Good morning, ladies and gentlemen. Thank you for standing by. Welcome to the Cogent Biosciences webcast. At this time, all participants are on a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automatic message advising your hand is raised. Please note that this conference is being recorded. I will now hand the conference over to your speaker host for today, Christi Waarich, Senior Director of Investor Relations. Please go ahead.
Thank you, operator. Today's call will review the positive lead-in data from our ongoing phase III PEAK trial, evaluating bezuclastinib and sunitinib in patients with GIST. These data were presented in a poster session at ASCO and released in a press release over the weekend. You can find the press release in the Investors and Media section of our website at cogentbio.com. Before we get started, please be reminded that remarks made during this call may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about our future expectations and plans, clinical development timelines, including future presentations of clinical data and financial projections. Please refer to our most recent filings with the Securities and Exchange Commission for a full discussion of risks and uncertainties associated with our business.
With that, it's my pleasure to turn the call over to Andrew Robbins, President and Chief Executive Officer.
Thank you, Christy, and thanks to everyone who's dialing into the call this morning. We're excited today to have the opportunity to discuss updated clinical data from the lead-in portion of our phase III PEAK clinical trial of bezuclastinib and sunitinib in GIST patients following imatinib treatment. Today, I'll be joined on the call by Dr. Jessica Sachs, Cogent's Chief Medical Officer, as well as a special guest, Dr. Andy Wagner from the Dana-Farber Cancer Institute, who will walk us through the data presented this weekend at ASCO. After our prepared remarks, there will be time to take questions on the call. On slide 4, I want to take just a couple minutes to remind everyone about our recent progress at Cogent.
We are excited to be enrolling patients across three clinical programs, APEX, SUMMIT, and PEAK, and based on emerging clinical data from both systemic mastocytosis and GIST patients, have increased our optimism that bezuclastinib has the potential to become the best-in-class selective KIT mutant inhibitor for three distinct patient populations. First, for patients with advanced systemic mastocytosis, we announced in late April that we've moved into the registration-enabling Part 2 phase of that study, collecting a once-daily 150 milligram dose with plans to enroll approximately 65 patients, which we estimate will occur by the end of 2024. Second, we are on track to share initial clinical data later this year from Part 1 of the SUMMIT trial in patients with indolent or non-advanced systemic mastocytosis.
We look forward to learning more about the benefits that this patient population may expect from a treatment which can reach clinically relevant mutational target engagement. Finally, with regard to the PEAK trial in imatinib-resistant GIST patients, we remain on track in the global phase III portion of the study to enroll approximately 388 patients by the end of 2024, and again, are excited to review clinical results from 39 patients enrolled in the lead-in portion of that trial on today's call. In addition to the great progress we made advancing bezuclastinib through its three clinical programs, we are just as excited with the progress our research team has made with our selective and potent FGFR2 and CNS-penetrant ERBB2 programs. We also look forward to talking more about other earlier-stage targets in our portfolio later this year.
With over $220 million on our balance sheet as of the end of the first quarter, we remain well-funded to continue advancing Cogent toward its goal of delivering best-in-class, small-molecule, targeted therapies to patients fighting genetically driven rare diseases with high unmet medical needs. Turning now to slide 5, I'd like to provide some background on gastrointestinal stromal tumors. Up to 6,000 new patients are diagnosed each year in the U.S. with GIST, while imatinib, also known as Gleevec, was an amazing step forward for patients fighting this disease, unfortunately, up to 60% of these patients progress on imatinib, resulting in approximately 2,500-3,000 new patients every year searching for an effective and well-tolerated second-line treatment for this disease.
It has been well documented that patients who progress on imatinib frequently develop resistance mutations in either or both of the KIT activation loop and/or ATP binding domains. The ideal second-line treatment would provide mutational coverage across all of these exons, 13, 14, 17, and 18 driver mutations. This treatment profile is the basis for our clinical program, exploring the benefits of combining the current second-line standard of care for GIST patients, sunitinib, which has demonstrated effectiveness against the ATP binding domain mutations, with bezuclastinib, a selective and potent inhibitor of KIT activation loop mutations.
You can see here on slide six that one of the main benefits of bezuclastinib, differentiating it from other previously studied KIT activation loop inhibitors, is its impressive kinase selectivity, avoiding the unnecessary inhibition of other related kinases, which have been linked to off-target toxicity, rendering it difficult to combine these other agents clinically. Based on positive results from a previous clinical study known as PLX121, the combination of bezuclastinib and sunitinib was shown to be well-tolerated in clinically active, leading Cogent to initiate the PEAK program in 2022. Before we move into our clinical data, I would also like to remind listeners that over the past 20 years, three new drugs have been approved for patients with imatinib-resistant GIST, each of which demonstrated in a pivotal trial, less than 6.4 months of median progression-free survival and less than 9.1% objective response rate.
Results from these 3 FDA-approved medications suggest there is an urgent need for more effective treatments for this patient population. With that background, I'd now like to introduce Dr. Andy Wagner to help us walk through the new clinical data from this weekend. Dr. Wagner?
