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 speaker's remark, there will be a question and answer session. If you would like to ask a question during this time, simply press star, then the number one on your telephone keypad. To withdraw your question, press the pound key. If you are listening to the audio webcast, please mute your computer speakers while you are asking your question to avoid background noise. Thank you. I would like to turn the call over to Peter Dannenbaum, Vice President, Investor Relations. Please go ahead.
Thank you, Jerome. Good afternoon, everybody. Welcome to Merck's 2020 virtual ASCO investor call. I'm joined by Dr. Roger Perlmutter, President of Merck Research Laboratories, Dr. Roy Baynes, Head of Global Clinical Development and Chief Medical Officer of Merck Research Laboratories, 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 Litigation 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 underlying 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-K, 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&A. With that, I'd like to turn the call over to Roger.
Thank you very much, Peter. 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. If I could advance the slide, we would have first our safe harbor statement, which you've already heard from, Peter. If we go to the next slide, this slide is one that you're familiar with in some ways. That is , we've talked a lot about our broad oncology strategy designed to improve outcomes for more 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. That includes, of course, patients who have microsatellite instability and also high tumor mutational burdens. Next slide. 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.
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 from the right, it's pretty extraordinary. Right next to it is classical Hodgkin lymphoma, which is really quite dramatic. It's also quite dramatic in the response to melanoma or non-small cell lung cancer. As you can 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 and the tumor advancing. It's really special.
These responses, these overall responses that we see demonstrated in these kinds of waterfall plots, are mirrored in outcome measures. 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, all of which were shown in the overall response diagrams on the previous slide. That includes, of course, melanoma, a relatively responsive tumor, but also non-small cell lung cancer, based on our KEYNOTE-024 study, in those patients whose tumors express PD-L1 at a high level, or in the KEYNOTE-042 study in patients whose tumors express PD-L1 greater than 1%.
In lung cancer, of course, the combination data, KEYNOTE-189, 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-407 in the first-line squamous cell population, as most of you are aware. 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 six years ago. Next slide. The development program for KEYTRUDA, though, continues and in many ways is simply expanding. We have in excess of 1,200 ongoing clinical trials, of which about 90 are registrational. 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.
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. 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 commas, 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 are happy to respond to questions about the KEYNOTE-799 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. We also had the opportunity to talk about some novel mechanisms, some of which we'll mention here as well. Next slide. To begin, KEYNOTE-355 was 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 this study. The overall survival endpoint was not examined at this interim analysis.
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. We have the strong view that that will ultimately translate into overall survival benefit. Of course, we have to demonstrate that. I should say that this trial complements very much the KEYNOTE-522 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 in triple-negative breast cancer improved the pathologic complete response rate. That study continues to obtain event-free survival data. 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.
We also had the opportunity to show the data from KEYNOTE-177. 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, of 307 patients who were randomized either to receive KEYTRUDA monotherapy or to receive traditional therapy, investigator's 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. That trial as well is continuing for overall survival. We hope to have the opportunity to see that soon. 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.
Really quite an impressive result. The next slide shows you the results from the KEYNOTE-204 study, which is a head-to-head study comparing an antibody drug conjugate, shown here as BV, which is commonly used, a Seattle Genetics product commonly used in the late -line treatment of relapsed/refractory classic Hodgkin lymphoma, as compared with KEYTRUDA monotherapy. Here you can see that in this second-line plus setting, that KEYTRUDA monotherapy is clearly superior because, as I mentioned, classic Hodgkin lymphoma is really a very responsive tumor and is very responsive even after having been unresponsive to multiple prior therapies. Quite a good result in terms of progression-free survival on the trial here and also continues for overall survival. Next slide.
