Verastem, Inc. (VSTM) Earnings Call Transcript & Summary

Good evening, and welcome to the Verastem Oncology Investor Conference Call on Tuesday, January 24, 2023. [Operator Instructions] Please be advised that this call is being recorded at the company's request and will be available on the company's website for a period of 90 days from today. At this time, I would like to introduce Mr. Daniel Calkins, Vice President of Investor Relations and Finance at Verastem Oncology. Please go ahead.

Thank you. Hello. Welcome, everyone, and thank you for joining us today to discuss the interim data from Part A of the ongoing RAMP 201 international registration-directed Phase II study evaluating the safety and efficacy of avutometinib alone and in combination with defactinib among patients with recurrent low-grade serous ovarian cancer, which will be -- which we will be referring to today as LGSOC. The company will also provide our regulatory update following a productive meeting with the FDA. Today's speakers include Brian Stuglik, our Chief Executive Officer; who will provide an introductory remarks in -- regarding LGSOC program and the avutometinib and defactinib combination; Dr. Kathleen Moore, Professor at University of Oklahoma Health Sciences Center, Gynecologic Oncologist at University of Oklahoma Health Stephenson Cancer Center and RAMP 201 trial investigator, who will provide an overview of LGSOC, including recent clinical trials; Louis Denis, our Chief Medical Officer, who will summarize the interim data from Part A of the registration-directed RAMP 201 trial; and Dan Paterson, our President and Chief Operating Officer, who will provide an overview of the market opportunity, the outcome of our recent FDA discussions and next steps. Additionally, joining us today is Jon Pachter, our Chief Scientific Officer, who has also joined us in -- after the presentation, we will open up the line to Q&A. Earlier today, we issued 2 press releases: the first announcing a private placement of the company's Series B convertible preferred stock for gross proceeds of up to $60 million; and a second press release reporting the interim data from Part A of the RAMP 201 study and a regulatory update related to the company's LGSOC program. Those press releases are available on our website at www.verastem.com. Following the conclusion of today's call, a PDF copy of the slides being presented will also be available on our website. Before we begin our formal comments, I'll remind you that we will be making forward-looking assertions during today's call that represent the company's intentions, expectations or beliefs concerning future events, which constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Act of 1995. All forward-looking statements are subject to factors, risks and uncertainties, such as those detailed in today's press releases and in our filings with the SEC, which may cause actual results to differ materially from the results expressed or implied by such statements. In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update any such statements. We refer you to the disclosure notice section in the press releases we issued today and the Risk Factors section in the annual report on our Form 10-K and our quarterly filings for a discussion of important factors that could cause actual results to differ materially from these forward-looking statements. With that, I would like to now turn the call over to Brian Stuglik. Brian?

Thank you, Dan. Good evening, everyone, and thank you for joining us on today's call. We are excited to share the interim data from Part A of the RAMP 201 study, the selection of the combination of avutometinib and defactinib as the go-forward treatment regimen and provide an update on next steps for our LGSOC program. With the encouraging results of the RAMP 201 Part A interim analysis and the go-forward treatment regimen selected, we will work expeditiously to prepare to file for an accelerated approval for the combination of avutometinib and defactinib in all LGSOC patients encompassing the totality of the FRAME and RAMP 201 data. We are also in ongoing discussions with the FDA on a confirmatory study, and enrollment in RAMP 201 is continuing to expand the clinical experience in anticipation of initiation of a confirmatory study. Dr. Denis and Dan Paterson will provide additional details in their remarks. Before we jump into today's program, I'd like to take a moment to provide some background on our lead investigational agent, avutometinib, which we believe has the potential to be the backbone of combination therapy across RAS pathway-driven tumors. Avutometinib is a novel RAF/MEK clamp that induces inactive complexes of MEK with ARAF, BRAF and CRAF, potentially creating a more complete and durable antitumor response through maximal RAS pathway inhibition. Avutometinib also offers a novel intermittent dosing schedule and convenient oral regimen with the possibility of better tolerability than currently available MEK-only inhibitors. These characteristics make avutometinib an optimal partner for combination therapy with agents from multiple target classes that may deliver better patient outcomes where they are needed most. Avutometinib in combination with defactinib has received breakthrough therapy designation from the FDA and reoccurring LGSOC regardless of KRAS stats after one or more prior lines of therapy, including platinum-based chemotherapy. There is a compelling scientific rationale, which has predicted that the combination of avutometinib and a FAK inhibitor should yield stronger antitumor responses in LGSOC and another RAS-dependent pathway cancers relative to avutometinib alone. In the left panel, you can see preclinical studies have shown that the inhibition of RAF or MEK activates FAK, focal adhesion kinase as an adaptive resistance mechanism. This activation of FAK can, in turn, activate tumor growth through the AKT, YAP, RhoA pathways, bypassing the efficacy of RAS pathway inhibition. The combination of avutometinib and defactinib may therefore block resistance pathways leading to more complete inhibition of the signaling, which drives tumor growth. In the middle panel, preclinical observations have been validated clinically in patients with KRAS mutant tumors treated with avutometinib and defactinib as shown by increased possible FAK. Treatment with defactinib in addition to avutometinib brought possible FAK down in these patients, alleviating the adaptive resistance mechanism. In the right panel, in preclinical studies, in patients with patient-derived tumor models from patients who both KRAS-mutant LGSOC or KRAS wild-type LGSOC treatment with a FAK inhibitor along with avutometinib resulted in greater tumor growth inhibition and tumor shrinkage than avutometinib alone. I'd now like to turn the call over to Dr. Moore.

