Okay, I think we'll get started. Welcome back to the TD Cowen Healthcare Conference. Next up is a panel discussion of various development programs, companies in the breast and lung cancer space. From over to my side here, we have Jack Bailey from G1 Therapeutics, Filip Janku, the CMO from Monte Rosa Therapeutics, Eric Poma, CEO of Molecular Templates, Shane Kovacs, the COO and CFO of Olema Oncology, as well as Alan Auerbach, CEO of Puma Biotechnology. Maybe to start off, we're gonna start the conversation with some general topics that hopefully are a bit interactive between the various company representatives, then we will dive into some company-specific questions. I think Joe's gonna lead off with one of those, the general questions. Thanks, Mark. Just a reminder for the audience, if you do have any questions for our panelists, feel free to email us at salonf@cowan.com, we can try and get those into the discussion. Maybe just to start off, we've seen two instances over the past several years in the breast and lung cancer space, where clinical trial designs have been updated based on the emerging standard of care that we're seeing in the real-world setting. If the companies can opine a little bit on what's the bar for making these changes, and how often do companies assess the current standard of care in making these adjustments to their clinical trials? Maybe Jack, we can start with you. Yeah, sure. Thanks, Joe, and a pleasure to be here with everyone. you know, it's important, I think, in any disease category, but especially in oncology, obviously, to really monitor the landscape, the technologies, how the science is progressing, obviously approvals, et cetera. It's certainly something I'm sure all five of us will comment on that we do. I think in terms of, you know, what actually qualifies to either change the design of an ongoing study, et cetera, is sort of case specific. I know in our case, when we had our, a phase III, TNBC study that had already initiated, and Trodelvy had gotten their sort of accelerated approval and then full approval on some later lines, we ended up dropping our second-line study. It was a first second line study, and, I mean that was a perfect example where it was just clear that the nature of that approval, the timing, and the, and the likely impact, it was not gonna help us to be able to fulfill our study on time. I think that's one where it did meet the bar. We've had others. Our second, third-line non-small cell lung, that's a space, as we all know, that has gone under tremendous change. We actually ended up dropping that study just because of the regimen design from several years ago had changed. I think there's ample examples of it, but, at day's end, it's really about monitoring it and making that call of what is significant enough. For us, it's, if it's gonna really change the standard of care, if you're gonna see a high penetration or rapid adoption, then you really have to look long and hard about do you still have, should you retain the design, original design of your study? 'Cause, you know, how meaningful will it be in terms of growing the knowledge base for that particular indication, tumor type, et cetera. Maybe, Alan, I know you've wrestled with this issue, you know, at various times in the lifespan of NERLYNX. Maybe, I'm not sure if you have some thoughts there? Yeah. I think that that's something, you know, you asked the question, when should it be assessed? I think it's something you have to constantly assess, because if you think of a, you know, a phase I trial takes one year, a phase II can take two years, a phase III can take three years. With all the innovation that we're seeing in both lung cancer and breast cancer, you have to take that into account at all stages because the design of and your path to market can be constantly changing. I think that one of the things you need to take into account is, you know, let's say you run a phase III trial, and what you run against is the, you know, current standard of care. If by the time that trial is done, that's not the standard of care anymore, you know, what's the commercial adoption of that going to be? What would the challenges to that be? You have to be constantly assessing that, but also kind of forward-thinking in terms of, let's say I win on this phase III trial, but I don't have data showing my drug works after whatever the new standard of care might be, you're gonna have a problem commercially from that perspective. I think it's something that has to be constantly assessed, and you have to have kind of, you know, plan Bs and things like that in case your trial design is no longer valid, either, you know, scientifically, regulatory, or commercially. how do you think about this in the particularly in some earlier lines of, in particular breast cancer, where the timelines of the trials can be very long? Yeah. You have to, think through, you know, game out which trials may or may not work that are also that are in the middle of running that could conceivably, kinda change practice by the time you actually get to data, given the timeline. To me, maybe that's a good one for Shane. I'm not sure. I'm sure this is one that you probably are wrestling with right now. I mean, yeah. I mean, for us, one was the, obviously the penetration of CDK4/6 in the first-line setting. If you look at some of our... We're in this sort of estrogen receptor antagonist or SERD space, and it's been a competitive landscape that seems to be thinning. If you look at some of the earlier trials, for instance, they didn't necessarily require prior experience with CDK4/6, and so you had mixed populations in your second, third-line setting of who had or hadn't seen it. Today, I think we know, yeah, absolutely, that's first-line standard of care, and so we, in a second, third-line study, it makes sense to ensure that all patients have seen that new standard of care first-line treatment. You know, it's slightly different. There's a recent approval in early February of a new drug from Menarini that would be a competitor to us, and we've had questions from investors, "Well, does that change the standard of care? For us initiating our first pivotal study later this year, the answer to that question is no, because one, that drug just got approved in the U.S.. It's really hasn't changed the treatment landscape yet, and it's not yet approved ex-US, where probably the majority of enrollment will happen. It's sort of I think you have to evaluate it. Certainly for us, CDK4/6, absolutely, you adjust your study design to make sure everyone's experienced with CDK4/6. In the case of a new SERD that just got approved, that doesn't really impact our study design. Okay. Great. For earlier stage development, when you're thinking about a patient population to pursue, how do you balance taking a broader approach where it's relatively easier to get safety experience, and you can dose escalate a little faster, versus focusing on a more targeted specific population where enrollment might go slower, but you might