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 effects of KEYTRUDA administered in non-small cell lung cancer, renal cell carcinoma, or melanoma. You can see on the left-hand side a final analysis, a pre-specified final analysis for KEYNOTE-189, demonstrating the extraordinary window that's opened up between individuals receiving KEYTRUDA in combination with chemotherapy, as opposed to chemotherapy alone. It really is quite remarkable, and something that we hear about frequently from our colleagues who are practicing thoracic oncology is that they are just seeing more and more patients surviving for a longer period of time. You can see it at 24 months; the overall survival is around nearly 46% for the KEYTRUDA plus chemotherapy combination. The hazard ratio for this comparison at that point is 0.56.
It's really quite an impressive result for what would otherwise be considered to be a completely refractory disease. KEYTRUDA in combination with chemotherapy has really changed the treatment dramatically. Similarly, if you look at renal cell carcinoma, the updated analysis from KEYNOTE-426, which is a combination of KEYTRUDA plus axitinib, continued to demonstrate really impressive activity versus sunitinib in this case. 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-054, for which, in this case, we had the opportunity to look at three-year follow-up data from EORTC for adjuvant treatment of melanoma with KEYTRUDA. You can see as we look at those curves, the KEYTRUDA curve at the top, the green curve, separates early from the placebo in this adjuvant setting.
These are individuals who have undergone definitive resection of malignant melanoma but are at high risk of recurrence. This is resected high-risk Stage 3 melanoma. When you look at those individuals, what you can see is that at three years, the recurrence-free percent alive and recurrence-free is nearly 64%, which is quite remarkable compared to the 44% from those who just underwent surgical resection. The hazard ratio for that comparison, again, is 0.56. There is no doubt that this three-year 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. We are interested in a variety of them, but we're also interested in new mechanisms. One of those is MK-6482. We had the opportunity to show data from 6482 in the von Hippel-Lindau setting.
Von Hippel-Lindau disease is a disease that results from typically an inherited mutation in the VHL protein, which results in the relative persistence of a transcription mediator called HIF-2α. MK-6482 is a HIF-2α inhibitor. If you look in von Hippel-Lindau disease and you look at patients who have clear cell renal cell carcinoma, which is an extremely frequent complication of von Hippel-Lindau, the most prominent complication, although there are many other tumors, I'd say it's the one that was dealt with most frequently. The overall response rate in the setting of 6482, which is the first time this has been examined in a small study in VHL disease, overall response rate nearly 28%.
Maybe more profoundly, 87% of the patients saw a decrease in target lesion size because these target lesions, these tumors, really are driven by the stabilization of HIF-2 alpha as a result of the lack of the VHL protein. MK-6482 can be very effective, we believe, in that setting. A phase III trial is underway studying MK-6482 versus everolimus in patients with advanced second-line renal cell carcinoma who've progressed following currently accepted standards of therapy. Next slide. Looking 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 and neoadjuvant setting. We've already talked about KEYNOTE-054, which was approved a couple of years ago, and I already mentioned our triple-negative breast cancer neoadjuvant/adjuvant study, KEYNOTE-522.
There are a variety of other important studies in cutaneous squamous cell carcinoma, in head and neck cancer, non-small cell lung cancer, melanoma that we'll be rolling out over the next several years. 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-stage disease, that we will see meaningful improvements in patients' responses and, in fact, in recurrence-free survival, perhaps even in overall survival in some settings. We're quite enthusiastic about that. Next slide. KEYTRUDA, of course, in addition to being used with chemotherapy, can also be used in combination with two other molecules that we are pursuing, LYNPARZA and LENVIMA. for LYNPARZA, of course, LYNPARZA as monotherapy is already an extremely important drug.
It has been demonstrated to have activity in the maintenance of treatment response in ovarian cancer, in breast cancer, and in pancreatic cancer. 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 based on the POLO1 data for the use of LYNPARZA in that extremely refractory setting, rare patients with BRCA1 or BRCA 2 mutations with pancreatic cancer, but still an important proof of concept. Of course, the profound data in prostate cancer, which is extremely important. Going forward, a lot of combination studies will be pursued in each one of these things. It gave us the opportunity to see whether, as we believe based on our early studies, KEYTRUDA in combination with LYNPARZA can be used effectively to further improve patient outcomes. Next slide.
