumor system. The response to KEYTRUDA is so dependent upon the characteristics of the tumor itself. And of course, we're learning an awful lot about tumor biology in the course of studying this because all of us grew up with the idea that cancer is a somatic genetic disease and it's a cell autonomous disease and malignant clones evolve by stepwise accrual of mutations and they eventually lose growth factor dependence and substrate adherence and no longer respect basement membranes and then individual clones seed out and there's this environment that selects for them. And in fact, it appears that the situation is much more complicated than that, in that the cancers are very dependent upon the sustaining cells, what we refer to broadly as the tumor microenvironment.
And those sustaining cells participate in tumor growth. And that interaction between immune cells, sustaining cells, myeloid derived cells, some of which are described as suppressor cells, as well as the cancer itself, the malignant cell itself is very important. As we know in most tumors, the majority of cells are not the transformed cell population. There are other cells and KEYTRUDA is very much interacting with those. I would say that all of the evidence that we have from everything that we've done pre clinically and clinically indicates that KEYTRUDA reveals the pre existing immunity directed against tumors.
And as a result, those tumors either shrink or just disappear. In many cases, it will hold the tumor in check, even though there are a few malignant cells left. Some people call that sort of reestablishing a balance between immune function and the tumor. But there's everything that suggests that those mechanisms remain intact, both in the metastatic setting, where obviously we have a huge amount of data, but as well in the earlier settings. And I think our adjuvant data are very clear in that point.
And that's true when you look in the breast cancer population, that's true when you look in the melanoma population, that's true in a whole variety of settings. So I feel quite confident about that. And I think these are really quite distinct. But then you had another question, but that one broke up a bit more. So Tim, what was that?
I think we're going to go to the next question. Tim, if you want to email me your second question, perhaps we can get that toward the end. Thank you. Next question please, Jerome.
Your next question comes from the line of Seamus Fernandez with Guggenheim Securities. You may now ask your question.
Great. Thanks very much for the question. Hopefully, you guys can hear me okay.
Yes, we've got it.
All right, great.
So just a couple of questions. Roger, just hoping you could comment on what
feels like
a couple of gaps in your internal development pool and you've been accessing that by buying companies like ArQule. We're seeing a lot of encouraging early data with point mutation kinase inhibitors. Just hoping you could give us a general sense of the Merck philosophy around kinase inhibitors development there and the ability or Merck's interest in potentially building out that space. Incremental to that, I think we're starting to see more ADCs actually showing some really interesting data in the CPI refractory patient population or the PD-one refractory area. And also more ADCs kind of building out into that space.
Wondering what Merck's efforts are there currently outside of direct collaboration? Thanks so much.
Right. Thanks, Seamus. I think, first of all, the idea of looking at kinase inhibitors, of course, we are interested in them, potentially and are using LENVIMA as a way to probe the protein tyrosine kinase inhibitor field. So field, of course, that I know extremely well and have been involved in it for better part of 40 years. So, have a lot of experience in looking at these molecules.
I have to say that the a lot of our attention has been drawn, of course, to immuno oncology mechanisms because of what we found with KEYTRUDA. And we've naturally gone and asked, well, okay, what can you do to improve KEYTRUDA responses to get beyond where we are because we want to do better? And what we've learned some things about that. We've certainly shown that combinations in a variety of different settings can be helpful. And that includes a lot of things that just kill tumor cells.
So chemotherapy, working as cytotoxic agents, traditional chemotherapy, radiotherapy, and of course, signal transduction targeting agents. And all of them I think have similar kinds of effects. We're interested in them and what we're trying to do is improve the benefit risk profile. So where we can find more selective compounds that have fewer adverse effects, in general, my guess is that those things will pair pretty well with KEYTRUDA and we are interested in those. And we have tried to address them principally by taking advantage of the very large number of companies out there, small and large, that have pursued such things.