get some early meaningful efficacy data there? Maybe, Filip, if you wanna. Yeah. Yeah. I don't see this as a one or the other. I actually think you can do very effectively both. I mean, we have actually tools which now you can quite effectively use. I mean, if you actually select your target population which you enroll, you can actually select the tumor types which are heavily enriched for the target population which you are looking for. If I try to link it, let's say, to our program, which is obviously looking for the MYC-driven cancers, I mean, our design is adapted to that to include cancers in which we know that there is a high representation of tumors which are actually MYC-driven. In that case, actually, you don't actually sacrifice the speed by looking for some molecular alterations, but at the same time, you actually have a chance of seeing the population in which you have a presence of the target in which you can actually demonstrate efficacy. I guess along these lines of, maybe kind of merging the those two questions is, you know, how's the IRA and impacted your how you guys approach, selecting, you know, prioritizing indications, and also thinking through the potential business development strategy around partnering and things like that? Maybe if you wanna start with Jack. Yeah. I think, and certainly in a lot of our meetings, you know, the IRA, I think folks are just beginning to appreciate the multi-decade effect it's gonna have on this industry, in all fronts, right? Whether you're a Part B or a Part D product. I think to your question in terms of how it impacts things like, you know, sort of the approach, whether it be on, you know, the route of administration, right? Whether it is the indication that you pursue. In the case of G one, because we had already gotten approval and we had initiated five different studies, it was sort of a moot point at this phase for us. I can tell you that, you know, if we were, you know, five years prior, we would be looking long and hard about what indication we would be pursuing first. You wouldn't go, we went with, initially a relatively small tumor type and small cell. I think you'd re-assess that. Absolutely. The fact that we're also, you know, a small molecule, you know, obviously, isn't optimal with the nine versus 13 challenge. There's much talk on the Hill, I'm sure, you know, that maybe they'll square that up. It just seems really ironic that, you know, a policy decision, a legislative decision out of D.C. is gonna dictate, you know, what route of administration, what tumor types, what, you know, development plan you should take. I'm just not sure. I mean, the science is hard enough without trying to incorporate all that. From our standpoint, we are just at the very first stages of something that I think is really gonna fundamentally change the landscape, so. Right. Maybe Eric, you may have something to add here, particularly you have a bit of a platform aspect to where you could take things in a variety of ways. Yeah, look, I think I'll pick up on Jack's comment that the science is hard enough. The science is what leads here. We have a new scaffold. We're looking at larger indications. You're really being driven by where you're seeing pharmacodynamic effects, where you're seeing single agent activity. That's still I think that's still the hardest part, as Jack says. That's what you have to solve for. We still think that if you're providing unmet, you know, if you're providing benefit in high unmet medical need, you should be okay here. It is gonna be, it is gonna be a wrench in the works here that you're gonna have to think through. Still, though, science leads. Over the past couple of years, obviously, we've seen a lot of advancement in terms of sequencing and NGS panels to assess different mutations. Maybe how is this progressing? If we look out, you know, five to 10 years, are we gonna continue to see advancements here, and how does this impact your clinical development strategy? Anyone that would like to opine would be great. Maybe Filip. Filip, yeah. Yeah. There's I think obviously we've been witnessing really this kind of a evolution which really allowed the development of personalized medicine at a large scale and development of medicines for targeting the alterations which had relatively low relatively low frequencies. I mean, currently, I mean, it's not that long since I crossed to biotech from the academia. I mean, it became actually pretty standard even at that time to offer next-generation sequencing to pretty much all the patients who might be at some point the candidates for clinical trials. This is, I think, an important component because, I mean, you test the patient when the patient is actually potentially candidate for clinical trial or targeted therapy, if there is a targeted therapy available, not necessarily having specific targeted therapy in mind, which is kind of a key of success, especially when you are looking for the low penetrance of alterations. It's becoming more cheaper, more affordable. I mean, there are FDA approvals which happened actually several years ago for some major players in the field. I think this trend will continue, and the assays will be more robust. Actually, we'll have more broader panels of alteration, specifically these which can be targeted and will be probably more affordable. It will be probably more ctDNA representation or other potential sources which can be more easily obtained than, let's say, tumor tissue. How it actually links to what we do in the personalized medicine, I mean, we are obviously targeting MYC. MYC expression, which is one of the markers which we are actually looking at, is not necessarily that represented at the moment. Part of it is because often these things are driven by if there are actually effective therapies. I mean, we have, we have our own program actually to look at the diagnostic component that could develop the diagnostic simultaneously. I'm actually pretty sure if, once this therapy actually makes it to the patients and outside of the clinical trial arena, that the diagnostics will catch up very quickly. Anyone else wanna add? I saw Eric and Shane nodding their head a little bit. Is there anything you wanna add to that? I would just say for us, for instance, you'll get a baseline panel and look at different mutations, but it's interesting, you know, to look at what new resistance mechanisms will develop with treatment and to get concurrent panels over time. These studies is super important data that could inform future drug development. You know, with the cost coming down over time, I think it's helpful as we run these studies. Great. I think with that, we'll maybe turn to some company-specific questions, and maybe Jack, we'll start with you and G1 Therapeutics. Maybe just to start on the commercial presence, can you just touch a little bit on what you're seeing in the ES-SCLC SCLC space right now with COSELA, and over the next 12 months, what should investors be looking for in terms of launch dynamics? Yeah. We