For the LENVIMA program, LENVIMA also is approved as monotherapy, for example, in urothelial carcinoma. Here we have a large number of combinations, including some approved combinations. For example, in the second-line endometrial cancer setting, the combination of KEYTRUDA and LENVIMA shown in the KEYNOTE-146 study was extremely effective. We also have data that is emerging in renal cell carcinoma, in hepatocellular carcinoma, and in a variety of other tumor types. We expect that we'll have a chance to see those going forward. If I could now go to the next slide, and I understand that maybe the audio is not so good. I'll try to speak a little bit more clearly.
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. I should emphasize here, as I have on earnings calls, that to date, despite the fact that we have studied many different mechanisms, including immune agonists, including those things that inhibit negative regulators, as KEYTRUDA itself does, but also LAG-3 antibodies, CTLA-4, TIGIT, and the ILT-4 agonist; personalized cancer vaccines, which we have a number of; 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. We continue to pursue those different molecules that are mentioned here. We'll have a chance to update you on those at future meetings, including, of course, future ASCO and AACR meetings. The next slide mentions that while we have generated a lot of these different molecules ourselves, we also have had the opportunity to acquire important molecules. I talked about one of those, which is the HIF-2α inhibitor that we acquired from Peloton, which is currently in phase III 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-2α 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 II 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, it has been shown to be active in individuals whose tumors have sustained a mutation of BTK, such that they are no longer susceptible to the cysteine -acting covalent inhibitors.
We've also had the opportunity to gain new oncolytic viruses, for example, from our acquisition of Viralytics, and to have collaborations, for example, with Taiho Astex for the development of various different KRAS inhibitors, which in fact target the entire RAS pathway, including both GDP- and GTP bound and other isoforms besides KRAS. 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.
Over the next five years, you have a sense of what we'll 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 Frank can talk about a little bit later. Beyond five years, the pipeline is extremely rich, and as I've said, we're optimistic that many new molecules will be used with KEYTRUDA in combination and some as single agents that will be important. Over 10 years, of course, well, that's out at the horizon of what can be predicted.
I have to say that the expertise that we've developed in fundamental biology, in understanding malignant cells, and in understanding the tumor microenvironment bodes very well for improved therapies for many years to come. 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&A. I request that questioners limit themselves to one or two, perhaps, so that we can get through as many questions as possible.
Ladies and gentlemen, as a reminder, if you would like to ask a question, please press star then the number one on your telephone keypad. Again, to ask your question, please press star then the number one on your telephone keypad. 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's now open.
Umer, are you muted? Okay, let's go to the next question, please, Jerome.
All right. Your next question comes from the line of Steve Scala with Cowen. You may now ask your question.
Thank you. Roger, many novel IO 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. 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? That's the first question. Second, Frank, if Roche anti-TIGIT phase III data replicates phase II, then how do you see Merck's competitive position changing in lung cancer? Thank you.
Roger?
Steve, thanks for that. 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, of course, 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 atezolizumab as monotherapy doesn't really provide that much benefit as compared to what we see with KEYTRUDA. If you compare the KEYTRUDA O24 results, for example, which are pretty impressive. We don't know how much headroom there is beyond what KEYTRUDA O24 does. We are looking at our molecule, our TIGIT 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 two looks pretty intriguing. 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. 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 ab initio. 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 again a remarkable spectrum of activity. That could be because KEYTRUDA, for example, is superior to other anti-PD-1s for reasons that we can't establish exactly preclinically.
It could be because of aspects of clinical trial design. Without really seeing that kind of information and having it come out broadly in a lot of studies, it's pretty difficult to make a comparison. Frank?
