Amgen Inc. (AMGN) Earnings Call Transcript & Summary

Good afternoon. My name is Sarah, and I will be your conference facilitator today for Amgen's post-ASH 2020 Annual Meeting Conference Call. [Operator Instructions] I would now like to introduce Arvind Sood, Vice President of Investor Relations. Mr. Sood, you may begin.

Okay. Great. Thank you, Sarah, and good afternoon, everybody. Thanks for joining us today for this post-ASH update. Looking forward to our discussion. So among the data presentations we made during the scientific sessions, we presented a Phase I first-in-human study of AMG 701, which, as you know, is an extended half-life BiTE targeting BCMA in relapsed/refractory multiple myeloma. We also felt that this is a good opportunity to discuss our broader hematology/oncology strategy, including our broader BiTE portfolio, including AMG 160, targeting PSMA in prostate cancer and AMG 757, targeting DLL3 in lung cancer. We have posted some slides on our website to guide this discussion. And also joining me today are Dr. David Reese, our Executive VP of R&D; and also Dr. Greg Friberg, our Vice President of Global Development and our Oncology Therapeutic Area Head. Dave will make some introductory comments, followed by a brief presentation by Greg. After which, we'll be happy to address any questions you might have. Dave?

Thanks, Arvind, and good afternoon, everyone. Thanks for joining us here at the conclusion of the ASH conference and as we wind down what's been the extraordinary year of 2020. For those of you following along the presentation deck, if you want to move to Slide 5, I'd like to just open the remarks by reminding everyone that we're quite pleased with our oncology portfolio right now. The majority of our molecules are first-in-class. That's always our aspiration. We are developing multiple molecules that can be used in monotherapy, but also sequentially or in combinations, and our goal is really to achieve a significant effect size. The portfolio is built around sotorasib in lung cancer, and more on that in just a moment as well as our BiTE platform. A little later, Greg is going to give you a perspective on where we are in the BiTE platform with both solid tumors and put into context the AMG 701 BCMA data that we presented here at the ASH meeting. I think, in 2020, we feel that we have demonstrated proof of principle with the half-life extended BiTE platform. We're very happy with where we are in the performance of these molecules. And again, Greg will be saying a little bit more about that. And of course, we'll be happy to take your questions. Turning to Slide 6. I just want to provide an update on sotorasib or AMG 510, our first-in-class KRAS G12C inhibitor. This is a once-daily oral drug. Of course, we have now treated more than 600 patients across 4 continents with, we believe, the largest data set in the field in a global program. We're very happy with where we are in lung cancer. Extremely pleased with the data you're seeing there, where we've demonstrated objective responses across a broad range of mutational profiles and subgroups of patients, such as those with brain metastases. We'll be providing updated data at a scientific congress in January on this, including updated biomarker data that will help guide therapy. We're also increasingly confident that we have a best-in-class tolerability profile with a low rate of dose reductions and discontinuations. To date, we observed no treatment-related deaths in the program, nor have we observed QTc prolongation or significant GI toxicity. So very, very pleased with the tolerability profile. If you turn to Slide 7, you can see an overview of the program. I'd like to call out just a few things here. On the top line, you see our monotherapy Phase III head-to-head trial against docetaxel. I'd like to reinforce that, that is now up enrolling globally. That will be an important trial for access and reimbursement in many jurisdictions in the world, and we're quite keen on driving that program to completion. And then I'd also like to highlight the CodeBreaK 101 study in the middle of the slide. We now have 9 combinations enrolling. As you can see, more will be opened in the not-too-distant future. And this really is built around combinations that have both a biologic as well as a clinical rationale that can be tailored to different indications. And as we've indicated previously, we expect to see first data from many of these combinations over the course of the first half of 2021 or so. And then finally, I wanted to conclude on Slide 8 my portion of the presentation by giving you a brief regulatory update. Many of you will have seen a release we issued earlier today, but we're very pleased to announce that sotorasib has been granted Breakthrough Therapy Designation by the FDA. You can see on the slide, for those following along, the indication statement, which is for the treatment of patients with locally advanced or metastatic non-small cell lung cancer with the KRAS G12C mutation as determined by an FDA-approved test, following at least one prior systemic therapy. Breakthrough Therapy Designation is designed to expedite both the development and regulatory review of promising drugs. It makes a drug eligible for all Fast Track designation features, and we are quite pleased with this action on the part of the agency. In addition, we'd like to report that sotorasib has been accepted into the Real-Time Oncology Review pilot program. And in fact, we have already initiated transference of files to the FDA as part of the package. We expect to complete the submission, the entire submission within the next few weeks or so, certainly by year-end, and we'll look forward to the FDA's review. So this program is just over 2 years old, and we anticipate completing filing again in a couple of weeks and are quite pleased with where we are. And of course, I'll be happy later on to take any questions about that. But now I'd like to turn things over to Greg, who will provide an update on the rest of the portfolio, and in particular, where we feel we stand with some of our important BiTE programs. Greg?