just sort of hitting our two-year mark on the market. Obviously the first year was a little tough. We were in a co-promotion, which we terminated after year one, then opted to build our own sales force for year two. I think the team's shown some really good growth because of that. They've just much more experience on the oncology front, nearly 15 years experience on average. They were able to get in. It's still bumpy. Small cell with about 20,000 patients were approved for extensive-stage small cell lung cancer. It's about 20,000 patients a year. Top 100 organizations, the MSKs, the MD Andersons, the Texas Oncology, Florida Cancer, all the players you guys know, both on the academic and community network side, treat about half of all the patients. What we've learned, and I think really tighten the aperture on, is that's where we wanna focus is on those top 100s, and even beyond that. The community is just adopting this much quicker than academia is. Not unusual, given just the nature of operating in some of those large academic medical centers. We are getting them on board. MD Anderson adopted this, MSK just recently. I think we've learned really focusing on the community, and really these top 100s, and right now we've got 71 of them that have adopted it in some form or fashion. Really then it's focusing on the depth within those top 100. We're sitting right now at about 15%-16%, depending on the account. Really like to drive that much deeper, and we know it's possible because of those top 100s, we've got some that are literally capped out at 100%. They usually have got full corporate endorsement of it, not just from a clinical side, but a financial side. They have tended to put it in their EMR system to make it easier for docs, but not just straight up as a choice, literally as an opt-out, where, you know, the physician has to give a reason why they would not use COSELA with the requisite regimens for small cell lung cancer patients. We know we've got a lot of open field running here, but again, we've learned a lot in the 1st full year of our own sales force, and I think we're getting better and better at unlocking that right combination. It really consists, as I said, it's the top 100, in particular the community, and looking to really drive it in an opt-out status. On a select basis, we are doing some contracting too, which helps it. Perfect. We are gonna see some combination data with Trodelvy in the second quarter of this year in triple negative breast cancer. Can you just comment a little bit on what you've seen on a early safety standpoint, and what should we be looking for in that Q2 data set coming up? Yeah. For those not as familiar, I mentioned we, you know, initiated five studies, about two years ago. Two of them were phase III studies, and three of them were phase II studies. One of the phase IIs is with a combination study with Trodelvy. Trodelvy, as we know, is one of the top ADCs, but it's really the next big class. One of their challenges, they've talked about it as recently as ASCO last year, is, you know, they've got some myelotoxicity and other challenges to the tolerability that prevent getting sort of maximum or optimal exposure. We thought that would be a good place to be able to utilize COSELA with. We did roll out the initial safety data last fall. We saw a dramatic decrease, about 80% decrease in the neutropenia, especially the grade three/four, which can be pretty harmful, and then also the grade three/four diarrhea. They had 11% in their ASCENT study. We had 0% at that point in our data cut. We think that was a good initial indication from a safety standpoint. We'll have mature safety data in Q2 of this year, along with our initial PFS, again, under the thesis that if you can reduce these myelotoxic effects, you can get more therapy and then hence get better PFS. That's what we're looking forward to in Q2. We think it's very much a platform play when you look at how many different ADCs are in development. Okay. Thanks. We'll move on, to Monte Rosa now. Filip If you provide an overview of kinda the QuEEn platform and how it differs from other approaches to developing molecular degraders, glues and glues in particular. Then maybe while you're using that as a model, just you can describe GSPT1, the first target that you're going after, kinda what, why is the degrader the right modality to address MYC driven tumors with a degrader there? Let me start with the first question, like, about a platform and why it's actually so crucial, part of our development and discovery engine. I mean, the molecular glues in general have been actually pursued as a kind of serendipitous, which really has been kind of a consequence of the whole IMiD, thalidomide, and lenalidomide story. I mean, what Monte Rosa is really doing, actually showing that you can do this one very effectively and very programmatically, and it's actually what QuEEn help us to deliver. Actually, if you look at the our discovery engine, QuEEn, I mean, one of that is actually modeling in silico, how the relationships between the neosubstrates, between the target protein and the E3 ligase, and how actually the molecular glue exactly fits in to facilitate its interaction. That's actually in silico approach, which use a lot of AI-enabled enabled strategies. The another component is actually chemoproteomics, in which you actually assess the protein-to-protein interactions, proximity to E3 ligase, as well as degradation itself. Obviously, you need also actually unique chemical space in which you have a unique compounds which actually allow you to do all of that. That's actually how the QuEEn. What are the essential components of QuEEn which allow to do that, and which also actually were essential component of our first clinical program, GSPT1, which is currently in the clinic. Why GSPT1 and why degrader? I'll start with why degrader. GSPT1 is actually which is a translation termination factor, which is responsible for effective termination of translation. It's not, it's a undruggable protein, so there is not really way to go after that with the small molecule inhibitor or some other technology. It's an intracellular protein, of course. The degrader can actually overcome that and molecular glue degrader can overcome that and by facilitating the interaction between the E3 ligase and GSPT1, the subsequent degradation, you can actually effectively remove GSPT1. Why we think GSPT1 degrader is actually good approach for the MYC-driven cancers, that actually goes back to how we even ended up in that space. I mean, it's, when we were actually looking at how we can effectively target the MYC-driven tumors at that time, the screening our library, actually the compounds which scored really well were some of the GSPT1 degraders. It was actually. What we actually, at that time, there was not really any literature linking GSPT1 and MYC, so we had to do a lot of work internally to kind of clarify that relationship between GSPT1 and effect on the MYC-driven tumors. Obviously, the MYC-driven tumors or