Good morning, and welcome to the Verastem Oncology Corporate Update Conference Call. My name is Betsy, and I will be your conference operator today. As a reminder, this call is being recorded. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star, then one on your touchtone phone. To withdraw your question, please press star then two. I would now like to turn the conference over to Julissa Viana, Vice President of Corporate Communications and Investor Relations.
Thank you, Betsy. Good morning, and thank you for joining today's conference call to discuss the regulatory update for avutametinib and defactinib combination in low-grade serous ovarian cancer, the top-line data from a recent data cut from RAMP 201, and initial interim data from the RAMP 205 first-line metastatic pancreatic cancer trial. We issued two press releases, one yesterday afternoon and this morning, detailing these announcements, which are available on Verastem's website, along with our corporate presentation. Before we begin, I would like to remind you that any statements made during this call that are not historical are considered to be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995.
Actual results may differ materially from those indicated by these statements as a result of various important factors, including those discussed in the Risk Factors section in the company's most recent annual report on Form 10-K and current report on Form 8-K filed this morning, as well as other reports filed with the SEC. Any forward-looking statements represent Verastem's views as of today. Delivering prepared remarks on today's call will be Dan Paterson, President and Chief Executive Officer, Dr. John Hayslip, Chief Medical Officer, Colleen Mockbee, Global Head of Regulatory Affairs and Development, and Mike Crowther, Chief Commercial and Business Strategy Officer. I will now turn the call over to Verastem President and CEO, Dan Paterson. Dan?
Thank you, Julissa, and thank you all for joining today's call. It's an exciting time for Verastem, and we're excited to share several meaningful updates with you today regarding our initiation of a rolling NDA submission for avutametinib and defactinib in low-grade serous ovarian cancer. Top-line RAMP 201 data and initial interim data from our RAMP 205 trial in first-line metastatic pancreatic cancer. For our call today, John will take us through the data for both RAMP 201 and RAMP 205. Colleen will take you through the regulatory interactions and the update on our rolling NDA, and Mike will follow up with both market opportunity and LGSOC and some of the prep work we've been doing over the last 18 months for an anticipated launch in 2025. We'll conclude with a review of next steps before opening up the call for Q&A.
Before we discuss the updates we have, I do want to also point out that our trials in non-small cell lung cancer are continuing, and recently we added defactinib to the RAMP 203 trial in combination with avutametinib and sotorasib. In addition, the IND has been filed in China for the KRAS G12D on/off inhibitor we have partnered with GenFleet. As soon as the IND is cleared, they will begin the phase 1 in China, and we'll be taking a look at the data and prepare for our approach in the U.S. First and foremost, we conducted our pre-NDA meeting with the FDA last week and have aligned on a path forward for filing for accelerated approval for avutametinib and defactinib combination for the treatment of recurrent LGSOC.
We did agree to have the complete data set for parts A, B, and C of RAMP 201 included, even though minimum follow-up is at five months and the data still needs to mature. We're incredibly pleased to share that the FDA gave us the go-ahead to begin the rolling submission, and we'll discuss that further shortly. Along with a preview of what we have as the first mature cohort from our pancreatic study, which will be presented at ASCO. At a high level, in that first mature cohort, where we have six months of follow-up, we had an 83% response rate in frontline metastatic pancreatic cancer combined with chemo. With that, I'll hand the call over to John.
Thank you, Dan. First, I'll discuss the new information coming from our study in pancreatic cancer, and then we will transition to low-grade serous ovarian cancer, or LG SOC. I'd like to first highlight a few points about the design of the RAMP 205 trial. This is a study of avutametinib and defactinib combination with standard chemotherapy for metastatic pancreatic cancer, gemcitabine and nab-paclitaxel. As a reminder, this is a phase 1/2 study, which enrolls patients who are newly diagnosed with metastatic pancreatic cancer with no prior systemic chemotherapy. The study starts with dose finding cohorts to ensure that the dose level is safe and below the maximal tolerated dose. As the dose levels are cleared for DLTs, then there are small expansions that can occur at those dose levels. This is referred to as part A of the study.
