Risk factors contained in our 10-K. With that, I'm gonna hand it over to Dean.
We're here today. As we discussed, Eliav will outline the progress made since the last ASCO sort of investor meeting we had in 2021. I mean, since that time, I just reemphasize, I think there's 12 U.S. approvals across eight tumor types since the last time we had an event like this. Now, Eric will update a subset of the 20 novel mechanisms that we are advancing as we seek to advance and diversify our impact on oncology. Then Jannie will provide a commercial landscape of our ability to touch the lives of patients and their families.
Then Scot and Greg, who will provide color and just through my early morning discussions with some of you know, some of the questions that were asked of me, Scot and Greg would be perfect people to give even more color to some of those questions. This is what we have from a sort of clinical development standpoint. We have a rich set of clinical experiments composed of internal programs and clinical trials with external partners. If you look on the left side, many of these studies are often in combination therapies. What we're trying to do is learn what are the best mechanisms on their own or in combination that can move the needle for patients.
As you see in the top right quarter, we are aggressively moving into earlier stages of cancers, where the opportunity to change the course of cancer is profound. I also wanna highlight that many of these clinical trials that we lay out when we say 1,300 greater than 1,750 are really ones that are both internal and in partnership with others. Those readouts from these clinical studies are what fuel our business development transactions. Our progress to date continues to inspire us to achieve more. We seek to expand and listed here is we seek to expand into new tumor types, and we've done that successfully just over this past year. We are very interested in extending our reach from late-stage metastatic disease to early stages of cancers.
I would just emphasize, you know, when we moving into earlier stage cancers, and you'll see many of those readouts, those are readouts that come from clinical trials that were begun quite some years ago, simply because it takes longer for the early stages to mature. Clearly, we need to deepen the response in combination with other IO agents, and that range from checkpoint inhibitor for T cells and myeloid cells to cytokines and innate activators. We also want to deepen our response in combination with non-IO agents like chemo, Lynparza, Lenvima, and too many other cancer intrinsic mechanisms, some which Eric will touch. With that, I will now turn to Eliav, who will recount some of the progress we've made since the last 2021 ASCO meeting. Eliav?
Good morning, everyone, and thanks, Dean. Merck Oncology has had a really productive year since the last ASCO. We've continued to deliver on our commitment to improve patient outcomes. As Dean noted, we've received 12 U.S. approvals, including six in metastatic stage cancers across eight different tumor types, and you can see those here. In addition, Keytruda was approved for treatment of adjuvant therapy following nephrectomy in certain patients with renal cell cancer and triple-negative breast cancer, in locally advanced cutaneous squamous cell cancer, and as adjuvant treatment following surgery for high-risk stage 2B or 2C melanoma. Lynparza was approved as adjuvant therapy for certain patients with HER2-negative high-risk early breast cancer with BRCA germline mutations and who received neoadjuvant or adjuvant chemotherapy.
You can see that we're moving into earlier lines of therapy and combining our assets with surgery to hopefully help patients achieve cure. We've also had a new molecular entity, Welireg, the first-in-class HIF-2 alpha inhibitor for treatment of adult patients with certain kinds of von Hippel-Lindau related tumors. This was approved and, as Eric will point out, there'll be other opportunities to look at this very important and exciting new molecular entity. We also have had three readouts of pivotal trials, including KEYNOTE-394, which showed Keytruda improving OS versus placebo in patients with advanced HCC previously treated with sorafenib. A really important finding for patients with hepatocellular cancer.
We've also had, of course, KEYNOTE-091, for which one of the dual primary endpoints showed that Keytruda improved disease-free survival versus placebo as adjuvant therapy in certain types of Stage 1B to 2 to 3A non-small cell lung cancer following resection, regardless of PD-L1 expression.
The trial will continue to analyze disease-free survival in patients who express high levels of PD-L1, so TPS greater than 50%, which was the other dual primary endpoint of the study, which had not yet met its statistical significance based on the pre-specified plan, but we will have further analyses of that. Finally, considering Lynparza again, we had the PROPEL study which showed that Lynparza with abiraterone reduced the risk of disease progression or death versus abiraterone alone in first-line metastatic castration-resistant prostate cancer. Regardless of biomarker status, this is a really important finding in a very large set of patients with prostate cancer and a very exciting opportunity for those patients to improve outcomes.
Now, over the year, we've made, I think some really exciting presentations and published some important results at several meetings, including studies that forming the basis of new indications for Keytruda and evaluations of new compounds that are coming through the pipeline. At this year's ASCO, we really reinforced the breadth and depth of the oncology portfolio. We had over 150 abstracts presented with results of our compounds. About two-thirds of them were with Keytruda. You know, these data emphasize the broad nature of our oncology program, the long-term durability of responses we're observing for patients and the continued progress into earlier lines into early stage settings. Overall, we're really confident in our ability to continue this momentum and to improve patient outcomes.
Let me review some of those abstracts in a bit more detail to explain what we were able to show. First and foremost, KEYNOTE-716, which evaluated pembrolizumab or placebo as adjuvant therapy among 976 patients 12 years or older who had undergone complete resection for Stage 2B or 2C melanoma. As published recently in The Lancet, administration of pembrolizumab Keytruda reduced the risk of death for local, regional or distant recurrence of Stage 2B or 3C melanoma by 35% compared with placebo. The study continued to collect further data, including distant metastasis-free survival, which is a key secondary endpoint. Now, why are we so excited about these results that we presented?
As you know, distant metastases, especially in the brain, liver, lung or soft tissues can really portend a poor prognosis for patients. This is particularly true in melanoma. Here we were able to demonstrate that Keytruda reduced the risk of these types of recurrences by 36%. At a median follow-up of 27.4 months, we also showed sustained improvement in the primary endpoint of the study, which was recurrence, when compared to placebo. It was exciting to see that the 24-month recurrence-free survival rates were 81.2% for Keytruda and substantially lower for placebo. These data add to the body of evidence that Keytruda works very well as adjuvant therapy for patients with earlier stage melanoma.
