Good afternoon, and welcome to Verastem Oncology's third quarter 2026 earnings conference call. My name is Didi, and I will be your call operator today. Please note, this event is being recorded. All participants will be in a listen-only mode. After today's presentation, there will be an opportunity to ask questions. I will now turn the call over to Julissa Viana, Senior Vice President of Corporate Communications, Investor Relations, and Patient Advocacy at Verastem Oncology. Please go ahead.
Thank you, operator. Welcome, everyone, and thank you for joining us today to discuss Verastem's third quarter 2026 financial results and recent business updates. This afternoon, we issued a press release detailing these results, along with the slide presentation that we will reference during our call today. Both are available on the Investor Relations section of our website. Before we begin, let me point out that we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and actual results may differ materially. We encourage you to consult the risk factors discussed in our SEC filings for additional detail. Additionally, today, we will be discussing certain non-GAAP financial measures. Reconciliations to the most directly comparable GAAP measures are provided in the press release we issued today.
Joining me on today's call to deliver prepared remarks and take your questions are Dan Paterson, President and Chief Executive Officer, Dan Lyons, Chief Commercial Officer, and Dr. Michael D. Kauffman, President of Development, and lastly, Dan Calkins, Chief Financial Officer. I will now turn the call over to Dan.
Thank you, Julissa. Good afternoon, and thank you for joining our call today. We are encouraged by the progress we have made across our commercial business and the VS-7375 development program. We generated net product revenue of $24 million in the third quarter, with demand holding steady for AVMAPKI/FAKZYNJA CO-PACK, and strong refills offsetting new patient starts after significant growth in Q2. As Dan Lyons will discuss, we feel that there is still considerable opportunity to be realized for the CO-PACK. While we continue to see a positive impact from the changes we have made throughout the commercial organization, we are making additional efforts to gather feedback from physicians to understand patient experiences and educate on new and existing initiatives. We are also excited to share that our new blister pack NDA has been accepted by the FDA with priority review and a PDUFA date of February 2027.
This is an important step we are taking to further support patient convenience and adherence to the CO-PACK. Turning to the VS-7375 program, in October, we announced new clinical data from our TARGET-D 101 trial, including, for the first time, U.S. efficacy data and updated safety and tolerability results in KRAS G12D-mutated pancreatic, colorectal, and lung cancers. As Michael Kauffman will discuss in more detail, we set a new efficacy benchmark in pancreatic cancer with compelling and confirmed response rates across lines of therapy, and we demonstrated encouraging anti-tumor activity in both colorectal and non-small cell lung cancers. With longer follow-up, VS-7375 continued to demonstrate a favorable and manageable safety profile at both the 600 and 900 mg dose level.
Overall, we believe that VS-7375 has a potential best-in-class profile, and with the recent agreement with the FDA to start our first-line PDAC study, we have an opportunity to bring a chemo-free option to patients with pancreatic cancer. Building on these encouraging VS-7375 data, we further strengthened our balance sheet by raising gross proceeds of approximately $250 million in October. Together with our current cash position and expected revenues from the AVMAPKI/FAKZYNJA CO-PACK, the financing proceeds are expected to fund operations across our broad clinical development plans into the first half of 2028. This funding supports our opportunity to expedite the development pathway for VS-7375's phase II trial readouts and initiation of three phase III trials, including our phase III PDAC trial. We look forward to advancing parallel development paths in pancreatic, colorectal, and lung cancers, with multiple opportunities to create value along the way.
Lastly, in October, we announced that I will be stepping down as President and CEO at the end of 2026, with Michael Bailey, current Verastem board member, stepping into the role. This transition follows my planned retirement, though I will continue serving on the company's board of directors and as an advisor. Michael is an accomplished biopharmaceutical executive and brings a wealth of experience in oncology drug development and commercialization experience. Most recently, Michael served as President and CEO of AVEO Pharmaceuticals, leading the organization to their acquisition by LG Chem, and subsequently led the integrated company through June of this year. Michael will be an important leader through Verastem's next phase of commercial growth, clinical advancement, and operational execution. I am extremely proud of all that we have accomplished in my 15 years at Verastem.
Our work has benefited patients, physicians, families, and the broader healthcare system, and I have great confidence it will continue to make positive impact with our promising future ahead. With that, I will turn the call over to Dan Lyons for our commercial update. Dan?
Thanks, Dan. In the third quarter, net product revenue for AVMAPKI/FAKZYNJA CO-PACK was $24 million. This revenue was driven by expanded prescribing across both community and academic accounts, with increasing refill rates throughout the quarter serving as the foundation of our performance. We also saw moderation in new patient starts after significant overall growth in the second quarter, reflecting seasonal headwinds in the late summer. Given the episodic nature of treatment persistence in rare diseases like low-grade serous ovarian cancer, new patient starts can fluctuate quarter to quarter. As we are in our first full year of the launch, we continue to see broader physician adoption and remain confident in our ability to grow the AVMAPKI/FAKZYNJA business as more physicians gain experience with the CO-PACK.
