Good day, and welcome to the preliminary monotherapy results from the ongoing phase I trial of CFT1946, presented at ESMO conference call. All participants will be in a listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star, then one on a touch-tone phone. To withdraw your question, please press star, then two. Please note, this event is being recorded. I would now like to turn the conference over to Courtney Solberg, Senior Manager, IR. Please go ahead. Good afternoon, everyone, and thank you for joining our call to discuss the monotherapy phase I dose escalation clinical data of CFT1946, our orally bioavailable small molecule BiDAC degrader targeting BRAF V600X mutations in solid tumors. These data were presented at the ESMO Congress earlier today. We will be making forward-looking statements today, and slide two contains our legal disclaimer on this matter. Those presenting on today's call are Andrew Hirsch, our President and CEO, and Len Reyno, our Chief Medical Officer. We will begin with opening remarks and then walk you through the clinical data. We will end today's call with a Q&A session with the management team. Those joining us will also include Stew Fisher, our CSO, and Kendra Adams, our CFO. I will now turn the call over to Andrew Hirsch for some introductory remarks. Thank you, Courtney. Good afternoon, everyone, and thank you for joining our call. At ESMO today, we shared with the medical community preliminary CFT1946 phase I data, which demonstrated proof of mechanism and early evidence of proof of our degrader concept. Before I turn the call over to Len to walk through the data, I'll provide a quick overview of C4T for those of you who are new or less familiar with our company. C4 Therapeutics is focused on delivering on the promise of targeted protein degradation science to create a new generation of medicines that have the potential to transform patients' lives. Our TORPEDO platform has been incredibly productive, and I think has gone largely underappreciated. To date, we have discovered and advanced four development candidates for our own clinical pipeline and delivered two development candidates to Biogen for a total of six. These degraders have been designed for high catalytic activity and oral bioavailability across a wide range of target classes. Four of those have cleared the FDA IND process, and three have entered clinical trials, with a fourth to enter clinical trials shortly through our partner, Betta Pharma. All three programs we've put into the clinic have established proof of mechanism. Each degrader has demonstrated desirable drug-like properties with dose proportional exposure and oral bioavailability, and most importantly, robust degradation of the target, as our preclinical models predicted. That productivity has led to the pipeline we have today. While today's discussion is focused on the first clinical data from our phase I/II study of CFT1946, we're equally excited about our other clinical stage programs. Our IKZF1/3 degrader, cemsidomide, is currently in a phase I dose escalation study for multiple myeloma in combination with dexamethasone and for non-Hodgkin's lymphoma as a monotherapy. In December of 2023, we shared the completed monotherapy data in multiple myeloma and data on the first two dose cohorts of the plus dexamethasone arm. We continue to progress this program, escalating through two additional dose levels and enrolling expansion cohorts at the highest three dose levels during 2024. We are looking forward to sharing data in both multiple myeloma and non-Hodgkin's lymphoma in the fourth quarter. CFT8919 is our EGFR L858R degrader. The phase I dose escalation trial will be conducted in China by our partner, Betta Pharma, in non-small cell lung cancer patients with an L858R mutation. Importantly, we retain ex-China rights and can decide to start further development beyond Greater China based on the phase I dose escalation data. 2024 has been marked by strong execution across our research and development programs, and we are on track to achieve our remaining milestones that we established at the beginning of the year. Today's presentation of the phase I data from the ongoing study of CFT1946 achieves one of these milestones. These data support the potential for CFT1946 to achieve our vision for the molecule to be the therapy of choice for patients with tumors driven by BRAF V600 mutations. Specifically, these data will demonstrate three key points. First, CFT1946 has a well-tolerated safety profile, with an absence of Grade three or greater toxicities typically associated with wild-type inhibition, which supports further development as a monotherapy and in combination with a MEK inhibitor or an EGFR antibody. Second, we demonstrate dose-dependent exposure and oral bioavailability with resulting