Thank you, Andy, and good morning, everyone. I'm pleased to present the safety, pharmacokinetic, and clinical activity of bezuclastinib and sunitinib in patients with previously treated GIST. The results, as Andy just described, from part one of the PEAK phase III study, phase III PEAK study presented this weekend. On slide 8, we present the study design for the global phase III randomized PEAK study. The key entry criteria for the study are patients who have histologically confirmed gastrointestinal stromal tumor with at least one measurable lesion per modified RECIST. They have to have locally advanced, unresectable, or metastatic disease, with documented disease progression on or intolerance of imatinib, an ECOG performance status of 0 to 2. There are 3 different subsets of patients who have been enrolled on the study.
The focus of the current presentation is on Part 1A and Part 1B. Part 1A is the optimized formulation lead-in cohort, which included patients, treated, in a cohort, 300 milligrams of bezuclastinib, and sunitinib 37.5 milligrams, both, daily administered, medications. A second cohort of patients at 600 milligrams, of bezuclastinib and sunitinib 37.5 milligrams, followed by an expansion cohort at this dose. In addition, Part 1B, included a drug-drug interaction study of bezuclastinib, in combination with sunitinib, where patients were randomized to start, one of these 2 medications for 2 weeks, and then the second medication was added, at that point.
An ongoing study is the Part 2 randomized study, where patients are randomized to receive either bezuclastinib in combination with sunitinib or sunitinib alone. On slide 9, you see a little bit more details about the objective endpoints and enrollment status of these parts of the study. Again, Part 1-A, the objective was to identify a dose of an optimized formulation of bezuclastinib, administered in combination with sunitinib, in order to achieve target drug exposures, defined based on the previous phase 1/2 study. The primary endpoint was the pharmacokinetics of bezuclastinib, and this part of the study has completed enrollment. Part 1-B was the drug-drug interaction study, again, looking at pharmacokinetics of each of the medicines, as well as the primary active metabolite of sunitinib, and has also completed enrollment.
Ongoing enrollment is occurring for Part 2, which is the randomized portion, comparing bezuclastinib with sunitinib to sunitinib alone. Slide 10 shows the patient disposition of each part of Part 1 of the study. Part 1A had five patients at the initial dose of bezuclastinib. Three of those five patients elected to increase their dose to 600 milligrams as of the data cut. 14 additional patients received a starting dose of 600 milligrams, for a total of 19 patients at this part of the study. Part 1B enrolled 20 patients who were randomized to either start with two weeks of bezuclastinib or two weeks of sunitinib, followed by combination therapy.
A total of 39 patients have been enrolled in Part 1 of the study, and as of the data cut, 25 patients were remaining on study treatment. Slide 11 demonstrates the demographics and baseline characteristics of these patients, which are quite typical of patients with advanced GIST. The majority of patients enrolled were men with excellent performance status. About 18% of patients had 1 prior line of therapy, 28% with 2 prior lines, and over half the patients had 3 or more prior lines of tyrosine kinase inhibitors. Primary mutation in most of these patients was exon eleven KIT mutations in 69% of patients, with exon nine being the next most common mutation of the primary tumors.
As again, as typical of most patients with GIST, they, many have had prior anticancer surgery. Slide 12 demonstrates the safety and tolerability data of the combination of bezuclastinib and sunitinib for Part 1 of the study. The safety profile was similar for both Parts 1A and Part 1B, with very few patients experiencing Grade 3 or greater toxicity. The most common side effects experienced were diarrhea, fatigue, nausea, and hair color changes. The most common laboratory adverse events included neutropenia, elevation in AST or ALT, decreased white blood cell count, and anemia. These patterns are all consistent with the pattern of toxicity that we see with sunitinib alone.
To summarize the safety and tolerability on slide 13, the combination of bezuclastinib and sunitinib in Part One was well-tolerated and does not appear to add to the frequency or severity of adverse events associated with single-agent sunitinib. The majority of treatment-emergent adverse events were of low grade by CTCAE and reversible. There's a low rate of Grade 3 or higher events. 9 of 39 patients had dose reductions of any study medications due to treatment-emergent adverse events, and there were only 2 discontinuations due to these events, 1 patient with rash and 1 patient with abdominal pain and diarrhea. Only 2 patients experienced serious adverse events that were possibly associated with study medications. 1 patient had a Grade 2 neutrophil decrease and pyrexia and Grade 3 platelet decrease.
Another patient had Grade 2 bacterial peritonitis and Grade 3 febrile neutropenia. The steady-state exposure of bezuclastinib increased in an appropriately dose-proportional manner from 300 mg to 600 mg following once-daily administration of bezuclastinib and sunitinib. The Part 1a data supports the selection of 600 mg of bezuclastinib and 37.5 mg of sunitinib as the dose for Part 1b and for Part 2 of the PEAK study. Slide 14 shows the swim plot for treatment duration and disease assessment in Part 1a and b. First, I'd like to note that the arrows pointing to the right demonstrate patients who had treatment ongoing at the time of the data cut, and you can see this represents the majority of patients.