It builds on the positive results we've already seen in for Keytruda in earlier stages of cancer, especially those where there's a hope for curative intent. Now we also continued to make progress in earlier stage settings. We all know that patients who are diagnosed early and receive timely treatment are generally more likely to survive and experience improved quality of life. We've successfully shown the efficacy of Keytruda in reducing recurrent disease in certain earlier stage settings, one of which I just mentioned. Now we've expanded our observations with exploratory analyses to fill the details of a bunch of studies that were already reported out, but have real important findings that deepen the understanding of the value of Keytruda in these settings.
For example, on the left, if you take a look at KEYNOTE-522, this is our study of perioperative pembrolizumab in high-risk triple-negative breast cancer. We showed that event-free survival benefit of pembrolizumab may be based on both the preoperative and postoperative anti-tumor effects. This is really important as there's been questions about whether, you know, giving the drug after surgery adds value. I think we're able now to provide data that demonstrate that. The middle is KEYNOTE-564, which showed the efficacy of Keytruda's adjuvant therapy post nephrectomy in certain kinds of renal cell cancer patients.
Here we show the continued benefit of therapy, including benefit with distant metastasis-free survival, the same kind of endpoint that I described for melanoma, where we're looking at really bad things like brain mets and lung mets and so on, as well as the need for second therapy and the time to progression-free survival after that second therapy. That durability of efficacy that we would anticipate with immunotherapy is there, and now we're able to demonstrate that and the study will continue on to evaluate endpoints such as OS. Then on the right, KEYNOTE-091, again, we talked a little bit about that before. This study evaluated the efficacy of Keytruda's adjuvant therapy following resection of certain Stage 1B to 3A non-small cell lung cancer.
We were able to provide further efficacy findings in key subgroups, including those related to surgery, disease burden, the type of adjuvant chemotherapy. All of the results were consistent with respect to disease-free survival at that dual primary endpoint for all comers. We're building a body of evidence in non-small cell lung cancer for the benefit of pembrolizumab here in adjuvant therapy, and I would remind you that there's a further study. As I will look at pembrolizumab as neoadjuvant and adjuvant, and we're excited to share those data when they become available. Finally, one of the things that's we've begun to see is the fruits of a lot of work to rationally design new approaches to investigate the treatment of cancer.
One of these approaches is to explore ways to deepen the immune response to Keytruda through co-formulated combinations with antibodies that target complementary immune pathways. A good example of that is favezelimab, which is our investigational anti-LAG-3 therapy. Here at ASCO, we presented data on two cohorts from the phase 1/2 study that evaluated the safety findings of combining favezelimab with pembrolizumab in patients with relapsed or refractory classical Hodgkin's lymphoma who had not received prior anti-PD-1 therapy, so that was cohort 1. Those who had already progressed despite having therapy with anti-PD-1 drugs. I point out that pembrolizumab has shown great efficacy as in patients with relapsed refractory classical Hodgkin's lymphoma.
In both cohorts in the phase 1/2 we studied, the co-formulated drugs showed manageable safety profile and demonstrated antitumor activity in the two different kinds of patients. Particularly notable in my mind is the efficacy that was observed in those who had already failed single PD-1 therapy, where we had encouraging objective response rates of 30%. Now, finally, we had additional presentations of both Keytruda and Welireg, demonstrating again the efficacy that's been maintained over time in providing durable benefit to patients. We followed up on these studies with phase 3 evaluations, and you can see the three trials that are described here.
For inoperable Stage 3 non-small cell lung cancer, we're conducting KEYLYNK-012 and KeyVibe-006, which follows up on the results here of KEYNOTE-799 in the Stage 3 non-small cell lung cancer. We're looking at our new combinations with KeyVibe-006, evaluating our co-formulated pembrolizumab/vibostolimab therapy. For the first-line HCC, which is in the middle, we continue to see durable antitumor activity for Keytruda based on KEYNOTE-224, and we'll be following that up with other studies, including with Lenvima. For Welireg, we have an extensive program that takes the exciting results in VHL disease-associated RCC and moves that into patients with sporadic renal cell cancer in order to determine whether the drug has efficacy in a broader population of RCC patients. It's a very exciting program going forward.
With that, I'll turn it to Eric. Thanks.
Thanks, Eliav. Before I begin, I wanna take a moment to reflect on the progress that's been made since the first presentation of interim phase I data for Keytruda at ASCO in 2012, 10 years almost to this day. That first poster included just nine patients, and it's been my privilege to have been involved in the development of this medicine and to see the practice-changing impact it's had on cancer. Keytruda has fundamentally changed the way we think about cancer and has set a high bar for ongoing development programs across our oncology pipeline. Our current pipeline today is guided by a deeper understanding of cancer biology and informed by insights from clinical evidence amassed over the past decade through the extensive Keytruda clinical development program.
We have a rich and deep pipeline of assets spanning all stages of development, targeting multiple aspects of cancer biology and immune-based pathways, as well as leveraging new modalities and platforms. Eliav has already mentioned favezelimab, which is one of three ongoing phase III IO/IO programs that we are studying as co-formulations with pembrolizumab. We have now advanced 5 candidates into phase 3 studies largely over the past year, including favezelimab, vibostolimab, quavonlimab, zilovertamab vedotin, which is our anti-ROR1 antibody-drug conjugate, and as Eliav mentioned, Welireg, our HIF-2 alpha inhibitor. Vibostolimab, favezelimab, and quavonlimab were each developed internally by our scientists, and each is being evaluated for its potential to deepen responses that are observed with pembrolizumab and thereby extend benefit to more patients. We also have successfully used business development to secure externally sourced assets that complement and augment our pipeline.
One example is Welireg, the first HIF-2 alpha inhibitor therapy, which received approval in August of 2021, only two years following the acquisition of Peloton Therapeutics. We're also advancing collaborations evaluating novel cell-based therapies as well as T and NK cell engagers with A2, Artiva, Janux, and Dragonfly. At Merck, we follow the science. Taken together, we are advancing a diverse pipeline of candidates that leverage biological insights gained from our deep expertise and large clinical data sets. Now to an area of research that has been in the news recently, our anti-TIGIT program. Vibostolimab is a humanized anti-TIGIT monoclonal antibody that is designed to restore antitumor activity by blocking the TIGIT receptor from binding to its ligands CD112 and CD155, thereby triggering T lymphocyte activation towards tumor cells.