degradation of mutant V600E, supporting the proof of mechanism, and third, we will share evidence of monotherapy antitumor activity in BRAF inhibitor-exposed patients, supportive of early proof of concept. I will now hand it over to Len to walk through the clinical data that was presented at ESMO. Thank you, Andrew. The bulk of today's presentation will focus on data from our first-in-human CFT1946 clinical trial, as presented earlier in an oral presentation at the ESMO annual meeting in Barcelona by participating investigator, Dr. Maria Vieito. Although this trial is still ongoing, the monotherapy phase I data provides strong support for both proof of mechanism and early evidence of clinical proof of concept in patients with metastatic disease driven by mutant BRAF V600 and refractory to current standard of care regimens. ... Data shared today demonstrates that CFT1946 is well tolerated over the range of doses tested. We observed no grade three or greater cutaneous adverse events that are often associated with BRAF inhibitors. Tissue-based studies demonstrate degradation of BRAF V600E in biopsies collected at study entry in patients enrolled in pharmacodynamic cohorts. The drug also demonstrated early evidence of proof of degrader concept, including evidence of monotherapy anti-tumor activity in patients who have been previously treated with BRAF inhibitors at some point in their therapy for metastatic disease and are refractory to standard of care regimens. We are particularly excited about these data because there are approximately 100,000 patients annually in the United States who are diagnosed with BRAF V600X mutant cancers. BRAF V600X mutations are most common in melanoma, colorectal cancer, and non-small cell lung cancer. We believe CFT1946 has the potential to disrupt the treatment landscape and become an important option for patients with BRAF V600X solid tumors. The majority of patients treated with BRAF inhibitors eventually progress due to resistance mechanisms. These resistant mechanisms are not the same as the mutations in the binding pocket that arise with TKIs. BRAF inhibitor resistance occurs when the inhibited protein forms a dimer, and the dimer activates the MAP kinase pathway. These BRAF V600X-based dimers can induce a variety of complicated and complex biological mechanisms, including BRAF splice variants, RAS activation, and BRAF amplification. Additionally, approved BRAF inhibitors only address V600E or V600K mutations. Despite these limitations, the market for BRAF inhibitor therapies is approximately $2 billion annually and is estimated to grow to $3 billion by 2028. We designed CFT1946 to be orally bioavailable and selective against class one mutants, which make up approximately 80%-90% of all BRAF mutations in solid tumors. CFT1946 utilizes the cell's own proteasomal machinery for targeted degradation of oncogenic BRAF V600X via the E3 ubiquitin ligase complex. Catalytic recycling enables a single drug molecule to degrade multiple proteins in repetitive degradation cycles. BRAF V600X is an optimal target for a protein degrader strategy, as the removal of the actual protein prevents BRAF signaling by the mutant form and the formation of activated dimers. Importantly, because of the unique selectivity of the degradation machinery, CFT1946 spares wild-type BRAF, thus reducing the risk of cutaneous adverse events commonly associated with BRAF inhibitors. As we shift to the clinical data, let's start with where we are in development. We've enrolled patients with tremendous speed across 15 academic research centers in Spain, France, and the United States, thanks to strong investigator enthusiasm. Eligible patients have known BRAF V600 mutations with measurable disease and are refractory to at least one line of prior therapy. This prior therapy must include a BRAF inhibitor, unless access is limited by regional regulatory approvals or reimbursement. The eligible patient population thus includes patients with melanoma, colorectal cancer, and non-small cell lung cancer, as well as other tumor types with the known BRAF V600X driven tumor. Patients with stable and treated CNS disease are eligible to participate, provided they received adequate CNS therapy prior to study entry and are clinically stable. CFT1946 is orally administered on a twice-daily basis, and patients are dosed continuously in the absence of drug-related toxicity, progression of disease, or removal of patient consent. The treatment cycle is defined as a 28-day dosing interval. RECIST criteria and anti-tumor activity is measured after every two treatment cycles. Dose escalation utilizes a Bayesian logistic regression model to inform both cohort size as well as decisions to open the next dose level. As such, the cohort size at each escalation step is not fixed, but