Yeah, Roger, thank you. To just follow up on Roger's point, I think the data we are seeing from Roche from CITYSCAPE in non-small cell lung cancer is scientifically interesting, but I think we'll have to wait and see how the data continues to materialize. 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. 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 that over 8 out of every 10 eligible patients that do not have a genomic marker of ALK or EGFR are being treated with KEYTRUDA. In the high patient population, PD-L1 50 and above, KEYNOTE-024 is a very strong monotherapy regimen.
Probably about 60% of the patients in the U.S. are being treated with monotherapy. The rest are on a combination with chemotherapy. 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. 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 about whether or not it is relevant based on human experience. 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? I think there's been a question mark over whether it would make sense to be doing that down the road when competitors have made further progress.
Finally, could you 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. First of all, with respect to effector function, what I would say is that we don't have any information that's germane here. As has been mentioned, of course, we have an intact IgG1 in terms of the TIGIT molecule. 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. 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. Understanding what you're doing is very important. I wouldn't say that we're in any way lagging behind on this. I think when our data comes forward, I think you'll be pleased with the way we've prosecuted that program.
With respect to the Peloton molecule, yeah, the results look terrific, and we are engaged, in fact, in registration-enabling studies in the renal cell carcinoma setting, as I mentioned. The question, of course, is beyond that. I really believe based on what we've seen thus far in early studies in VHL, that we'll see activity there. I think the question is, will we see an activity in other tumor types? Roy, maybe you'd like to say a few words about this.
Thanks, Roger. Yeah. Firstly, on the VHL side of the discussion, remember, this is a multi-system disease, and the most problematic is the development of malignancies, including kidney, pancreas, and pheochromocytoma. Interestingly, the natural history of this disease is one of recurrence. 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. While the response rate now is approximating 30%, we're quite early in the course of this, and what we've seen is our responses continue to accrue over time. 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, and hemangioblastomas involving the brain and the eye. This does look as though it's going to be a fundamentally important treatment for this disease. This is a good area to focus on because clearly deranged VHL and HIF-2α biology is a hallmark of renal cell cancer, and particularly in the advanced setting. We have, as you've already seen, had some salvage data to establish proof of concept. We have, as Roger mentioned, phase III studies in the relapse setting, comparing the HIF-2α molecule to everolimus. We are also moving into additional lines of treatment. These are under design at the moment.
As Roger mentions, we are also looking at other solid tumors where indeed VHL biology and HIF-2 alpha biology seems to be an important axis. 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 biologically, would you expect TIGIT?
To be additive to efficacy with a chemo PD-1 combination in non-small cell to PD-L1 low tumors, number one. The second question is in reference to your KEYLYNK-006 and KEYLYNK-008 phase III non-small cell lung cancer trials. As you seek to use PARP inhibitor maintenance therapy in first-line lung to extend your franchise. There have been some papers suggesting that biallelic 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?
Yeah. Thanks, Andrew. The first question is, okay, an anti-TIGIT antibody, where would it work? It appears to be a separate inhibitory input to T cells and NK cells. The question is, how important is that inhibitory input? What is the population in which that inhibitory input is important? The poliovirus receptor interacting with TIGIT does what exactly? That's an important thing to understand, but ultimately, I don't think we get much without going into the clinical setting, and that's, of course, the setting we're exploring, and we're doing a lot of studies in which we measure the activity of the molecules. Ultimately, it depends on accruing data in those places. Not much I can add to that. Then with respect to the KEYLYNK program and a 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. The question is, what's sort of the burden of those mutations on mismatch repair in tumor populations? Keep in mind, of course, that the tumor itself may be heterogeneous. To the extent that tumor cells are actually dying 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. All of this is a bit of hand-waving. We just have to do the studies and see. I'm optimistic, actually, that we'll see responses in that combination.
Indeed, we have had both preclinical and clinical data that suggests that that's true. Roy, am I missing something?