Thanks, Dave. If we could move ahead to Slide 10. I just want to ground people in the menu of molecules that, of course, sit in our oncology pipeline. As Dave mentioned, sotorasib is listed here. And of course, we can answer questions there. This was a program that we presented updated lung cancer data from our Phase I at ESMO this year as well as there was a publication around the same time in The New England Journal of Medicine from our entire Phase I experience. And we will be updating our Phase II data at the World Conference on Lung Cancer in January. When one looks at the rest of the oncology portfolio, it falls into a couple of bins. Certainly, one can look at the solid and the hematologic malignancy aspect of this, but you can also look at it by modality. As you see again, we have quite an investment in BiTEs across prostate and lung cancer. We're going to talk about those a little bit more today. And we have additional targets in the solid tumor space with gastric and glioblastoma as well. Not to be forgotten, we have the first approved oncolytic virus in IMLYGIC. And we'll be turning over cards, hopefully, in 2021 for our ongoing Phase III study in combination with pembrolizumab. Focusing on hematologic malignancies. Today, we're going to speak about the BCMA BiTE, AMG 701. This is our half-life extended BCMA BiTE. And we'll focus a little bit on BLINCYTO as well. Over 5 years in the clinic as the first CD3 bispecific, the first BiTE that's approved. And certainly, we've learned quite a bit from BLINCYTO as time has gone on. We won't be touching on the AML portfolio today, though we did give an update as recently as ASCO. Moving on to the next slide. I just want to summarize, from the BiTE portfolio, we've treated over 3,000 patients to date with this portfolio. We've certainly learned quite a bit. We have industrialized this platform to the point where, from the standpoint of end-to-end, not only for discovery and research grade molecules, but from a manufacturing standpoint, we're able to bring these fairly rapidly into the clinic and test for proof of concept. These, of course, are incredibly potent molecules, probably 5 to 10x the potency that we've seen with some of the other platforms in the field. And we think that this will ultimately pay off on the manufacturing side as well. I'll just add that, and this is now past history from a few months ago, but we do have demonstrated activity both the liquid and the solid tumors. We're going to dive into that a little bit more. And as you'll see, BLINCYTO has taught us, of course, that these drugs are not just single agents. It's nice to see single-agent activity. But perhaps the most effective way to deploy them maybe in logical combinations and in sequential use. We'll come back to that idea, but ultimately deploying these into the disease states that we're treating will be more than these first chapters that we're going to talk about today. If one moves to Slide 12, I'll just very briefly remind you that when we talk about the BiTEs, the bispecific T-cell engagers, we're talking about the CD3 bispecifics. Variable regions from 2 antibodies are taken, one targeting CD3 on the T cells, one targeting a tumor-selective antigen of choice. And of course, BLINCYTO is the prototype. BLINCYTO was the first generation molecule. And as we'll go through, we've evolved this platform to now include half-life extended molecules, and I'll highlight those as we go through. Moving on, if we can skip ahead 2 slides to Slide 14. We're going to focus a bit on the prostate cancer portfolio. This is data that was presented again several months back. I don't need to probably tell this audience, prostate cancer is still a highly prevalent disease across the globe, over 1 million diagnoses each year. And sadly, despite the advances with anti-hormonal therapies, which have been truly revolutionary in the last decade, about 1/3 of patients will still develop metastases within 2 years. And of course, when they do, their 5-year survival rate is well under 50%. If we focus on Slide 15, just to review the data that was presented this year at ESMO by Dr. Tran. AMG 160 is our PSMA-targeting half-life extended BiTE, and we presented data from the first 43 patients that were treated on the Phase I study. As a quick reminder, these patients were fairly heavily pretreated. Most of them were on the order of fifth line therapy. And even across various dose levels, we saw an active drug that had about a 70% rate of PSA responses, and about half of those were so-called PSA50 significant reductions. And of course, we saw in those patients that did have RECIST measurable disease, we saw tumor shrinkage as well. The update for you here and building on what we said at ESMO, we, of course, reported our CRS profile was both reversible and manageable at that time. We walked through some of the learnings that we had, had, including using what we call our priming doses as well as dexamethasone and IV hydration. We still have seen no grade 5 treatment-related adverse events or treatment-related discontinuations to this date. And with our additional work, we've seen, as we had alluded to then, we've continued to see an improved CRS profile. We've also seen reduced antidrug antibody formation with some of this optimization work. And we're feeling confident enough right now that this program has moved into its dose expansion cohort. So again, feeling quite good about what we've seen with the profile, and we'll look forward to presenting additional data for this additional work in the coming year. If we move on to Slide 16, I just want to briefly highlight that we don't view prostate cancer as a single drug, single disease space. There is a portfolio of assets that we're developing here. And a drug called AMG 509 is targeting STEAP1. We presented this data from the preclinical package at AACR this year. This is a target that increases in its expression as tumors become more advanced, particularly in metastatic lesions. And there is a Phase I study that is currently enrolling patients using this XmAb platform. Shifting gears a little bit to small cell lung cancer and so-called AMG 757, if we move to Slide 18. Again, just very briefly, small cell lung cancer represents about 1 in 8 lung cancers across the globe. And of course, chemotherapy remains the backbone of treatment for this disease. It really has for multiple decades now. And this is the case, like prostate cancer, where immunotherapies really have shown limited benefit to date. Of course, PD-L1 and PD-1 therapies are part of the standard treatment regimens, but the survival still remains quite dismal in this disease. This particular half-life extended BiTE targets the delta-like ligand 3, DLL3, highly upregulated on neuroendocrine tissues, including small cell lung cancer. And 757 represents a half-life extended BiTE that, again, is looking forward to take advantage of this T cell activation, T cell killing phenomena. Moving on to Slide 19. We just summarized very quickly the data that was presented this year at SITC. We presented the poster in an oral presentation there. And just very high level, the first 40 patients that were treated on this Phase I, 38 of them had scans, and we had already seen 6 partial responses. So this is an incredibly proliferative disease. These patients sadly often don't live into their third and fourth lines of therapy. Most of these patients have had 2 prior therapies, and we were pleased to see 6 partial responses. Interestingly, those responses also seem to follow a dose-response relationship. 