typically includes three to six patients. The primary endpoints of the study are safety and tolerability, as well as to determine the recommended phase II dose, both for monotherapy as well as in combination with cetuximab or tremelimumab. Secondary endpoints include assessment of anti-tumor activity, as well as characterization of the pharmacokinetics and pharmacodynamics across multiple dose levels. We recently announced that the 640 milligram dose level has been declared safe. We are now enrolling patients in the 640 milligram pharmacodynamic backfill cohort. We are also evaluating monotherapy exploratory expansion at 320 milligrams in patients with melanoma. Finally, we are conducting the phase 1b expansion phase, evaluating CFT1946 as a combination in colorectal cancers, starting at the dose of 160 milligrams. The data cutoff for today's presentation was July 19th, 2024. We will share data on the first five dose levels, 20 to 640 milligrams, and the pharmacodynamic backfills from 160 milligrams and 320 milligrams. This is indicated by the green outlines on the box, as shown here. Since 640 milligrams is the last dose level to be enrolled, we have limited follow-up data from this dose level. On this slide, you see the characteristics of the 36 patients in today's data analysis. The median age of participating patients is 55, with a qualitatively similar mix of male and female patients. It was a mix of tumor types enrolled. However, as expected, the majority were patients with melanoma or colorectal cancer, which is in line with their expected incidences. We also enrolled patients with non-small cell lung cancer, small bowel carcinoma, cholangiocarcinoma, pancreatic carcinoma, and papillary thyroid cancer. 33 patients were diagnosed with a V600E mutation, two patients had V600K, and one patient had a V600R mutation. All patients had advanced metastatic disease, and all patients except one had prior BRAF inhibitor therapy. Nearly two-thirds of patients had prior immunotherapy and nearly half of the patients, prior radiotherapy. We'll turn now to the safety profile. Monotherapy is very well tolerated over the range of doses tested to date. In fact, no protocol-defined dose-limiting toxicities have been observed. As expected in a phase I population, most patients did experience treatment emergent adverse events. However, there was only one Grade 3 or greater treatment emergent event related to CFT1946. This is hypertension in a patient treated at 640 milligram dose level. This patient continues therapy with no change in their dosage. Importantly, there were no treatment emergent severe adverse events related to CFT1946 recorded at any dose level. Additionally, no treatment-related adverse event led to discontinuation, interruption, or dose reduction of CFT1946. Here we summarize the treatment emergent adverse events, regardless of attribution, occurring in greater than or equal to 10% of the 36 subjects treated to date. The majority of adverse events were mild to moderate, and the majority of these AEs were Grade 1 or Grade 2. Again, none of these adverse events met criteria for protocol-defined dose-limiting toxicities. Note that on the previous slide, there were no cutaneous adverse events occurring in 10% or more of patients, and none of them were Grade three or four. Here we summarize cutaneous adverse events across all dose levels. Recall that approved BRAF inhibitors typically have high rates of these cutaneous adverse events. Summarized on this slide are the initial monotherapy pharmacokinetic data and tissue-based pharmacodynamic data. On the left, the plasma exposures resulting from doses administered from 20 milligrams to 640 milligrams are summarized. These preliminary data demonstrate dose-dependent bioavailability, as summarized in the first 12 hours of dosing during cycle one on day 15. That is, after two weeks of oral dosing. Current preliminary data does not permit the accurate determination of half-life, but the absence of significant accumulation implies a half-life of 12 hours or less and supports BID dosing. For the tissue-based evaluation of BRAF V600E, we have performed IHC staining using BRAF VE1 clone from Roche. H-scores, combining percentage of cells stained for BRAF and at what intensity, with a maximum score of 300, are used as a surrogate to measure protein levels in pre- and post-biopsies. The middle panel illustrates BRAF V600E degradation resulting from a dose of 320 milligrams in a patient with melanoma. The first image is from a core needle biopsy done prior to dosing, stained for V600E, with a calculated H-score of 250. Adjacent to this panel is a core needle biopsy obtained on cycle one, day 15, demonstrating a qualitative and quantitative reduction, H-score now one hundred, in BRAF V600E. The final panel on the right