Well, good evening, everyone, and I very much appreciate the opportunity to speak to you briefly about the very unique patient population within which we are advancing the avutometinib program, and that is in low-grade serous ovarian cancer. So low-grade serous cancer is an epithelial ovarian cancer, but it's relatively rare. I'm going to take you through why it is unique as compared to what we typically consider ovarian cancer, which is most likely high-grade serous. And its uniqueness is really based on this fact that it is largely RAS pathway driven and is a tumor of high unmet need. And these are just some -- you can see outlined on the left just some factoids that are true about low-grade serous ovarian cancer. It can affect women at any age. So we can't see older women develop low-grade serous ovarian cancer. But we see a lot more women, 30s, 40s, early 50s, developing low-grade serous ovarian cancer. So the preponderance really favors the younger phenotype. You can see that it's 1,000 to 2,000 patients in the U.S. are diagnosed each year in about 15,000 to 30,000 worldwide. But because it is characterized as an indolent tumor, which I don't know that I like because it kind of implies friendly, but that is how we talk about it, it's slow growing, doesn't really respond. But we kind of can keep patients going with a patchwork of therapies for many, many years. And so the prevalence is actually quite high. 10-year prevalence about 80,000 worldwide, 6,000 at any one point in the U.S. with disease on treatment with low-grade serous ovarian cancer. And as I mentioned in the blue highlight is I hate this term, indolent. Even though it's indolent, it doesn't mean that patients are sort of just living their life with this cancer. This can have significant symptoms. These can be incredibly kind of fibrotic, invasive, muscle invasive tumors that don't respond well to typical therapy, and so it leads to significant pain and symptoms that lead to suffering over time. The majority of our research, which has been amazing in the past few years for epithelial ovarian cancer with recently a new indication in high grade serous with mirvetuximab and others in the pipeline, we're very grateful for that, and we heard investment in them. We have made headway and hopefully in the front line as well. But we have -- that is all -- those are all therapies that entirely exclude low-grade serous, PARP inhibitors, antibody drug conjugates. These are not medications that have shown any signal of benefit in low-grade serous ovarian cancer because it is a very histologically and molecularly distinct tumor from high-grade serous ovarian cancer. And you can see the beginnings of that in the figure on the right-hand side, where about 30% of patients with low-grade serous will have a KRAS mutation of a variety of types, which doesn't tend to be important for this agent. But then you'll have 70% with some sort of RAS pathway alteration, and you can see that broken down. But the vast majority of patients will benefit from this class of drug. Next slide, please. This table really breaks down and kind of tries to dichotomize a complicated set of criteria, but it is useful for differentiating low-grade serous ovarian cancer from high-grade serous ovarian cancer in the olden days before Malpica scoring, these were called Grade 1 and Grade 2, 3. We don't use that criteria anymore for serous cancers as they're low grade or they're high grade. And they're very distinct in terms of differences in nuclear atypia, differences in mitotic indices, differences in chromatin and variations in size of the nucleus, but really it differences in mutation. As I talked about in the last slide, low-grade serous are characterized by KRAS and RAS pathway alterations largely. We can see BRAF V600E mutations in this tumor, it's about 10%, but we can see those. And almost ubiquitously, these are estrogen receptor positive and, to some extent, progestin receptor positive, so we do borrow a lot from hormone receptor positive breast cancer literature and try to extrapolate to this population when needed, whereas high-grade serous ovarian cancer has ubiquitous loss of TP53. Like if you don't have loss of TP53, you have to question whether or not it's a high-grade serous ovarian cancer. And then this is where we can see BRCA1 and 2 alterations that is not a feature of low grade at all. It's almost -- it's mutually exclusive. And the precursor lesions vary as well. You can't have precursor lesions low-grade serous, and these are those serous borderline tumors. And then for high-grade serous, we call them TICs. But these tubal intraepithelial neoplasia, we think that many, if not all, high-grade serous ovarian cancer originates in the 2 with loss of TP53. Next slide, please. So this is really, as I mentioned, a group of patients of high unmet medical need. We really have -- even though, for whatever reason, the FDA still considers this in the rubric of epithelial cancer, so approved therapies for ovarian cancer are technically approved for low grade. We know from randomized trials, I'm going to show you in a moment, that those chemotherapies have very limited efficacy in this patient population, unlike high-grade serous where you expect responses to platinum. Like durable, deep complete