As the launch matures, prescribers are increasingly choosing the CO-PACK at a patient's first or next recurrence, as appropriate LGSOC patients are prescribed their next treatment. We have shared before, we have seen physician-directed utilization outside of LGSOC, primarily in solid tumors such as pancreatic cancer. As a reminder, this is not an approved indication of the CO-PACK, and we do not promote its use in this setting. With the recent availability of allele-specific and pan-RAS clinical trials, as well as a recently approved RAS therapy in pancreatic cancer, we anticipate an impact on the business as the treatment patterns evolve. Importantly, our commercial strategy remains focused firmly on the approved indication in KRAS-mutated recurrent LGSOC and helping physicians identify appropriate patients and initiating CO-PACK therapy earlier in the course of recurrent disease.
Our CO-PACK commercialization efforts remain centered around three priorities: driving consistent new patient demand, expanding use earlier in the treatment journey, and helping patients stay on therapy to realize the full benefit of treatment. Let's talk more about our progress with these efforts. First, we are prioritizing growth in new patient starts. While new patient starts moderated in the third quarter, we continue to see adoption broaden through the addition of first-time prescribers and new accounts across both academic and community settings. We continue to work closely with gynecologic oncologists, as they are the primary prescribers of the CO-PACK, and learn from their role in managing patients with LGSOC from diagnosis through the course of their disease. In the community setting, we continue to work with practices to identify patients through site-specific alerts and greater awareness around the disease and how to manage patients.
Adoption in this market is influenced by both ongoing promotional engagement and physicians' experience with the treatment. Many of our community gynecologic oncologists may only see one to four patients with LGSOC per year, making education prior to prescribing and continued support as they gain experience especially important. Second, we are prioritizing initiatives to drive use in the right patients at the first or next recurrence. Throughout the third quarter, we continue to monitor several indicators that physicians are initiating treatment earlier. These observations are informed by our internal prescribing data, field insights, physician discussions, and market research. As we have discussed previously, the early launch included a meaningful proportion of patients who were heavily pre-treated and further along in their disease. As we see treatment duration increase as the launch matures, we are confident the initiatives are working.
Third, we are focused on helping patients to stay on the CO-PACK longer and making the treatment experience as simple as possible. Refills were a key contributor to third-quarter revenue, and strong refill rates tell us that our efforts to support patients in remaining on therapy are gaining traction. As prescribers gain experience with the CO-PACK, they are becoming more confident in proactively managing adverse events and helping patients remain on treatment. Patients who successfully navigate the early cycles of therapy tend to stay on treatment longer, creating a growing base of refill demand. Building on that momentum, we are focused on further improving the patient experience through our new AVMAPKI tablet formulation and blister pack presentation of both AVMAPKI and FAKZYNJA. As Dan mentioned, the NDA has been accepted by the FDA with priority review and a February 2027 PDUFA date.
If approved, the new formulation would replace the four 0.8 mg AVMAPKI capsules taken per dose with a single tablet, meaningfully reducing pill burden. The new blister pack presentation would also make it easier for patients to track and manage their medication, including dedicated packaging for reduced dosing, while eliminating the current refrigeration requirement and making the CO-PACK easier to store and travel with. Taken together, we believe these enhancements can simplify the day-to-day treatment experience, support adherence and consistent refills, and ultimately help patients stay on therapy longer. Importantly, these proposed changes do not change the approved indication, efficacy, or safety profile of the CO-PACK. In closing, we remain confident in our ability to capture the significant opportunity that remains in KRAS-mutated recurrent LGSOC.
We are continuing to refine our commercial approach based on what we are learning from the launch and from physician feedback, with a sharp focus on three growth drivers: expanding adoption, driving earlier use at first or next recurrence, and keeping patients on therapy longer. As physicians gain experience with the CO-PACK and prescribing patterns evolve, we believe new patient starts and the growing base of patients receiving refills will support continued revenue growth and be amplified by the blister pack formulation. While we recognize that adoption in a rare disease market takes time and growth may vary from quarter to quarter, we believe focused execution against these priorities positions us to build a sustainable commercial business and capture the meaningful opportunity ahead. I'll now turn the call over to Michael Kauffman.
Thank you, Dan. Now, I will cover key highlights from our VS-7375 R&D update in October. If you haven't viewed the webcast, I urge you to visit our website to watch the replay or review the slide presentation. We think you will find the clinical data quite compelling. VS-7375 is a highly selective, potent, oral, dual KRAS G12D on/off inhibitor with a long residence time on the target. These attributes are key to a strong efficacy and tolerability profile that may provide deeper tumor reductions and improved quality of life compared with pan-RAS inhibitors for patients fighting difficult-to-treat cancers, such as pancreatic cancer. As Dan Paterson said, we have set a new KRAS G12D benchmark for a potential best-in-class profile with both compelling efficacy and a highly manageable tolerability profile.