describes data in seven patients interrogated with pre- and post-core needle biopsies at 80 milligrams, a hundred and sixty 160 milligrams, and 320 milligrams, respectively. As expected, the pretreatment biopsies done at screening demonstrate moderate to high IHC staining of BRAF V600E, with a median H-score of two hundred. On day 15, these patients demonstrated substantial reduction in staining, median H-score now one hundred, consistent with proof of mechanism where BRAF V600E degraded in tissues after oral administration of CFT1946. On this side slide, you'll see a waterfall plot that highlights early signs of anti-tumor activity across the range of doses tested, as well as treatment indications. The bars are color-coded as green for melanoma, blue for colorectal cancer, and purple for other malignancies. Green arrows below any bar indicate the patient is still receiving ongoing therapy. If the patient has a V600 mutation other than V600E, it is noted above the bar. 27 patients were evaluable for antitumor activity at the time of the data cutoff. In order to be evaluable, patients must have gone through two treatment cycles. At the time of this data cutoff, two patients achieved a partial response. These include a patient with pancreatic cancer treated at 640 milligrams, and a patient with melanoma harboring a V600K mutation treated at 320 milligrams. Therapy is ongoing in both patients, and I will dive a little deeper into both of these patients in just a moment. We have 11 patients who remain on therapy. All 11 patients have achieved stable disease or better. 10 patients who remain on therapy have reductions in their tumor size since study entry. On this slide, we revisit the waterfall plot based on the indications of the participating patients. The three panels represent melanoma on the left, colorectal cancer in the middle, and other indications, including non-small cell lung cancer and pancreatic cancer on the far right. As expected, based on the preclinical biology, the melanoma patients showed antitumor reductions and of greater depth when treated with CFT1946. It is important to note that this waterfall plot includes three subjects with non-BRAF V600E mutations. As it relates to colorectal cancer, it's not surprising to note that while there are antitumor reductions in some patients, they are less than what is seen in melanoma. This is compatible with the hypothesis that preexisting activation of the EGFR pathway will require concomitant EGFR blockade. We do note with interest that several of these patients have RNF43 gene expression, which has been described in the literature as associated with good responsiveness when BRAF V600X inhibitors are combined with EGFR blockade. Finally, the third panel includes non-small cell lung carcinoma, as well as other tumor types with BRAF V600X-driven tumors. While the sample size here is small and heterogeneous, monotherapy antitumor activity is again noted, including a confirmed PR in a patient with refractory pancreatic cancer and an unconfirmed PR in a patient with small bowel carcinoma. The evidence of monotherapy antitumor activity is further supported by the swim lane plot, as shown on the next slide. Data on this swim lane plot provides further evidence that CFT1946 is a well-tolerated drug. The longest patient on study has melanoma and has been treated at 20 milligrams with tumor shrinkage, and the best response is stable disease for approximately 16.6 months. The far left of the slide annotates each patient's best overall response to their prior BRAF inhibitor therapy per medical records, as well as the immediate prior therapy, prior to study entry. As expected, patients at higher dose levels were enrolled more recently and have relatively shorter durations on study. However, multiple patients treated at both 320 milligrams and 640 milligrams remain on therapy. We look forward to continuing to follow these patients through the duration of treatment. Now, I'd like to walk you through two patient vignettes. The first is a 72-year-old male with BRAF V600K, stage two melanoma, which was initially diagnosed in 2019. In addition to prior surgery, the patient had four lines of antineoplastic therapy prior to study entry, including both dabrafenib and trametinib, as well as nivolumab and ipilimumab. The patient's best response on prior therapy was stable disease. They enrolled on the 320-milligram cohort in February 2024. The radiographs on the right illustrate measurable disease at baseline, as well as their multi-cycle tumor reductions, as annotated with the yellow arrow. Post cycle three, measurable lesions demonstrated a 64% decrease from baseline, and post cycle five demonstrated a 67% decrease from baseline, resulting in a confirmed PR. This patient remains in response and is still on treatment. It's