responses, the paclitaxel et cetera. We don't see that here, and I can demonstrate that to you in the next slide. And so when patients have recurred, we do use those in the frontline paclitaxel and carboplatin. But the time of recurrence, these are our options. Clinical trial #1, obviously. We do have NCCN listings for trametinib and binimetinib. Binimetinib is a Category IIb because of the study. If there's BRAF V600E, which is rare, but we do find that. We can use BRAF MEK inhibition. Endocrine therapy is a mainstay. Chemotherapy is on the list, and you can see all of the regimens that we can try. But if all of these sort of empiric treatment with very limited expectation of benefit. And really, the best thing that we have, our MEK inhibitors, next slide. And we did 2 big Phase III studies. They took 8 years to do. So they're doable, but they take a bit to do. MILO and which was binimetinib. You can see the progression-free survival curve on the left. And Gynecologic Oncology Group Protocol 281 on the right is trametinib. These are similar but different studies. I don't want to take too much time to go through all the nuances, but MILO was recurrent low-grade serous ovarian cancer. The -- it was binimetinib versus physician's choice chemotherapy. So it's only chemotherapy as an option. Progression-free survival was the endpoint, and that was measured by blinded independent radiographic review. GOG 281, also recurrent low-grade serous ovarian cancer with central pathologic review in both. So both had confirmed low-grade serous. Trametinib versus physician's choice therapy, which included the same chemotherapies, but also endocrine therapy, which is important because letrozole probably the most effective thing used in either study and was investigator's assessment for progression free survival. And so the findings were relatively consistent but statistically different enough that MILO is considered a negative study and GOG 281 is considered a positive study, which is why there was a IIb NCCN listing for binimetinib. But both are available, in my opinion, are kind of equally as moderately effective. You can see the response rates here and it may differ based on BICR versus investigator assessment. 26% on investigator response rate, 16% of binimetinib with BICR response rate, and then standard of care 6% versus 13%. So that's the expectation, 6% with chemotherapy alone. And if you add an endocrine therapy, you jump up to a whopping 13%. So this really is a high unmet need population. Now the median progression free survivals are relatively long because it is slow growing. So you do buy kind of cobbled together this [indiscernible] progression-free survival so patients can keep living. But if their quality of life depends on our response, shrinking of tumor, it's -- you don't get it very often. And MEK inhibitors alone are not easy to use. You can see in both very consistent over 30% of patients discontinuing because of adverse events that range from cardiac toxicity to rash and everything in between. So that's a pretty high discontinuation rate that we hope will be improved with this novel combination. Next slide. So this is the FRAME study, and this really kind of sets the stage for development of avutometinib in combination with defactinib. And you saw that mechanistic slide at the very beginning, which is just so important because we are addressing 2 mechanisms of acquired resistance 2 MEK inhibitors alone, one RAS pathway and one FAK. So this really is a science-based combination. And you can see the response rates here in green, confirmed in green, unconfirmed in blue. And several of these in the hash lines, the horizontal hash line, had a prior MEK inhibitor. And here they are with kind of deep and durable responses yet again. The Spider plot, even more the waterfall plots sometimes when they look like this, and you see patients really kind of going out and staying on therapies for 16, 18, 20 cycles in the recurrent setting. That's indicative of a tolerable and effective regimen. So here, you see an overall response rate of 46%, higher than anything I just showed you. I will say this is a smaller sample size that's still 46%. KRAS mutant 64%. TRS wild-type, 44%. Both those are really good. So justification for opening it up beyond just KRAS mutant. Both of those are far better than anything else we have. Certainly, KRAS mutant is a little bit better, but there's really no indication to select with this high of a response rate. And disease control rate, 100%. 100% of patients were stable disease or better. With responses in previously treated MEK inhibitor just really shows the efficacy of this regimen. And your medium progression free survival, I showed you on the past slide, with 8 and 10 months. Now we're 23 months across all low-grade serous. So you know that deviates down a little bit, it's not going to cut in half. So this is really -- this was the kind of Phase I study that Dr. Banerjee did that got us all really excited about the RAMP study, which is running now and leads to really the oncology community's excitement about this combination for our patients who desperately need. It will be predictably effective therapy in this space. So I thank you for your attention. I'm going to turn it over to Dr. Denis. Thank you.