The dashed vertical line indicates 4 treatment cycles, with a treatment cycle being 28 days, this represents 16 or more weeks on treatment, you can see the majority of patients have exceeded this point. The white horizontal bars represent patients who have not yet had their first assessment. Again, many patients are ongoing, but many patients already exceeding 16 weeks of treatment. The blue dots represent patients who have attained a partial response to treatment, the inset on the lower right-hand corner indicates the subset of patients who had received only one prior TKI, in this case, imatinib, again, with 4 patients treatment ongoing, and one patient not yet evaluated for response.
Slide 15 summarizes the response outcomes according to investigator assessment. Among the six patients in Part 1a and 1b who were evaluable and had only one prior TKI therapy, 100% of patients had disease control, defined as complete response, partial response, or stable disease for at least 16 weeks. This included one patient or 16.7%, who had a partial response, and 83% of patients with stable disease. For patients who had two or more prior TKIs, there's a disease control rate of 44%, including 12% with partial response, and 68% stable disease. The median time to response was 4.2 cycles, the data remained too immature to estimate the median progression-free survival.
Slide 16 shows the waterfall plot of the patients, the 31 patients, who enrolled in Parts 1a and 1b and had evaluations for treatment response. Again, showing the majority of patients with treatment ongoing, as indicated by the horizontal arrows. Four patients with the partial responses, but the majority of patients having reduction in size of the target lesion, shown by the decrease in best overall change, and very few patients having had early progression of disease. I'll show you a few cases of patients with apparent benefit from the combination of bezuclastinib and sunitinib.
This first case is a patient who has an ongoing partial response with prior treatment with imatinib, a 56-year-old man who has a KIT exon nine mutant gastrointestinal stromal tumor. Before treatment, he had resection of intestinal and mesenteric masses. He was treated with imatinib, 400 milligrams daily for the remaining peritoneal metastases, developed progression of disease with recurring intestinal, mesenteric, and peritoneal disease. He enrolled on the study and was treated with bezuclastinib 600 milligrams and sunitinib 37.5 milligrams. He did not have any serious adverse events or dose modifications, and the sum of the tumor diameters continued to decrease over time, with a 37% reduction noted at cycle 9. Currently, he's on cycle 11 of therapy.
On the CT scan on the right, there's a mesenteric tumor measuring over 19 centimeters, that by cycle 9 had reduced in size to just over 13 centimeters. The graph on the bottom right shows a reduction in size of the target lesion compared to baseline. Slide 18 shows a patient with ongoing partial response in a patient who previously was treated with imatinib and ripretinib. This is a 54-year-old man who has KIT exon 11 mutant GIST, previously had resection of tumor, followed by adjuvant imatinib. At the time of recurrence of disease, was treated with ripretinib, 150 milligrams daily. Had been on this treatment for 17 months, with the best response of stable disease.
Upon disease progression, analysis of circulating tumor DNA demonstrated KIT mutations in exons 11, 13, and 18. Enrolled on the study, was treated with bezuclastinib 600 milligrams and sunitinib 37.5 milligrams daily, with a significant decrease in the mesenteric, peritoneal, and liver metastases. Also had no serious adverse events or dose modifications for either drug. He experienced a partial response by RECIST, beginning at cycle 3 and currently is on cycle 11. The CT scans on the right show a reduction in size of hepatic tumor, from 3 centimeters to about 1 centimeter, and mesenteric and peritoneal disease, from about 5 centimeters to about 3 centimeters, in both of those examples.
Slide 19 demonstrates a tumor nearing a partial response in a patient who has had multiple prior lines of treatment. This is a 43-year-old woman who has a KIT exon 9 mutant gastrointestinal stromal tumor. Initially resected, arising from the small bowel, treated with adjuvant imatinib for 6 months, had resection of recurrent abdominal and pelvic disease. Upon further recurrence, was treated with sunitinib for 17 months with the best response of a partial response. At progression, treated with ripretinib for 3 and a half months, with the best response of stable disease, followed by avapritinib for 2 months, again, with the best, well, in this case, the best response of progressive disease.
She enrolled on the study, was treated at 600 milligrams of bezuclastinib and 37.5 milligrams of sunitinib. No serious adverse events or dose modifications. The cycle 5 tumor assessment is nearing a partial response, and she's currently on cycle 6. On the slide on the right, you can see the percent change from baseline, including data that follow the ASCO data cutoff represented there. On slide 20, the conclusions so far are that there is encouraging safety, tolerability, and clinical activity in Part 1, which are consistent with the previously reported clinical data from the phase 1/2 PLX121-01 trial. Majority of adverse events were low-grade and reversible, with a low rate of Grade 3 events reported.
Combination has been well tolerated, with limited dose reductions, or discontinuations due to adverse events. The combination does not appear to be adding to the frequency or severity of adverse events compared to single-agent sunitinib. The clinical activity supports the potential for durable disease control in patients who have imatinib-resistant GIST, including patients who are heavily pretreated, with 4 patients with partial responses at the early stage of the trial. Responses developing at later time points suggest that the response rate may continue to increase over time, and the data currently are immature to estimate the median progression-free survival. Part Two is enrolling patients who have progressed on or are intolerant to imatinib, only at the selected starting dose of 600 milligrams of bezuclastinib and 37.5 milligrams of sunitinib. Thank you very much.