The study will then transition as we select the recommended phase II dose and will then transition to part B or the phase II portion of the study. As we transition now to the results, you can see that dose level 1 is now mature for efficacy evaluation, and 5 of the 6 enrolled patients, or 83%, have achieved confirmed response by RECIST criteria. An early patient enrolled to dose level 1 experienced a dose-limiting toxicity of neutropenic fever at dose level 1. The dose level was expanded, and we enrolled a total of 6 patients. No additional dose-limiting toxicities occurred, and the dose level ultimately was cleared.... Shortly thereafter, additional dose levels were further activated to evaluate potential alternative doses that may further optimize the safety and tolerability. Specifically, that's dose level minus 1.
This is a dose level where the schedule of chemotherapy given on days 1, 8, and 15 of a 28-day schedule remained at the same dose as dose level 1, except for the nab-paclitaxel, which was reduced from 125 mg/m² down to 100 mg/m². That's dose level 1. Additionally, dose levels 1A and 2A were activated. In the A cohorts, day 8 of chemotherapy is dropped out or omitted. Therefore, the chemotherapy is administered on day 1 and 15 of a 28-day schedule in these dose levels. And in these dose levels, the avutametinib is increased to 3.2 mg twice weekly. The reduced intensity chemotherapy in cohorts -1, 1A, and 2A were carefully considered and chosen after speaking with multiple investigators and pancreatic cancer experts.
Often, even when patients begin treatment with full or package insert type dosing of gemcitabine and nab-paclitaxel, patients often need to reduce or modify the doses for tolerability. Therefore, the dosing can be quite individualized for each patient. Therefore, we thought the types of the modifications tested here are largely consistent with how therapy may be dosed in real-world settings. These other dose and schedule approaches are designed to see if the combination dosing might be further optimized in terms of tolerability. We'll show you where we're at with each of these different dose levels in the upcoming slides. For some additional context, let's take a look at the historical data in first-line metastatic pancreatic cancer. Here we show results for standard treatment regimens currently used to treat metastatic pancreatic cancer.
With the gemcitabine and nab-paclitaxel regimen that we have combined in this study, response rates in the 20s and 30s percent have been previously reported. Other available treatment regimens, such as FOLFIRINOX, which may be viewed as more toxic than gemcitabine and nab-paclitaxel, has reported somewhat higher response rates, here shown at approximately 42%. Here we show the swimmer's plot of every patient we've enrolled in this study, and they're grouped by the dose level that they were enrolled to. At the bottom of the slide in the navy, this is dose level 1 that is mature for follow-up. The timing of responses are interesting and unique. If you can see in the black letters, those are the responses at each time point as they've been seen.
At dose level 1, at the 2-month point, 1 of the 6 patients had achieved a partial response, and in between 3 and 4 months, a second patient achieved a partial response. If you continue on to the right, between months 5 and 6, this is when the 3 other patients have enough shrinkage to fully characterize the tumor response as an objective response. The other cohorts do have individual patients with objective responses, but most of these patients have only been on study long enough to have 1 assessment, if any. Again, even in dose level 1, which now has 5 of 6 responses, at the 2-month point, it was only at 1 out of 6. The other dose levels are relatively early for efficacy assessments.
In addition to following the currently enrolled patients for a few additional months to understand how those enrolled more recently are doing, we expect to have further conversations with the investigators regarding two additional options. First, we may reinitiate another enrollment at dose level one to further characterize the efficacy and safety. Secondly, the protocol allows for us to initiate additional dose levels and add, for example, prophylactic preventative support, attempting to improve the neutrophil or the white blood count. Dose level one had one patient with a dose-limiting toxicity of neutropenic fever, but this dose level didn't require or stipulate prophylactic antibiotics, prophylactic G-CSF or growth factor support, because those things are not typically given with the gem-nab treatment regimen.
But if the efficacy appears greater here ultimately, and there are some concerns about neutropenia and the potential for infection, we could potentially add G-CSF and enroll a similar dose level to see if adding the growth factor support might make it even more tolerable. I expect that we will discuss the available options with the study team and make those decisions over the coming weeks. Another way to look at efficacy is the percent change in the size of the tumor masses, as shown in this waterfall plot. On the far right are the plots for the patients enrolled in dose level one. By the time of this analysis, these patients have had multiple cycles of treatment and have had multiple sets of CT scans at dose level one.