Thank you, Dr. Moore. Much appreciated. So RAMP 201 is a registration-directed Phase II trial of avutometinib with or without defactinib in patients with recurrent low-grade serous ovarian cancer. The study is an international collaboration between the European Network of Gynecological Oncology trial groups or ENGOT and the Gynecologic Oncology Group of the U.S. GOG, and it's sponsored by Verastem Oncology. This slide reflects the design of the trial, eligible patients with recurrent LGSOC both KRAS mutant and KRAS wild-type disease were randomized 1:1 and assigned to the respective investigational study arms. Part A of the trial, also known as the selection phase, has the key objective to select the go-forward regimen from the respective treatment arms under study. In addition, an assessment would be made on the efficacy in KRAS mutant and KRAS wild-type low-grade serous ovarian cancer, respectively. The objective of Part B or the expansion phase of the trial is to determine the efficacy of the optimal regimen identified in Part A. The primary endpoint of the trial is objective response rate as assessed by blinded independent central review, which is still considered the gold standard for imaging assessment. The final analysis is going to be conducted on all eligible patients treated on the go-forward regimen with a target sample size of about 72 patients with recurrent LGSOC. Next slide please. And so today, we are pleased to provide you with an update on Part A, the selection phase of the trial, and share with you the initial data from our planned interim analysis of all evaluable patients enrolled in Part A. The safety data will be presented from all patients enrolled to date in Part A and B. The key findings are as follows. The patient characteristics confirmed that this was a heavily pretreated study population who received a median of 4 pride lines of systemic therapy. Clinical development will continue in all patients with recurrent LGSOC, regardless of KRAS status. The combination of avutometinib and defactinib was selected as a go-forward treatment regimen. And for the combination arm, the objective response rate was 28%, which was independently confirmed. And the response rate was similar in KRAS mutant and KRAS wild-type disease, 27% and 29%, respectively. Avutometinib and defactinib continues to show a tolerable safety profile with no new safety signals and a low discontinuation rates. Importantly, the follow-up of patients in Part A continues as the majority of evaluable patients remain on study treatment at the time of the data cut. I will provide more details on these findings in the next few slides. Next slide, please. Based on characteristics, reflects a relatively young age of heavily pretreated -- of this heavily pretreated patient population. Dr. Moore has alluded to this. The median patient age was in the early 50s with some patients as young as 27 years old. Patients have a ECOG performance stat for 0:1. They received a median of 4 but up to 11 prior lines of systemic treatment, including platinum-based chemotherapy, endocrine therapy and bevacizumab in most patients. So from that perspective, patients were more heavily pretreated in this clinical trial as compared to FRAME all of the other trials with recurrent LGSOC that Dr. Moore mentioned. In contrast to other LGSOC trials, patients who are previously treated with the MEK inhibitors are also eligible for the study. This was based on the objective response rate that were observed in the FRAME trial. Next slide please, and now for the key efficacy results. This slide shows the analysis of evaluable patients enrolled in Part A for the primary endpoint of objective response rate by blinded independent central review. We would like to highlight a few points. The 28% overall rate of confirmed responses for the combination arm with avutometinib and defactinib is higher than the objective response rate for avutometinib monotherapy. This clinical data does support the selection of the combination of the go-forward regimen and validate the preclinical data and rationale for the combination of avutometinib and defactinib in low-grade serous ovarian cancer. Interestingly, and as we've seen in the FRAME study, the number of responses in both KRAS mutant and KRAS wild-type disease is similar, 27% and 29%, respectively, confirming the potential of this combination for all patients with recurrent LGSOC, irrespective of the KRAS mutation status. While these initial confirmed response rates are encouraging, they may further increase as the rate of confirmed. And unconfirmed partial responses to date is even higher, and the late onset of responses is well described in LGSOC. As we will further highlight on the next slide, the high rate of disease control of 90% for avutometinib and 93% for the combination of avutometinib and defactinib, along with tumor shrinkage in the vast majority of patients, is particularly meaningful in this heavily-pretreated population who have exhausted all treatment options. Next slide please. The waterfall plot on this slide provides a graphical display of the extend of LGSOC tumor shrinkage for each of the 29 evaluable patients treated with the combination of avutometinib and defactinib. The waterfall plot reflects both the high rate of disease