Great. Thanks so much, Dr. Wagner, for that excellent discussion of the PEAK lead-in clinical data. Before I turn over the call to the operator for some questions, I just want to emphasize a couple points from your presentation. First off, we here at Cogent are extremely impressed with the safety and tolerability profile presented this weekend at ASCO from the lead-in study. When compared to the frequency and severity of adverse events related to sunitinib monotherapy, as described both in the original Sutent registration trial and then more recently as the control arm in the INTRIGUE study, we noticed that the combination of bezuclastinib and sunitinib has similar or less frequent adverse events on every preferred term other than hair discoloration.
Additionally, so far in the lead-in portion of PEAK, we're reporting less frequent dose reductions and fewer discontinuations due to adverse events than would be expected from Sutent monotherapy alone, using results published from those benchmark trials. Overall, the data suggest that bezuclastinib is not adding to the frequency or severity of adverse events as expected from sunitinib, which further reinforces the profile of bezuclastinib as a very selective and well-tolerated molecule. Second, with regards to clinical activity, the data presented this weekend are really intended to be an initial look at the lead-in population. We are certainly pleased that 25 out of the 39 patients continued to receive treatment as of the data cutoff. In a heavily pretreated patient population, where all FDA-approved agents have published median progression-free survival between five and six months, we see these results heading in a very encouraging direction.
Specifically among those seven second-line patients that Dr. Wagner showed in the inset on the summer plot, as of June 1st, four of those patients, the ones with the arrowheads, are now out past 10 cycles, continuing to receive combination treatment. When you also consider the results of four second-line patients we enrolled in the earlier PLX121 study, that means that now seven out of the 11 second-line patients treated to date with a combination of bezuclastinib and sunitinib have demonstrated treatment duration of at least 10 cycles.
Similarly, when you consider that 2 of those 4 second-line patients from the PLX121 study achieved a partial response, this means that out of the 10 second-line patients treated to date with at least 1 post-baseline scan, 3 have achieved partial response, and 3 additional patients remain on this lead-in study, 1 of whom has already shown evidence of a 25% tumor burden reduction as of their last scan. Taken together, the ongoing response data and emerging duration of therapy results suggest that this combination has the potential to become a new standard of care for GIST patients after imatinib and strengthens our excitement about the ongoing global phase III PEAK trial. At this point, maybe now I'd like to ask the operator to open up the call for questions from the listeners.
Certainly. Ladies and gentlemen, to ask a question, you will need to press star one on your telephone and wait for your name to be announced. To withdraw your question, press star one again. Please stand by while we compile the Q&A roster. First question coming from the line of Chris Raymond with Piper Sandler. Your line is open.
Hey, thanks, congrats on the data. Maybe just a couple of questions. Just, you know, Andy, I heard your commentary about, you know, expected activity in this, the 5-6 months data, maybe just put into context, and maybe Dr. Wagner could chime in on this. You know, the phase III INTRIGUE study did show 8.3 months in the, you know, for Sutent in the control arm. Just in terms of what we should expect, I know we've heard a lot of KOLs in the past talk about 2-3 months improvement in PFS would be clinically meaningful. Can you maybe sort of put into context the 5-6 months versus, you know, the 8 months that we saw in INTRIGUE? You know, what should we be expecting there?
I got a follow-up.
Thanks, Chris, for the question. Certainly, I'll ask Dr. Wagner to speak to clinical relevance in a second. Just from our perspective, Chris, to sort of level set, the current patient population of the 39, remember that only 7 are that sort of classical second-line imatinib only pretreated, and so we sort of are, as you say, judging the performance of those patients versus a historical, most recent historical, performance of Sutent in the INTRIGUE study. Sutent performing at around 8 months of PFS. We're looking certainly for that subset of patients in the second line to significantly, you know, outperform that number.
I think as we sort of mentioned on the call, we now have evidence that 4 out of 7 on this study and then 7 out of 11 taking this study with PLX121, have at least 10 cycles of duration of treatment. Many of those patients are ongoing, so I, you know, that gives us that encouragement for how those patients are going to do. The other 32 patients in this study are in that more heavily pretreated, third-line plus setting, where the only things to date that have, you know, demonstrated in a well-controlled large clinical study are regorafenib in its pivotal and then ripretinib in its fourth-line study. Each of those performances were, I think, between 4.8 and 6.3 months for PFS.
When you can find third, fourth, fifth-line patients that are out, you know, noticeably past 6 cycles, then I think that that's also very encouraging for the activity of the combo. I'll ask maybe Andy to speak to the clinical relevance of how much you would need in the combo to be excited.
No, thanks. I think, I mean, there are a couple of additional points. One is, I think it's a very strong rationale for this approach of combining these two different kin inhibitors that appear to be safe to combine, but based both on the PLX121 study as well as what we've seen in part one of this study. The idea being that they together should cover a wider spectrum of resistance mutations than any currently approved drug alone would do. From a theoretical perspective, this is an approach that I'm really excited about.