The patients in dose levels minus one, one A, and two A are earlier in their treatment, and most have only had one set of scans since starting treatment. That said, most patients are seeing early reductions in the size of their tumor masses, and while admittedly early, I view these signals as encouraging. Transitioning now into the low-grade ovarian cancer data or LGSOC. We recently had a pre-NDA meeting with the FDA to discuss the rolling NDA submission in recurrent LGSOC. We reviewed with them the data as they are right now, which includes at least five months follow-up for all enrolled patients, which I'll show you here in a few slides. After discussion, we have agreed to pool together parts A, B, and C of the RAMP 201 study.
which in total is up to 115 patients with LGSOC, who are treated at the go-forward dose of avutametinib and defactinib, with 58 patients having a KRAS mutation in their cancer and 57 patients have KRAS wild type LGSOC. The FDA guided that they view the data as they are right now, with 5 months minimum follow-up on all the patients, as sufficient for us to move forward to initiate a rolling submission, which means we can submit the portions of our application as they become complete and ready for submission. Importantly, to complete the submission, we plan to provide more mature clinical data, which will include approximately 12 months minimum follow-up on all patients. Colleen will provide more insights into our plan going forward with our NDA submission in a few minutes. Here is shown a schema of the RAMP 201 study.
The study was conducted from left to right, in that Part A enrolled patients first, then Part B, then Part C. All parts of the study are now fully enrolled. Part A of the study was the first part to enroll, and therefore is the most mature data. A few key points I'd like to elevate from this slide. The median time to response in Part A was 5.5 months, and additional patients continued to have enough tumor shrinkage to qualify for a RECIST criteria response out until 15 months into treatment on Part A.
With that background, it may not be surprising that the response rate with 5 months minimum follow-up for all of the patients shown on the left was 28% and improved or deepened to 45% by the time there was at least 12 months follow-up for all patients, as shown on the right. Another key point we can estimate from patients enrolled in Part A with longer follow-up is the typical duration of treatment. While duration varies from patient to patient, the median duration for all the patients was 11 months. Looking specifically by KRAS mutation status in the patient's LGSOC, the median duration of treatment is 18 months when KRAS is mutated and 8 months when KRAS is wild type in the patients in Part A with more mature follow-up.
Here are the data pooled together across Parts A, B, and C and reflect key endpoints we reviewed with the FDA last week. Part C of the study enrolled before the analysis, most recently before the analysis, and about 40 patients were in Part C, and the entire group, including C, has a minimum of five months of follow-up. Across all the patients with this minimum five-months follow-up, the response rate is 27% at the time of this data cut in February 2024. When KRAS is mutated, the response rate at five months follow-up is 37, and when KRAS is wild type, the response rate is 15% with five months minimum follow-up.
The right side of the slide identifies that 14 patients both remain on treatment and are assessed as either stable disease or unconfirmed partial response by the RECIST criteria at the time of this analysis. While patients who have already been assessed for progression or response would not be expected to change in the total count of response rate, for the final analysis later this year, these 14 patients have the potential that some may continue to see further cancer shrinkage and may be assessed as in response by the time of the 12-month minimum follow-up analysis. The low end of the range is shown on the right middle portion of the slide, represent the data as they are with the 5-month follow-up.
The upper end of the ranges are what they could be if all the 14 patients were to be assessed as responding by the RECIST criteria by the time of 12-month data cut. I would believe it's likely that what will actually go into the final submission package likely rests somewhere in between those boundaries for the overall group and the KRAS-mutated and the KRAS wild-type subgroups. Here we show the waterfall plot representing all patients who were actively taking treatment at the time of the data cut in February that I described. In the orange are the patients who were assessed to have stable disease by the RECIST criteria. This represents 13 of the 14 patients I spoke about. One patient has an unconfirmed partial response by the RECIST criteria and is reflected by the blue and black hashes.
You can, you can see there's a dashed line there at about 30%. That shows how deep the response assessment will need to go over, with approximately 7 months of additional follow-up, in order for each patient to be characterized as having an objective response by the RECIST criteria. Based on the experiences of earlier patients, it's reasonable to expect a good portion of the patients with substantial tumor reductions, but somewhat short of the formal RECIST response measures, may continue to deepen as we move towards a 12-month minimum data cut follow-up. Now, I'd like to turn the call over to Colleen Mockbee to walk us through the regulatory portion of our updates.
Thanks, John. I'm excited to share with you our regulatory strategy for LGSOC. Looking at slide 18, we have an overview of the unmet medical need and a summary of our key regulatory achievements and anticipated milestones. I'll note that we recently received orphan drug designation for the treatment of LGSOC as a distinct disease, not as a subgroup of ovarian cancer. There are no FDA-approved therapies specifically for LGSOC. Our intention is to submit for potential accelerated approval, which requires a drug to demonstrate advantages over available therapies.