Progress in our CRC cohort is in an earlier stage, but we've shown that we can combine with EGFR inhibitors and are seeing early anti-tumor activity. In lung, while the data we've shared to date is at 600 mg and our go-forward dose is 900 mg, as more data are generated, we expect to see the same dose response in non-small cell lung cancer as we have seen in other tumors. A quick reminder on our data. All patients who receive 900 mg are included in our dataset, meaning this is a modified intent-to-treat analysis, so-called MITT, which is what the FDA looks at. Secondly, all responses are confirmed, again, the way FDA and other regulators judge responses. Now, jumping to our waterfall plot for PDAC patients in the 900-mg monotherapy cohort. First, none of the patients on the study saw their tumors grow.
Second, four out of the eight patients who had second-line pancreatic cancer and had confirmed responses, and five out of the 14 patients who had third and fourth line disease had confirmed responses. We also want to call out the unprecedented nature of all confirmed responses from a 22-patient dataset of patients with heavily pretreated PDAC, including two single-agent complete responses. Here, we demonstrate the durability in the PDAC cohort with this swimmer plot. This highlights the need for multiple scans before observing a response in some patients, but note that all responses are continuing except for one. That patient had progressive disease based on his CT scan, but is continuing many months now with stable disease and minimal side effects. In fact, he remains on the study today. Overall, we had 16 out of the 22 patients continuing with treatment at the time of the data cut.
We are highly encouraged that with a median follow-up time of 6.4 months, we have not yet hit the median progression-free survival, and this is well beyond the 4.3 months PFS that was observed in third or fourth line PDAC in daraxonrasib's phase I trial. To clarify, RevMed has not disclosed their actual PFS or overall survival for their KRAS G12D PDAC dataset from their phase III study, so we don't have a clear picture of a benchmark for second line. But we do know that our ORR, namely 50% in second line PDAC, is higher than the 24% ORR that daraxonrasib had in the second line setting in the KRAS G12D population. Let me reiterate. With a 67% landmark six-month PFS rate, we feel confident that we are just beginning to uncover VS-7375's true potential and believe the trends in anti-tumor activity will continue to mature positively.
While it's difficult to draw conclusions from direct comparisons between our data and that generated for other G12D-selective or pan-RAS inhibitors, we've included key data points for ease of reference. In the second line, as noted above, we broke ground with a 50% confirmed ORR, standing above daraxonrasib's 24% ORR in KRAS G12D-driven tumors recently disclosed in their FDA approval documents. In the third line for us, we observed 36% confirmed ORR with VS-7375, while daraxonrasib demonstrate 21% in the third and fourth line G12X population, which leads us to believe that in the G12D, specifically the ORR, is very likely to be lower for daraxonrasib relative to VS-7375, given the worse outcomes for patients experienced.
Looking across other molecules and data points on the slide, and including updates from ESMO, we believe that VS-7375 has best-in-class potential, and we look forward to building upon that in the phase II trial. Transitioning now to CRC, colorectal cancer, while the data are still early, we cleared the 600-mg dose and are encouraged by the anti-tumor activity at the 900-mg dose level. We will provide an update on this CRC cohort with 10 patients' worth of data in the coming months, dependent on CT scan schedules, but remain encouraged that five out of these six patients remain on treatment. Of the six patients in the MITT analysis, 33% demonstrated a response with median follow-up of 6.1 months. As you can see in this waterfall plot, every patient experienced tumor shrinkage, incredibly encouraging to see in heavily pre-treated colorectal cancer.
Next, we'll turn to lung at the 600 mg dose level. With a 43% confirmed overall response rate, strong durability, and a favorable tolerability profile compared to other available therapies, we believe these data support the potential for accelerated approval with VS-7375. While one patient's tumor is slightly growing, our waterfall is still compelling, with one patient closing in on a potential complete response. Patients previously treated with taxanes are in the gold bars, and we see great responses in these patients as well as in the other subgroups. Now looking across the swimmer's plot, you will see that responses tended to occur very quickly. As of this data cut, all partial responses were observed in the first scan, and we feel very good about how well VS-7375 is penetrating the lung tumors as shown here.
Lung cancer generally is more susceptible to these therapies, and every one of the partial responses here is confirmed and continuing. Moving to frontline lung. These are the first eight patients treated with VS-7375 at the 600 mg dose, along with standard of care chemoimmunotherapy. We have achieved a 75% overall response rate to date. Some of these responses are confirmed, some of these unconfirmed, and some of these responses are just with KEYTRUDA because the patients who had a high PD-L1 or TPS score are indicated to receive KEYTRUDA monotherapy. The expected ORR in G12D lung cancer overall using upfront chemoimmunotherapy is on the order of only 35%-40%. To reiterate then, these KRAS G12D adenocarcinomas therefore fare much worse than the overall population with triplet treatment, and that's because G12D is a bad actor.
