Verastem, Inc. (VSTM) Q3 2026 Earnings Report, Transcript and Summary

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. [Operator Instructions] 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'll 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'll 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're encouraged by the progress we've 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's still considerable opportunity to be realized for the CO-PACK. While we continue to see a positive impact from the changes we've made throughout the commercial organization, we're making additional efforts to gather feedback from physicians to understand patient experiences and educate on new and existing initiatives. We're 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 antitumor 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-milligram 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 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 Phase II trial readouts and initiation of 3 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'll 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'll continue serving on the company's Board of Directors and as an adviser. 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'm extremely proud of all that we've accomplished in my 15 years at Verastem. Our work has benefited patients, physicians, families and the broader health care system, and I have great confidence that we'll continue to make positive impact with our promising future ahead. With that, I'll 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 a 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 3 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 1 to 4 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 are heavily pretreated 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 4 0.8 milligram 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 the 3 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 antitumor activity. In lung, while the data we've shared to date is at 600 milligrams and our go-forward dose is 900 milligrams, 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 received 900 milligrams are included in our data set, 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-milligram monotherapy cohort. First, none of the patients on the study saw their tumors grow. Second, 4 out of the 8 patients who had second-line pancreatic cancer and had confirmed responses and 5 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 data set of patients with heavily pretreated PDAC, including 2 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 response in some patients, but note that all responses are continuing except for one. That patient had progressive disease based on the 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 data set 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 6-month PFS rate, we feel confident that we are just beginning to uncover VS-7375's true potential and believe that trends in antitumor activity will continue to mature positively. Now 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 [ frst ], we observed 36% confirmed ORR with VS-7375, while daraxonerasib demonstrated 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 worst outcomes for patients experience. 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-milligram dose and are encouraged by the antitumor activity at the 900-milligram dose level. We will provide an update on the CRC cohort with 10 patients worth of data in the coming months, dependent on CT scan schedules, but remain encouraged that 5 out of these 6 patients remain on treatment. Of the 6 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 pretreated colorectal cancer. Next, we'll turn to lung at the 600-milligram 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 swimmers 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 8 patients treated with VS-7375 at the 600-milligram dose, along with standard of care chemo immunotherapy. 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 chemo immunotherapy is on the order of only 35% to 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. So again, 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-milligram dose level across 48 patients in the Phase I trial. Patients were consistently able to stay on the 900-milligram 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 the 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 milligrams 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 2 to 4 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 stopped the drug temporarily then restart at the full 900-milligram 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 events again of VS-7375 are gastrointestinal disorders, only 1 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% to 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 the 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 3 ongoing Phase II trials, the 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 and 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 3-arm trial, 1:1:1 randomization. So 2/3 of the patients will be getting VS-7375 upfront. 1/3 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 progress based on independently reviewed CT scans. Given that all patients, therefore, have 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 has allowed a Phase III randomized controlled trial for approval in frontline pancreatic cancer to move overall survival to a secondary endpoint. FDA also have allowed us to include overall response rate as a dual primary endpoint. Some of you are aware of the program FDA has called the FrontRunner program, where you're 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 FDA will accept an accelerated approval based on ORR from this study, but FDA has allowed ORR to be one of the dual primary endpoints. In fact, FDA has also allowed other companies to include ORR in their primary endpoints in metastatic pancreatic cancer. So now we have the potential to use the 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. And 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 and increased 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 3 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 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, 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 3 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 3 potential accelerated approval trials ongoing in the second line of each of these diseases, but the front line 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 data set 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?

[Operator Instructions] First, we have a question from Cantor.

It's Eric Schmidt. First, congrats to Dan on 16 years at Verastem. And if this is his last call, he's certainly going to be missed. My question is around next updates around 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 Ib 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?

Sure. Thanks, Eric, for the question. Julissa, why don't you give kind of top level and then Michael can give a little more detail.

Sure. Yes. So I think if we look at the first of the year, we're planning to give an update across the program. So we'll have some PDAC data. We will give an update on the colorectal cohort that we just wait for some more follow-up on the patients. Michael can comment more on that. And then a little bit on the lung side of things, we are planning for multiple medical meetings. So we anticipate in the next couple of months, we'll be multiple updates across the program.

Yes, I don't have much to add. We're really looking at the schedule of 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 study, but we'll give other updates as appropriate.

Maybe -- and just one follow-up. What would be rate limiting right now to starting patient enrollment in the pivotal study in frontline PDAC?

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. There's really -- it's just logistics at this point.

And next, we have a question from Guggenheim.

This is Michelle on for Michael Schmidt. 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?

Yes. Thanks for the question, Michael -- maybe since you're in the midst of this, what...

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 in this presentation, and we're excited about starting that study as soon as we can.

And next, we have a question from Jefferies.

And I also just want to extend my congratulations as well on the well-deserved retirement. I have 2 quick ones. For the TARGET-D 301 study, you have an interesting kind of piece of the enrollment here that says that cycle of standard of care therapy is allowed for enrollment into the study. Can you just educate us on what advantage this provides compared to sort of a typical inclusion/exclusion criteria? And then we have one follow-up.