control as well as the extent of tumor shrinkage in the vast majority of patients. It also highlights the activity in both KRAS wild-type disease as shown by the pink bars, as well as the regression in KRAS-mutant LGSOC as reflected by the green bars. Clearly, the set criteria for a RECIST response of 30% regression of the longest diameter as shown by the dotted line, doesn't do justice to the extent of tumor shrinkage that is observed in almost all patients, especially in this heavily pretreated group of patients. On the left of the slide, we remind you that while the objective response rate and the disease control rates are very encouraging, these are initial data. The follow-up of patients in Part A that as short as 5 months for this planned interim analysis, and it may take up to 6 or 12 months for a response to occur. As you can see from the aspiration depicted under the bars, the majority of evaluable patients, 62% to be specific, remain on study treatment at time of the interim data cut. And are depicted in the middle of the graph, several of the patients remaining on study show tumor regression that approach 30% that is needed for a potential response to be declared. Next slide. This slide shows the waterfall plot from RAMP 201 on the left next to the waterfall from the FRAME study, which we described earlier, but we have called similarly as the RAMP 201 trial, respectively, to the KRAS mutation status. We do not intend to cross trial comparison as in contrast to FRAME. The RAMP 201 trial is an international trial with blinded independent center review of efficacy, and we should also point out that patients enrolled in RAMP 201 have more prior lines of systemic therapies than in FRAME, namely a median of 4 versus 3 prior lines. And in addition, more patients in RAMP 201 were also pretreated with bevacizumab. Interestingly, we do note the following similarities between the studies. Both studies evaluated the combination of avutometinib and defactinib in patients with recurrent low-grade serous ovarian cancer. Both studies show a high rate of disease control and documented tumor regression in the vast majority of patients. Both studies show confirmed objective responses in both KRAS mutant, as KRAS wild-type disease. And both studies show objective confirmed responses in low-grade serous ovarian cancer patients pretreated with MEK inhibitors. So we are very pleased to see that the initial data from RAMP 201 reinforce the clinical findings of the FRAME study, and we look forward to the final results of this trial. Next slide. Regarding the safety and tolerability of the combination, there were no new safety signals, and the rate of discontinuation remains low. The table reflects the most common treatment-related adverse events reported in more than 20% of treated patients and ranked according to the rate of adverse events for the combination arm. As you know, the events listed are expected for MEK inhibitor and the FAK inhibitor class of agents. The majority of adverse events are mild to moderate. They are considered monitorable, manageable and reversible in most cases. As reported earlier, the rate of discontinuation due to adverse events was low. It was 9% for the combination arm. This 9% reflects 5 patients, which include 3 patients who were actually discontinued protocol due to elevated blood levels of Creatine phosphokinase or CPK. Moving forward, the study will allow our symptomatic elevation of CPK levels to be initially managed by interruption under dose reduction of the study drugs rather than by discontinuation. And we will hope that this will have a favorable impact, an even more favorable impact on the discontinuation rate due to adverse events that remains a reflection of the tolerability of the combination of avutometinib and defactinib are the studies dosing schedule. Next slide. So to conclude, this positive interim data support the selection of the combination of avutometinib and defactinib for continued development in recurrent LGSOC, regardless of KRAS mutation states. We believe that this preplan interim analysis, the objectives of Part A had been achieved, namely: number one, the combination of avutometinib and defactinib is declared as a go-forward regimen; and number two, the objective responses support continued development in all patients with recurrent disease, irrespective of KRAS mutation status. The efficacy and safety data were obtained in a heavily pretreated population in a multinational clinical brand in academic and community centers. The objective response rate of 28% in evaluable patients and disease control rate of more than 90% were all independently reviewed, and well-tolerated safety profile showed no new safety signals. So we expect this clinical data to continue to mature as the majority of patients are still on study treatment, and particularly, as LGSOC takes a long time to respond as we've learned from prior clinical experience. So again, we believe that these results will reinforce the findings from the FRAME study, and we are pleased on what the combination of avutometinib and defactinib to potentially mean for patients. Dan Paterson will now provide an update on the outcome of our recent FDA discussion and market opportunity in LGSOC and on the next steps with the program. Thank you.