interesting to note that this partial response in our study drug represents the patient's first objective clinical response to a therapeutic regimen. The next vignette relates to a 63-year-old male with a BRAF V600E-positive pancreatic carcinoma with metastatic disease characterized by progressive liver metastases prior to study entry. This patient received four lines of antineoplastic therapy, including standard of care chemotherapy, as well as dabrafenib and trametinib. Patient's most recent response to prior chemotherapy before study entry was progressive disease, and his best response to any prior therapy was a partial response. On the far right of the slide, the BRAF V600E allele fraction measured in ctDNA using whole exome sequencing is shown. It reduces to below the limit of detection by day 28 and persists through at least day 84. This patient enrolled in April 2024 in the 640 milligram cohort, and scans post cycle three and five confirmed a partial response, characterized by 46% decrease of target lesions, including reduction in the size of liver metastases. They remain in response and are still on treatment, and the investigator treating this patient recently commented that the patient's participation on this study has been a life-changing opportunity for them. Today's monotherapy data supports our enthusiasm and belief that CFT1946 could disrupt the treatment landscape. In terms of proof of mechanism, we've demonstrated three key points. One, CFT1946 has a well-tolerated safety profile with no dose-limiting toxicities. The data also shows an absence of wild-type BRAF inhibition-driven toxicities. Two, the drug has good oral bioavailability with dose-dependent increases in exposure. And three, CFT1946 degrades the BRAF V600E target, resulting in antitumor activity. Of the 27 patients available for efficacy, 16 patients with a range of V600E mutations have seen a reduction in their tumors since study entry. This includes eight melanoma patients who have had tumor reductions. Taken together, the data disclosed today strongly supports the continued development of this drug as monotherapy and/or in combination with MEK inhibition or EGFR blockade. This is an ongoing study. We've recently completed enrollment in the exploratory monotherapy melanoma cohort at 320 milligrams and have now opened an exploratory cohort for melanoma at 640 milligrams. Continued execution for the remainder of 2024 will set us up for additional data readouts for this program over the course of 2025. As we advance towards these milestones, we're grateful for the patients and their families who have participated in the trial to date, and thank our investigators and C4 colleagues for their continued efforts to advance CFT1946 to patients. Operator, please open the lines to Q&A. We will now begin the question-and-answer session. To ask a question, you may press star, then one on your touch-tone phone. If you are using the speakerphone, please pick up the handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star then two. At this time, we will pause momentarily to assemble our roster, and our first question today comes from Gavin Clark-Gartner with Evercore ISI. Please go ahead. Hey, guys. Congrats on the data, and thanks for taking the questions. First, I just wanted to ask on degradation. So understanding, I think you only have seven patients with IHC data at this point. I'm just wondering how dose and exposure correlated to degradation? Sure. Thanks, Gavin. I'll have Len answer that one. Sure, so first, I start off by saying that we continue to collect pre- and post-biopsies, and analyze the data across all dose levels. So we made the decision to aggregate the dose levels for the purpose of today's presentation, because in fact, at any given dose level, we have a maximum of three patients at this time, and really, the strength of the inference at the moment is that all drug exposures we've tested to date have been associated with degradation. One of the comments I would make is it's important to note the challenge in measuring degradation in these patients. These are core biopsies, and stained for IHC. As you can appreciate, for any given patient, the quality of the specimens is variable, depending on what's accessible at the time of the interventional radiology tissue acquisition. As we get more data, we'll be in a better position to actually then try to aggregate the degradation levels per dose and ultimately start to see if there's a relationship between degradation levels and outcome. The one point I would caution is these are also degradation specimens taken at day 15. These are unbiased specimens. It's not a assessment of responder versus non-responder. This is looking at tissue changes in IHC expression of V600E, irrespective of their eventual response