I think it's consistent with what we're seeing, as Andy was just describing, both in the PLX121 study as well as what we've seen to date in the PEAK study, both for patients who are early in their treatment course, with second line or heavily pretreated patients. Again, I think reflecting that the latter part, the heavily pretreated patients, reflecting that what we hypothesized in the design of these studies is probably really what we're seeing clinically, is that the combination is much more likely to suppress a wider variety of resistance clones than sunitinib alone.
From I think, you know, you're right that the study showed, the more recent study showed a slightly longer disease progression-free survival rate with sunitinib alone, but we'll see some variability from study to study. I think that the range, both from the earlier studies as well as the more recent study, is consistent with the clinical activity, but of sunitinib. What we're seeing so far with the combination, as Andy was just describing, provides a much more clinically meaningful benefit than what we would expect to see with sunitinib alone.
Great. Okay, thanks.
Sure.
Okay, thanks. I have a safety question. I think you guys noted in the presentation that 23% of patients had dose reductions due to treatment-emergent AEs. Sunitinib obviously, you know, has its toxicity. Is there a little bit more color maybe you can provide on how the dose reductions were handled? Was this, did the modifications skew sunitinib or bezuclastinib or both? Maybe just some, any color there in terms of what was the driver?
Yeah, it's a good question, Chris, and I can give you a little bit of color, without, you know, going through each one individually. Among, if you do the math, you know, I think it worked out that nine patients had a dose reduction. The way that it sort of fell out is that three patients had a dose reduction of bezuclastinib alone, three had a dose reduction of Sutent alone, and then three had dose reductions on both drugs. One of the things that, you know, is important for us to do, not with someone like Dr.
Wagner, who is obviously quite well-versed in treating GIST patients, but as we expand this phase III study to, you know, north of 100 sites around the globe, is a ongoing education program with investigators and actually using, you know, the top key opinion leaders like Dr. Wagner to help us to help people understand or investigators understand that are maybe not as commonly treating GIST patients, which AEs might you want to reduce which drug at which point. As an example, you'll see one of the patients on the current lead-in discontinued due to Grade 3 diarrhea and abdominal pain. Unfortunately, I wish we could go back in time, but that patient was only dose-reduced on bezuclastinib.
I think that they presented with diarrhea, were reduced on bezuclastinib, you know, continued at that lower dose, continued the diarrhea, reduced bezuclastinib again, continuing the diarrhea, and eventually discontinued. It would be nice if we had a time machine to go back and see if just reducing sunitinib, which, I think is, you know, in a monotherapy setting, associated with high frequency of low-grade diarrhea. If we could have reduced sunitinib, could we have kept that patient on longer? One thing that you learn in lead-in studies or phase I studies, to sort of replicate into phase III, is exactly how you might want to go about reducing in a combination, one or the other drug, to give patients the best chance of well-tolerated and long-term durability.
Awesome. Thank you so much.
Our next question coming from the line of Charles Zhu with Guggenheim, Milana Losic Seljev .
Hi, good morning, everyone. This is Edward on for Charles from Guggenheim. Maybe a bit more of a question for Dr. Wagner, but it looks like two-thirds of the patients in the waterfall plot showed some form of tumor shrinkage with, you know, as you said, I'm getting close to the -30% threshold. Can you speak to, like, how common this is to see this type of shrinkage with in GIST patients? You know, how similar or different would that be from the sunitinib monotherapy? I've got a follow-up after that.
Yeah, no, it's a good point. I think, you know, one of the things that we've learned in treatment of GIST is that stable disease actually is as good of an outcome as partial responses. Sort of emotionally, we all get very excited about crossing that magical threshold of 30% reduction in target lesion size. Clinically, it doesn't have a lot of relevance. We like to see high response rates, but the outcomes, the overall survival of patients with stable disease is the same as that who have partial responses. Just, you know, from a research perspective, we characterize them as achieving a partial response or not.
I think what we're seeing with the combination of bezuclastinib and sunitinib is quite promising in terms of seeing reduction in target lesion diameter. But we also see other changes commonly as we treat GIST that are not necessarily represented by a shrinkage of the tumor. Sometimes we see, for example, a decrease in the density of the tumor, which is a treatment response. The size alone doesn't capture everything, but I think what we're seeing in the study is a significant proportion of patients having a reduction in size of their tumors, whether it's meeting the RECIST criteria or not.
Compared to sunitinib, it's hard to say, again, because we focus so much on the RECIST metric, when we're reporting data. You know, my... Again, the idea behind the combination is that each of the drugs would, could cover a resistance mutation in individual tumors. Again, we're measuring a limited number of tumors by using RECIST, but we're more interested in the more global, progression-free survival metric instead. I'm sorry, I don't know if I'm answering your question clearly enough, but I think seeing a reduction in size of the tumors is definitely promising. Crossing that magical line of 30% reduction is exciting, but it's probably of less clinical relevance than the progression-free survival rate.