MYC-driven cells, they are heavily addicted to translation. The translation really has to function at a high level. If you actually disrupt a translation termination by degrading GSPT1, you actually induce multiple effects, and one of them is actually the accumulation of the ribosome, which kind of causes the traffic jam in those late stage of translation, resulting in the synthetic lethality. There is also actually the feedback loop, which ultimately reduces the MYC expression, and by doing that, actually reduces the oncogene addiction to on MYC by just reducing the MYC itself. Okay. Maybe back to the testing piece that we asked about and general questions. Just, you know, how can you test for MYC driven tumors? Like, wait, how are you assessing whether something really is MYC driven? Do you need to use specific platforms to really interrogate that well? There is obviously the MYC family gene, MYC family of MYC genes, which includes L-MYC, N-MYC, and c-MYC. This effect, which I just described, is actually mutual to all of them. When it comes to what you can use as a biomarker, the dependency seems to be quite straightforward for L and N-MYC expression. When you have a high and high LN and MYC expression, then you have a dependency on the MYC pathway. When it comes to the c-MYC, it's a little bit more complicated because c-MYC is more ubiquitous, and that's actually something which we are still looking at, actually, how we can, how we can utilize the c-MYC as a biomarker. The expression actually can be tested by multiple ways. I mean, most of our data are based on RNA expression, that's actually what we are looking at. We are also looking at how it translates to some other means of testing, such as looking at the protein itself. Okay. I guess, I'll do the next one. Hey, Eric, just can you give us a brief overview of the ETB platform and kinda how it differs from other kinda toxin delivery ADC-like technologies? Yeah, sure. We've been building an antibody-targeted platform based on Shiga-like toxin A, which is a bacterial protein that has some unique biologic properties. When it's delivered to the cell surface via the antibody binding domain, it can induce internalization of non-internalizing receptors. It routes all the way to the cytosol, trafficking through the endoplasmic reticulum. We've learned that it's a pathway to drop off class one antigen to alter tumor immunophenotype. Once it gets to the cytosol, it enzymatically depurinates and destroys ribosomes, so you have a differentiated mechanism of action. We're not the first group to try to put a bacterial therapeutic in the clinic, so we knew that. If you look historically when people have tried that, you know, a third to half of the patients will develop capillary leak, and it can be severe in about a third of those cases, and it can result in fatality. We knew that that was a challenge here. Bacterial proteins will trigger innate immunity. We spent probably four years altering every surface-exposed residue of the protein to inhibit interactions with TLR4 and inhibit innate immune sensing. Now we have about 100 patients' worth of data across three of these molecules in different phase I studies, and we've seen a 0% rate of CLS. This is pretty unprecedented to just really eliminate the major impediment to this biology. What we've also seen across these three different targets, PD-L1, HER2, CD38, is that we can drive single-agent activity in patients who have progressed on all other modalities because, again, this is a completely different MOA. We've also been really excited with the PD-L1 program that we can, you know, in about 10% of non-small cell lung cancer patients who are HLA-II CMV positive with high PD-L1 on tumor, we're seeing nice clinical data. We can alter tumor immunophenotype by bringing in this CMV class one antigen and see those T-cells to that antigen now respond to the tumor. It's a lot of unique biology, very different than an ADC, where you're dropping off a stoichiometric payload that really, you know, doesn't have a lot of biology on its own. The big hurdle was eliminating immunogenicity. Again, now I think we have a database that really demonstrates we've done that. When you talk about internalization, being able to drive internalization of a non-internalizing receptor, it, I guess, strikes me as, you know, there's gradients of internalization. How do you assess, you know, what's meaningful amounts of internalization versus, maybe just, you know, some small. Yeah. There's a functional definition, I think, which is really what can you build an ADC to, right? If you look at CD20, there's never been an ADC. If you remember the old days, there was radioisotopes to CD20 'cause it just didn't internalize. Kind of in a more updated fashion, CD38's another target where, you know, you look at the BCMA space, and you've seen ADCs go into the BCMA space in myeloma, but you have not seen that approach with CD38 'cause it's a very poorly internalizing receptor. For both those, we've put agents in the clinic that can efficiently internalize those. It's really a functional definition. Again, we've seen lots of other targets that fit in that space. Okay. Go ahead. Shane, last fall, Olema presented updated phase I, two results for your novel CERAN OP-1250 at the EORTC-NCI-AACR Symposium. There was solid activity at the recommended phase II dose of 120 milligrams QD. There is a 39% clinical benefit rate. Can you just briefly discuss some other significant highlights from that dataset? We've expanded across two different dose levels of 60 and 120, and we presented data on 68 patients last fall. Since then, we expanded and fully enrolled our phase II at a 120 milligram dose. That's a dataset we'll present later this year. It'll be about 75+ patients at that 120. I think, you know, as you look at the competitive landscape in this sort of SERD, CERAN SERD space, the recent approval of ORSERDU, which based on our preclinical assays, we could classify as more of a SERM SERD. In the EMERALD pivotal phase III study, their ORR was a little under 5%, I wanna say. In the ESR1 mutant population, which was about half, their ORR was a little shy of 7%. And yet in the ESR1 mutant population, they had about a 55% hazard ratio versus standard of care. For us, in our early data, we've seen probably close to double that response rate in the broad population and significantly higher that in ESR1 mutant. I think it gives us a high degree of confidence in the path forward for us as we move into a pivotal study, which would be restricted to just second, third-line patients, versus the data we've shown so far has had a lot of fourth and fifth and later line patients that we've enrolled. We're optimistic about the path forward into a pivotal study, and we'll present more phase II data later this year. Looking forward to the Phase II update. You mentioned it was around 75 patients. How much additional follow-up can we expect, and how will it advance the data that you showed last fall? We fully enroll it by late October, early