Thank you, Louis. Clearly, we are very encouraged by the data being reported today as we hope to be the company that brings the first FDA-approved options specifically for recurrent LGSOC to patients. I'd like to give a regulatory update and discuss the path forward. As you just heard from Louis, the combination of avutometinib and defactinib has been selected as the go-forward treatment regimen, and development of the combination will continue for all patients regardless of KRAS status. We're seeing encouraging efficacy with responses confirmed by blinded central review of scans, a low rate of discontinuation due to adverse events, and the majority of patients remain on treatment. Now let's turn to where we're going from here. The company has achieved the current target enrollment in the combination arm of RAMP 201 in both Part A and Part B. The company intends to file for accelerated approval and to include mature data from the RAMP 201 and the investigator sponsored FRAME studies to potentially support this filing. Continued enrollment in the RAMP 201 combination arm is planned to maintain momentum and expand the clinical experience in anticipation initiation of a confirmatory study. The agency requested that we schedule a meeting to discuss the confirmatory study. We intend to do this as soon as possible, and we'll provide an update after agreement on study design. The company is planning a RAMP 201 presentation of updated data at a major scientific medical conference in 2023. As we talk about market potential for LGSOC, a couple of important points. Patients tend to cycle through a lot of treatments. Therefore, we believe that most patients post frontline therapy will be potential candidates for our treatment. So we view the prevalent population, not just the number of newly diagnosed patients or incidents, as our market where avutometinib and defactinib in LGSOC. As you can see from this slide, because of the long duration of therapy, the potential falls just behind KRAS G12C non-small cell lung cancer and pancreatic cancer at about 60,000 to 70,000 patient months per year and a significant untapped patient population given no specific approved therapies in suboptimal current treatments. In summary, LGSOC is a unique RAS pathway-driven cancer with an unacceptably high unmet need. The results of Part A of RAMP 201 trial and determined that the go-forward regimen will be the combination and independently confirmed response rates in both KRAS mutant and KRAS wild-type with a favorable safety profile and tolerability profile in a heavily-pretreated patient population supports the continued development of the combination in all recurrent LGSOC. We plan to build upon our breakthrough therapy designation for the combo of avutometinib and defactinib in LGSOC patients who've been previously treated with platinum-based chemotherapy and filed for accelerated approval based on mature data from RAMP 201 and data from the FRAME study and finalization and implementation of our confirmatory study plans. With our remarks concluded, we'll now like to open the call for questions, and I'll turn it over to the operator.