Edward, just to jump in, just, you know, to point out one thing, we tried to present a lot of data on this poster, sometimes the nuances get lost. We are all, you know, very excited on that waterfall plot you referenced. If you take a look at the little white triangles underneath the bars, it's evidence that all six of those second-line patients, that's the population we're enrolling in the phase III trial, that had at least one post-baseline scan, showed some evidence of primary target lesion reduction. You know, sort of reinforcing the point that while, you know, response rate isn't everything, I think, having an impact on tumor burden size, it probably helps leads to long-term durable response.
Seeing every one of the post-baseline second-line patients seeing some tumor reduction benefit is also encouraging for us.
I agree with that. Thank you.
Great. Yeah. Then maybe just on the mutations, how are you thinking about the KIT genotype distribution in second-line GIST? And are there any possible gaps in the coverage from the Beza-Sutent combo? Thank you.
Yeah, I'll take a stab, and then certainly Dr. Wagner knows more about this than I do. As we sort of tried to reference in the prepared comments, we see bezuclastinib as a very potent inhibitor of exon 17 and 18 mutations, and I think it's well documented that Sutent has activity against exon 13, 14 mutations. That there, you know, I think there's ongoing research, both here in the States and in Europe, at, you know, some impressive sites about exactly which clones and which resistance mutations are dominant in driving progression of this disease. I think as Dr. Wagner said, this is probably the first clinical exploration of a treatment that all in one covers across the board, the activation loop and ATP binding main mutations in a resistant setting.
We're excited. Certainly in the phase III trial, collecting baseline and progression, ctDNA, and where available tissue, you know, genotyping to determine exactly what is going on in individual patients is part of that protocol. We look forward to having those data as part of the larger phase III readout. Maybe I'll ask Andrew Robbins if he has, you know, additional comments on that.
Yeah, the, I don't think there are clear gaps in the coverage, but of course, tumors are smart, and they evolve and, you know, who knows what we'll see in the future? I think from a treatment perspective in the, in the current landscape, you know, we tried to do this in the past with sunitinib and regorafenib, which theoretically would also have similar coverage, but we never thought we could combine them together because they both have potent VEGF receptor inhibitor activity, which contributes to most of their toxicity. We tried in the past doing short alternating cycles of these drugs, but were not successful, probably because we couldn't achieve good pharmacokinetics in an effort to try to suppress all the clones in a patient.
I think the tolerability of this combination does provide that coverage across the most common resistance mutations in exon 13, 14, sunitinib, and 17, 18 with bezuclastinib. We've yet to see any true pan KIT mutation inhibitor demonstrate that type of spectrum of activity in clinical trials. Are there gaps? I, you know, I don't know. I mean, I think at least across the most common resistant mutations that are seen, this combination should cover them based on both preclinical data and probably what we're seeing so far clinically.
I think, again, both from that preclinical rationale as well as the clinical data, it seems to be a pretty comprehensive coverage of those most common mutations.
Great. Congrats on the progress. Thank you.
Thank you. Our next question coming from the line of Yun Zhong with Jefferies. Your line is open.
Thank you. Just a quick follow-up and one question. In terms of a 23% dose reduction overall, is that in line with the patients when they start Sutent in second-line at a 37.5 milligram starting dose? phase III PEAK trial, maybe a question to Andy at Cogent. Are you pre-specifying analysis for the exon 17, 18 subgroup patients as well as totality of the data?
Thanks again for your questions. I'll kind of go backwards. The your answer about subsetting or analyzing based on baseline resistance mutations in PEAK, the answer is yes, we will do analysis at the end, but we are not using genotyping to stratify patients. My impression is it'll look probably pretty similar to what the INTRIGUE study had. After, at the end of the study, we'll be able to analyze patients based on their entry and progression, secondary resistance mutations. So I would say we should expect that, you know, at the end of the top-line results. Just very quickly, and I'm interested to hear Dr. Wagner's comments on this. I'll give you the benchmark. As you probably know, there hasn't been a large, well-controlled.
study of Sutent at continuous dosing, which is now the most commonly used, sort of practical dose of Sutent in the community. The dose reduction statistics on Sutent in the original pivotal study that was used to garner FDA approval, they had a 28% dose reduction rate. More recently in INTRIGUE, which was a blend of intermittent dosing Sutent and continuous dosing Sutent, they had a 48% rate of dose reduction. Maybe I'll ask Dr. Wagner of your expectations sort of in the real world for continuous dosing.
Yeah. Our experience has been that the 37.5 milligram continuously is actually better tolerated than the 50 milligrams, 4 weeks on, 2 weeks off. What we're seeing in the study is very consistent with those modifications that we typically need to do with single agents in it. Most of them are, I mean, keep in mind also that this is a fixed dose of a drug, regardless of a patient's size or metabolism or things like that. It's not unusual for us to have to modify doses for sunitinib or other tyrosine kinase inhibitors, either in GIST or in other diseases. What we're seeing here in the combination is very similar to what we would expect to see with sunitinib alone.
Thank you. Can I ask you one more question, Andy?