November. I think to be sort of more fully mature, you wanna get every patient at least six months, have an opportunity for six months on therapy or longer. It would really depend on where we present the data this year when we do that data cut. If we were to do it in the second half of the year, it would enable every patient at least six months of duration or longer. That's probably a good idea. Great. looking ahead to the pivotal monotherapy trial, what are some of the main takeaways from ORSERDU's pivotal experience and some other late stages? As you mentioned, most of them are restricted to very late-line patients. What are you thinking about incorporating from those trials into your potential pivotal plans, and how could they build on that? You know, the Menarini, RADIUS post-hoc analysis that they've since presented at ASCO last June, then at ESMO, and then at San Antonio is super interesting, and they've done a really great job at some of the publications. It's really clear, I think, one, you absolutely want all of your patients to be CDK4/6 experienced 'cause that truly is first-line standard of care today. For breast cancer, for metastatic breast cancer. Two is, it's very clear that patients that have seen chemo in the advanced metastatic setting do worse on these endocrine agents. The reason for that probably is that patients that are getting chemo second-line are patients that have probably progressed very quickly through their first-line CDK regimen. They probably have more aggressive tumors, and it indicates those physicians are deciding, "Okay, you progressed very quickly through first-line standard of care. I'm gonna debulk that tumor with chemo before I might go to another endocrine therapy." By, and some of the studies now are saying, "Well, we're not gonna allow any prior chemo in the advanced setting," you're getting patients that are more likely to be responsive to an endocrine agent in the second, third-line setting. That's probably important as well, is to not allow a prior chemo. A close ESR1 mutant is an indication where you're gonna see higher activity here. That's very clear because these drugs bind both wild type and ESR1 mutant estrogen receptors. We know that standard of care, which is either an aromatase inhibitor or fulvestrant, is ineffective or certainly less effective on a mutant receptor than it is a wild type. That just goes to binding affinity and the fact that that mutation almost always occurs in the ligand binding pocket on the receptor and reduces the receptor's affinity for ligand. Where you have exposure issues, like with fulvestrant, you're gonna be less effective. With these drugs, because they're oral, you get much, much higher exposure, and so you can still bind a wild type and a mutant. Great. I'm thinking ahead to possible OP-1250 CDK4/6 inhibitor combinations. Last December, you presented phase I data demonstrating that OP-1250 was combinable with Ibrance. Unlike a lot of the other oral SERDs and SERMs that have been tested previously, you didn't have any effects on drug exposure or tolerability, specifically around neutropenia. What can we expect from in terms of an update from this study later this year? What more do you need to learn from this group before thinking about a frontline pivotal study of a combination? Yeah, it's super interesting because if you think about the two big market opportunities for these oral SERDs, the second and third-line opportunity often gets dismissed by the investor community. Yet it's a multi-billion dollar opportunity, and even more so now when you look at the ORSERDU pricing, which is over $20,000 for a course of therapy. Nonetheless, it's very clear that first line metastatic is probably twice the size, not because of the number of patients, but because of the duration that you stay on therapy, which is today's standard of care is about 24 months. You know, we've seen an evolving landscape where many of these SERDs have had some type of drug-drug interaction with palbociclib or ribociclib, I think mostly with palbo, either affecting DDI with respect to adverse event profile or either increasing or decreasing the exposure of the CDK4/6. There's been a lot of hiccups over the last 12-24 months with that. Our early data we presented at San Antonio Breast last December, that was 12 patients, three patients per cohort, four cohorts, and we had no DDI issue, no increased or decreased metabolism of palbociclib or our drug, OP-1250. The early data says we've got great combinability with palbociclib. We've been expanding since last September at our phase II dose. We'll expand with palbo combo in up to about 40 patients, and we'll present that data this year. Hopefully we hope to be able to confirm the early data that we showed, which is good combinability with palbo. We also have a collaboration with Novartis, and we're doing in the middle of dose escalation combination studies, both with ribociclib and alpelisib, their PI3K mutant drug. That dose escalation data, at least with ribociclib, we plan to present the second half of this year. Great. Alan, some of Shane's comments around duration in different settings, I think, good transition to efforts that you're making to push out dose titration in a kind of alternative dosing schedule to get up to doses and keep people on therapy. You know, the impacts that you think that will have on long-term compliance and persistence, the use of that dose titration protocol, also layer in there just what you're seeing from a marketing perspective and COVID impacts on your ability to get into physician offices. Are we back to normal or perhaps at a new normal that will be durable going forward? Let me answer the second one first, because it's a bit easier. Now the new normal we're seeing is about, you know, 80% of the interactions are happening in person and about 20% virtual. That's been pretty stable for the last couple of quarters. I assume that's the new normal. In terms of the efforts that we're doing with our drug, NERLYNX, from a, you know, tolerability perspective and aid dosing. When NERLYNX first got approved, the side effect profile of NERLYNX is that it causes a severe diarrhea in the first month or so that the patient is on it. This tends to have a taxane toxicity to it. It's only the first month or two, and then the bowel seems to adapt. you know, trying to keep the patient on in those first month was quite difficult. When we first got approved, the only thing that was in our label was using loperamide and using high doses of it instead of having problems with diarrhea. The problem was with the constipation. We had first looked at either using loperamide or combining other antidiarrheal agents like budesonide or cholestyramine. Some docs were successful in doing that, some were not. We then also developed, much later, a dose titration, which was in that first cycle to start with half a dose of the drug titrate up such that by the end of the first month they're on full dose and then continue from there. That was extremely