No, Roger, I think you've got it right. Just to remember that we have multiple other signal detection projects ongoing, looking at other doublets and other triplets. This is a very active field, and we are quite compelled by the PARP data, and we're confident enough to move that forward into phase III.
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. One on TIGIT and one on HIF alpha. On the TIGIT, if Roche's TIGIT were to show low monotherapy efficacy at AACR, say low single digits, for example, 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-regulated IL-2. Because of the weakness of those latter two products that I mentioned, or mechanisms that I mentioned, I think there was a shift in strategy to perhaps not go forward with assets that looked weak on a monotherapy basis. 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?
A follow-up question on HIF alpha.
Roger?
You want to do that seriatim? First of all, what would I say about the general question of what it takes before you want to advance a molecule? What we have tried to do with a very large set now is 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. 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.
I would say the molecules that we are advancing at this point have really pretty weak monotherapy activity. Nevertheless, we're optimistic based on what we're seeing in combination therapy, which could prove to be important. 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-1 antagonist, certainly KEYTRUDA has. On the other hand, we can still potentially gain some benefit. There's still some headroom in terms of certain response rates, and we hope for 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. Now on to HIF 1 alpha, I guess.
How do you think about a potential synergistic effect with a VEGF TKI? Then also, are you concerned at all about potential downregulation that HIF alpha could cause in a tumor microenvironment, offsetting any efficacy with KEYTRUDA? 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-2 alpha? I would say that it's early days here. We have a relatively small amount of data from monotherapy with 6482. We don't really know, but maybe Roy, you have a few comments.
Sure. I think in the frontline treatment of renal cell cancer, we would all agree that the results of IO VEGF combinations, particularly the KEYTRUDA plus axitinib combination, is pretty impressive. Again, how much headroom you will have there is not terribly clear, but it still merits pursuit. Yes, absolutely. We're thinking quite diligently about where we might fit HIF-2 alpha into that mix. Probably more important will be, at least initially, in the salvage situation where patients have failed an IO and a VEGF modulator. That's sort of where we're pursuing things fairly actively right now. 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. There is an emerging program there which is again going to be fairly broad.
Certainly, frontline is in the mix, but the headroom may be quite limited just given the efficacy that we see with VEGF IO combinations.
Great. If you could state your second question upfront, that'd be helpful, please. Next question, please, Jerome.
All right, your next question comes from the line of Daina Graybosch with SVB Leerink; you may ask your question.
Great. Thank you for the question. Two from me. First, we've noticed you recently posted many new umbrella studies, and you've added one or two cohorts. I think some of these have TIGIT or your STING. I wonder if you can speak to your approach to those trials if you're going to include single agent KEYTRUDA randomization arms in that. 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, lenvatinib, and cabozantinib, in particular in relation to cancer immunity. Also, if you can, give an update on when we could expect data from the CLEAR trial.
Great. Thank you. Roger?
Yeah, I'll just provide a brief introduction, but this again is something that I think Roy can comment on and provide more detail on. Part of what we try to 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 the contribution of components, but more often we're looking at signals. I'll let Roy speak about that more. Of course, with respect to the first-line RCC, all we can do is look at the numbers. Absent head-to-head comparison makes it pretty hard to tell. 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.
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 of renal cell carcinoma. 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. 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's referred to that we have brought in, we do need to have an efficient signal detection mechanism. As Roger's mentioned, some of these can actually pave the way to accelerated approvals if indeed big effect sizes are seen. You reference 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 I-SPY, 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 a TKI to it, as in the case of axitinib, clearly we've demonstrated remarkable efficacy. We've already shown phase II data in combination with lenvatinib, which is quite dramatic, and we had data at ASCO, as you know, in the PD-1 experience population also, that was really quite impressive. We do think that both as a frontline treatment and potentially as 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, Wolfe Research. You may now ask your question.