We are developing MK-7684A, which is the co-formulation of vibostolimab and pembrolizumab in a single vial currently delivered through 1 30-minute infusion. Vibostolimab is the only anti-TIGIT medicine that's being evaluated in combination with pembrolizumab in phase III trials and builds upon the high bar set by Keytruda in lung cancer as the only anti-PD-1/PD-L1 therapy to demonstrate an improvement in overall survival in five phase III clinical trials. The encouraging signals we observed in preclinical and early studies with vibostolimab have informed the systematic development strategy for the co-formulation across tumors in eight ongoing studies, including four phase III trials in lung cancer, all of which are designed to provide clear answers to the incremental benefit of the antibody when added to pembrolizumab. Notably, in the KeyVibe-003 study, we're enrolling TPS or PD-L1 TPS greater than 1% patients, not just TPS greater than 50%.
We wish to evaluate the effect size for adding an anti-TIGIT antibody in the TPS greater than 1% as well as the TPS greater than 50% non-small cell lung cancer populations. We've taken a targeted and thoughtful approach in how we proceed with the evaluation of our checkpoint modulators and continue to follow the science to inform which combinations to advance with a focus on areas of high unmet need. Based on the favezelimab data presented during the conference and discussed earlier by Eliav, we plan to initiate a second phase III study of favezelimab in patients with relapsed refractory Hodgkin's lymphoma who have progressed on prior anti-PD-1 therapy. There's currently no standard of care for these patients.
We also have an ongoing phase III study of co-formulation in PD-L1 positive microsatellite stable colorectal cancer, which is an area of significant unmet need as colorectal cancer is the third most common cause of cancer death, and 96% of metastatic colorectal cancer is classified as microsatellite stable. We will continue to leverage insights and clinical learnings across our oncology development program to help inform additional development decisions for the favezelimab and pembrolizumab co-formulation. Based upon the efficacy observed with CTLA-4 targeted therapy as monotherapy in renal cell cancer, our phase III study with our CTLA-4 agent is evaluating quavonlimab as a co-formulation with pembrolizumab plus Lenvima as we look to build on the strong foundation established by Keytruda in combination with Lenvima in the first-line advanced renal carcinoma setting.
Following on from the strong long-term data Eliav described, Welireg is the first HIF-2α to come to market and the first systemic treatment for VHL-associated tumors. It is based on the Nobel Prize-winning science pioneered by Bill Kaelin, Greg Semenza, and Peter Ratcliffe. Building on the establishment of clinical proof of concept in VHL that was central to the FDA approval for Welireg for the treatment of patients with certain VHL-related tumors, we are now evaluating its potential in sporadic renal cell carcinomas. VHL dysregulation and abnormalities are quite common. In fact, a majority of sporadic renal cell cancers have this abnormality. Based upon this, we've extended the program very rapidly through a series of registrational enabling trials into different lines of therapy in the adjuvant setting, as well as either in combination with Keytruda or as a triplet with Lenvima.
We look forward to sharing readouts from these studies as data become available. From the beginning, we approached the evaluation of Keytruda with an open mind, seeking to maximize our understanding of monotherapy across various cancers using precision medicine tools to identify those patients most likely to benefit, while also recognizing that for some patients, a combination approach would likely be needed. Our pursuit of first a biomarker and then a companion diagnostic for the ligand PD-L1, particularly in lung cancer as a means to inform treatment decisions reflects our strong patient focus. This strategy ultimately led us to evaluate novel combinations incorporating chemotherapy and culminated in the practice-changing results from the KEYNOTE-024 and KEYNOTE-189 studies. We've continued to build on this legacy of biomarker-driven development.
Our proven track record of developing precision medicine strategies to inform treatment and enable better outcomes is evident in our 14 biomarker-driven indications and two tissue agnostic approvals, including the first tissue agnostic approval in the field for MSI. We also have the TMB high, tumor mutational burden high, tissue agnostic approval. The development of biomarkers beyond BRCA to predict response to Lynparza also provides a good example of the need to follow the science and further demonstrates our leadership in precision medicine with indications that leverage HRR and HRD biomarkers to identify patients most likely to benefit. More recently, Welireg represents our company's commitment to build out a compelling portfolio of treatment options for patients, many of which are targeted therapies and guided by biomarker measurement.
We're also looking at mutations beyond VHL that we think are important in the HIF-2 alpha pathway to help inform additional patient populations that might benefit. In summary, we are leveraging the immense data and insights gained from Keytruda, Lynparza, and Lenvima to build and advance a growing portfolio of innovative early and late-stage oncology candidates across our pipeline. New technologies and our deeper understanding of cancer biology are fueling innovations in cancer diagnosis and treatment. We routinely conduct next-gen sequencing and RNA sequencing on our database of patient biopsies to better understand resistance and potential new targets. Through our extensive external collaborations network and partnerships, including those involving large and geographically diverse clinical genomic databases, we are accelerating innovations and discoveries that will have a profound effect on the patient outcomes and the treatment of cancer. With that, I will turn it to Jannie to provide a commercial update.
Thank you, Eric, and good morning, everybody. It's good to be with you. Thank you for joining us this morning. I'm excited to highlight how we believe the data and ongoing efforts to address unmet patient needs continues to drive significant commercial opportunity and growth for Merck. This slide is a reminder of our broad oncology portfolio and the progress we have made since ASCO 2021. In particular, since last ASCO, we received FDA approval for WELIREG, a first-in-class HIF-2α inhibitor with strong growth potential. Across the portfolio, we have seen an increase in the number of approved indications, tumor types, and the number of patients treated. Particularly, the number of patients treated exemplifies the impact that we are having on patients with this expansion into tumors and lines of therapy and across the product portfolio.