status. As time goes on, we'll be better able to characterize which, if any, of these patients do enjoy, you know, objective responses and then aggregate the data across multiple dose levels. So I guess the short answer is it's premature to really try to break it down much more than we have, but we will be continuing to analyze the data, and we'll present a more robust display of it in the coming months. Yeah, that's very helpful. And then on the efficacy side, just for the one patient who had the very long, stable disease at 16 months at the 20-milligram dose, it almost looks like they could have been a partial response, but just kind of missed. So I'm wondering if you can give any kind of qualitative commentary on their tumor reduction? Sure. Also wondering what kind of exposure they had. Yeah. No, I'm happy to do so. So this is a patient with metastatic melanoma, which is characterized by nodal disease. And prior to study entry, I think the maximum size of their RECIST criteria lymph node was 13 millimeters. They've been reduced below 10 millimeters or one centimeter for some time, so actually in the normal lymph node range, had met criteria for PR but continued to have measurements that are less than one centimeter, but are bouncing around between 7 millimeters and 9 millimeters and 6 millimeters. So the site has elected to call it stable disease, but there's actually been evidence of tumor shrinkage, and the patient continues on therapy, feeling incredibly well. Awesome. And last question from me. I mean, there's really not very much to ask on safety since it's very clean. But maybe just for the grade two rash and acneiform dermatitis, what dose did that happen at? I don't have that in front of me at the moment. What I can tell you is that there's no emergence of those. Those features do not seem to be dose dependent, though they've occurred sporadically across all dose levels. Very helpful. They're listed by the investigator as appropriately so, possibly related, but they're not deemed to be, you know, classically of concern for the classic BRAF inhibitor toxicity one worries about. Thanks for taking the question. Thanks, Gavin. Our next question comes from Etzer Darout with BMO Capital Markets. Please go ahead. Great. Thanks for taking the question and congrats on the data. I guess the first question for me is, have you discussed how many patients you would plan to enroll in the expansion cohort? So just to sort of compare versus sort of the three to six patients that were enrolled in those escalation. And then I have a follow-up question. Sure. So each of the- Yeah. Go ahead, Len. Yeah. Each of the exploratory expansions, we target enrollment at 10 to 12 patients. The part to give participating investigators a chance to enroll. So it's a first pass look at an efficacy signal in a group that has been recruited with a homogeneous diagnosis, and a chance to get a better sense on an early efficacy read. We haven't made a decision vis-a-vis a further expansion of any dose level beyond that number at this time, and we'll await making those decisions till we at least see the data at 320 and 640. Got it. Thank you. And then just looking at sort of the melanoma data and the level of sort of tumor reduction that you're seeing, I guess when do you kind of see sort of the appropriate time to kind of engage regulators on sort of a path forward there in terms of sort of ultimately, you know, what a registration path look like? Is it really after maybe the data you plan to disclose in 2025? Is that how we should think about timing of engaging with regulators on the data, particularly in melanoma? Yeah. So we haven't made- Yeah. Do you wanna answer that? Yeah, we haven't made it. No, go ahead. Yeah, so, sorry, Len's at ESMO, and we're here in Watertown. So, yeah, so, we're not at this point we're not gonna comment on plans for any regulatory dialogue. I think when we have, you know, we determine as a robust data set that it's a fruitful discussion, we'll do that. But as a policy, we're not gonna give any guidance or comment on kind of when and how we do that and for now. Got it. Thank you. Our next question comes from Kelly Shi with Jefferies. Please go ahead. Hi. Congratulations on the data. I have two questions. The first one is, is your rationale to choose 160 milligram for CRC and 320 or 640 for melanoma. I wonder, what's the rationale for this, those choice? Second is that, do you have - did you observe any trend of time to response during your dose escalation? Thank you. Thank you for the first question in particular, 'cause it, it does get a little confusing. The choice of 160 for starting the dose with cetuximab is based on a trial design consideration. And it's based on the principle that when you start testing combination therapy for safety, you can