Yes, Michael, why don't you take that. It's really a logistics thing, but go ahead.

Yes, 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 misdiagnosis 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 on to whatever randomized cohort they are in order to make sure that 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?

Well, I mean, we're in a lot of dialogue with FDA across all 3 diseases, obviously, colon and pancreatic are with the DO3 group there. And we want to -- 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 -- you 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.

And next, we have a question from RBC.

It's Leo from RBC. Just wanted to ask on sort of the accelerated approval, but maybe from a different angle. So assuming that the FDA is amenable and you actually are able to get an ORR-based approval, 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 is something that would require education? Or do you think that there's opportunity for you guys to educate around some of the advantages?

Yes. Thanks for the question. Just my view on this is the results of the drug are going to speak for itself. And 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. It will be a short-term issue that I'm not sure it's going to be a problem at all.

Yes. I think there's a few -- maybe for me a little bit more elaboration. I mean the first thing is we did -- we've seen actually an uptick in accrual to our Phase II study, not only in the second line, but in the frontline setting. We actually overenrolled our frontline 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 are 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 will 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. And 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.

Next, we have a question from Mizuho.

This is Sam on for Greg. Maybe one AVMAPKI FAKZYNJA. The press release mentioned something about episodic nature of treatment resistance. Given the quarter, just curious if there's been any changes in terms of -- in the median months on therapy versus what we saw in RAMP 201 in terms of duration of treatment?

Sam, thanks for the question. We are seeing improvements. I don't know, Dan, if you want to give a little more detail around that.

Yes. 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. And so 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 attribute 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.

And next, we have a question from H.C. Wainwright.

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 next 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 the either correlation or the divergence of those 2 data sets in the context of upcoming readouts. So want to really probe them, how much read-through is there between those data sets? Is that going to continue? Or where do you see the biggest points of divergence? And 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?

Yes. 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. And in our original formulations where we launched, one of the drugs was refrigerated and the other was room temperature. And those complications especially for patients, and Dan mentioned the seasonality, going on vacation, going around, it's a pain. And so this is going to be a lot easier for people to take. And also, we can't underestimate the impact of now having a specific pill size, so they don't have to take multiple pills. So 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 add any more.

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 and the ability to travel with the drug better because it doesn't require refrigeration and just managing your treatment and your dose 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. And so we're very excited about what blister pack is going to bring, and it's a core focus of our teams in 2027. Michael, I think the first question was for you.

Yes. Not a lot to say about it. I think the GenFleet data have generally been directionally helpful. We've seen -- they've seen activity across PDAC, lung and CRC as if we. I think specifics on response rates and that sort of stuff are not helpful across the ocean. And certainly, on the safety side, tolerability side, we've -- for reasons that remain, frankly, pretty unclear, we've just seen a much, much cleaner safety profile. And I can 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 don't think -- I wouldn't use those data for our U.S. and Europe, what will become Europe soon focused cohorts in any quantitative way.

And next, we have a question from B. Riley.

This is Liwen on for Yuan. Our question is about the G12D inhibitor. So some of other inhibitors will have the rash signal. And can we talk a bit about like what level of rash would not be tolerable when we have the skin toxicity contribution from both G12D inhibitor and the EGFR inhibitor. So how should we think about maybe like a Grade 3 rash? Is that like significant enough?

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 I mean it's just...

I think it's not good to get mixed too much mixed stuff. I mean cetuximab has been around for decades and as is panitumumab. And those -- the rashes from those are largely acneiform and hence the name, they respond to acne medications and prophylaxis with the standard minocycline, doxycycline, a little bit of steroids here and there, very easily handled, very easily. Almost no patient stops those drugs due to rash. So that -- 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 should -- those are out of our discussion. We've never seen anything like that. We -- 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. So 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. So we have no mucositis or stomatitis at all, which is very different than the pan-RAS inhibitors.

And next, we have a question from Wolfe Research.

This is [Gugen] on for Kalpit. 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 6 months to 1 year from now?

Mike, do you want to...

Yes. 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, the 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. I mean 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.

And next, we have a question from U.S. Bancorp BTIG.

This is Jeet Mukherjee. Congrats on the progress. So 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. So 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? And ultimately, is your design one that your competitors could avail themselves to?

Yes. 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. It's -- 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.

Yes, if you remember, when you have a CR complete response and we had a couple and have a couple, they're both doing great on the study, continue 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 to 8 millimeters 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. And I also point out that the reason OS would move to a secondary is that we want to provide patients who put their -- 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. And they agreed with that -- and therefore, they agreed to move OS down out of the primary endpoint into secondary.

Yes. 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 5 years ago.

Our final question comes from AGP.

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 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?

Yes, very good. Q1.

Early Q2, yes.

Early Q2, somewhere next year early. It's wonderful. I mean we're at full dose intensity on 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 -- and 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.

Thank you. This concludes our question-and-answer session and today's conference call. Thank you for participating, and you may now disconnect.