Thank you. Roger, I pressed you on the potential risk that the PD-1s don't make it in the adjuvant setting in contrast to their consistent activity in metastatic disease based on the idea that the underlying biology may be different in solid -tumor disease versus metastatic. You have a bit of a mixed track record; I know that's a positive result in melanoma. You've been adamant that this is a misconcern. You've said ones that will work even better earlier. I'd like to get your perspective on this in light of IBRANCE adjuvant. I know that's a different tumor type and it's a different class of drugs, but it does lend support to the idea that early -stage versus advanced -stage cancer might act differently. This question, Sanofi and Regeneron generally keep talking about their PD-1 as having activity to KEYTRUDA in lung.
An important difference in their trial: they excluded smokers. I'd like to get your opinion on what sort of insight that might make in interpreting the results. Thank you.
Tim, you were breaking up quite a bit when you asked the question. 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-1 adjuvant versus metastatic. Roger, could you understand the questions?
Well, I think the question, Tim, if I'm not mistaken, had to do with whether the tumor environment is different in metastatic versus the early stage. What gives me confidence is 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?
Yeah. I'm just wondering if there's risk in adjuvant, especially in light of IBRANCE failing, even though that different mechanism, it lends support to the idea that maybe early -stage single -tumor disease is going to look like metastatic disease activity.
Yeah. Of course, and as you said, you can't really reason from IBRANCE and their observation to KEYTRUDA. The mechanisms are so different. A 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. 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 the malignant clones evolve by stepwise accrual of mutations, and they eventually lose growth factor dependence and substrate adherence and no longer respect basement membranes. Then individual clones seed out, and there's this environment that selects for them.
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. Those sustaining cells participate in tumor growth. 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. KEYTRUDA is very much interacting with those. I would say that all of the evidence that we have from everything that we've done preclinically and clinically indicates that KEYTRUDA reveals the preexisting 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.
Everything that suggests that those mechanisms remain intact, both in the metastatic setting, where obviously we have a huge amount of data, and in the earlier settings. I think our adjuvant data are very clear on that point. 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. I feel quite confident about that, and I think mechanistically, these are really quite distinct. You had another question, but that one broke up quite a bit more. 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.
Yeah, we've got you.
All right, great. 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 inhibitor 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-1 refractory area. Also more ADCs are kind of building out into that space. Wondering what Merck's efforts are there currently outside of direct collaboration. Thanks so much.
Right.
Roger.
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. It's a field, of course, that I know extremely well , and I've been involved in it for the better part of 40 years. Have a lot of experience in looking at these molecules. I have to say that a lot of our attention has been drawn, of course, to immuno-oncology mechanisms because of what we found with KEYTRUDA. 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? 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. Chemotherapy, working as cytotoxic agents; traditional chemotherapy; radiotherapy; and, of course, signal transduction targeting agents. 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. 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. 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. 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. We're 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. 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 two 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-524, 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.
Just to say that the KEYNOTE-524 data are really quite strong, as you saw, and relate to the broader LENVIMA combination studies that we have. Roy, maybe you could comment specifically on those data and also on the larger control data with respect to hepatocellular carcinoma.
Sure. The combination that we showed was obviously a single-arm phase II experience; 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. We think that portends a very favorable outcome for this combination in HCC. 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 JP Morgan. You may now ask your question.
Great. Thanks very much for the questions. Just two here. Maybe just update next steps with the BTK program. Maybe more broadly, 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? My second question was maybe less ASCO related, but just an update on some of the near-term KEYTRUDA dynamics as we're starting to move beyond some of the peak COVID containment efforts there. Are you seeing any 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've received a covalent cysteine-acting BTK inhibitor? What is the right approach to treating individuals from the time that that mutation occurs? Is that the time at 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? Are there other approaches that you should use?
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 and 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 a response? 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. Frank, on KEYTRUDA dynamics?
Yeah. 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 regard 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, is that 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 would exclude foreign exchange. 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.
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. We look forward to seeing you soon.