Very well for key data sets later this year. To summarize the findings that I'll share in subsequent slides, 8520, the first direct KRAS G12C on-off inhibitor, the data we've generated, and I'll cover it subsequently, positions it to be the combination agent of choice for earlier line KRAS G12C non-small cell lung cancer. What we've observed so far is monotherapy efficacy with an overall response rate of 65% and very promising durability with 83% of patients that were eligible for six-month follow-up, staying on study for greater than six months. As I'll show you, our safety profile is clearly differentiated from off inhibitors, particularly with liver toxicities, and this, very importantly, has translated to our combination with pembrolizumab, where we're able to dose at a fully active dose and continue to have that very differentiated safety profile.
We believe this is very important for earlier line patients where safety is paramount. We have also observed an early encouraging signal in a very resistant patient population, STK11 KEAP1 co-mutations, where of the first five patients we've dosed there, all of them have responded. BBO-11818 is our pan-KRAS inhibitor. It is also a direct on-off inhibitor. It is a close cousin to 8520. The same structure-based design elements that were used to discover 8520 were applied to 818. This program has showed very encouraging and de-risking dose escalation data that I'll cover, including a confirmed partial response in a heavily pretreated pancreatic patient. We see anti-tumor activity across dose levels with tumor reductions at higher dose levels, and the early safety profile is differentiated, and the PK exposure is increasing nicely with dose. Third is BBO-10203.
This is our novel RAS PI3K alpha breaker, what we refer to often as 203. Here, the clinical data so far supports our approach, where we have achieved all our phase one monotherapy objectives. We're able to dose and identify a recommended dose for expansion and have very differentiated safety from all other inhibitors of PI3K alpha. We have no restrictions on either HbA1c status or glucose levels, and we see no hyperglycemia of any grade. In contrast, all other inhibitors that I'm aware of PI3K alpha have both restrictions and still observe significant grade one, two, and three hyperglycemia. We have selected the dose for expansions. We have achieved our preclinical target exposure levels, and importantly, in patients, we have full target engagement. Based on the rapid progression of that monotherapy dose escalation, now all three combination cohorts with standard of care are open and enrolling.
As I mentioned, 8520 is a direct on-off inhibitor of KRAS G12C, and we believe this profile enables an improved therapeutic index of all other G12C inhibitors that we're aware of. The direct on activity enables it to directly block effector binding and signaling, very distinct from off inhibitors, and that on state drives potency, and importantly, it drives that potency at much lower drug levels, and this, we believe, as I'll show you, is supported by the clinical data, enables us the therapeutic index where we can dose with pembrolizumab at fully active doses and still have a better safety profile. In addition, the on state mechanism should prevent adaptive resistance to on inhibitor, excuse me, off inhibitors, where about 60% of that resistance is non-genomic in nature and just generating more on state.
As I mentioned, the mechanism of action here enables us the PK/PD disconnect that enables a therapeutic index. When you are a covalent inhibitor against the active protein, you can have residence time on that protein, still inhibit it and clear the circulation. Off inhibitors are unable to achieve that. Here's the schema for the ONKORAS-101 study. This is a phase 1 dose escalation and expansion study. Here you can see that we've escalated both of monotherapy from 100 mg QD to 700 mg QD, and we've also escalated with pembrolizumab. If you're familiar with the space, all off inhibitors de-escalate. The study is a standard phase 1 study where safety PK are the primary endpoints, but we'll also show you what I believe are very encouraging efficacy signals as well. I should mention here, we're also focused on KRAS G12C lung cancer.
Here I show you the monotherapy activity and efficacy of evaluable patients. This is robust monotherapy activity across dose levels in previously treated KRAS G12C non-small cell lung cancer who have no prior G12C inhibitor experience. You can see here we have overall response rate of 65% and disease control rate of 100%, and you can see we have tumor shrinkage in every single patient across all dose levels. Here is the spider plot that shows that the responses appear durable with 83% of patients eligible for six-month follow-up remaining on treatment for at least six months. The safety is shown here on the table on the left, where it shows generally differentiated safety profile with no grade three or higher liver toxicity reported. The table is the treatment-related adverse events reported in greater than 15% of patients. We also include the AEs of interest.