5 of them had occurred at the higher dose levels. And 5 of the 6 total responders were still receiving therapy at the time that the data snapshot happened. You see some of the other tales of the tape there, including there being, in addition to the confirmed RECIST responses, disease control rate at that first scan of about 45%. So quite early, but nonetheless, we're quite pleased to see this kind of activity in a disease that really doesn't respond to single-agent immunotherapies all that broadly. The AE profile was manageable. We saw cytokine release in 45% of patients. But again, details are important when we talk about cytokine release. And so in that regard, most of these, more than half of them were grade 1, and we didn't see any grade 3 toxicities. Most of these were fever, decreased blood pressure, some nausea in there as well. So we're continuing to do work with the profile on this molecule. We haven't reached an MTD. We're continuing to escalate. And that dose optimization, we're looking forward again to being able to present additional data in the coming year. So I'm going to shift gears to discuss AMG 701 that was presented at ASH this year. AMG 701, on Slide 21, is our half-life extended anti-BCMA BiTE. And this is the first presentation of this half-life extended molecule. We foreshadowed some of this with a predecessor molecule in previous presentations. But this is the presentation of the first 85 patients treated on this Phase I study. If you move to Slide 21, you can see that Dr. Harrison, again, was the lead investigator and was able to present this data just a few days ago at the ASH virtual congress. Moving on to Slide 22. We have a summary of the data that was presented, as I mentioned, 85 patients. They were treated at a variety of target doses across about 15 different cohorts. These were heavily pretreated patients, 6 median prior therapies. And what we saw was, first and foremost, an active drug and a manageable safety profile. This was a drug where we saw across all of the cohorts, we saw some cytokine release syndrome, but only about 9% of those reached grade 3. As I mentioned, cytokine release needs to be -- the details need to be discussed when we talk about it. And these were mostly grade 3 because of LFT abnormalities, though there were some hypoxia cases as well. Good news is that those seem to be well manageable and none of these patients needed to come off therapy for those. Interestingly as well, we saw that there was encouraging signs of single-agent activity across the entire cohorts. We, again, had 2 factors that we were continuing to optimize. One was the target dose and the other was how one gets there. So we call that the step-up or the dose density. And what we presented was the most recent cohort. There were 6 patients treated, 83% overall response rate, including about half of those were quite deep responses. We've received some questions, what was the exact dose there. These were patients treated at a 9-milligram target dose with a dose dense step up. And we've continued, again, to escalate and do additional refinement. We're hopeful that, again, this will foreshadow good things to come. So the last factor I would just highlight here is, if you look across the whole program, those patients that reach a very nice stringent complete response, patients can be tested for MRD negativity. And we saw that 6 out of 7 patients actually did have quite significant and deep responses. So we've seen a predictable PK profile. It's supportive of once-weekly dosing. We've also not seen any problems with antidrug antibodies. I know that, that's been a question that's come up. We've seen a handful of them, but none of them have been neutralizing or affecting PK. So this is a nonissue with our B-cell targeting BiTE therapies. And we're continuing to do dose optimization with this program, hopeful, again, that both from a safety as well as an efficacy standpoint, we can continue to optimize the profile here, and that includes testing subcutaneous delivery. If we move on to the next slide, I just want to wrap up by taking us back to really the first molecule, BLINCYTO. And we presented some data that we're quite proud of for acute lymphoblastic leukemia. If you move on to Slide 24, you see the presentation that was done here. Over 100 patients with pediatric ALL. As many of you know, pediatric ALL is a disease that, thankfully, chemotherapy cures, about 80%, 85% of those patients, but these are the patients who were not so fortunate. These are the patients whose disease was chemotherapy refractory. And of course, salvage therapies involve intensive chemotherapy. This particular study attempted to insert BLINCYTO, an orthogonal therapy, non-chemotherapy, again, using the immune system into that regimen with one of the single blocks exchanging for chemotherapy and asking, do you get better outcomes in these highly refractory patients. And what we found, if you move to Slide 25, was indeed a single cycle of BLINCYTO popped into that regimen improved event-free survival, see the hazard ratio, 0.33, improved MRD remissions, almost doubling the MRD negativity that was seen in those patients. And of course, because it's an orthogonal therapy, again, you see the theme here, while there is a different sort of side-effect profile. We saw some neurologic toxicity. I believe it was 6% with BLINCYTO, 2% with chemotherapy. We saw much less toxicity in general. And this is a theme, of course, we're thrilled to see this. We're thrilled to see an improvement in overall survival, at least trend initiating there. The investigators have called this really a potential new standard of care for treatment of first relapse ALL in children. But it also is a good case example of how one can deploy these T cell engaging therapies into a group of patients who might not be well served by chemotherapy, by standard therapies and hopefully achieve great things. So we're hoping again that this will be the prototype for us. And using these arrows that we now have in our quiver that these BiTEs may be able to be deployed into other complex regimen. So shifting forward, I'm going to hand it back to Dave, and I believe we're going to move into the question and answer. Thank you for your time today.