Given there are no available therapies for LGSOC, the FDA will find the best available data to make a comparison. In our case, and based on our recent discussion with the FDA, the best data at this point in time really comes from the two randomized studies done in LGSOC, and that's GOG-0281, and the MILO/ENGOT-ov11 study by Monk. From the control arm of those studies, the options were chemotherapy or a choice of chemotherapy or hormonal therapy. The overall response rates observed in those studies were between 6% and 13%, and were associated with a relatively high rate of discontinuation due to adverse events of 17%-30%. I'll note that though this is the best available data, it still has some things lacking.
For example, there's not really information on response by KRAS status for patients in the control arm of these studies. If you look at the MILO study, this is also largely a second-line patient population, less heavily pretreated, as was discussed in the GOG-0281 study publication. In the GOG study, the median number of lines of prior therapy was approximately 2.5-3. Our study is closer to a median of 4 prior lines of therapy. Typically, you do see decreases in overall response rate by line of therapy. That's not new or surprising. So when you stand our data up for KRAS mutant compared to this data, it compares very favorable, favorably. So a pretty straightforward path for initiating the rolling submission of our data with the core KRAS mutant patients.
In terms of next steps, we will meet with the FDA to review the mature data set and have a discussion with them at that time regarding the KRAS wild type patients, and then ultimately decide what we will move forward with. No matter what, all of this data from RAMP 201, including KRAS mutant and KRAS wild type, will be submitted to the FDA, and at any time during the review, FDA can, in reviewing the data set, expand the indication, similarly to what has been done where they review and narrow indications. So we will have opportunities to discuss the KRAS wild type population prior to the final approval. This sets us up for a potential for accelerated approval in 2025.
I'll also note that we have the confirmatory study ongoing, RAMP 301, and the study will be well underway at the time of the final efficacy submission, and we expect full enrollment for this trial by the end of 2025. Beyond RAMP 301, we also plan to discuss the path forward in the EU and in Japan. Now we can turn it over to Mike to discuss the commercial opportunity.
Thank you, Colleen. So I'd like to start by highlighting the epidemiology of this disease. Around 1,000-2,000 patients are initially diagnosed on an annual basis with LGSOC in the U.S., and conservatively, the prevalence is somewhere between 6,000-8,000 living with the disease today. Of those, epidemiologically, 30% are KRAS mutant and 70% wild type. But in the largely de-risked mutant type, due to the longer durations of therapy introduced by John, as well as the much higher penetration rates we anticipate, we believe that KRAS mutant represents approximately two-thirds of the revenue opportunity, with wild type being a short-term upside opportunity. Of these patients, 80% or greater will experience a recurrence, and these are often much younger women than is common with ovarian cancer, as young as their early twenties.
The current standards of care, as noted, offer poor efficacy and difficulties with maintaining therapy due to toxicities. These are a patient group that live with this disease on median for around 10 years and often see multiple lines of therapy with repeat use of mechanisms due to the shortage of available therapies. As mentioned, there are no FDA-approved treatments currently for this disease, so it has been largely historically managed through application of NCCN guidelines, and there has been no company actively promoting drugs within this space to date. We have done extensive market research using TP-blinded TPPs, consistent with the levels introduced by John during his section.
One interesting point to note is that as we varied those levels, the rate, depth and speed of uptake did not vary that much, which we believe indicates a high recognition of the degree of unmet need in this disease currently. The majority of oncologists indicate they will begin to initiate treat patients on A plus F at their next point of recurrence, but rapidly move upfront to, in essence, second line, the first point available for us in our targeted label. And 85% of them indicate they will begin using the therapy within the first six months of approval. I noted earlier that we believe the prevalent pool is potentially conservative, and that's because of the limited number of therapies. A large number of patients in this condition, often outside the commercial domain in clinical trial.
But physicians indicated that many of those patients would be returned for an opportunity to experience A plus F once commercially approved. We have been active in the marketplace for 18 months preparing, and this is a disease we recognize that is highly concentrated. Over 50% of the patients are currently managed in only 100 centers, so we'll be able to execute through a lean and focused commercial launch. Identifying and finding patients in rare diseases is often a point that people discuss. We have done very broad work with both the patient advocacy groups and the patients individually, and currently have over a third of the prevalent patient population, over 2,200 patients, signed up with permission to communicate compliantly with them for DTC purposes.