For Keytruda, we currently have more than 30 U.S. indications, the most of any oncology medicine, which we anticipate doubling in the coming years. Another important Keytruda milestone is that we have reached the 1 millionth commercial patient and are on track to probably reach 2 million patients by the end of 2024. We are creating meaningful impact and transforming the clinical landscape in the earlier stage setting with seven approved indications to date. Last year at ASCO, we only had three approvals in the early stage setting, so four additional ones leading up to this ASCO.
I want to particularly highlight the impact that the KEYNOTE-522 regimen is having for patients with triple negative breast cancer, which as we all know, has the highest risk of recurrence within the first five years after diagnosis and is associated with worse outcomes compared to other forms of breast cancer. Looking ahead, there are important readouts coming up, including three in lung with KEYNOTE-091, KEYNOTE-671, and KEYNOTE-867, and two in head and neck with KEYNOTE-412 and KEYNOTE-698. As we evaluate this horizon, we anticipate the early stage setting to reach roughly 25% of our total Keytruda revenue by 2025. With a wave of new indications in the early stage setting, we realize that approvals alone will not transform patient care.
It requires a concerted effort to ensure we can reach and provide access to eligible patients. To that extent, we are working to ensure the full scale and capabilities of the organization, the commercial organization are meeting the needs of our customers by delivering highly relevant information to them when they need it and in the channel that they prefer. We have learned how important it is to innovate both scientifically and commercially. An example is our ongoing clinical development of a subcutaneous formulation of Keytruda to be of particular importance in the early stage setting and our approach to a digitally enabled commercial model that will continue to support excellent execution and take us into the future. As Eric already provided a nice introduction to Welireg, I wanted to iterate a few key points. Welireg is the first HIF-2α inhibitor to come to market.
It is the first therapy targeting a gene transcription factor which developed on the back of Nobel Prize-winning science, and it's the first systemic treatment for VHL-associated tumors. It is also a treatment, a testament to our successful business development endeavors. In two months, we will hit our one-year anniversary of the Welireg FDA approval. Ongoing execution is progressing well, and adoption of the regimen is increasing steadily across quarters. Unsurprisingly, much of the early usage is in the 40 or so clinical centers of excellence for VHL disease, involving a multidisciplinary team in the U.S. We continue to see significant long-term potential with four phase III trials addressing areas of high unmet patient need, including expanding into advanced RCC across various lines of treatment as both mono and combination offerings.
We believe this medicine has blockbuster potential and are excited about its ability to help patients in need of new treatment options. Our significant investment and broad clinical program in oncology are expected to result in more than 80 potential approvals between now and 2028, and you see that on the left-hand side of the slide, and the different colors depict the different assets for which those indications will be added. As you have heard from Dean, Eliav, and Eric, new tumor types, earlier lines of therapy, including adjuvant and new adjuvant, new mechanisms, combinations, and co-formulations will all be important growth drivers as we aspire to be the world's leading oncology company. On the right-hand side, you can see how our position on oncology overall is forecasted to evolve over the next few years.
I am very confident that our company is on track to become the leading oncology company and to have an enduring and meaningful impact on patients' lives through this decade and beyond.
With that, I hand it over to Dean for the closing remarks.
Thank you, Jannie. I hope this graphic is useful. You know, at Merck, we continue to transform the landscape of cancer therapy. What we have achieved to date, you know, continues to drive us to do more for the patients. Our team conducts a systematic science-led program aimed at harnessing the potential of a wide range of portfolio and pipeline assets. They span internal and external innovation. They span IO mechanisms and targeted cancer mechanisms. They span modalities ranging from small molecules to biologics to cell therapy and everything in between. They span biomarker-driven as well as all-comer strategies. We look forward to providing further updates throughout 2022. I did wanna close. Unfortunately, Roy, because of what we would call travel mayhem, is not with us.
He's on the line, and he probably got wind that we were gonna do this, the travel mayhem and the embarrassment that he sometimes feels when I do this. He is on the line, and I just wanna say a closing thanks to Roy Baynes. Here he is in front of many of the phase three trials that really showed incredible monotherapy and combination survival results that really have reshaped the field of oncology. I need to point out to many different things. I would just also emphasize it's not just Keytruda, Lynparza, Lenvima oncology, it's also things, for example, like GARDASIL.
I know that oftentimes we think of ourselves as a cancer company, but we should recognize that GARDASIL is a vaccine that essentially reduces the rate of HPV driven cancers by 90% or so, which is an incredible tribute to the team, to Roy's team. I sometimes joke that the path of Merck, as Eric has laid out for the last sort of 10 years, have. There's a favorite book that I had my kids read back in the day, which is The Emperor of All Maladies, and essentially you're gonna have to add multiple chapters on the revolution of IO. What I would say is Roy and his team have rewritten those chapters.
I just had this pulled out because, you know, the chapter, when I say rewritten the chapter, this is the Keytruda label. This has fundamentally altered every cancer patient, every cancer training program, every hospital throughout the globe. I just wanna give just enormous credit for Roy, and Roy would want me to emphasize it's not just Roy, it's this remarkable team that you've seen here and the remarkable physicians, organization, the operational organization that has been able to allow us to have this impact. With that, I wanna leave that to have Peter come up here. But before I go, just Roy, I know you're on the line. I won't embarrass you by asking you to say something right now, but I just wanna say on behalf of all of us here, thank you.
I know many of the investors here have come to say goodbye to Roy, but unfortunately, Roy is only available here by signing in, but not in person. Roy, thank you very much.
Okay. Thank you very much, Dean. We're ready to turn it over to Q&A. We have Steve and Dominic have mics. Why don't we start with Steve since Steve was the first one here this morning, and got the front row seat.
Thank you very much. This is Steve Scala from TD Cowen, and let me just say thanks to Roy for all your contributions to patient care. Two questions. First on vibostolimab lung trials, two of the four trials still have PFS endpoints, so I'm wondering how Merck is allocating the output between OS and PFS in those two trials. Why not make the decision now just to drop PFS since it doesn't look like it may get you anywhere? The second question is two trials have shown up on ClinicalTrials.gov in the last month or so for Merck endpoints or Merck targets, which I don't believe the mechanism has ever been revealed. Maybe you could tell us the mechanism.