Very early data, but very exciting and a consistent water-only fell profile. Finally, I will cover the key points from our safety and tolerability profile from the 900 mg dose level across 48 patients in the phase I trial. Patients were consistently able to stay on the 900 mg dose, as best highlighted through the dose modification statistics. Only a single patient, or 2%, discontinued treatment due to either a treatment-emergent or treatment-related adverse event. Coupled with the median relative dose intensity of 97%, we believe VS-7375's profile is extremely favorable compared to any class of targeted therapy. The vast majority of adverse events are gastrointestinal in nature, and because the tolerability profile at 600 and 900 mg are practically identical, there is no reason for a dose reduction, as it doesn't lead to a reduction in GI adverse events.
Therefore, we consistently see dose interruption rates higher than reductions. A short interruption of two to four days can mitigate and effectively manage these AEs, supported by VS-7375's favorable half-life, long residence time, and a 97% dose intensity. Patients who stop the drug temporarily then restart at the full 900 mg dose. Another important note is the lack of grade 4 or 5 treatment-related adverse events. Only 10% of patients experienced a grade 3 treatment-related event. While the predominant adverse event, again, of VS-7375 are gastrointestinal disorders, only one patient experienced a grade 3 GI TRAE, namely transient nausea, which rapidly responded to therapy. Looking deep at GI events, the most frequent were nausea, diarrhea, and vomiting. These were predominantly grade 1, with around 10%-20% of patients experiencing a grade 2 GI AE.
Beyond GI AEs, VS-7375 showed a very low rate of rash and no reported mucositis or stomatitis in this study, highlighting a potential tolerability advantage versus pan-RAS inhibition. As we look ahead to our future development plans and approaches, we believe that the safety data seen to date demonstrate VS-7375 is highly combinable and eventually can address a very wide population with KRAS G12D-driven cancers. Now, let's talk about our broad ongoing program where we've made great progress. We have three ongoing phase II trials that TARGET-D 200 series in pancreatic, lung, and colorectal cancer that are enrolling patients. We expect to complete enrollment in pancreatic and colorectal cancer around the end of the year, and in the first half of 2027 for the lung trial. We then move to the frontline phase III, which is the ultimate goal here.
We are very cognizant and focused in that we want patients to have the best chance to get their tumor under long-term disease control by moving expeditiously to the front. Along those lines, we recently reached agreement with the FDA on the protocol of the frontline phase III TARGET-D trial in PDAC, and we expect to initiate the trial before the end of 2026. In parallel, we look forward to reaching alignment with the FDA on the protocol for the frontline phase III TARGET-D trials in CRC and non-small cell lung cancer, and plan to initiate these trials in the first half of 2027. Before I hand it off to Dan Calkins, I want to spend a few minutes on the unique trial design of our phase III first-line PDAC trial, TARGET-D 301.
It's a three-arm trial, one-to-one-to-one randomization, so two-thirds of the patients will be getting VS-7375 up front. One-third will be getting standard chemotherapy. We went to the FDA with the argument that it is medically suboptimal for any patient in this day and age not to have at least a chance to get a RAS inhibitor if they have pancreatic cancer. As such, the FDA agreed to allow patients on the chemo arm to cross over once their tumor progressed based on independently reviewed CT scans. Given that all patients, therefore, had the opportunity to receive VS-7375 initially or on crossover, it becomes a study essentially of 7375 in the front line versus getting the drug in the second line. That makes overall survival as an endpoint very difficult to interpret. It confuses the endpoint, and FDA agreed with this logic.
So far, as far as we are aware, for the first time ever, the FDA have allowed a phase III randomized controlled trial for approval in frontline pancreatic cancer to move overall survival to a secondary endpoint. The FDA also have allowed us to include overall response rate as a dual primary endpoint. Some of you are aware of the program the FDA has called the Project FrontRunner Program, where you are allowed to potentially go to the FDA with data in hand and discuss the results of ORR analysis with them. We do not have explicit agreement that the FDA will accept an accelerated approval based on ORR from this study, but the FDA has allowed ORR to be one of the dual primary endpoints. In fact, the FDA has also allowed other companies to include ORR in their primary endpoints in metastatic pancreatic cancer.
Now, we have the potential to use the Project FrontRunner Program to garner accelerated approval in frontline disease. This is potentially very important, as ORR will mature before the other dual primary endpoint, which is progression-free survival. We believe these elements are really good for patients who have a very serious disease, PDAC, and recognize and applaud the flexibility of the FDA in this rapidly changing landscape. We are actively contracting this trial across multiple international sites, and reception has been extremely positive. It's why we expect to open this phase III TARGET-D 301 trial by the end of the year, as I mentioned. With that, I'll turn the call over to Dan Calkins.