Thanks, Greg, and thank you, everyone, again. Sarah, why don't we go ahead and open up the line for questions.

[Operator Instructions] Our first question comes from the line of Mohit Bansal with Citigroup.

Congrats on all the progress. Maybe talking about sotorasib a little bit. So you will have data from many of these cohorts you are running trials on in combination. Could we be looking at one of those trials moving into pivotal next year itself or do you think it will take more time for that?

Yes. Thanks, Mohit. That's a great question. And one thing we should point out is that the CodeBreaK 101 study is designed in a way that each of those arms can very quickly expand into what is, in essence, a Phase II trial. And if given the clinical setting, if it were appropriate to think about registration of the combination based on those data, of course, that is something that we would consider and discuss with regulators. So it's got a very nice adaptive design that allows us to move seamlessly into very large expansion cohorts that are essentially the equivalent of a Phase II study. We can also add and drop arms based on emerging data. So I think that's going to be a very powerful engine to take the combination program forward. Thank you.

Our next question comes from the line of Terence Flynn with Goldman Sachs.

I was just wondering, Dave, given the data you're seeing in solid tumors thus far in prostate and small cell, is the level of efficacy high enough there to go forward with monotherapy or do you think you have to further optimize that? And what steps could you possibly take there? And then maybe can you just remind us, over the weekend at ASH, we did see some data on formulation, where it looks like subcu is able to also help with the CRS. So just remind us for each of your half-life extended BiTEs, are all those subcu formulation or do you have a path to get to subcu?

Yes. Thanks, Terence, and very good questions. Our sense is that in the prostate cancer and small cell lung cancer, solid tumor BiTEs, given the efficacy that we're seeing and as we move forward with target doses, that's potentially sufficient as monotherapy. We are also exploring, for example, combinations with checkpoint inhibitors. And these tumors are largely refractory in the monotherapy setting to checkpoint inhibitors. The question is whether with the sort of immunologic activation that you get with the BiTE, can you also then get a synergistic effect with checkpoint inhibitors. So that's something we're interested in exploring as well. But there may well be a monotherapy path forward there. I will mention on AMG 701, in regards to your second question, that we are exploring a subcu formulation. The investment decision, that will be made program by program, target by target based on the setting. The overall goal here is to drive these towards being convenient regimens that are largely administered in an outpatient setting, so that they're off-the-shelf and can be largely, if not wholly, administered in an outpatient setting. And so more on that to come. But certainly, subcu approaches are something on our radar and being investigated.

Our next question comes from the line of Michael Yee with Jefferies.

Following up on the sotorasib question. If you take a step back, Dave, I know there's a lot of enthusiasm for the combos that are going on, and you laid out the 9 arms. Could you just maybe comment about, specifically on lung cancer, what do you need to see? What is a good result to say, yes, that combo is definitely better than monotherapy. And is that response rates that are higher than 35%? How do you think about things in Phase I to say, yes, that looks really exciting because you already just made a comment about adapting to pivotal. So maybe just kind of tie those 2 things together for me.

Yes. That's a great question, Mike. And I think, look, you want to see relative increments of 20% to 30%, I think, in most settings that we would be talking about where sotorasib, AMG 510, would be relevant. But the response rate is one metric. And then the question would be, do some of the combinations perhaps enhance response rates somewhat, but lead to greater duration of response or greater progression-free survival? So we'll be looking at all of those outcome measures as we think about which ones to take forward.

Our next question comes from the line of Yaron Werber with Cowen.