You can see that the safety profile appears generally tolerable and manageable and with a very differentiated liver toxicity profile. We have no dose-limiting toxicities, no grade four or higher AEs, and no treatment-related serious adverse events. The most common adverse events were nausea, vomiting, and diarrhea, and the instances of grade three through investigator assessment were mainly due to suboptimal management. We have a couple of AST/ALT elevations, but these occurred at very low frequency, were low grade, transient, and clinically asymptomatic. Now looking at the combination with pembrolizumab, here is the promising efficacy data in that combination in a patient population that includes both those that were pretreated with prior checkpoint inhibitors and G12C and those that were IO-naive, our first line patients.
In these efficacy-evaluable patients in the first-line, we have three of three partial responses, and in those that have been pretreated, we have two of five partial responses. Importantly, all have tumor shrinkage, even though some are very heavily pretreated, and all remain on study except for one who withdrew consent despite a PR at the first scan. You can see also that we have activity across TPS scores with partial responses confirmed even with TPS scores of 2%. The safety that we observe in monotherapy has importantly carried over to the combination with pembrolizumab, and this is very important that not only is the safety differentiated from off inhibitors, we are also able to achieve this at the highest dose we've evaluated, 500 mg QD.
These are the treatment-related adverse events reported in greater than one patient, and you can see that in combination, it's generally tolerable, manageable, and differentiated on liver toxicity compared to off inhibitors. The only grade three liver elevation we observed was considered by the PI to mainly be due to co-medications, and it was not dose-dependent. Importantly, this patient was heavily pretreated with pembrolizumab and two off inhibitors as well as chemotherapy, and this patient's liver enzyme elevations have resolved, and this is the patient you can see on the far right where four prior lines of therapy and is still in response at greater than 36 weeks. Now, this safety profile with pembrolizumab is not a serendipitous finding. This was driven by the science. So here you can see the relative exposure levels of off inhibitors versus 8520 at 500 mg QD.
On the left is the graph, and on the right is the table. By covalently inhibiting or binding to both the on-off state, you get this PK/PD disconnect, which is clearly demonstrated here, where you can see the exposure of the off inhibitors are multiple folds greater than 8520. For example, sotorasib and adagrasib are greater than 700-fold higher exposure. Merck and D3 Bio are greater than 150-fold, and Lilly and Roche are greater than 10-fold higher. So very active compound, very promising efficacy achieved with very low levels due to the hit-and-run mechanism of covalently inhibiting the on state directly. When you put this into context, this profile positions it very well for earlier line KRAS G12C mutant non-small cell lung cancer, where you can see the combination with pembro at active doses leads to a better safety profile as well.
This grid on the right shows you the monotherapy response rate of 8520 at the doses we've combined with pembrolizumab versus pembro monotherapy and different TPS scores versus off inhibitors that have shared data in combination with pembrolizumab. You can see that the response rate of 8520 is much greater than the off inhibitors, and it has much less toxicity. All off inhibitors have had to significantly reduce their dose to suboptimal levels when combined with pembrolizumab due to liver toxicity, and this suggests that the data I'm showing you in the grid could even be lower because their doses are lower than what I'm representing here. Even at the lower doses of the off inhibitors and combined with pembrolizumab, patients experience anywhere from 30%-70% grade three toxicities.
We believe this superior safety profile and able to combine at a highly active dose positioned it to be best in class in earlier line G12C non-small cell lung cancer patients. As I mentioned earlier, we have a very promising early signal in STK11 KEAP1 mutants. This is a very underserved patient population where standard of care does not work very well, and these patients really have no options. You can see that all five of the patients that we've dosed to date have responded, and this is a significant patient population where 25%-35% of patients with KRAS G12C have either an STK11, a KEAP1, or have both these mutations. Pembrolizumab is very ineffective in this patient population where the PFS in this population is roughly about two months. Off inhibitors also have not reported good data here.