As well as the patients being dissatisfied potentially with their treatment, many of the physicians recognize their limitations too. And so over a quarter of them have indicated they'll reach out to half or more of their current patients to discuss whether or not they would benefit from an active switch to A plus F upon approval. We will naturally supply. And because this is a condition where patients can remain on therapy for long periods, we'll ensure that we have programs in place to ensure support of patients to optimize their time on therapy. And with that, I'll pass back to Dan.
Thanks, Mike, Colleen, and John. As the team here noted, we've achieved several significant milestones, both on the clinical side and the regulatory side. We're eager to keep executing and advancing our entire pipeline, but specifically our RAMP 201, RAMP 205, and our G12D programs. We have a drug that's approvable and has shown early signs in a much larger opportunity. I'm incredibly pleased to be one step closer to realizing this commitment in the near term for the potential to bring a new treatment option to patients with LGSOC. We thank all the patients and investigators that have been involved in our trials. With that, we'll now transition to Q&A. Operator?
We will now begin the question-and-answer session. To ask a question, you may press Star, then one on your touch tone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press Star then two. At this time, we will pause momentarily to assemble our roster. The first question today comes from Pete Stavropoulos with Andrew Fitzgerald. Please go ahead.
Hi, good morning, and congrats on the updates and progress. And thank you for taking my questions. First one, for part B of RAMP 201, you know, can you just sort of help us understand if the patients in part B are responding in a similar manner in terms of time to response, as in part A, or is it slower? And, how do the baseline characteristics sort of compare to part A?
Thanks, Pete, for the question. John, you want to take that?
Certainly. Pete, can you clarify? Was the question regarding the 201 trial, or were you saying that the 205 trial in pancreas? Could you clarify the question?
No, the 201, LGSOC.
I think the question is, how the patients in part A are comparing to the patients in the later parts of the study.
In part B, in terms of times of response. You know, to say the 30% threshold, is it moving at the same rate or is it moving at a different rate?
Yeah, I think I understand. So, as we reported here, what we're reporting is the data on all the parts pooled together, parts A, B, and C. And we're doing this because this is the information we reviewed last week with the agency and represents the totality of the information we'll be submitting for the rolling new drug application. So I would say in any group of a modest size, you know, there may be modest differences in the baseline characteristics, but in general, roughly comparable.
Okay. All right, and now, moving forward to RAMP 205. Maybe if we could just start off on the efficacy side. Just curious with respect to looking at the combo outcomes, you know, how would we, how should we think about the levels of activity, you know, as attributed to avutametinib, you know, and defactinib versus gemcitabine and nab-paclitaxel for the exact patient population and, you know, potential additive or synergistic effects of combining these agents?
Yeah. Maybe I could, I could offer you two pieces of information to, for some insight on that. Maybe so first, before the study was initiated, there was, non-clinical testing, of course, was done, and in non-clinical, pancreatic cancer models, we definitely saw, basically saw tumor growth inhibition in, you know, with chemotherapy at the doses tested and, and similarly with, with our combination. But then the combination of avutametinib, defactinib with the gem and nab, we saw, substantial, tumor regressions or shrinkages in the non-clinical model. So non-clinically, it looked, pretty convincing. And then now as we're moving into the clinic, what gem and nab has reported in other trials are response rates in the 20s and the 30s percentile ranges.
What we've seen in dose level 1, that's the dose level that's mature for the efficacy follow-up, with 5 out of 6 objective responses. So, you know, the signal, you know, perhaps is early, but the early indications are highly encouraging.
Okay, and the last question I have is, you know, 90% of the pancreatic patients have KRAS mutations. You know, with these patients are genotypes and, you know, is there rationale for, for taking it forward in, let's say, the, KRAS wild type, patients, you know, similar to, LGSOC?
Yeah, so as you mentioned, over 90% of pancreatic cancer has mutations for KRAS. And so, you know, the way this study is written, patients can enter study, you know, regardless of KRAS mutation status. We have seen responses really across the spectrum of the 41 patients, but it's a bit early to say whether those responses will be differential, be dependent on KRAS mutation status and pancreas. So at this time, the study is open for all patients, regardless of KRAS mutation status, which it does make up more than 90% of the patient population. And we evaluate the activity as the study moves on.