This is Leo on for Yaron. I was wondering about for the ASH data for AMG 701, it was helpful that you mentioned that the most recent evaluable cohort was targeting 9-milligram. In the same kind of overall response rate chart there, there are some patients that look like they were either at the 12- or the 18-milligram dosage. I was wondering if you could provide any more color on how some of that data is looking. I assume you have some evaluable patients at that dose. And do you expect the upside to continue to go up now that you've passed the 9-milligram, which seems to have made a difference?

Yes. And a great question, Yaron, and I'll ask Greg to comment more fulsomely here in a moment. But I would point out that in the 12- and 18-milligram cohorts, those were cohorts that we were dosing a little earlier that didn't have the sort of step dosing or dose intensity over the first week or so. So it's a little hard to do apples-to-apples. And as Greg mentioned in his presentation, we're quite pleased with what we saw in the later cohorts with the sort of dose intensity upfront, both from an efficacy as well as a safety perspective on CRS. I'm absolutely convinced that we can get and they were very, very close to actually having the clinical profile that we want with AMG 701. And then it's just a matter of determining as we go forward where this best fits in the treatment landscape, and we'll be providing our thoughts and guidance on that as we move forward. Let me just ask, Greg, if you want to add anything to that explanation around the dose cohorts?

No, Dave. I think you've covered very nicely that there's 2 issues. One is, of course, the target dose and the other is how you get there. And they're intimately linked, of course. And so as we progressed to the more dose dense step up, we're hopeful, again, that we can get a handle on the side-effect profile that, again, we'll have this in a space that it's tolerable for patients. And we have seen that the target dose is an important factor for the efficacy as well. The numbers are small. It's hard to say much more. But I would say that each step along the way actually has allowed us progress in both dimensions, both from a safety as well as an efficacy standpoint.

Our next question comes from the line of Evan Seigerman with Crédit Suisse.

Kind of a follow up to the last question. So given the numerous BCMA targeting assets we saw at the meeting, bispecific, CAR-Ts, how do you think 701 fits into this crowding space? And where do you think it will be used if eventually approved?

Yes. Great, Evan. Thank you. And it's a great question. Of course, there are numerous BCMA targeting molecules now in the world, ranging from our BiTEs, other bispecifics, CAR-Ts, antibody drug conjugates. Our belief continues to be that the different modalities are all going to be used as they always are in oncology. They will find a home. And as I just mentioned, for AMG 701, we want to find a spot where we think we can really make a meaningful difference for patients and for physicians. Uncertain we'll get a clinical profile that's consistent with that. And certainly, over time and not much time, would want to move towards earlier lines of therapy. We can take probably a lesson from BLINCYTO here, which had the first approval based on MRD status. And one can imagine AMG 701, for example, in earlier lines of therapy, after induction, where the goal would really be to try to eradicate the disease. And so these are all the sorts of things that we are thinking about and planning for in the development program as we move forward, and we'll talk more about that as we go along. But as you mentioned, look, it's an incredibly crowded space, no one can deny that. If you were conscious at ASH, it was clearly the year of BCMA. And so we'll find the right spot here.

Our next question comes from the line of Geoff Meacham with Bank of America.

Just had a few for Dave or for Greg on 701. On efficacy, was there any patterns in the responding patients really at any dose that you think could help inform the Phase III design? Just kind of looking for maybe biomarkers or speed of MRD negativity. And then on the topic, just to your last response, to move upstream, I think MRD negativity is going to have to be pretty important. Is FDA still a big TBD when allowing that as an approval endpoint or a surrogate endpoint?

Yes. Maybe I'll address the last part of your question there, Geoff. And then pass it over to Greg, who can talk about patterns of response. I think we have a few insights there. In terms of the FDA, there's more than one effort ongoing right now. And I'm, I would say, optimistic that there will be a pathway to incorporate MRD data into the regulatory approval process in multiple myeloma. And I think that's going to be important for the field because, for example, in first-line myeloma now to conduct a formal overall survival trial would take perhaps a decade or more using the formal hard endpoint, and that's going to slow drug development to a trickle in that setting if we can't think about surrogates such as MRD. So we are engaged with industry partners and discussions with academia and with regulators on really defining in a scientifically rigorous way what a pathway forward here is and have had very positive interactions with some, not only those entities, but a number of the foundations that are sponsoring efforts in this regard. So I think more to come there. But I think the field is getting ready to move, and we're amassing the sorts of data sets that are going to allow this to happen. Greg, do you want to talk a bit about Geoff's question around patterns of response, predictors?