Divarasib has reported that the response rate in these mutations is 25%-33% compared to roughly 55%-60% in the wild-type patients. We're excited by this early signal. We will follow this up with more patients, but if this holds, this will be an exciting opportunity for BBOT and 8520. Moving on to our pan-KRAS inhibitor, BBO- 11818. As I mentioned, this is a close cousin to 8520. So the key structure-based design that we use to 8520 is applied now to 818. This is a pan-KRAS inhibitor. It is non-covalent, but it binds directly to the switch-II pocket. It's orally bioavailable and highly potent. It's a direct on state inhibitor, and importantly, it's a pan-KRAS inhibitor with high-level selectivity over HRAS and NRAS of about 500-fold. We believe that this approach is the best way to drive to the therapeutic index that these patients deserve.
It's very potent in cell assays with no shift in potency between the mechanistic and cell viability assays. Preclinically, we have very strong monotherapy activity in mouse models. We also have very promising combination activity with EGFR antibodies and, importantly, with our RAS PI3K alpha breaker 203. The KONQUER-101 schema is shown here. This is a phase 1 monotherapy dose escalation study where so far we've evaluated doses from 50 mg BID to 800 mg BID Once we define the dose, we will also open up combination cohorts with standard of care, including pembrolizumab, cetuximab, and chemo in KRAS mutant non-small cell lung cancer, colon cancer, and pancreatic cancer, and we will also open up a combination with our breaker 203. Here is the initial best overall response for patients in the dose escalation portion.
You can see there's nine patients here, and we demonstrate anti-tumor activity at predicted efficacious doses with anti-tumor benefit for all patients and then tumor shrinkage when we start to get to the efficacious range. And importantly, we now have a confirmed partial response in a pancreatic patient. Here on the left in the waterfall plot at the cutoff, that patient at the first scan had about 45% tumor reduction, which has now been confirmed at 56% tumor reduction. These are all, as you can see, heavily pretreated patients with some, including that lung cancer G12V patient entering our trial as eighth line therapy. The safety of 818 appears generally tolerable and manageable. Here, this is N of 13, 800 mg BID is included in the safety, but we don't yet have the efficacy readout, so it's not included in the waterfall plot.
You can see there's no dose-limiting toxicities, and the treatment-related adverse events are mainly GI-related. I will mention that the two grade three GI events, one at low dose, one at a little higher dose, both were in patients with pre-existing GI conditions and were very short-lived, one or two days as grade three adverse events. The pharmacokinetics are shown here, and it's generally approximately dose proportional across dose ranges. You can see at the 600 mg BID, we now cover both the G12D and the G12V alleles, which we think is very important for a pan-KRAS inhibitor. So we've just reached the efficacious ranges here at 400 and 600, and that correlates with where we're seeing tumor shrinkage, so exactly as we anticipated. Next is BBO-10203, our RAS PI3K alpha breaker program. This is a novel approach that inhibits signaling in PI3K alpha in a RAS-dependent manner.
This is a protein-protein interaction inhibitor. It's not a kinase inhibitor. It binds specifically and selectively to the RAS binding domain of PI3K alpha, and that binding there blocks the ability of K, H, and NRAS to activate it. Importantly, this activation of RAS of PI3K alpha has been found to be very important in tumorigenic settings, but it doesn't play a role in glucose homeostasis. We do not inhibit the kinase activity, so if you are an adipocyte or a muscle cell that's insulin signaling, you can signal fine in the presence of our compound, and that's how we avoid the hyperglycemia. This mechanism is agnostic to the mutational status of either partner. That profile opens up a very large addressable patient population for this mechanism, not only those that are driven by PIK3CA mutations, but also those that are driven by KRAS mutants.
203 has excellent brain levels in mice, and preclinically, we saw no hyperglycemia at three times the efficacious doses. Consistent with all inhibitors of this pathway, the PI3K alpha pathway or AKT pathway, development path will be in combination going forward. Here is the BREAKER- 101 schema, phase 1 dose escalation and monotherapy, as well as combination cohorts. Our monotherapy went from 100 mg QD to 700 mg QD. The monotherapy dose escalation is complete. We have selected 500 mg as the recommended dose for expansion. I'll show you the data to support that in the next couple of slides, and importantly, we went through that dose escalation rapidly. We achieved all our objectives for that program, and we've now opened up all three combination cohorts in standard of care.