It's MK-1088 for solid tumors, and it's MK-4334, it happens to be for schizophrenia. Thank you.
Why don't I ask Greg to comment on the vibostolimab, especially in relationship to lung?
Sure. Thank you, Dean. Happy to do that. Keytruda is the backbone of the oncology development program or at least a large portion of it, and we've opted to combine vibostolimab with pembrolizumab, Keytruda, as part of our development plan. It is true that many of our trials employ the strategy of dual primary endpoints, where either PFS or overall survival, if either is positive, then we can declare the study positive. We are reviewing external data related to this pathway as well as looking at our own internal data and applying that appropriately to the design of the clinical studies in question.
Just really quickly, I'd like Eliav to make some comments, and it may be really important to separate the difference between a dual and a co-primary.
Yeah, I think it's important to understand that there are many ways to manage statistics in a clinical trial. In our circumstance, we have one of our secret sauces is our extraordinary biostatistics group that has been able to develop techniques that enable us to apply output to differing in different ways based on emerging data. I think that there are substantive differences in what we've heard, again, we've not seen the primary protocol for other studies compared to our own. In particular, our trials are designed such that one or the other can succeed, not if one is negative, then the other is negative.
We have to be careful about thinking about these trials as individual experiments that have quite different characteristics. The last thing I would point out is that as we mentioned, as Eric mentioned, our trials are actually designed to look at different populations than those of other compounds. Although again, we don't have access to the protocols of other combinations, we're pretty confident that we have a very solid way of looking at the effect of adding vibostolimab to pembrolizumab.
Steve?
The second part of your question, Steve, was.
1088.
MK-1088. Yeah, we might have to get back to you on that. Yeah. Next question. Dana?
Hi. Two questions from me. One on LAG-3 and Hodgkin's. You put up the PD-1 relapsed refractory data, and it was exciting, but the PD-1 naive did not look like it was adding that much over Keytruda. I wonder what it tells you about the mechanism, and if you'll take that into how you develop LAG-3 and other indications. My second question is, you highlighted your selective IL-2, which I noticed is in a new, clinicaltrials.gov, and I wonder if you could tell us how it's selective and anything else about why you're excited about that approach for IL-2.
Why don't I have Greg take the first one, and then Eric, if you could take the second one, that would be great. I think the first question relates to LAG-3, pembro and LAG-3 in hematologic malignancy. I got a question prior to all of this as to what do we see past the indications that we have in relationship to heme malignancies for that compound as well. Greg?
Great. Thank you. It is true, and we are very excited about the data that we saw with the favezelimab combined with pembrolizumab in treating patients with relapsed refractory classical Hodgkin lymphoma. You're absolutely right. The refractory setting, as was mentioned here, we saw a response rate around 30%. These are patients who would have had progression of disease within 12 weeks of their last administration of the checkpoint. Seeing a 30% response rate is very impressive. In terms of the checkpoint naive cohort, there we did see a response rate of around 70%. I will say that this was with a relatively early data cut, and so we are continuing to watch that data mature and see how that evolves.
In addition, though, we are certainly also looking at some other tumor types that have been treated with favezelimab, some non-Hodgkin lymphoma, as well as multiple myeloma. We're waiting to see how those cohorts complete enrollment and seeing how those data mature. That at least handles within favezelimab. Then I'll just briefly mention that within the heme malignancy space, just to demonstrate Merck's commitment to trying to advance care in that area, we also are developing nemtabrutinib, which is our non-covalent reversible Bruton's tyrosine kinase inhibitor, as well as zilovertamab vedotin, which is our ROR1 antibody-drug conjugate.
The nemtabrutinib, now that we've identified a dose, is being explored in a multi-cohort study of a number of diseases that should be sensitive to that mechanism of action. Our zilovertamab vedotin program is opened up initially in diffuse large B-cell lymphoma with a phase II study and a large phase III study, and then it's being explored in a number of other non-Hodgkin lymphomas as well.
Eric, on the cytokines and IL-2 specifically?
Right. Our IL-2 compound is biased towards the beta gamma receptors rather than alpha. This should improve the therapeutic window of IL-2 targeting and allow development of both a monotherapy and in combination with Keytruda.
Great. Next question please. Terence Flynn?
Thanks. Terence Flynn, Morgan Stanley. You touched on this a little bit here, ROR1. You guys obviously have some ADC programs moving along. I think some of the feedback we've heard from physicians at conferences, given some of the maybe less than inspiring IO/IO combo data, maybe ADCs is kind of the way to go, particularly for maybe some other solid tumors. As you guys think about building out your ADC efforts, maybe help us think about how you're thinking about strategically, internally, externally, and where we are in the field. Thank you.
I'll take a first stab at that. Really, that's a good point that you've made, especially in relation to the combination of IO with other, what we would call non-IO mechanisms, whether it be chemotherapy, whether it be ADCs, whether it's with targeted agents, you know, this is something that Merck has had a deep interest in. I would just emphasize, you know, the advancement of chemo, the advancement of lymphoma and lymphomas is along those lines as well. In relation to antibody-drug conjugates, we're very interested in antibody-drug conjugates. We have a series of partnerships. I think this is public. If I'll be corrected later on by Peter, I'm sure. We have partnerships with Gilead, we have partnerships with Daiichi Sankyo, we have partnerships with Seagen.
We clearly have an interesting relationship to VelosBio, and we have other internal and other programs as well. This is a place that we think is really important to keep our attention to. The other point that I would just emphasize is, at least for us, we have a view that the combinability of medicines is really important. That's very important that we're not just interested in the antibody drug conjugate per se, but also what's their ability to combine with standard of care. We happen to have the privilege of having an important standard of care with a PD-1. I think that becomes an important sort of standard for us to think about it.
As there was discussion, I think the ability to sort of define, not from a, you know, academic or theoretical position, but from a real world, how do you actually change the biomarker field that Eric spoke about. We also think that will be critically important as we see that field advance. I hope that's Eliav or Eric or anyone else wanna add anything?
Great. Thanks, Terence. Mohit.