Yes. And I would just say that, thankfully, actually, there's a nice figure in the presentation, Geoff, from ASH, where we took the 21 responders and actually mapped out sort of the timing of how those patients progressed through time. And I think, again, there's 2 moving targets as we've been evolving the cohorts. Of course, there's the target dose. And then there, again, is the step-up, this regimen of how one gets there. And both are important. And I think the the overarching trend is, at the very low doses, we saw that perhaps they were slower to get to the depth that it's been much swifter as we've progressed the way that we've been dosing the drug and gotten to the target levels that we think are important. Now I don't want to overread this, of course. These are heavily pretreated patients. They are incredibly heterogeneous with regard to their number of prior therapies. What we haven't seen is any pattern that precludes responsiveness, for example, patients with prior transplant aren't precluded from responsiveness here. But clearly, moving forward, we're going to want to once we've reached the optimized way of giving the drug, we're going to want to ask that question and deploy this drug into a place that we think it offers the most value.

Our next question comes from the line of Jay Olson with Oppenheimer.

Congrats on getting the breakthrough designation for sotorasib. On 701, I think you said you saw up to 26 months of durability. Was that the duration of response in the MRD-negative patients? And then just in terms of the target clinical profile, it sounds like you're getting close. So I was wondering what is the remaining dose optimization work that you have left to do. And then I know it's early, but maybe if you could compare 701 to some of the other CD3, BCMA bispecifics, like, for example, Regeneron's?

Yes. Thanks, Jay. Let me address the last part, and then I'll have Greg talk about durability. We're moving very quickly on dose optimization. I think we're going to be there very soon. And then the question will be, again, defining an appropriate path forward. And so we'll share more information into the first part of next year as those plans develop. The durability question, I think, is a very good one. We're quite pleased with what we're seeing in patients who are developing the sorts of deep responses that Greg described. Greg, let me ask you to add a little more color around that.

Yes. Of course, these are Phase I studies. They're like relay races. And the longest follow-up that we have around the patients that are on the lowest doses. That being said, the median duration of response hadn't been reached. There's, again, a very nice figure in the presentation from ASH, and responses were ongoing. Of those 21 patients, they were ongoing in 17 of the 21 patients when last assessed. I would add as well that, again, this is the kind of data that we're going to continue to follow very closely. And we certainly expect that depth of response is something that we'll track with durability of response. So we look forward to being able to update that when the patients have reached the sufficient milestones.

Our next question comes from the line of Umer Raffat with Evercore ISI.

This is Bo for Umer. So on the AMG 701 data, could you remind us what's the CRS and the timing and whether it will allow use in the outpatient setting? And a related question is, how important is the outpatient use for the potential commercial uptake of BiTEs in various solid and liquid tumor settings? And maybe you could speak to your commercial experience with BLINCYTO.

Yes, let me address the latter. I think the question about outpatient administration, as I said, that's our aspiration for almost all these programs for the vast majority, if not all, of the doses. And we'll continue to provide updates there. Certainly, I think, we think that will be important in the marketplace in terms of commercialization, and that's something that we're really building in as a goal in each and every program. Greg, let me ask you to briefly talk about CRS again.

Yes. I would just add that like with the predecessor molecules, like BLINCYTO, CRS is a phenomena that we typically see when the patients first start their therapy. So within particularly the first 2 days is an area that we are following patients very closely. It's not exclusively in that time. Any time that we see a step-up of dose or additional dosing, there's the possibility, but a great majority of these are first cycle phenomena. I would just add as well as the question about outpatient, our goal is to optimize this therapy and have this be something that's convenient not only for patients, but for society to administer, and the goal is to be able to have outpatient therapy. So we'll continue to work on that. And what I would add is, we've been quite pleased by the steps we've taken recently, both with regard to the step dosing as well as additional mitigation factors. It's probably worth noting that we're in the luxurious position of testing various mitigation factors across the different BiTE molecules, learning from them and having them help inform one another. Of course, not all CRS is the same. This CRS, in particular, a lot of these grade 3s are driven by asymptomatic LFT abnormalities. And that's something very different than hypoxia or low blood pressure. And so details are important, but we feel confident that we're making progress, and we're going to continue to work towards having this as an outpatient therapy for patients.

Our next question comes from the line of Robyn Karnauskas with Truist.

I guess I won't ask another CRS question on BCMA. But big picture, I think we're coming out of this meeting feeling like people have got a lot of proof-of-concept data, and we're trying to compare how these different reagents, what their efficacy is and their safety. But we're also seeing how different companies are doing combos, and that was brought up earlier. Maybe talk about strategy-wise, like how you're going to remain competitive with other people who are trying different strategies and different combinations? What differentiates your program and your strategy versus you think your competitors in the BCMA space as well as the AML and ALL space?

Yes. Thanks, Robyn. It's a very good question. And I would broaden it beyond hematologic malignancies to solid tumors. The solid tumor programs that we discussed today, we're in the lead. We plan on staying in the lead. And as I mentioned, we're already starting to investigate combinations, for example, combination immunotherapy. That approach in any disease is going to be dictated by the underlying biology and what combinations make the most sense. Let me ask Greg to provide a little bit more in terms of specifics. But I think the take-home message here is, this is really a tailored approach in each setting.