Sure.
Yeah. In the phase III PEAK trial, are you also enrolling wild-type KIT patients? The reason why I'm asking is that sunitinib is, has a pretty good efficacy in a wild-type, and if you are enrolling patients with a wild-type, are you actually kind of limiting the percentage of patients or wild-type to be enrolled in your trial? Thank you.
Again, you, we aren't specifically, prospectively genotyping patients for entry criteria, but we are using historical knowledge. We're excluding patients that have known PDGFR D842V mutations, and we're, I think, looking with partnership with the investigators for patients that have evidence of confirmed KIT mutant GIST disease, which in the second-line setting, you often can get a very good idea because you would have been, you know, sequenced or genotyped during your imatinib treatment.
Thank you.
Thank you. Our next question coming from the line of Sam Suskin with LifeSci Capital, Yelena Sopen .
Hey, thanks for the questions and great work on the update. Just two for me. For the four patients in the prior Plexxikon study who received bezuclastinib plus sunitinib in the second-line setting, you had mentioned that two of four responded. Do you recall how long each of those four patients remained on therapy for, and at what cycle those responses occurred?
Hey, Sam. Thanks for the question. Yeah, from memory, in the PLX-121 study, each of those responders had first response around 7, 8 cycles into therapy. Again, continued evidence that the combination can often lead to, we'll call it sort of late onset of response. I think that gives us, you know, encouragement for a lot of these patients on the lead-in portion of the study that have only been on for, you know, 2, 3, 4 cycles at this point.
To your specific question about length, the PLX121 study that was done in a way where there was a defined course of treatment and allowed patients to go on to expanded access and continued getting the drugs, where we have less data about what exactly was going on. Each of those responders had approximately 2 years of combination therapy before moving on to the expanded access, and I think anecdotally, one of those patients made it out past 36 months. Both of those PRs from the PLX121 were very, very long-term duration patients.
Okay. Then for the other 2 patients, what was their kind of response and duration, do you remember?
Yeah. The other two patients, I think one of the patients was on for four or five cycles, and then I think discontinued for adverse event, and then the other patient was on about 10 cycles and then had progressive disease. Of the four, something like four cycles, 10 cycles, two years, three years.
Okay. Lastly, too, based on the prior CTOS presentation, I think that one of the second-line patients was started on the lower 300 mg dose. Which patient was that, and did they dose escalate to 600?
Yeah. From the 5 patients from part 1A that started at 300, we know that 3 of those 5 made the decision to move up to 600 milligrams. Interestingly, I think the patient you're referring to remains at 300 milligrams, and it is the longest bar of that second-line patient population. Now that that patient at 300 milligrams is out to 14 cycles, I think, as of June 1st. I think, you know, it's an interesting conversation. Should the patient move up to 600 milligrams in an attempt to try to cross that arbitrary 30% disease reduction? Should we just be happy, and I'm sure the patient is, that they are now having a very long-term durable response, which, as Dr.
Wagner said before, the goal here is, overall survival, is giving patients a longer lifespan, not necessarily hitting, arbitrary scan metrics. It, I think it's an ongoing conversation with the patient, but right now we're really pleased with how long that patient is, currently in disease control.
If I may, I think she's actually my patient.
Oh, there you go.
We, yeah, I've had this discussion with her many times, but she's doing so well, we didn't see a reason to increase her dose.
Okay, thank you.
Thank you. Our next question coming from the line of Joel Beatty with Baird. Your line is open.
Hey, thanks for the presentation. For the patients that are kind of the latest line patients in the study, you know, such as 2 plus prior TKIs, could you provide kind of some benchmarks for how what would be good efficacy markers for those patients?
Yeah. What we tried to do is just bring forward the data from the regorafenib and ripretinib INVICTUS trials that garnered them a third line and fourth line FDA approval. I'm probably gonna get it precisely wrong, but approximately right, hopefully. Regorafenib did, I think, 4.8 months of median progression-free survival in the third line, with about a 5% objective response rate, and that was compared to placebo, which was like a month and a half of PFS and essentially no responders. In the fourth line, ripretinib did around 6 months of median progression-free survival and I think 9% response rate, relative to placebo, again, in the fourth line setting, did, you know, a month or two of PFS and essentially no one got a response.
While, you know, I think folks like Dr. Wagner are always looking to move those numbers up, they're pretty anemic at this point, and so any activity that you see in third, fourth-line patients, moving them out 4, 5, 6+ cycles, I think, is a signal that, your treatment is doing something important in those patients.
Got it. Thanks. One last question. On the two patients that had possibly related severe adverse events that seemed related to cytopenias, could you discuss a little bit more about the course of their resolution of that?
Yeah, we do have a couple of patients, interestingly, that reported, you know, the serious adverse events. Both of those patients, you know, remain on study as of the data cutoff date. They. I think in both cases there was probably an interruption of dose, but in neither case, I think, was there a reduction in dose. The resolution as we sort of say here, there were, most of the treatment-emergent adverse events were low grade and reversible, and even in the case of the serious adverse events, the patients, you know, eventually, resumed treatment, and are, as of the cutoff date, continuing on study.