This includes HER2- positive breast cancer with trastuzumab, hormone receptor- positive HER2- negative PIK3CA mutant breast cancer with fulvestrant, and then in KRAS mutant CRC with FOLFOX/BEV. Here is the pharmacokinetics and the target engagement assay. You can see on the left the pharmacokinetics. We get good exposure with all patients at 500 mg QD covering the mouse predicted efficacious exposure. We do not see increased exposure from 500 mg to 750 mg. On the right is a target engagement assay. This is an assay we validated in mice, in human cell lines, mouse tumor models, and mouse blood, where you can see target engagement by dose on day one is rapid and near complete across the dose levels. Certainly, at 500 mg and 750 mg, you see more rapid target engagement. Importantly, I'm not showing you is the steady state levels because it's a flat line.
All four doses completely engage the target at steady state. So we've achieved our mouse exposure targets, and we've completely engaged the target across all four of the dose levels evaluated. Here on this slide is the safety. So 203 demonstrates a potentially differentiated safety profile in heavily pretreated patients. On the left part of the table is the monotherapy, and these are treatment-related adverse events in greater than 10% of patients. And then we have early combination safety as well. From the monotherapy, you can see no dose-limiting toxicities and no treatment-related serious adverse events, no hyperglycemia, even though we allow patients in the trial regardless of their HbA1c levels or glucose levels. Again, very distinct from any other PI3K alpha inhibitor that we're aware of.
We have one incidence of grade three, which was an abnormality, no dose reductions, and our combinations with standard of care so far are very well tolerated with no grade three or greater treatment-related adverse events. The efficacy in monotherapy, we do observe benefit in both CRC patients and hormone receptor- positive breast cancer patients who were heavily pretreated, and we do observe tumor reductions in these patients. Of the 24 patients in our monotherapy study, 16 of them were KRAS mutant CRC patients, and 14 of them were third line or greater patients, so heavily pretreated patients. Even though these are heavily pretreated patients, we do see a disease control rate of 62% in the monotherapy study. As I mentioned earlier, we believe we are uniquely positioned to combine our internal assets in a synergistic manner for KRAS mutant patients.
What I show you here are arguably the two most important oncogenic signaling pathways, PI3K or MAPK, and PI3K alpha AKT. The idea of simultaneous inhibition of these pathways is not new. It's something that I personally have probably been working on for roughly 20 years. When we first tried this, we had MAPK inhibitors, we had PI3K alpha inhibitors or PI3K inhibitors. The data was encouraging in preclinical models, but even the mice did not tolerate it well, and some tried to take it into the clinic, and it didn't go well. We believe we are now uniquely positioned to do this very important combination because of the nature and selectivity of our inhibitors. By combining 8520 and 818, our KRAS mutant inhibitors, with the breaker, we think we can now finally drive the high levels of inhibition safely in patients.
Our data so far in the clinic further supports that we'll be able to do this combination. We're very excited to do this combination. We will open 8520 and 203 combination this year, and later this year, we'll open 818 and 203 combinations as well. Just to remind you a little bit of the preclinical activity that we've observed, this is one model. We published multiple examples of this combination. This is 818 and 203 in a hard-to-treat KRAS G12V model. You can see that both compounds on the left give you tumor growth inhibition, but when you combine them, you turn that into regression, and we've observed this multiple times. In the middle is the mechanism, which is not new.
It's what you would see with a MAPK inhibitor and a PI3K alpha inhibitor, where after a single dose, you get profound decrease in proliferation and induction in apoptosis. What's different is that's right. The mice are fine. It's very well tolerated. We do believe this will translate into patients, and we're very excited to do this combination, which we, as far as I know, are the only ones that have KRAS mutant inhibitors and a breaker. Okay, so in summary, we're very excited about what we've accomplished so far. The focused execution has delivered across the portfolio, and it has positioned us very well for additional data sets in the coming year. For 8520, that additional data catalyst will be more combination data with pembrolizumab. For 818, that will be additional monotherapy data as well as combination and safety data.