start to test at one dose level below the highest monotherapy dose level declared safe. So because we knew we were interested in getting experience with EGFR blockade combined with CFT1946, we made the decision once 320 milligrams was declared safe, to open that safety assessment cohort at 160+ cetuximab. That is not to be confused with an expansion cohort, because we will What we will do once we can hopefully declare safety at 160, we will then do 320+ cetuximab, and if safe, also go to 640+ cetuximab. So those are still in dose-finding safety cohorts, which is distinct from the decision in melanoma. In melanoma, once we had declared 320 safe, we had also seen evidence of both degradation of the target and early antitumor responses. So we decided to do the 320 milligram exploratory cohort in melanoma, not because we think that's the recommended phase II dose, but we felt it would be helpful to get a better read on both safety and emerging efficacy at that dose level. Now that the dose level is complete, and we know that 640 is also safe, and at 640, we also have antitumor effect, that led to the decision to open 640 for expansion. So hope that clarifies your question. Yeah. Thank you. Your second question then? Yeah, what was your second- It's about time to- I didn't quite get that. Yeah, the time. So it's a little early to comment on dose response and the time to response. There are some clues in the waterfall plot- S orry, in the swim lane plot, in that there are a few patients at 160 and 320, which seem to have more evidence of tumor shrinkage earlier than patients earlier in dosing. We do anticipate that there obviously is going to be a dose level that's more effective than other dose levels. But I think we need more data before we really comment finally on the shape of the dose response curve. Thank you for your answer. That's very helpful. Thank you. Our next question comes from Brad Canino with Stifel. Please go ahead. Hi, this is Dara Azar on for Brad Canino. Congrats to the team on delivering clinical translation of the degrader rationale for BRAF cancers. I think both discussant and you guys spoke eloquently on the monotherapy activity that you're seeing in the TKI refractory patients in melanoma and outside of melanoma. But let's talk about colorectal for a second. Why expansion development in colorectal could be justified, absent monotherapy objective responses? Please contextualize the differential biology in CRC and upside in early line development relative to what Pfizer has going on in colorectal. And I'll come back for a follow-up. Sure. Dara, I'll let Stew address that, 'cause it's sort of this fundamental different biology, and there's a different resistance mechanism in colorectal than we see in melanoma and lung cancer. Yeah. Thanks for the question. It's a very good one. The key here is that colorectal cancer cells express RTKs and importantly, EGFR as part of their normal expression profile. And that EGFR protein can signal, particularly as you block BRAF, that will result in an activation of EGFR that can then activate KRAS or the RAS system and then overwhelm the inhibition that you see. So there's the, in this case, it's well known that you need to have co-administration of an EGFR blockade, usually done with an antibody, such as cetuximab, in addition to a BRAF inhibition, because of this basically this intrinsic resistance mechanism. So blockade of the BRAF node alone is insufficient generally to stop the MAP kinase pathway from firing. You need to add both. Helpful. Thank you. And how would you characterize benefit-risk of the 640 milligram dose based on your dose escalation learning? And finally, we know that Pfizer and investor community knows that Pfizer is developing next-gen TKI, but are you aware of Novartis' interest in a next-gen BRAF drug? And, like, what kind of factors did you consider in choosing Mekinist as your combination partner for MEK inhibition? That's it for me. Thank you. Sure. So in terms of the first question, around 640 and the benefit-risk, you know, Len can comment, but I think the high-level top line is we don't actually see any really safety differences between, at this point, you know, between 320 and 640, and so we don't see any difference in that dose, and that's why we were very comfortable exploring that dose and expanding that dose. You know, we're certainly aware of Pfizer's next-gen TKI, you know, BRAF inhibitor, and we're closely tracking that. And then in terms of picking a MEK inhibitor, right, that's standard combination that you look at. You know, while we think this potentially has monotherapy activity and doesn't need a MEK inhibitor, we wanna be able to explore, does it make it even better, right? And some of our preclinical models were mixed. Some of them showed no difference