Great. Thank you.
Thank you. Our next question coming from the line of Christopher Lee with SVB Securities. Your line is open.
Hey, guys. Thanks for the questions. Just wondering, in terms of the treatment-emergent adverse events, did you guys see any bleeding or cognitive impairment?
It's a good question, certainly nothing is reported on the TEA tables associated with either of those. I'd have to go back and check if there was any evidence of either things. I think, you know, headache is on the table, grade 1 headache, you could, you know, suggest that that is under the broad umbrella of cognitive impairment. We saw nothing concerning. I think the spirit of the question is related to some other drugs in this class that have very severe bleeding, especially intracranial bleeding and high incidence of concerning cognitive impairment. There was no signal of anything consistent with those from this study.
In terms of, you know, you mentioned dose interruption. There wasn't a dose interruption rate in the poster, but just wondering if that was a data set that you had on hand in terms of dose interruption rate?
I don't have it handy. It's just one of those things where we tried to fit a lot of stuff into the poster. I would say it's consistent with the dose reduction and discontinuation rates. There's nothing concerning that. We have, like, a massive dose interruption rate or anything like that.
Got it. Gotcha. Thanks for the questions. Appreciate it, and congrats on the data.
Sure. Thank you.
Thank you. As a reminder, ladies and gentlemen, again, if you'd like to ask a question, please press star one one on your touchtone telephone. Our next question coming from the line of Ami Fadia with Needham. Your line is open.
Thanks. Good morning. Congratulations on the data. I wanted to just dig into some of the adverse events, and maybe this is a question for Dr. Wagner. It doesn't look like we are seeing, you know, much of a cumulative effect of the combination of the two drugs. What are some of the adverse events that you focus on as a physician and as ones that you want to manage more so than the others? Perhaps, you know, when it comes to some of the discontinuations that we saw in the study, can you talk to whether these patients were first, you know, either dose reduced or, you know, had an interruption in their dose before they decided to discontinue treatment? Thank you.
Yeah. Dr. Wagner, feel free to take that one if you're willing.
Yeah, sure. As far as the side effects, we don't typically see a cumulative toxicity either on the study or with single agents in sunitinib. The side effects that we tend to focus on or see more of or manage more aggressively are things like hypertension, diarrhea, or altered taste or pain in the mouth. Again, these are all class effects of these types of drugs. And as well as monitoring the laboratory studies, which, you know, obviously are usually asymptomatic, but they're things that we monitor on an ongoing basis. None of these things tend to be worsening with time. They just need to be monitored and managed.
For the vast majority of patients, all these side effects are controllable and improvable with supportive medications. I'm sorry, I forgot the other question.
Oh, the other one was, you know, with regards to the patients that discontinued treatment.
Oh.
Yes.
I don't know overall for the study about what was happening in terms of an attempt to reduce dose before discontinuation. I don't know, Andy, if you have those data handy. Typically, that's what we try to do, though, is to modify the dose first, before discontinuation, unless for some reason there's a particularly concerning side effect, which we're not seeing commonly in the study.
Yeah, just to follow up, there were two patients who discontinued. Each of those patients had attempts to dose reduce prior to discontinuation for AEs. I mean, I referenced earlier in the call that the patient with the diarrhea, we wish, kind of wish we'd go back in time because it looked like they were dose reduced on bezuclastinib because it was seen as my guess is it was seen as the new drug without a well-known safety profile. As I think most folks know, diarrhea is certainly linked as an AE to Sutent monotherapy. You know, it's one of those, I wonder what would have happened if that patient had their Sutent dose reduced, would they have been able to resolve the diarrhea and stay on?
We're going to, as I said before, go through a continuing education, especially as we broaden, the number of clinical sites in the phase III to ensure that physicians are aware of, you know, potentially the more appropriate way to reduce individual drugs on the combination to try to resolve some of these AEs.
Andy, I think just to add to that, I think a unique aspect of the study so far is that most of the patients on Part 1A, or and all the patients on 1B, have had prior sunitinib. I think the investigators rely on some of that experience that that individual patient had with prior sunitinib to help determine which medication might be contributing to side effects on the study. If they were on sunitinib before and didn't have any problems, now they're on the study, they're probably more likely to reduce the bezuclastinib dose.
I think in the Part Two of the study, where all patients are naive to sunitinib, I think the experience of investigators will help guide them about whether something is a typical sunitinib toxicity and to focus on dose reduction there.
Understood. If I could just ask one more question, regarding the partial responses out of the four of them, can you tell us which of the four were from Part A versus Part B? Thank you.
I don't have that information on the top of my head, but I can tell you just based on the 2 patients that have PRs that started at cycle 6 and cycle 8, just based on the physics of time, those are both Part 1A patients. The other 2, I think it's possible that they're Part 1B, but I'd have to go back and verify that.
Got it. Thank you.
Thank you. I'm showing no further questions in the queue at this time. Ladies and gentlemen, that does conclude our conference for today. Thank you for your participation. You may now disconnect. Good bye.