Thank you. Mohit Bansal from B of A. Two questions from my side. One on TIGIT. Looking at your trials, you are including 1%-50% TPS in your trial. Could you talk a little bit about the rationale there? Because it looks like TIGIT seemed to work more better in 50%+, but even that trial did not turn out to be positive for PFS. We'd love to get your thoughts on that. The second question is regarding non-small cell lung cancer. Pretty much everyone is trying to replace chemo in the chemo IO combo with either ADC or TKI. I would love to get your thoughts on everyone thinks that chemo is an easy bar to hit.
Your thoughts on, like, what Merck could do to actually have something in combination with Keytruda there, because you are the mainstay there. Would love to get your thoughts there.
I love that you highlighted that pembro chemo is the standard and is a high bar to lay out for any future combination to address, especially in the first line. I think that's an important point that should sink in, as someone who knows people who have this disease and are faced with those choices. Before I go there, let me just touch really quickly in relationship to the TIGIT sort of question, but I do think you highlight one of the things that I think is important is that our ability, given the broad label, and I don't just mean tumor types, but also the biomarker spectrum, allows us to be able to do certain experiments that potentially can't be done by others if you use a different PD-1.
With that, I just wanna make, Greg, did you wanna make any comments specifically?
Sure, yes. Thank you. So our non-small cell lung cancer program is actually quite broad. We believe in having a broad development program. I'm kind of answering the second one, and we'll go back to the first. There are multiple combinations that we're exploring. I mean, we've demonstrated the benefit of monotherapy, pembrolizumab with survival benefit relative to cytotoxic chemotherapy. Now we've also demonstrated benefit in combination with chemotherapy. We're building upon both the ability to use monotherapy as well as combinations with chemotherapy through a number of different programs. There are combinations with lenvatinib, the multi-targeted tyrosine kinase inhibitor. There are combinations with olaparib, with olaparib being administered in a maintenance setting.
There are, as has been mentioned, collaborations with Daiichi Sankyo using ADCs as well as Gilead. Things are quite broad. In addition, we're always looking for other ways that we can try and develop useful medicines for patients with non-small cell lung cancer. Specifically, and additionally as an area of our growth, we're also exploring the use of Keytruda in combination with vibostolimab as a co-formulation. There are studies without chemotherapy as well as with chemotherapy.
It is true that since pembrolizumab Keytruda does have its label for patients whose tumors have a tumor proportion score of 1% and greater, we are exploring that population in KeyVibe-003, whereas other companies may need to or choosing to explore it at 50% and greater. We're exploring at 1% and greater in that for that trial. Then when we're looking at the co-formulation combination with chemotherapy or in combination with chemotherapy, there it's an all-comers population in keeping with the label for Keytruda.
There's a number of questions on the webcast, and many of them involve TIGIT. I know we addressed it earlier, but I wanna make sure we're getting the full expanse of the question. Luisa Hector takes it up a notch and elevates it. It says, "How have recent competitor data on TIGIT changed your view of your own program?" Mara Goldstein from Mizuho says, "The recent readout of a competitor's anti-TIGIT trials has produced negative results in small cell and non-small cell lung cancer. Can you highlight points of differentiation between your vibostolimab programs, particularly in non-small cell lung cancer, and whether the SKYSCRAPER-02 data in small cell changes your view of that indication?
You know, let me just put out as a broad statement. I think one thing that I think I've emphasized to this community is pembro is different. It has a broad and just such a wide expanse of just in terms of tumor types and its combinability from late to early. When we thought about the IO/IO strategy, whether you're talking about checkpoint inhibitors for T-cells, whether you're talking about checkpoint inhibitors for myeloid cells, when you talk about cytokines, it is our view that those combinations will not necessarily have as broad of a sort of breadth and depth of tempo that pembro has. That it will be a little bit more bespoke and be a little bit more tumor tissue specific. That's why we've invested in a broad portfolio.
That's why there are others who, for example, have thrown totally into TIGIT or have thrown totally into LAG-3, or some have thrown totally into cytokines. We believe that it's very important that we have the availability of many of these compounds, and especially with Eric's group to be able to interrogate in specific patient populations, that becomes important. I just wanna give that as a sort of overview in relationship to that. In relationship to external and internal data, we have our own internal data. There are differences in the molecules. To be very honest with you, at the end of the day, the molecules have to show what they do in clinical trials. We'll see what those readouts are. We are informed by the external landscape quite significantly.
I don't know if Greg or Eliav, you wanted to add anything?
Yeah, just I would just add that, you know, the designs of the clinical trials are not the same across the board, and there's meaningful differences between them in each of the studies in each of the settings. You know, the questions about, for example, the 1%-49% show that in that context, because pembrolizumab is uniquely potent and has that very broad usability and history in that population, we're able to see whether incremental benefits can be observed in a situation where maybe PD-1 levels are not quite as high, PD-L1 levels are not quite as high.
I think that we have a unique capability to interrogate the breadth and depth of the lung cancer field, given the history that we've had with pembrolizumab. You know, obviously the clinical trials have to show us that early data are only indicative or directional or give us some initial impetus to take that forward to phase three. As Dean noted, you know, we'll see what the phase three trials show.
I'm very confident that our trials are designed to investigate this combination in a consistent way across a broad spectrum of diseases based on a very deep knowledge of lung cancer, particularly immunotherapy and lung cancer, that really Greg and his team have been able to provide to us uniquely over the past few years to establish pembrolizumab as the basis for treatment of advanced metastatic lung cancer.
I would just add that our design of KeyVibe-003 is based on our own data, looking at the combination of Keytruda and vibostolimab, where there has been an increase in the response rate for patients from 1%- 100% on the TPS scale.
Great. Chris?
Thank you. Chris Schott from Goldman Sachs. Two questions for Keytruda in the adjuvant lung setting, KEYNOTE-091. Can you provide us an update in the 50% plus in high subgroup, your confidence in terms of any regulatory considerations and dialogue for that ultimate adjuvant indication? Secondly, with the TIGIT program KeyVibe that you outlined here, the phase III studies, quite a few with primary completion dates in the 2025 and beyond period. Can you comment if there's any opportunity for interim analyses or incremental insights prior to that timeframe?