... All right, thank you for that, and, thank you for taking my questions. Thank you. Congratulations once again.
The next question comes from Gregory Renza with RBC Capital Markets. Please go ahead.
Great. Thanks. Good morning, Dan and team. Thanks for the updates, and thanks for taking the questions. Just, firstly on, of course, 201 and LGSOC. Dan, just wanted to get kind of your, your qualitative thoughts on how, some of the proceedings and the alignment with FDA has shared with your going-in position and just your expectations. Just curious how you think that's kind of, shaped up based on the agreements that you have going forward.
Colleen, you want to take that question?
Yeah, sure can. First, you know, I'd say that the discussions, Greg, have been very collaborative. You know, under Breakthrough Therapy, FDA, we're working with the FDA to find the most efficient path forward, and I, I think that the path that we're on really sets us up for, you know, an efficient review with the FDA, and so we're very pleased with our path forward.
Okay, thanks. Just building on some of Mike's call, which is really helpful, just on the commercial and the dynamics there. Just curious on KRAS status testing, how would you plan to incorporate that if that's eventually in the label?
Colleen, you want to take that?
Yeah. I'm sorry, could you repeat the question? Because I thought you were talking about commercial, but you want us to address the specifically how we would incorporate information into the label. Did I get that right, Greg?
Yeah, just as far as just KRAS testing, KRAS status testing.
Okay. KRAS status testing. So, so similar to other recent approvals, we expect that there will be a description of the requirement to select patients based on KRAS testing. And there are available, available tests right now, so we'll be working with the FDA in terms of the, the type of information that will be needed, as part of the submission. And then, did you have further questions on the, the, the current status of testing in the community as well, Greg?
Yeah. Yes, but sorry.
Maybe I'll let Mike. Mike should address that.
Yeah, Mike can take that.
Sure, in the prevalent pool, the vast majority of patients have been living with this disease for a period of time, so their KRAS status is well known, and given this is now identified as a distinct different disease, normal NGS panels include the opportunity for testing. So much of the incident population already are identified at the point of diagnosis as well.
The next question comes from Kalpit Patel with B. Riley Securities. Please go ahead.
Yeah. Hey, good morning, and thanks for taking the question. The first question I have is, can you help us understand if there's a lower bar of efficacy that the FDA wants, specifically for the KRAS wild type patients to allow consideration in that final clinical module?
Colleen, you want to take that question?
Yep. Sure. Yeah, so there's not a lower bar. When we discuss with the FDA, there's not a lower bar. It really is looking at the overall, you know, level of response rate, durability of response, and how this compares to available therapy. We're working to gather as much patient-level data as we can to better, you know, represent the overall response rates that you see in the available therapy, in particular, the control arms for the GOG-0281 and the MILO/ENGOT-ov11 study. So, you know, our job is to demonstrate that this is, in the KRAS wild type patient population, that it is offering an advantage over available therapy and is reasonably likely to predict benefit.
So, you'd look at the available therapy, again, less heavily pretreated patient population with response rates of 6%-13%, get the data by KRAS mutation status, and then, you know, when we get the mature data at 12 months, we'll make that assessment on, you know, does it meet that bar, and have a discussion with the FDA.
Okay. Okay, got it. You know, when we compare these data to the last ASCO update from last year, the response rates did go down, but, you know, obviously we don't, we don't have enough follow-up today. I guess, do you expect the response rates to go near that range, based on what you have seen before, in the 40% range?
John, you want to address that?
Yeah, glad to. And exactly as you said, the data that were presented at ASCO last year, all of those patients had a minimum of 12 months follow-up. And the median time to response, you can think of that, like the average time to response, was 5.5 months, in part A, presented at ASCO. And patients continued to respond out to 15 months after starting treatment. So I would expect, I do expect that the response rates that we lift up here for the entire study, which has a minimum of 5 months follow-up, I do expect those to continue to increase, over the additional 7 months of follow-up time.
As I said earlier, between the ranges of 27%-39%, those would be the anticipated somewhere in that range, would be where I would anticipate those to come in.
... Okay. Okay, and one last question on the regulatory front. Do you expect to complete enrollment, you know, for this confirmatory trial by end of next year, I believe you said? Do you need to complete enrollment first before the FDA grants accelerated approval, or does it only need to be substantially completed for enrollment?
Colleen, you want to take that one?