successful and ended up getting adopted, I think, roughly, you know, ballpark 65%-70% of the prescriptions we see are written in that way. We're definitely seeing that for the physicians who always were okay with managing a full dose to start with, either, you know, with their own abilities using loperamide or some of the other combinations we developed, that is their standard. For the ones who did not, using the dose escalation, which as I said, is about 65%-70%, that's their standard. I don't have the numbers in front of me, but I know our commercial group has said that they do seem to be seeing a trend up in terms of duration of therapy, which would suggest that we're having more success in keeping the patients on long term. Good. Apple, you wanna go? You want to get back to you? Maybe, Jack, we'll go back to you. We're gonna see some phase II data from the first-line urothelial trial of COSELA this year. We've already seen some initial response rate data. Maybe what level of improvement over chemo alone on PFS, and some disease control measures would you be looking at as an encouraging signal? Maybe why necessarily wouldn't the addition of COSELA improve response rate? A couple thoughts. As I mentioned, we initiated five studies. Three of them were phase II studies, and one of those was a bladder study. First line bladder, sort of built off the JAVELIN archetype, up to six cycles of chemo and induction, and then a maintenance therapy just on the value map. If you look at what patients get right now, it's about seven-eight months PFS. I think what we would be looking for is a meaningful benefit if we could pick up two months on that. Why that is occurring? The real intent of this study is to see if we can enhance the effect of checkpoint inhibitors in that maintenance phase. The uniqueness of a trial of cyclic COSELA is not only does it protect the bone marrow from the damages of chemotherapy, but it also protects and activates the immune system. By combining it with a checkpoint inhibitor, do you see enhanced immunity in that maintenance phase is really where we'd be looking at the benefit of it from? In terms of the Triple-Negative Breast phase III study, you're gonna have an interim look next year now. Kinda what data supported initiation of that phase III trial, and what should investors be looking for when you make that interim, and when could we see final data if the interim doesn't stop the study, I guess? Again, those five studies, two of them were phase III. One of those was this first-line triple-negative breast cancer study. That was the only one of the fve studies that was built off of or built upon phase II study, where we did see a quite a dramatic improvement in survival of... We We had hazard ratios of 0.31-0.4. That clearly motivated us to do the phase III study on this. Joe, to your point, I mean, at this point, we originally were modeling that we would see get the interim at the second half of this year. Because the events are accruing slower than expected, which is good for patients, obviously, we'll be looking at the first half of next year to get that interim analysis. s a transcript of a conversation between a patient and a doctor. The patient is a 65-yearold male presenting with symptoms of a urinary tract infection.</p> <p><strong>Doctor:</strong> Good morning, Mr. Smith. What brings you in today?</p> <p><strong>Patient:</strong> Good morning, Doctor. I've been feeling a bit off lately. I have this constant urge to urinate, and when I do go, it's not much, and it burns.</p> <p><strong>Doctor:</strong> I see. How long have these symptoms been going on?</p> <p><strong>Patient:</strong> For about three days now. It started subtly, but it's gotten worse.</p> <p><strong>Doctor:</strong> Any other symptoms? Fever, chills, back pain?</p> <p><strong>Patient:</strong> No, none of that. Just the urinary issues.</p> <p><strong>Doctor:</strong> Have you noticed any changes in the color or smell of your urine?</p> <p><strong>Patient:</strong> It's a bit cloudy, and it has a stronger smell than usual.</p> <p><strong>Doctor:</strong> Okay. Based on what you're telling me, it sounds like you might have a urinary tract infection, or UTI. It's quite common, especially in older men, though less so than in women.</p> <p><strong>Patient:</strong> A UTI? I thought those were mostly for women.</ Then we saw the results of the phase III colorectal cancer study this year. Maybe what are your most updated thoughts in terms of, you know, why you obviously saw the safety benefit there, but the efficacy didn't pan out? I think you've indicated on the last call that it could have been a drug-drug interaction with one of the chemo components. I guess, how are you thinking about additional investigation into colorectal cancer, and where do we stand in terms of understanding the findings? Yeah. About, three weeks ago, February thirteenth, we did release the results of our second phase II study, and that was in colorectal cancer. It did hit both co-primary endpoints in terms of significant reduction in the myelotoxicity and tremendous tolerability, we did get some early indicators of survival, so we did end up terminating the study. Right now, it's early days, where the next couple of months we'll be doing a whole bunch of various molecular and in vitro work. I think the leading hypothesis is that, it was the 5-FU, some type of interaction there, impact there. We should have much greater insight over the next couple of months, but it's sort of definitely heading down that path. We do think this was unique to this tumor type and this regimen, but we want to confirm that. Obviously, we've never seen this on any other tumor types or regimens that we have utilized COSELA in. I want to let our CMO and the scientists make sure we land everything on this here the next couple of months. Maybe Phil will continue the conversation on GSPT1. Just as you're going into the clinic now, or have been in the clinic for a bit, just what is the kind of target level of degradation that you think you need to achieve? I think one, in terms of peak, but I think at least as importantly, is kind of the duration of that degradation. Let me start with the first aspect of that question. Based on pre-clinical modeling, we anticipate that the level of degradation, which would be clinically meaningful, is actually in the range of 70% plus. When it comes to the range and duration of the degradation, there are actually several aspects to that, and some of that is what actually can be really effective, right? I mean, that's actually something which we looked at, which we looked at pre-clinically, looking at actually the continuous schedule versus the intermittent schedule. We ultimately decided to actually move to the clinic with the intermittent dosing. Simply one of the reasons behind that was that actually there were some indicators that perhaps the efficacy can be actually may be even better and this more sustained effect on the tumor. I don't think it's necessarily that entirely surprising. I