Thank you, Michael. Our full financial results are included in our press release, so I'll focus on the highlights here. For the third quarter of 2026, we recorded $24.0 million in net product revenue, a 114% increase when compared to the third quarter of 2025. Product cost of sales for the quarter were $3.7 million, an increase in line with the year-over-year increase recognized in net product revenue. Research and development expenses were $68.8 million for the third quarter, increasing as expected from the second quarter of 2026. These expenses continue to be driven by the ongoing phase I/II TARGET-D 101 clinical trial and the three phase II TARGET-D clinical trials in the U.S., as well as the costs associated with clinical supply and drug production activities related to our expanded VS-7375 program.
SG&A expenses were $26.5 million for the third quarter of 2026, and roughly in line with the second quarter. These expenses continue to be driven by commercial activities and operations, including personnel-related costs to support the ongoing CO-PACK launch. We look forward to building on the CO-PACK launch and progress into 2027, and as of Q3 of 2026, the LGSOC franchise is self-sustaining from a commercial operations standpoint. We continue to expect SG&A expenses will remain consistent on a quarterly basis in the fourth quarter of 2026, as we remain disciplined in our expense management while making the right investments to support the ongoing commercial launch efforts. For the third quarter of 2026, non-GAAP adjusted net loss was $72.8 million, or $0.72 per share diluted, compared to non-GAAP adjusted net loss of $39.1 million, or $0.53 per share diluted for the third quarter of 2025.
Please see our press release for a reconciliation of GAAP to non-GAAP measures. Moving to the balance sheet, we ended the third quarter of 2026 with cash equivalents, and investments of $172.8 million. Taking into account the $250 million of gross proceeds raised in October, our pro forma cash balance at the end of the third quarter was $422.8 million. Based on our current cash position, proceeds from the October follow-on offering, and expected revenues from the AVMAPKI FAKZYNJA CO-PACK sales, we believe we have the capital to fund operations into the first half of 2028 and deliver on our strategic priorities and key milestones, including completing our VS-7375 phase II studies and starting our three pivotal phase III studies in pancreatic, colorectal cancer, and non-small cell lung cancer. With that, let me now turn the call back over to Dan Paterson.
Thanks, Dan. Before we open the call to Q&A, I'd like to reiterate that our focus remains clear for the remainder of the year and as we enter 2027. Drive strong execution of our commercial strategy to expand adoption of AVMAPKI FAKZYNJA CO-PACK and continue to strengthen adherence. Expand clinical evidence of VS-7375's compelling and robust responses, with plans to share data from the phase I and II TARGET-D trials throughout 2027. Accelerate development of VS-7375 through completing enrollment in all VS-7375 phase II trials. We're excited about the three potential accelerated approval trials ongoing in the second line of each of these diseases, but the frontline is our ultimate goal and where we believe patients will receive the most benefit from VS-7375 treatment.
We plan to open the phase III TARGET-D 301 first-line PDAC trial by the end of 2026, and we look forward to reaching alignment with the FDA on the protocols for the frontline phase III TARGET-D trials in CRC and non-small cell lung cancer, and plan to open these trials in the first half of 2027. I'm proud of the progress we've made this quarter, reflecting the continued disciplined execution across the organization. We look to further optimize our commercial business and penetrate the considerable opportunity remaining in LGSOC, while building on our dataset in KRAS G12D mutated solid tumors and uncovering additional value-creating milestones with VS-7375. With that, we'll open the call for questions. Operator?
Thank you. To ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. First, we have a question from Cantor. Caller, please go ahead and introduce yourself and ask your question.
Oh, thanks. It is Eric Schmidt. First, congrats to Dan P. on 16 years at Verastem, and if this is his last call, he is certainly going to be missed. My question is around next updates around VS-7375 in either pancreatic, colorectal, or non-small cell lung cancer. I think at your R&D event last month, we had expected possibly to get some additional phase I-B data before seeing more phase II potentially accelerated approval supporting results in 2027. Can you just remind us what would be the next updates across each of the histologies and what form those might take place? Thanks.
Sure. Thanks, Eric, for the question. Julissa, why do not you give kind of top level and then
Yeah
Michael can give a little more detail.
Sure. Yeah. I think if we look to the first of the year, we are planning to give an update across the program. We will have some PDAC data. We will give an update on the colorectal cohort that we just waited for some more follow-up on the patients. Michael can comment more on that. Then a little bit on the lung side of things, we are planning for multiple medical meetings. We anticipate in the next couple of months will be multiple updates across the program.
Yeah, I don't have much to add. We're really looking at the scheduled CAT scans, and we'll provide an update. I think we're primarily going to move to a medical conference-based update for most of the studies, but we'll give other updates as appropriate.
Maybe thanks, and just one follow-up. What would be rate-limiting right now to starting patient enrollment in the pivotal study in frontline PDAC? Thanks.