Sure. Yeah, so thanks for the question, Kalpit. Of course, this is a big topic of discussion with accelerated approvals. Our understanding with the FDA is that the study does not have to be fully enrolled. It certainly needs to be near completion in terms of enrollment. But they'll be looking at the full picture, right? In terms of we've got mitigation strategies to ensure that we maintain the integrity of the study. We have the, you know, U.S. enrollment going on right now, and then we'll be able to, if we have an earlier approval, ahead of completing enrollment of the study, be able to complete enrollment outside of the United States.
So I think we have a, you know, a study that's, you know, well underway at this time, and then we'll be working with the FDA and keeping them updated on the status of our confirmatory study. But in short, we don't expect to have to have the study fully enrolled prior to the approval.
Okay, great. Thank you very much for taking the question.
No problem.
The next question comes from Kripa Devarakonda with Truist. Please go ahead.
Hey, guys. Thank you so much for taking my question. In case I missed it, can you remind me when the next meeting with the FDA is expected to be? And also, how confident are you that the number of... You know, you've had conversations with the FDA, okay, but that the number of mutant patients that you have is sufficient for accelerated approval? And also remind me, the last data last cutoff was for the data was February 2024. Is there a specific frequency at which you take these data cuts? And in the next few months, as you go through the NDA filing process, will we see an update before you present at a medical conference?
Colleen, do you want to take that?
Yeah. Kripa, make sure I got these. So first, you wanted to know, when we would have our next interaction with the FDA. Is that correct?
Yes.
Yeah. So we will have our next interaction with the FDA once we have the 12-month of follow-up data. So as you saw, the cutoff was February for the with 5 months of follow-up, and so, you know, another 7 months worth of data takes us out to September, and that's when- that will be the trigger for our time to meet with the FDA. And in terms of the updates and cadence of data, it really is driven by, the, you know, our discussions with the FDA and, you know, setting the path forward for the NDA and then the, you know, having sufficient follow-up. As you know, the median time to response is about 5 months. What we see is the best estimate of response.
Really, we need 12 months of data, so that's the rationale for that, at that time. But there, there's not a planned additional analysis between now and then.
Okay, great. And also, if since the initial focus is on mutant patients, is the number, you think, sufficient for accelerated approval if the focus is entirely going to be on mutant patients?
That is the... Yeah, we believe that's gonna be the data package that will be acceptable for FDA to review and make a decision on approval.
Okay, great. Thank you.
The next question comes from Justin Zelin with BTIG. Please go ahead.
Thanks for taking my questions. First, on the wild-type population, is there any good sources of what response rates look like with standard of care? I believe that some of the studies references didn't break out that I was just trying to get an idea of a benchmark here.
Colleen, you want to take that? Sure. Yeah, as I mentioned, there's not really great data, in particular on the control arms from their studies. There was some I would call sparse sampling, and it was not complete data to really make an informed assessment. What we do know is that KRAS wild-type patients do have a more poor prognosis overall, in comparison to KRAS mutant, which may be kind of the opposite of what people might think. So just to be clear, the KRAS wild-type patients have a less favorable prognosis. So that's what's known. And then in terms of, you know, how they respond, do they respond differently to, say, chemotherapy or hormonal therapy? That data is just not available. We'll be working to try to get patient-level data to really better understand that.
Understood. And Colleen, at this time, do you expect the FDA may ask for a companion diagnostic to be to go along with this filing for approval? Or do you think that the current available testing for KRAS mutant statuses would be sufficient?
Yeah, you know, those will be ongoing discussions. We have certainly been collecting data and are doing central testing of the data. So, we believe we'll have the data package needed to support approval.
Okay, great. And maybe my last, my last question for John. The pancreatic data, obviously, the response rates look quite impressive here. I was just curious on what you'd be looking for from a duration perspective, you know, to view this as kind of an improvement?
... Yeah, thank you. So it's interesting with this combination. Let me back up for a moment. The RECIST criteria, right? They set that the amount of tumor shrinkage needed to qualify for an objective response at the 30% threshold. But it's not as if when you're—if the shrinkage is just barely below that, you know, it's not as if that's not a benefit. And so what we see in the dose level 1 data is that patients can sometimes need a few months while the tumors are steadily shrinking, the CA 19-9 blood levels are rapidly declining, but it can take a few months before the images fully show a RECIST response.