Let me just give it to Greg to just talk briefly about Keytruda lung adjuvant in relationship to KEYNOTE-091. If you don't mind, I'd also, because there's been other questions that come up, I'd love Scot to just talk more broadly about adjuvant and other indications, which we think is critically important. Then we can come back to Eliav about abilities to see interim analysis for some of these trials and what the timing is. Greg, Scot, and then Eliav.
Thank you. KEYNOTE-091 is a study of patients who have non-small cell lung cancer, Stage IB to IIIA. After their tumor has been completely resected, they were randomized to receive either placebo or pembrolizumab as part of their adjuvant treatment regimen. At the second interim analysis for this study, it was identified that there was a 24% reduction in disease-free survival for those patients who had pembrolizumab as part of that adjuvant regimen, relative to those who did not. That was observed irrespective of PD-L1 expression and across all those stages that were included in the study. Therefore, we have great confidence that this pembrolizumab is providing benefit to all the patients who receive it.
In terms of the regulatory question, I'm not able to comment at this time on our regulatory interaction.
Scot, did you wanna talk about this broadly?
No, I think, you know, to try to put KEYNOTE-091 into a little bit broader context, it's important to remember that Keytruda was first approved in an adjuvant setting several years ago now in Stage 3 melanoma. We've really laid out a very careful development program in early disease states across a broad number of malignancies. Eli have very nicely outlined the contribution of data that we had at this particular ASCO, which was demonstrating the distant metastasis-free survival benefit of Keytruda in Stage 2 melanoma, as well as in renal cell carcinoma. We didn't talk at all or talk much about KEYNOTE-522, but that's another example of integrating pembrolizumab into earlier disease states. I think the other important thing is that we have roughly 20 pivotal trials ongoing.
They have around 20,000 patients in them that will further elucidate the value of pembrolizumab in early disease states. It's a really robust program and one that we're quite proud of and quite anxious to see continue to read out as with KEYNOTE-091.
Eliav?
The question had been about readouts. You know, obviously we have a series of interim analyses that we have, but I think it's the base case is that we would have readouts between 2024 and 2026 for many of these studies. We wanna make sure that we have a definitive answer to questions. Obviously, as data progress and if there are events that are meaningful, we would share those as we can. I'd also point out with KEYNOTE-091 that study continues and we'll continue to have further information that will be relevant to treaters and to regulators. We also have our neoadjuvant adjuvant trial, KEYNOTE-671, that will be reading out in due course.
Great. Thank you. Seamus.
Seamus Fernandez, Guggenheim Securities. Just a couple of quick questions. First, can you guys comment on your view on access to AstraZeneca's PARP1? I think some of those data look interesting and there's a little bit of controversy I think around that, whether or not you can access the PARP1 as part of that collaboration. The second question is just as you look across all of the collaborations, research collaborations that you've run, Merck established many times in conversations that you expected to have quite a bit more information to get better access to products on a go-forward basis. I think really the only product where we've seen unique benefit in combination with Keytruda is either chemotherapy or PADCEV.
Just trying to get a better understanding of when you feel we'll start to see emergence of new clinical mechanisms or if chemotherapy really is, you know, whether delivered by an ADC, the ideal combination agent for Keytruda?
Let me take some of those, and then I may send it back down to maybe Eric or Scot as I think through this. In relationship to PARP, I think the PARP story is an important story. We've had a great working relationship with AZ in relationship to it. I would just emphasize, you know, when I think about PARP was their focus on a biomarker specific BRCA, then it got extended to HRD, as Eric highlighted. We are exploring in our clinical trials what is the importance of PARP outside of those biomarkers, and especially in some of the key links that we just discussed. I think that will steer us to how important the combination and how to think about DNA recombination and repair is.
In relationship to our collaboration with AZ, we've had a strong collaboration in PARP. In addition, I think at a later time, we'll have a more fulsome discussion, but we look forward to continuing to work with them on Lynparza and PARP more generally as well. In relationship to your question about combinations, I just wanna sort of yes, it is. You've asked about PARP, you've also talked about chemo, but I just wanna emphasize that, for example, the readouts that we have with, for example, Lenvima, tells you something about maybe what the role is with angiogenesis. I'll just really quickly just ask, for example, Scot and Eric to make comments about that.
When you see wherever angiogenesis has a signal and there's a movement in that, and potentially in relationship to Keytruda, you start asking yourself, what are other modes to affect angiogenesis? I think, for example, Scot can speak about how he thinks about belzutifan as, you know, when you think about HIF-2 alpha or you think about HIF, you often think about angiogenesis. That driving of how you lay out your pipeline, both internally and externally, I think are on display with that. Just quickly, Scot, did you wanna mention anything in relationship to how you think about angiogenesis and Lenvima and how that might inform you about other compounds, for example, belzutifan or something like that, as a way to answer your question?
I think you make a very good point, Dean, that we've had, you know, really, I think, quite tremendous success with the Keytruda plus Lenvima program, you know, renal cell cancer being a great example. Of course, you know, renal cell cancer is sort of the poster child of an angiogenic tumor phenotype where VEGF kinase inhibitors have been sort of the cornerstone of therapy for many years, and they combine very, very well with pembrolizumab. If you think about HIF-2 alpha, it actually sits upstream of VEGF, and so it's sort of logical that that is gonna be critical in particular renal cell cancer, where there's a high rate of VHL loss, even in the sporadic disease setting.
Perhaps even in other tumor types where angiogenesis is a critical component of the tumorigenesis or the tumor progression pathway, and so we're investigating Keytruda, Lenvima, and belzutifan in combinations in certain GI tumors, for example, where angiogenesis is critically important to the pathogenesis of the disease.
You know, I'll just ask Eric to just make comment, especially in relationship to PARP and this concept of biomarkers, BRCA, HRD, HRRm, and also the importance of seeing how combinations can often sort of broaden it even past it in a biomarker-agnostic way. Eric?