So that's that. I don't think the answer is very different for the antibody drug conjugates. Of course, we've been doing experiments with these, particularly the EV data that you've seen in urothelial cancers working with Seattle Genetics and we are looking at a number of other programs. We set up at the beginning, as you know, a mechanism and Roy set this up, whereby we can provide KEYTRUDA to lots of people who are doing studies to get an early look at which sorts of things work in combination with KEYTRUDA. And that's been very helpful to us in terms of targeting licensing opportunities and acquisitions.
That's the general approach we're taking. And at the high level, I would say, it appears that things that kill malignant cells maybe because they have a pro inflammatory effect, perhaps for other reasons, tend to work pretty well in combination with KEYTRUDA.
Great. Thank you, Roger. We're at the top of the hour, but perhaps we could take questions from 2 more analysts. Next question, please, Jerome.
Your next question comes from the line of Mara Goldstein with Mizuho. You may now ask your question. Great. Thanks so much for squeezing me in. I'm wondering if you could maybe put KEYNOTE-five twenty four, the LENVIMA plus KEYTRUDA combination sort of in context with what we just saw the approval in first line liver cancer for the atezolizumab plus Avastin program?
Yes. I mean, just to say that the 5/24 data are really quite strong as you saw, and relate to the broader, lyndema combination studies that we have. Roy, maybe you could comment on specifically on those data and also on the larger controlled data with respect to hepatocellular carcinoma.
Sure. So the combination that we showed was obviously a single arm Phase II experience. And the magnitude of the response was really impressive. It's certainly among the probably highest response rates seen. And the responses at this stage of follow-up look quite durable.
So we think that portends a very favorable outcome for this combination in HCC. And then we do have a large Phase III study, which is exploring this combination versus standard care.
Great. Last question please, Jerome.
All right. Our last question comes from the line of Chris Schott with JPMorgan. You may now ask your question.
Great. Thanks very much for the questions. Just 2 here. Maybe just update next steps with the BTK program. And maybe more broadly, just do you see an ability for the reversible BTKs to move earlier in the treatment paradigm?
Or should we think of these as most likely kind of post IMBRUVICA type agents? And then my second question was maybe less ASCO related, but just an update on some of the near term key trigger dynamics as we're starting to move beyond some of the peak COVID containment efforts there. Are you seeing signs at this point that either treatment rates or new starts are beginning to normalize or is it still too early to get a look at how those dynamics are playing out? Thanks so much.
Thanks, Chris. Perhaps the first question, Roger or Roy and the second question maybe Frank.
Well, just quickly, Chris, on BTK, I think the fundamental question, which is we still don't know the answer to because it has to do with the way in which you explore it is, when do the cysteine mutations occur in individuals who proceed a covalent cysteine acting BTK inhibitor? And what is the right approach to treating individuals from the time that that mutation occurs? Is that the time in which because of course that resistant clone should expand? Is that the time when you should pursue aggressively a molecule like ours, which is, of course, unaffected by that mutation, or are there other approaches that you should use? And then more generally, you can ask the question, well, gee, is the right approach to use a non covalent?
And then at some point, you could come back with a covalent one in those who have escaped, but still have the cysteine intact. All of that remains to be explored. I think the first question is, in individuals who are clearly refractory, can you reintroduce response? And I think we already have data from a small number of patients that says yes. And we're clearly going to get an answer to that.
And Frank on Keytruda Dynamics?
Yes. And Chris, I think it's too early to give any additional COVID updates as we were discussing on our last quarterly call. We are seeing a dynamic where there is some new patient start declines or I should say with regards to just visits of new patients depending on the different cancer type and we'll have a chance at the end of the second quarter to give an update. I think the most important part though, Chris, we see oncology as being very resilient. We do not think this changes the fundamental picture of the opportunity.
As you can see the momentum that we had in Q1 of 46% growth if you were to exclude foreign exchange. So we do believe there'll be some impact as we mentioned across the portfolio based on COVID. But clearly for KEYTRUDA, we're very confident in the outlook. And I think the feedback that we're hearing coming out of ASCO has been very positive from both the community and KOLs about the data that Roger shared. Okay.
Great. Thank you all for your participation and your interest today. Really appreciate it. Please reach out to IR if you have any follow-up questions and we look forward to seeing you soon.