For 203, as I mentioned, it will be data in combination in three standard of care settings: HER2-positive breast cancer, hormone receptor-positive breast cancer, and KRAS mutants. In conclusion, we've really achieved everything we set out to do across the program so far, even ahead of schedule of a couple of these data releases, and it set us up very well for the remainder of 2026. I'm very excited about what the team has achieved to date. Finally, I'd just like to thank the patients and their families and the PIs that have had faith in us and their trust in what we're trying to attempt in our mission, because without their participation in our trial, none of this data would be possible. So thank you, and we'll now entertain questions.
So as the team heads up to the podium, does anyone have any initial questions for the BBOT team?
Hey guys, can you talk about combining 203 with 818 and 8520? Have you thought about combining it with, I'm sure you have, with other drugs that are, for instance, that could be commercially currently available or that are also in development?
In the KRAS mutant space? Yeah, do you want to take that, Pedro?
Combination of BREAKER with other KRAS inhibitors? Yeah, so I mean, there's no reason why BREAKER wouldn't help other profiles of KRAS inhibitors that we don't have. Obviously, for us, the internal combinations is a high priority, but a proof of concept experiment that would validate that hypothesis with an approved agent certainly would be something that we'd be willing to do.
So you provided a data update on all three programs. So why did you pick last week to do that?
Yeah, I mean, I think most importantly for us, as Eli mentioned, two of our programs, we're much ahead of the schedule, and we wanted to give a holistic picture across the portfolio because, A, we have the unique portfolio, and B, I think this sets us up very nicely for the rest of 2026. We wanted to give the teaser so that everybody can imagine the possibilities for the second half of 2026.
I can keep going, so unless anyone has any other questions, as they think of some. So the KRAS G12C space is very crowded, so how are you guys thinking about the competition within that space?
Ben, you want to take that?
Yeah, I think overall, if you think about small molecule in general, and then at the end of the day, differentiated molecule with best-in-class potential. So we have many examples. So the data we share today demonstrates the differentiation from both efficacy and safety point of view. So excited about the data. Hopefully, it will be a transformative option for patients in those much-needed diseases.
Can I ask the same question about 818? Why are you guys excited about that molecule?
Do you want to take that one again, or do you want me to do that?
I'm just too excited. Maybe go first.
Yeah, I think for 818, right, I think the idea of sparing HRAS and N RAS can drive to higher levels of inhibition in a safe manner, right? We don't see any rash. We don't see any stomatitis, mucositis. We don't see any hematological toxicity, so all very encouraging, and then I think the idea that you can inhibit multiple mutant alleles of KRAS and wild-type KRAS should also be advantageous. The tumor types that we're looking at, lung cancer, colon cancer, pancreatic cancer, KRAS is the driver, so our view is it's unnecessary to inhibit H&N, and it only brings therapeutic index issues from our perspective, so we believe that this data with 818, where we're the first with a pan-KRAS inhibitor to show a confirmed response in pancreatic cancer, de-risked the mechanism as well as the molecule. You're on a roll.
I'm on a roll. So the 203 data is early. So what gives you kind of confidence that you continue to enroll that trial?
Yeah, I'll start, and the team can chime in if they want. Yeah, so we've achieved all our objectives, right? Our strategy from day one was to go quick through monotherapy dose escalation. Inhibitors of this pathway do not have high response rates as monotherapy. Inhibition of AKT or PI3K alpha is known to be G1 arrest. So we weren't going into it expecting a lot of monotherapy activity. All reagents or inhibitors of this pathway are developed in combination, and in addition, the indications that we're looking at will be combinations, and so what we set out to achieve is to go rapidly in a diverse set of patients, and so any KRAS mutant could have enrolled, hormone receptor- positive breast, any line. So we just went quickly, defined the dose.
We have that target engagement assay because we were expecting a very clean safety profile, but that gives us confidence in the dose that we selected. We've hit our PK targets. So now it's really time to go into the combinations with confidence. And the fact that we can completely avoid hyperglycemia with no restrictions puts us in a unique space within this. And if you talk to KOLs, that profile is very exciting to them. They certainly view the safety profile in the PI3K alpha space still an unmet need that hasn't been resolved. Our combination data that we'll report in the second half of this year will be exciting, and we're very confident in the profile that it's going to be a very safe, an agent you can combine.
Amazing. Any other questions from the audience at this point? If none, I think we can thank the BBOT team for presenting today.
Thank you.
Thank you all.