Yeah. Maybe I'll just take one step back because I think it's an important question. You know, I think we probably have the broadest combination strategy for Keytruda. In part, this comes from our external collaborations group, where we're partnered with many companies, more than 100 trials involving very diverse mechanisms. I think while we have great basic scientists that have used, for example, post-treatment biopsies in patients who've gotten Keytruda to try to understand mechanisms of resistance and new targets, and those have led to things like our ILT myeloid targeting programs with ILT3 and ILT4. You know, we recognize that sometimes those models aren't all that predictive, and so we again a very diverse combination program that span IO combinations.
Chemotherapy, you mentioned, I think in the early days, people were skeptical whether that would work. In fact, it's quite effective, as you know. We have combinations of personalized cancer vaccines, KRAS, cytokines, very broad. You know, we're seeking to find the most active combinations by really studying them in the clinic in small groups of patients looking for large signals. Yeah, I think in some cases, of course, we, you know, we're always pursuing biomarkers for each of those to try to identify, you know, potential diagnostics that could further increase the effect size for the combinations.
Great. Thanks. We're running a little short on time, but I know I wanna get to as many questions as possible. There's a few more in the webcast, one related to Seamus's question on combos. Chris Schott asks, "Can you talk about the tolerability of your CTLA-4 as we think about the triple combo you are developing in renal with Keytruda and Lenvima?
Combinability and tolerability is always, I think, really important in relation to combo. Eric, is that everyone? And then Scot.
We very carefully developed our anti-CTLA-4 and careful dose finding studies, in particular, looking at the dose in combination with Keytruda. It's clear that for CTLA-4, dose optimization for monotherapy in combinations with anti-PD-1s is different. We have a dose that's 25 milligrams is our recommended dose, and it combines well with Keytruda, with a safety profile that's perhaps better than observed in other combinations where the dose is higher. It does lead to a tolerable combination as well with triplets such as with Lenvima.
Scot.
Yeah, I was just gonna add that, you know, we've got the triple combo in one phase three study in renal cell cancer as well as in an open label study in hepatocellular. I would say that the tolerability of the triplet is unlikely to be a concern or a problem at this point. It's
I just wanted to.
Go ahead.
Yeah. Emphasize the point that Eric and Scot made about specific programs, but this issue of combinability, I think is really important. It's something that we take seriously, both in the design of the molecules and the preclinical development and clearly the clinical. That's true in relationship to what the question was specifically with IO/IO. But I would also emphasize the same thing will be true for chemo, for antibody drug conjugates. I would also emphasize that for RAS inhibitors will be very important in relationship to that. Again, we've talked about CAR-Ts and such. I do think, you know, oncology is a place where there's lots of combinations and sequencing, and those considerations will be really important.
Another combo question. Tim Anderson from Wolfe. Can you talk about whether it is better to give LAG-3 and PD-1 as a bispecific like Roche is doing? Roche claims it is more targeted that way with less immunosuppression. What are Merck's thoughts on their early data?
You know, I will let Eric answer this one because there's always this question of how you think about putting a bispecific and what a bispecific does versus having two things added together. There's a complexity in relationship to PK/PD, but there's also a basic biology question that comes with that. Did you wanna-
Yeah. Again, I think it really has to test in the clinic, right? You know, we have clinical data with our LAG-3 combination that looks impressive and sufficiently impressive that we've taken it to phase III in both microsatellite stable colon cancer as well as PD-1 progressed lymphoma. Again, you know, the data sort of speak for themselves.
Great. Maybe final question. I see one last hand up in the auditorium here.
Thanks, Peter. Evan Seigerman from BMO. Sorry for my voice, it's allergies, not COVID. I wanted to touch on MK-1084, your KRAS G12C. Can you discuss or provide some color as to what differentiates this asset from Sotorasib and Adagrasib, where we've gotten lots of data at recent medical meetings, including this one? Just given your phase I trial design, how could you potentially accelerate development of this asset to, say, catch up to Sotorasib or Adagrasib?
Eric, did you wanna take a sh-
Yeah.
Take a shot at that, and then I can answer some questions.
Yeah, I think, you know, we've designed a very potent molecule that we do think has the potential to differentiate. Of course, again, we've got Keytruda as the backbone and, you know, I think. We have a lot of experience in designing efficient phase one clinical trials, and so we're working to quickly get to a dose as both a monotherapy and a combination with Keytruda in that study.
Yeah, I mean, just from a you know, broader sort of standpoint, I think when you have a covalent inhibitor, which is essentially a reactive molecule, having a potent molecule so that you don't have to put a whole bunch of that molecule in, will create the theoretical possibility of you being able to dose it with not as much potential off target. It may be really important in combinations. If you have a program where you don't have to reduce the dose of what you saw in monotherapy in combination, that would be really important. Those are the sort of, you know. That's. I come from the discovery end where we think about that, but having said that, at the end of the day, you have to play it out.
The other sort of thing is I would just emphasize the gain is initially G12C, but let's all recognize there are other ways to do it. There's also G12D. There's other mutations that will be really important. There is the possibility of thinking about from a pan-KRAS standpoint, how to address that. There's a lot of opportunity there, as well as combinations, not just in relationship to a PD-1 or something like this, but also other pathways. You know, some people talk in terms of shift, some people talk about that. We think it's a great advancement since that 2013 paper. But I think there's a lot of game to play in relationship to KRAS and RAS more generally moving forward.
Great. Thank you, Evan. Thank you all for coming out early on Tuesday of ASCO. We appreciate your live attendance, and thank you to all that tuned in via the webcast. Apologies to those of you that I didn't get to your questions. Please follow up with IR, and we'll try to get responses to you. We look forward to staying in touch. Dean, any final comments?
No, I would just the final comment is we're so happy to meet in person. I hope this was a useful update of looking at it, you know, a year ago, where we were, where we are now, and we hope to continue to do this in the future. I think you've also seen, you know, that the ability for us to really make this impact on oncology is a legacy of great leadership that is laid out here, but a great leadership that was laid out here that was trained and mentored by Roy Baynes, who is online as well, and someone that I know that many of us and many of you had wished was here to offer thanks for what he has done for the field. Thank you very much.
Great. Thank you.