mean, as the targeted therapies, there have been a lot of data coming on board over the last number of years that intermittent schedules actually can be very effective, especially by mitigating the adaptive mechanisms of resistance in certain instances. Probably a lot of time these things were not developed just because sometimes it's just hard to change the paradigm. I mean, if people are used to doing things a certain way. From that standpoint, we actually believe that the intermittent schedule can be actually very effective. Okay. Can you walk through the trial design for the phase I in terms of there's a number of tumor types, you know, but also how quickly do you think you could get to those target levels of degradation as you dose escalate? Yeah. The study actually started really well. I mean, let me just summarize with your first question, what tumor types we are focusing. I mean, it's we are focusing on lung cancer. We are enrolling patients with lung cancer, non-small cell and small cell, high-grade neuroendocrine tumors of any primary. We have quite exciting data from preclinical data from for this disease. diffuse large B-cell lymphoma, large representation of c-MYC-driven cases, especially in the advanced setting, and the solid tumors with N- or L-MYC amplification, using that as a surrogate for the for the high expression. so, that's that's what the study focuses on. I kind of forgot what was the second question. just, how quickly you think during dose escalation? Oh, yeah. you can get to that target level of suppression. Based on actually, again, the preclinical modeling, we were actually quite pleased to see that the phase I dose Level 1 for the phase I escalation was actually pharmacologically active. The study is actually moving really well. A lot of enthusiasm from the investigator side, and that's why we actually feel confident that we can actually have a first disclosure in the second half of this year. Okay. I mean, given that, how should we think about expectations for that data disclosure, in terms of the types of questions you'll likely have answered? You know, obviously, safety will be a big focus, obviously, with any phase I trial. Also, you know, should we be thinking about over, you know, RECIST type of responses that we should be looking for, given the potential for activity very early in the trial? You've gotten to a recommended phase II dose. We anticipate that we will actually have several dose levels. Obviously, in addition to safety, which you just mentioned, I mean, we will have PK, PDs and whatever response data are available at that time. What about do you think you'll have been able to get to formally selecting a dose and I guess potentially even a schedule to move forward with? Or will that still be a little bit of a work in progress, exactly which dose is going forward? I think, I think it's plausible that we will get to that within that time frame. Obviously, it's a little bit hard to, hard to guess beforehand, but I think, I think it's quite plausible that we will get to that within that time frame. When you mention PD markers, just what are, in your view, what's kind of key PD markers to kind of supplement the, that view of efficacy in addition to whatever, you know, RECIST response data type of stuff that you're able to present? Probably markers of interest, I mean, one of them is obviously GSPT1 itself. Look at the GSPT1 degradation in both tumor tissue. The biopsies are actually done at baseline and on treatment in our patients as well as in PBMCs from the peripheral blood. In addition to that, we will be obviously looking at the MYC levels as well. I mean specifically, the all MYCs, but specifically also L-MYC and N-MYC, which L-MYC and N-MYC high expression should be represented in patients actually enrolled to our clinical trial, given the tumor types which we selected to enroll and see how that actually links to potential efficacy. Also, we are actually looking at the MYC target genes and changes in the expression of the MYC target genes. Okay. Maybe turning to Eric, you know, before we discussed, kind of a bit about what makes the ETB platform unique among, you know, A-ADC like approaches. Most recently, I think you've decided to use that with a CTLA-4 targeting agent. Why is that kind of the right target? How is this really gonna kind of move that target forward given, you know, we do have approved drugs, but there's been some issues with this? Yeah, I think there's. You know, one of the things we've been seeing through our PD-L1 program is that if you know, the current PD-L1 antibodies don't clear MDSCs or PD-L1 positive TAMs or these other immune cells that the tumor's co-opted to create an immunosuppressive environment. We're clearing those out with our PD-L1 compound. We're seeing that can result in single, you know, monotherapy efficacy in patients. We're really excited about that approach. When you think about the TME, the big players there are MDSCs, TAMs. The other big player is Tregs. Tregs upregulates CTLA-4. If you look at the ipilimumab data, there's a very low likelihood that ipilimumab will clear Tregs in a patient. When they do see that, and it's typically in CD16 double positive staining patients, you see responses. The response rate of ipilimumab is 5%-10% as monotherapy. It's usually predicated on having, you know, a high effector cell population in that TME. Going after that with a mechanism that's independent of effector cell presence, we think will drive clearance of Tregs. That's exactly what we're seeing with our PD-L1 program. The other PCC with ipilimumab is that you get 24-hour-a-day, seven-day-a-week blockade of CTLA-4, CD80/CD86 in the, in the periphery, and that drives a lot of the talks. Here, given the half-life, given the low doses, we don't expect to see that. We didn't see any signs of that in any of our animal models. We think this is a very different approach to CTLA-4 than what you have out there. It's part of the, you know, what we're doing here in terms of trying to break down the TME through PD-L1, clearance of cells and then through CTLA-4. We think that adds really nicely to that. Okay. What are the timelines on this program? When should we expect to-? Well, we expect to dose the first patient probably middle of this year. Okay. Right. Shane, just going back to the second CDK4/6 inhibitor combination trial that you're running, what inspired you to run that second trial with ribo? In terms of future development, when you have data for both combinations in hand, what factors will have the strongest weighting when you're trying to decide whether to take V/Palbo or ribo combo forward, or possibly both? Yeah. I mean, going back to some of the history of Olema, we had some early interactions with Novartis before I joined the company in 2020, and had signed up that collaboration early before we had entered the clinic. There was obviously interest in ultimately moving into combination with CDK4/6 inhibitors. Right ahead of going public in the fall of 2020, we also signed up