So on account of that, you know, if you think about, like, other parallels, people sometimes talk about the duration of response, but really the dura-- if the response occurs later, patients-- if the response is categorized later, patients have been receiving, you know, potentially benefit at that whole time up until the response formally occurs. So I, I think maybe a reasonable surrogate is to look at the duration of treatment or the time until progression. And in our patients, you know, 5 out of the 6 patients are on treatment and benefiting more than 6 months in dose level 1, 5 out of 6. Whereas with GEMNAB, the median median time to progression in multiple studies is about 5.5 months.
So, you know, if five out of six are past that, these are early data, but certainly encouraging that the duration of benefit, you know, may well be longer with this combination.
Understood. And if I could just sneak in one last question, if you have offhand data from Part A and the FRAME study, just how many patients actually matured and improved from stable disease to kind of confirmed responses?
Well, that would depend on, you know... That would depend upon, you know, when exactly that you take the counting from. I mean, most patients—most of the responses, most of the shrinkages of the tumors are like a steady shrinkage. And so the median time to response in part A, it was 5.5 months. And so by 5.5 months, of course, patients have had a couple of rounds of scans. And so prior to that time, they would have been categorized as stable disease by the RECIST criteria, because even when there's tumor shrinkage, if you don't cross the threshold, that by the RECIST criteria, is considered stable disease.
So most patients initially have an assessment of stable disease before ultimately then having enough tumor shrinkage to formally classify as an objective response by the RECIST criteria.
Great. Thanks for taking all my questions.
The next question comes from Sean Lee with H.C. Wainwright. Please go ahead.
Hi, good morning, guys, and thanks for taking my question. My first question is just on the RAMP 201. I was wondering, compared to the last update in 2013, would we see an increased number of patients data with the mature data, or is this just the same patients extended for longer?
I think if I understand the question, it's this current data set is the complete data set, so the mature data, 12 months out, will be the same patients with longer follow-up. This is, of course, a much bigger data set than what we had at ASCO last year, which was just part A. So this is part A, B, and C together, and as John had mentioned, minimum follow-up of 5 months, and the data set that we'll ultimately take to the FDA is that same data set, but with 12 months minimum follow-up. Does that answer the question?
Yes. Thank you. That makes it more clear. And my last question is on the RAMP 205. So, considering that you're testing the combination of four different drugs, where do you expect to go for the next dose levels beyond what's been presented so far?
John, you want to comment on that?
Yes. So the active conversations that we're having, and of course, the ASCO meeting is coming up, in this coming week, and so we'll be continuing those discussions, and I expect having a formal steering committee meeting, just very soon. What we're discussing is the potential to reopen dose level 1 for further expansion. Dose level 1 had a case of neutropenic fever, a dose-limiting toxicity of neutropenic fever. But then with additional patients enrolled, a total of 6, there was no additional dose-limiting toxicities. So that actually does clear the cohort with only 1 of 6. So we're discussing reopening that dose level. I think an important additional consideration is, in addition, or potentially separately, is to reopen a dose level like that, but to prescribe-...
Prophylactic or preventative supportive treatment to see if we can further augment or support the white blood count. Maybe just for some context, you know, for example, other cancers like aggressive lymphoma or even breast cancer, the use of G-CSF or growth factor support is common and expected with certain chemotherapy regimens because those regimens can bring substantial benefit to patients, and then patients tolerate them and do better with growth factor support. That's not typically a part of the treatment regimen in pancreas cancer because they weren't needed for gemcitabine and nab-paclitaxel. And my understanding is even when those gem and nab were being studied, higher doses of gem and nab were not better for patients. And so they, you know, the treatment paradigm developed the way it did.
But just if that kind of dose intensity is necessary to deliver those kind of benefits, then testing whether we can even further simplify that and improve the tolerability by adding prophylactic growth factor support may be a very reasonable thing to evaluate. So these are the active discussions that we're having, and we'll expect to make some final decisions on that soon.
Thank you for your thoughts on that. That's very helpful. That's all I have.
The next question comes from Graig Suvannavejh with Mizuho. Please go ahead. Greg, your line is open. You may ask your question. It appears we're having some issues connecting with Greg. So-
All right, so-
Our question and answer session. I would like to turn the conference back over to Dan Paterson for any closing remarks.
Yeah. Thank you again for joining today's call. We look forward to sharing additional updates in the second half of 2024. Thanks again, and have a great day, everybody.
The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.