Yes, Dave, I would just reiterate, again, we want to follow the biology. And in certain settings, there are combinations that, from a preclinical standpoint, will make more sense. But I don't want to lose this thread of logical sequences. Again, in the leukemia world, they're familiar with these modules of therapy. And again, BLINCYTO has given us a good example of what one can accomplish if you layer in an orthogonal approach, a new arrow in the quiver into the treatment regimen. Now each disease, of course, will have its own baseline therapies. There will be practical considerations that we'll want to put forward. But right now, we have these monotherapy data that looking at least encouraging. And from that standpoint, we don't anticipate that the end of the line is the place that these will do their best lifting. Again, BLINCYTO has taught us that the earlier lines of therapy, the combinations, these can have quite significant additional effects when rolled into other active therapies. So difficult to talk about in the abstract, but that theme is one that we believe in, finding the patients who need more and thinking about folding this in appropriately into those lines of therapy. More to come, and we'll look forward to presenting data in the coming year.

Our next question comes from the line of Geoffrey Porges with SVB Leerink.

Congratulations on all the progress. First question, maybe for Greg, is in the case of BCMA, I know it's very early, but can you give us your thinking on how many bites at the BCMA apple a patient may have therapeutically? We've sort of learned quite a bit about CD20 and CD19, but what do we know about BCMA failures in terms of continued expression of the antigen? And then a little bit more insight, you've resurrected MCL-1. You have 2 molecules in development. What did you learn about managing the tox and what are the potential indications for those 2 molecules now that you have them back in development?

Thanks, Geoff. Maybe I'll take the MCL-1 question first and then Greg can talk about patterns of BCMA expression over time and does loss of antigen, for example, correlate with resistance. So we're just back in the clinic with the MCL-1 programs. We did a variety of work on the clinical data sets as well as additional preclinical work and to mitigate the potential cardiac toxicity that we previously reported. We're certain that, that's on target based on expression of the target. And the key question that we need to answer in those programs is, is there a therapeutic window? We know the drugs are actually active. We've seen antitumor responses. There's no question about that. And again, we're convinced that the potential safety issue is on target. So the question then becomes one of the time-honored questions in this field which is, is there a therapeutic window? And so I think we've got a focused development program designed to answer that question over the coming months. We're taking a look in AML as a target. And we're also doing work in, some work in myeloma as well. These are diseases where we know MCL-1 expression exists and is, in many instances, one of the sort of driver molecular alterations that is responsible for treatment resistance and progression of those tumors. So more to come there, just back in the clinic, have enrolled the first patients, we're following them and moving along right now. And that more to come over the first half of next year or so as we accumulate these data. Greg?

Yes. Geoff, it's the $1 million question in the field, again, is how BCMA expression might change over time. BCMA is a little bit more tricky than CD19. Of course, it's a prognostic factor, in addition to being potentially one that might predict responsiveness. And of course, there's a soluble fraction as well. But we do believe that BCMA expression remains relatively constant. And we're hopeful, again, that previous BCMA-exposed patients will still have the ability to respond to other therapies. Again, if CD19 has taught us anything, though, it's that the evolutionary pressure that's applied does have consequences for the downstream mechanisms of resistance. And of course, in that example, with CD19, the CAR-Ts, particularly a persistent CAR-T, may have a different pattern of BCMA loss than, say, an antibody drug conjugate that's at the other end of the spectrum. So what we're hopeful, again, is that particularly for the BCMA space, that patients may have multiple bites at the apple. It's to be determined. But particularly, the antibody drug conjugates were hopeful or not going to drive the kind of BCMA loss that would lead to outright loss of the antigen. I'll just add as well that preclinically, we believe that the CD3 bispecifics can see lower expression levels of protein than perhaps naked antibodies or antibody drug conjugates can. So of course, we have to prove this all in the clinic, but our current thinking is that these will be therapies that aren't just one shot for patients. There may be opportunities for multiple bites at the apple to use your term.

Our next question comes from the line of Kennen MacKay with RBC Capital Markets.

So let me offer my congratulations as well on the rapid path to market for AMG 510. So you're advancing AMG 509 as the first XmAb, CrossMAb. Is this finally a strategic shift towards full antibody bispecifics from BiTEs or is this just an expansion of the bispecific strategy or should we be reading into this? And if not, why not target STEAP1 with a BiTE?

Yes, Kennen, thanks for that. I think you hit the nail on the head. This is an expansion. It adds another platform. This has been done in collaboration with Xencor. It doesn't signal a shift to another platform at all. You shouldn't overread anything there. There are rare targets where we feel one platform for structural reasons may have an advantage over another. But in general, our first choice and what would be the case for the large majority of our molecules, it will be our core half-life extended platform. So thanks for that question.

Our next question comes from the line of Cory Kasimov with JPMorgan.

A bigger picture one for you. I'm just curious, given the number of bispecific updates at ASH this year with a lot of exciting new data and as you accumulate more and more information on your own programs, how confident are you at this stage in your BiTE platform relative to the competitive platforms out there? And kind of what's the basis of that overall that you think has Amgen well positioned here?