[Operator Instructions] Our first question comes from the line of Gregory Renza of RBC Capital Markets.

Congrats on the update and the progress. Brian, maybe we can just start on the efficacy side. Just curious with respect to looking at the mono versus the combo outcomes. How should we think about the levels of activity as attributed both to avutometinib and defactinib? And just your thoughts on basically the clinical presentation at least of the potential synergy that has previously been demonstrated.

Yes. Thanks for the question, Greg. I'll open and then turn it over to Dr. Denis. So when we look at the preclinical story around avutometinib and defactinib. I think Dr. Moore mentioned what we saw there really played out in the clinic. And again, there's a very high disease control rate for avutometinib in the monotherapy arm. And it looks -- and then Dr. Denis can describe the data a bit more. But the fact that is seems to be pushing them over that partial response threshold, and it seems to be deepening the response. And again, we don't see any difference in toxicity profile between the 2, so we're excited to see the preclinical translate through to the clinical. So Louis, if you want to maybe give a bit more color on what we see in the monotherapy versus combo.

Thank you, Brian. Indeed, just highlighting again, we saw a very nice 90% of disease control rate for monotherapy as well. Recognize that the rate of confirmed responses was lower. Nevertheless, the waterfall plot not shown today does show a regression in the vast majority of patients, but not the sustained that as we nicely illustrated for the combination. And so 2 points. One is it indeed support the rationale, the scientific rationale for the combination. We're very encouraged by the level of activity of the combination in both KRAS mutant and KRAS wild-type disease as well as the activity seen in patients previously treated with a MEK inhibitor. And lastly, but not least, the overall tolerability, as I alluded to, less than 10%, of which even the majority of patients, unfortunately, have to be discontinued due to a symptomatic elevation of the block levels of CPK, that is now being addressed with this new amendment moving forward that we manage it as it's being managed for other MEK inhibitors with interruption and dose modification first. So we believe that clearly, the contribution of defactinib to the combination has been clearly established, and it's the combination that we're taking forward for further development and eventual registration pending the data.

If you don't mind me asking a follow-up. And I just want to make sure, Louis, just understand, as you mentioned the management strategy around the CPK elevation. Maybe just help us just double click on that a little bit. And even if Dr. Moore is available, just your thoughts clinically on the impact and really what the execution is. Just wanted to make sure we were -- we had that loud and clear.

Yes. So Louis, why don't you go through what was in the original protocol and where we revised it to? And then Dr. Moore, if you've got any experience or observations, feel free to add to what Louis will cover.

Thank you. So just a reminder that while defactinib was extensively in development by Verastem in the past. The majority of the early development actually occurred outside of the U.S. So the initial IND, which supported the RAMP 201 study was written in a way to, of course, mandate a very somewhat conservative approach in the management of elevated CPK levels and mandate when the grade for elevation occurs that these patients would be de facto discontinued, even if they were symptomatic. Our findings to date illustrates that the majority of the -- the vast majority of the patients are actually are symptomatic. We understand from some of the investigators that particularly in younger patients with a heavier muscle mass some of the elevations are observed that it's easily manageable by temporary interruption, and so that is our plan moving forward. It's been very unfortunate that some of the patients have to be discontinued due to a protocol-defined criteria, but we're looking forward to manage that as is being done in the clinic now for other MEK inhibitors similar to ours, just interruption and dose modification as needed. Dr. Moore, not sure if you're still on the line and available.

I don't know that I have much to add. It was frustrating as an investigator. I think just to hear, none of mine has this issue. But to hear Dr. Grisham and others talk about patients who are responding that had to discontinued for really an asymptomatic lab value was just -- was frustrated on their behalf. And so I think the protocol amendments are appropriate and done with patient safety at the highest concern, but also not discontinuing an effective therapy when you can use intermittent dose interruptions to manage this kind of laboratory abnormality. So I think that the amendments are going to go a long way towards ameliorating that.

Maybe to expand on that further, indeed. Despite this initial finding with discontinuations due to asymptomatic-elevated laboratory findings, the overall rate of discontinuation due to AEs relative to other MEK inhibitors appear to be quite favorable, and we look forward to continuing to follow-up patients studied of this intermittent dose level.

Our next question comes from the line of Srikripa Devarakonda of Truist Securities.

Can you remind us when the expansion portion of RAMP 201 was completed? I'm just trying to get a sense of time lines. And how will you know when you have mature enough data to submit the application for accelerated approval? What sort of durability data do you think is needed? And also, how important is the data from the monotherapy cohorts of the trial for this approval?

Yes. Thanks for the questions, Kripa. I'll ask Dan Paterson to kind of go through the logistics and regulatory interactions and then ask Louis to comment further. Dan?

Sure. Thanks for the question. We actually just recently put the last patient on for Part B. And it's very clear based on our interactions with the FDA that durability of response will be important. And as Louis mentioned, patients can take around 6 months to respond, and we're going to want to see 6 months of following those patients after they respond. So that can give you a sense of overall timing we're hoping to do a rolling submission. So again, subject to discussion with the agency, we may not have to have fully mature data to start with submission, but those are discussions to be had in the future when we talk around the logistics of the filing.