We're contracting. We're actively contracting and scheduling SIVs. We're in the midst of it, and as soon as we get the sites open, they have to go through their site initiation visits. As soon as that happens, we'll begin screening for G12D frontline, and we'll get the patients going. It's just logistics at this point.
Thank you, Michael.
Thank you. Next, we have a question from Guggenheim. Caller, please go ahead and introduce yourself and ask your question.
Hi, this is Michelle on for Michael Schmidt. Thank you so much for taking our question. I just had a question around TARGET-D 303. With RevMed starting its own first-line G12D colorectal phase III, I was wondering if you could touch on if that changes anything about your TARGET-D 303 design ahead of the upcoming FDA meeting, and just generally how you're thinking about differentiation there. Thanks.
Yeah. Thanks for the question. Michael, m aybe since you're in the midst of this, why don't you give a quick comment?
Yeah, we're set to meet with FDA in the coming months. We expect this study to start off in the first half of the year. It absolutely doesn't change a thing to us. We believe we have the strongest G12D inhibitor out there for all the reasons that you all saw in October and in this presentation, and we're excited about starting that study as soon as we can.
Thanks.
Thank you. Next we have a question from Jefferies. Caller, please go ahead and introduce yourself and ask your question.
Hey, thank you guys. I also just want to extend my congratulations as well on the well-deserved retirement. I have two quick ones. For the TARGET-D 301 study, you have an interesting kind of piece of the enrollment here that says that one cycle of standard of care therapy is allowed before enrollment into the study. Can you just educate us on what advantage this provides compared to sort of a typical inclusion/exclusion criteria? Then we have one follow-up. Thank you.
Yeah, Michael, why don't you take that? It's really a logistics thing, but go ahead.
Yeah, exactly. I mean, depending on the site and the turnaround time and samples and so on, getting the G12D genotyping done in time, we don't want patients to have to sit around and wait. The last thing you want to do when you've gotten this diagnosis is to have to bite your nails and have therapy held up. So, as advised by all of our key opinion leaders, and this is true across, frankly, all of our frontline studies, patients can receive a single cycle of standard of care therapy before enrolling, and then they'll get onto whatever randomized cohort they are in order to make sure this drug is available to the most patients possible.
Got it. Excellent. And then, with respect to the breakthrough therapy designation discussions, can you just give us an update on at what point you expect those discussions to occur? Thank you.
Well, I mean, we're in a lot of dialogue with FDA across all three diseases. Obviously, colon and pancreatic are with the D203 group there. And what we want to do when we go in for breakthrough therapy is to have the longest DOR possible, and we want to beat the pants off the competition. So you guys know all the metrics. We will attempt to surpass those metrics with our drug, and then we'll have those discussions. Should be a lot easier.
Sounds great. Thank you.
Thank you. And next we have a question from RBC. Caller, please go ahead and introduce yourself and ask your question.
Hey, guys. It's Leo from RBC. Thanks for taking my question. Just wanted to ask on sort of the accelerator approval, but maybe from a different angle. Assuming that the FDA is amenable and you actually are able to get an ORR-based approval, just how would physicians view it on the ground given that this is typically an indication that's required, more time-driven data? I guess, how would you compete if you had ORR, but some competitors had PFS or OS as something that would require education? Or do you think that there's opportunity for you guys to educate around some of the advantages? Thanks.
Yeah, thanks for the question. My view on this is the results of the drug are going to speak for itself. The feedback we're getting from physicians is just incredible. Michael, you're closest to it, but I don't know if you want to add any more color, but it'll be a short-term issue that I'm not sure is going to be a problem at all.
Yeah, and I think there's a few, maybe for me, a little bit more elaboration. First thing is, we've seen actually an uptick in accrual to our phase II study, not only in the second line, but in the front line setting. We actually over-enrolled our front line cohort in G12D, and there's uniform agreement across our sites that patients could potentially enjoy a similar kind of outcome or better on an efficacy side. But obviously, our safety profile is very, very different than what you see with a pan-RAS inhibitor, including RASONQUE, which is approved. So people, at least right now, in terms of the trial, are putting patients on the trial with no trouble at all. We will certainly, in the label, expect that it'll be ORR plus duration of response, so they will have a little bit of that insight.
And in the publication, wherever it were to come out, there will be additional data which people can refer to, including PFS and OS for this cohort. We'll certainly be providing all those data at medical meetings. So while we won't be able to commercialize on anything outside of the label, we certainly will be able to speak medically about this, and people will have access to all those data. In addition, we'll have on the label the safety profile, which we believe is very clean and really reflects primarily GI tolerability and no real significant other issues. So I don't think doctors and patients are going to have a lot of trouble discerning which kind of drug, if you have a G12D pancreatic cancer, they might want to go on first.
Thank you. Next we have a question from Mizuho. Caller, please go ahead and introduce yourself and ask your question.