Yes, Cory, thanks. It's an important question. And I would say the massive data that we've accumulated across now multiple half-life extended molecules, in both hematologic malignancies and solid tumors, is what really gives us confidence. And what we're seeing in the clinic largely mimics what we had predicted from our preclinical models, which have become quite sophisticated in terms of their engineering and our ability to plot the clinical development programs. I would point out that as we think about BiTEs, we always want to emphasize that target identification and validation remains critical. And that while some messages are generalizable, much of what one will encounter in the clinic will be target-specific. That's an area given the very extensive validation that we do on target, including with engineered animal models that express parts of the human immune system, for example, that, and then the industrialization of the platform, all of those put together, I think, would give us increasing confidence. And we feel very good about where we are. This was a big year in terms of proof of concept. Next year will be a big year in terms of advancing some of these key programs. So thank you for the question.

Our next question comes from the line of Alethia Young with Cantor Fitzgerald.

I just want to talk a little bit about with your platform, BiTE versus the XmAb technology, which you have. Obviously, looking at Slide 10, more BiTEs. So I was just curious about your interest, continued interest in the XmAb bispecific platform?

Right now, we're focusing on the prostate program that we've talked about. It's a great collaboration. And should we move forward with other targets, of course, we'll let you know. But as I said, our major emphasis is on our core half-life extended platform right now, Alethia.

Our next question comes from the line of Ronny Gal with Bernstein.

Let me take a slightly different tack. Cancer vaccines, you've been involved with IMLYGIC for some time, but I haven't seen you putting anything interesting into the clinic recently. I was wondering if you could give us an update about where you stand on that platform and how you think about it. And second, you made a big partnership in China with R&D being a big part of it. Can you help us understand if and whether this partnership will help you accelerate some of that hematological programs forward? And if you can just give us a bit more details there.

Yes. Let me take the latter, and then I'll ask Greg to comment on the IMLYGIC program, which remains in Phase III. We're very pleased with the partnership with BeiGene. As we've announced on the last couple of earnings calls that we are moving along. We'll provide periodic updates there, Ronny. But I would say, very, very good working relationship established. And this is something that we feel is really important to introduce our drugs in China in the coming years in the oncology portfolio. So more to come there, but quite happy with that. Greg, do you want to talk about IMLYGIC?

Yes. I'd love to, Dave. So IMLYGIC, of course, has now been in Phase III testing in combination with pembrolizumab. We initiated the planning for the study back in 2015. This has been, again, asking the quintessential question, can you use an injectable oncolytic virus, release antigens into the system, almost an autovaccine, if you will, and help PD-1 inhibitors do their job better? And part of the challenge up until now has been that thankfully melanoma patients are actually doing quite well, and this is an event-driven study. And so we're hopeful again that when we turn the card over, we'll be able to see effects on the time-based endpoint that will definitively answer that question of whether or not, again, those are additive. Similarly, with a drug like T-VEC for injectable disease, whether it's liver lesions or other diseases, we have ongoing early phase studies, and we're hopeful that it can be an important part of the armamentarium to help drugs like PD-1 do their job better. Looking forward to turning over that card from the MASTERKEY study, and we're anticipating 2021 at some point on the event-driven relationship that, that's going to be something we'll be able to share more broadly.

Our last question comes from the line of Michael Schmidt with Guggenheim.

I just had one more on sotorasib. I was just wondering regarding the upcoming World Lung conference presentation of the Phase II data. Will you include another later data cut in this analysis or will it essentially be the same cutoff as the recent top line release? And then I was wondering on CodeBreaK 200, the randomized Phase III, I was just wondering if you could give us an update on how the study is enrolling in context of the continued coronavirus pandemic and how we should think about potential time lines here, rest of world?

Yes. Thank you, Michael. I can handle those questions as we wrap things up. Yes. So there will be a later data cut presented at the World Conference on Lung Cancer in about 6 weeks or so, and then we look forward to sharing those data. And then CodeBreaK, I think, is enrolling moderately well. We have had some, I would say, a bit of a slowdown because of the pandemic and its real resurgence this fall. We continue to open sites. We've got lots of sites open around the globe right now. And I think over the first few months of next year, we can start giving better estimates on time lines. But I feel pretty good overall in terms of where we are with that study. I think we'll do well. And there's just intense interest on the part of investigators and patients in terms of having a shot at having access to sotorasib. So more to come there, but we're moving forward quite aggressively. And Sarah, I think given we're a couple of minutes past the top of the hour, we should probably wrap things up. Thank you, everyone. And we'll look forward to talking to you in the not-too-distant future, if not this year, early next year and in the context of the JPM Conference. Arvind?

Thank you, everybody, for your participation. If you have any other comments, thoughts you would like to share, feel free to reach out to us. Thanks again.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.