the collaboration with Pfizer. We had both collaborations signed up and the opportunity to look at combinability with both Pabo and ribo. You know, interestingly, the OS data that's come out is certainly in favor of ribociclib now, we're starting to hear changes in prescribing behavior of switching to using ribo as the first-line CDK4/6 of choice versus Pabo, we'll see how that plays out. It seems to be playing out in favor. A lot of market share growth for, I think, for ribociclib. Clearly, Pabo is still the market leader there. In terms of which one we would move forward with in a first-line pivotal study, we'll see how the combo data plays out later this year with each of those two drugs. We're also in potential partnering discussions about going forward in the first-line setting, and depending on who that partner might be, they may also influence which drug we would move forward with. Great. Finally, I guess to wrap up on that, in terms of where the ER-positive breast cancer paradigm is moving with new agents such as ADCs coming into the space, what are your latest thoughts on where a novel endocrine therapy could fit in the paradigm, and how big ultimately is the potential opportunity? In our view, there's really no question that this is going to be a new e-class of drugs that's going to do better for breast cancer patients than both fulvestrant or aromatase inhibitors. You know, we feel highly confident, you know, with this first approval of ORSERDU, and ultimately, the first-line studies are going to start reading out, we think, with Giredestrant combo next year. We think that these drugs are better for patients than both standard of care, which is AI or fulvestrant. In terms of the ADCs, like in HER2, we get a lot of discussion about that. Where does an HER2 fit? Some patients will go to, today, chemo second line, typically that's if they progress rapidly through their first-line treatment. The DESTINY-Breast04 study showed that in previously treated chemo patients that enhertu did better than chemo. Where should enhertu potentially move up in the treatment regimen is where you would otherwise use chemo, you may go to a drug like an ADC, like an enhertu. It's targeted chemo. It really doesn't compete with the endocrine agents. I mean, the overall goal of therapy is if patients are still endocrine sensitive, then you wanna push off the chemo as long as possible or the ADC. Those patients that are now endocrine resistant are not responding to a monotherapy endocrine agent. You're gonna go to chemo, or you may in the future go to enhertu. I think that there's sort of different drugs in the in the oncologist regimen as they're thinking about the patient. Okay. Maybe turning to Alan, on neratinib, there's been activity shown in a handful of different settings, you know, some of which you've tracked down to all the way to labeled indications, others less successful. How should we think about that label? Is this now a finished product, or is there still more work to be done with neratinib itself? Yeah. Neratinib, Nerlynx, has FDA approval for the extended adjuvant treatment of HER2-positive early-stage breast cancer and as a third-line agent in combination with capecitabine for HER2-positive metastatic breast cancer. We were also looking at the drug in, as you mentioned, a couple of rare mutations, which was HER2-mutated breast and EGFR-mutated lung, exon 18 mutated lung. These are very rare mutations. Based on, you know, precedent as well as discussions with the FDA, it was clear we needed a randomized trial. The challenge you have with a lot of these rare mutations, that you could spend years just screening the patients just to be able to enroll it. With it now being 2023 and the composition of matter patent on the drug expiring in 2030, it just wasn't a good risk reward for the shareholders for us to, you know, go into a large randomized trial that probably took, you know, much longer than anticipated to enroll just from a screening and also a much larger cost than expected. We recently announced that we would not be taking those indications forward. Yes, I do think that this label is a final one. There might be additional safety things put in there or maybe, you know, additional dosing things and things like that. But I think, yes, this is final. Okay. Then late last year, you did bring in another molecule, alisertib, from Takeda. You know, this molecule's been around for a bit. I guess, what, in your mind, changed in the understanding of the drug itself, the pathway? Yeah ...that, you know, made you want to act and bring that in and try to develop it further? Yeah. We actually first approached Takeda in 2019 about licensing alisertib from them. You know, during the two years we were discussing this with them, what we were, you know, most impressed with was that the drug is an aurora kinase inhibitor that had been tested in a number of solid tumors as well as liquid tumors, but especially things that were involved in the aurora kinase pathway, which were, you know, c-MYC amplification, RB1 loss and things like that. That's where the tumor was showing the best activity. It was clear to us that taking a, you know, biomarker-focused approach with the drug, you know, had a high probability of success. That was really what engaged us and led us to license the asset. Okay. I think you've said that you plan to meet with the FDA to kind of determine and finalize some development plans. What are the kind of key questions you need to get answers from in small cell and then HR-positive breast cancer? In HR-positive breast, I think we wanna understand what the registration path looks like, trial design, and I think that one's a little more straightforward. In small cell lung, there has been a precedent, which was Zepzelca, which is lurbinectedin, where the FDA did allow an accelerated approval on a single-arm trial, or a confirmatory trial that was randomized. We think that might be a pathway that might be open for this asset, and I think that's what we'd like to discuss with them, is whether, you know, a similar path with alisertib could be taken in small cell lung, which obviously could, you know, bring it to market in a much quicker timeframe. If you need randomized trials in both indications, is that... You know, that could be time and capital intensive. Yeah ...to run two at once. Is that something you think Puma's able to do, or, would you look to maybe more stage them? Yeah. Our guidance for 2023 is that Puma will be a revenue-generating company and also a net income positive company and a cash flow positive company. Those last two are the most important, being a net income positive company and a cash flow positive company. That's something we don't want to just be in 2023, but also 2024, 2025, et cetera. If we are able to do both side by side and maintain those, we will do that. If not, we can stagger them as you suggest. Okay. Unfortunately, we are going to have to cut it off there. We want to thank the panel for joining, as well as everyone in the room.