Hi, this is Sam on for Graig. Thanks for taking our question. Maybe one on AVMAPKI FAKZYNJA, sorry. The press release mentioned something about the episodic nature of treatment persistence. Given the quarter, just curious if there's been any changes in terms of median months on therapy versus what we saw in RAMP 201 in terms of duration of treatment.
Hey, Sam. Thanks for the question. We are seeing improvements. Dan, if you want to give a little more detail around that.
Yeah, thanks for the question, Sam. In terms of any changes in duration on treatment, I mean, again, I want to remind everyone, we are still in the first full year of our launch. As patients are joining, seeing how long they are on the medicine varies from when they start, and obviously, their time on therapy. We saw really encouraging activity from a refill perspective, the persistency of the drug in the third quarter, and that, I think, we can contribute to the work across our field teams in driving that third priority of keeping patients on therapy and expanding persistence. So nothing to note there, Sam.
That's helpful. Thank you.
Thank you. Next we have a question from H.C. Wainwright. Caller, please go ahead and introduce yourself and ask your question.
Hi, guys. It's Andres from H.C. Wainwright. I want to also congratulate Dan on a great career, and we wish him the best of luck in his endeavors. Two quick ones from us. I guess in the context of the recent R&D update and the subsequent update from GenFleet, how is your thinking on either correlation or the divergence of those two datasets in the context of upcoming readouts? I want to really probe them. How much read-through is there between those datasets? Is that going to continue, or where do you see the biggest points of divergence? Then maybe a quick one on the CO-PACK. Just trying to understand the conversion to the blister pack. The impetus there is it just for ease of use, or how much could that either increase new patient starts, increase durability?
Just trying to get a sense of when it goes online potentially, what do sales look like? What should we account for there? Thank you very much.
Yeah, thanks for the questions. I'll take the second one first. It is kind of a complex dosing regimen, and we think having the blister pack will just make it much easier for patients. In our original formulations where we launched, one of the drugs was refrigerated and the other was room temperature. Those complications, especially for patients, and Dan mentioned the seasonality, going on vacation, going around, it's a pain. This is going to be a lot easier for people to take. Also, we can't underestimate the impact of now having a specific pill size so they don't have to take multiple pills. We think it's going to be really convenient for patients and will help a lot. I don't know, Dan, if you want to say anything more about that.
Yeah, you covered a lot there, Dan. I think when you think about when this will launch in the first half of next year, one, I think this is a transition that we will make very well from moving patients from the CO-PACK to the blister pack. It provides an opportunity for patients to have, as Dan said, a reduced pill burden, the ability to travel with the drug better because it doesn't require refrigeration. Just managing your treatment and your doses is easier in a blister pack. The other thing that I would add is that as you look at the future for AVMAPKI and FAKZYNJA, one of our core priorities is to make sure that patients are able to stay on their therapy. This is a clear improvement for patients in that way.
We're very excited about what the blister pack's going to bring, and it's a core focus for our teams in 2027. Michael, I think the first question was for you.
Yeah. Not a lot to say about it. I think the GenFleet data have generally been directionally helpful. They've seen activity across PDAC, lung, and CRC, as have we. I think specifics on response rates and that sort of stuff are not helpful across the ocean. Certainly on the safety side, tolerability side, for reasons that remain frankly pretty unclear, we've just seen a much, much cleaner safety profile. I'm happy to tell you all on the phone, that safety profile continues to be what it was a couple of weeks ago. I mean, we've got patients that are just continuing on therapy, some crossing a year now, and no cumulative toxicities and so on. I think it's helpful directionally, but I wouldn't use those data for our U.S. and Europe, what will become Europe soon, focus cohorts in any quantitative way.
Thank you. Next we have a question from B. Riley. Caller, please go ahead and introduce yourself and ask your question.
Hi, this is Liwen on for Yuan. Our question is about the G12D inhibitors. Some of other inhibitors will have the rash signal, and can we talk a bit about what level of rash would not be tolerable when we have the skin toxicity contribution from both G12D inhibitor and the EGFR inhibitor? How should we think about maybe like a grade 3 rash? Is that significant enough? Thanks for taking our question.
Well, I mean, we see very little, if any, rash with our G12D inhibitor, and the kind of rash you see with cetuximab is just fundamentally different than what you see with the pan-RAS. I mean, Michael, you treat patients and see this all the time. I mean, it's just-
I think it's not-
night and day
It's not good to get too much mixed up. I mean, cetuximab has been around for decades, and as has panitumumab, and the rashes from those are largely acneiform, and hence the name, they respond to acne medications and prophylaxis with the standard minocycline, doxycycline, and a little bit of steroids here and there. Very easily handled, very easily. Almost no patient stops those drugs due to rash. It's not an issue. Grade 3 rash is a significant medical condition with major skin breaks, bleeding, and easily leading to infections and bloodstream infections, including bacteremia and so on. Those are out of our discussion. We've never seen anything like that. Our rash rates, I mean, we had a couple of cases. One was, I think, pruritus. I think it was absolutely transient.
It's not clear to us, frankly, both rashes were transient on monotherapy, and the cetuximab is just not even a discussion with the doctors. I don't think we should really mix these kinds of rashes. Unfortunately, pan-RAS-based rashes are difficult to manage, and we're all aware of cases of patients who just go around suffering, and there's not much to do. The other point, rash and mucositis are similar. Mucositis is basically a rash inside your mouth. We have no mucositis or stomatitis at all, which is very different than the pan-RAS inhibitors.
Thank you. Next we have a question from Wolfe Research. Caller, please go ahead and introduce yourself and ask your question.
Hey, this is [Gugen] on for Kalpit. Thanks for taking our question. Regarding the cadence of site openings for the 1L PDAC phase III, do you expect meaningful overlap with some of the other developers in the space? And if you can comment, how many sites are you targeting by six months to one year from now? Thanks.
Michael, do you want to
Yeah. I mean, we're scaling that. Typically, these phase IIIs are 100 sites, so give or take, that's a nice round number for you all to take. We don't see any. Like I said, phase II, there's plenty of competition right now in the second-line PDAC space, and in frontline, obviously, including on the market. We've just not seen a slowdown. And we'll update you guys with our accruals, we've said, by the end of the year for both colorectal and pancreatic. So, there's a lot of interest in this drug. I don't think there'll be a problem.
Thank you. Next, we have a question from BTIG. Caller, please introduce yourself and ask your question.
Great. This is Jeet Mukherjee. Thanks again for taking the question, and congrats on the progress. You obviously have the benefit of having ORR and PFS as dual primaries for your frontline PDAC phase III. However, I did notice your competitors at Incyte seem to be pursuing their frontline PDAC study with PFS and OS as co-primaries. I guess I was just trying to understand this difference. Is there something about your molecule that the FDA saw that kind of had them agree to this particular design? Ultimately, is your design one that your competitors could avail themselves to? Thanks.
Yeah. I think in general, what we've seen at the agency is a lot of cooperation because of the tolerability of the drug and the efficacy of the drug. You start there, and I don't want to say you get cut a break, but they look at it, and they look at the risk-benefit to patients, and have been very cooperative in moving this forward. I know, Michael, you've been in the middle of those discussions. I don't know if there's anything more you want to add.
Yeah. If you remember, when you have a CR, a complete response, and we had a couple and have a couple, they're both doing great on the study, continuing to do great in the third and fourth line, and we fully expect to have, in earlier line studies, complete responses. This is a different ballgame from the agency. To eradicate the tumor on a CAT scan that has a detection limit of somewhere around 5- 8 mm, and not have detectable tumor, and those patients all have CA19-9 levels that are normal, starting in the thousands, going down to below 40. This is a different kind of a drug. Our 41% overall response rate compares favorably to the confirmed rate of about 29%, 30% for zoldonrasib and for Incyte for G12D, and they didn't have complete responses. They also note that our waterfall plot showed water falling only.
It's a pure waterfall. They haven't seen it. As Dan said, FDA, we made these points to FDA. They apparently agreed because they agreed with our plan. I also point out that the reason OS was moved to a secondary is that we want to provide patients who literally put their lives on the line in the control arm, we want to allow them to cross over to our drug and be followed in our study, but with the benefit of getting 7375 in the second line. They agreed with that, and therefore, they agreed to move OS down out of the primary endpoint into secondary.
Yeah. I mean, Michael and I have both been at this for a long time. I obviously a little longer, which is why I'm retiring. But I never thought I would see a day where pancreatic cancer was treated with an oral pill with relatively minor side effects. I mean, you never could have envisioned this 30 years ago, or even five years ago.
Thank you.
Thank you. Our final question comes from AGP. Caller, please introduce yourself and ask your question.
Hi, guys. This is Matt at Alliance Global. Congrats on the progress, and congrats, Dan, on the well-deserved retirement. I wanted to ask when we might expect VS-7375 plus gem/nab data, initial data from patients there, and whether the intensity of chemo that you can achieve there might be a differentiator for you versus your competitors. Thanks.
Yeah, very good. Q1.
Early Q2, yeah.
Early Q2, somewhere next year early. It's wonderful. I mean, we're at full dose intensity on VS-7375, full dose on gemcitabine, no skip doses, no reduction there, and full dose on the ABRAXANE as well. So, our side effect profile is such that we can easily combine. By the way, we will likely be able to achieve full dosing on all of our chemotherapy combinations. We haven't cleared all that yet, but we probably will.
Great. All right. Thank you guys for taking the questions.
Thank you. This concludes our question and answer session in today's conference call. Thank you for participating, and you may now disconnect.