between monotherapy versus combining our BRAF degrader with a TKI, but some of them did, and so we wanna be able to fully understand how the drug works, both as a monotherapy and in combination. We know investigators are gonna ask that question, so we wanna be able to provide that answer. And, you know, why we chose, I think it was the question was trametinib as the, that's just the approved one that's most commonly used. There's nothing special, I think, around, you know, why that was chosen. Awesome. Our next question today comes from Derek Archilla with Wells Fargo. Please go ahead. Hey, good afternoon, and congrats on the update. Just two quick ones from us. I guess, first, have you dosed anyone higher than 640 yet, or do you plan to in the near future? And then second question, just given your plan to partner some cemsidomide, I guess, based on today's data, you know, how do you think about prioritizing the R&D spend for CFT1946 or other programs? Thanks. Derek, do you wanna take the first one, and I'll take the second one? Yeah. So yeah, for sure. So no, we have not dosed anyone above 640 yet. We just declared that safe recently and made the decision that we wanna get more data at that dose level with the pharmacodynamic backfill. So we're enrolling more patients at 640 that are gonna have pre- and post-biopsies, as well as opening the melanoma expansion cohort. If you'll note on the PK slide that's shared in the deck, you'll see that at 640, we only have PK samples on four patients. And so prior to making a final decision about further dose escalation, we wanna get a better handle on the exposure level that results from the 640 dose, and we'll get that with the data being generated in these patients. I should add, however- that the investigators strongly support as further dose escalation. We just haven't made a final decision on when we would initiate that yet. And to your second question on capital allocation, look, I think, you know, that we've been consistent with, you know, our messaging and our approach that, for cemsidomide, we plan to partner, and that for CFT1946, we're prepared to invest in CFT1946 to take it forward and as well as our platform. And so as we think about capital allocation, that's sort of how we're thinking about it currently. You know, we have sufficient capital and runway into 2027, and that includes conducting the current studies that are ongoing, as well as the 2025 data readouts for the current CFT1946 study that Len outlined in our presentation. Again, if you have a question, please press star then one. Our next question comes from Eric Joseph with JP Morgan. Please go ahead. Hi. A couple questions from us. First, on a patient level, the patient that with an unconfirmed melanoma at 160 milligrams, before going on to progressive disease, can you talk a bit about that, you know, the site of progression there, and whether that might speak to, you know, any limitations in terms of drug distribution? And then secondly, just following up on the trametinib combination that you plan to start, can you just talk about your starting dose, starting dose levels, I guess, with CFT1946? And just what gives you confidence that the combination won't be additive or more challenging from a tolerability standpoint, if we're thinking about trametinib's single agent AE profile? Thank you. Sure. Len, you wanna tackle those? Yeah. The first question, I'm sorry, I don't have in front of me the actual site of metastatic progression in that patient that had the unconfirmed PR. So I think rather than speculate, we can get back to you with that information. Yeah. And then just on, I can mention, on the combination, I think this is pretty standard protocol, right? With that, you know, we would start at the dose level below the dose level, highest dose level that's declared safe. That's pretty standard in terms of starting a combination study. And so that's what we did with the cetuximab combo. As Len mentioned earlier, once we declared three twenty safe, we started that combo escalation at one sixty. And when we choose to trigger the trametinib combo, right, that will be starting at a dose level below the highest dose level declared safe. Okay, got it. And holding- I think our- Holding trametinib at label dose level. Yeah, and just on the AE, the combined AE, profile expectation. Yeah. Yeah, I mean, look, I think both BRAF inhibitors and trametinib or most MEK inhibitors carry their own toxicities. I think based on the data we've shown today, we don't expect to have contributing toxicities with a BRAF degrader. But you know, again, we'll have to find out. If you look at the trametinib label, it has its own host of toxicities, and so obviously those would be brought to the table in a combination. Again, I think that's you know, our degrader rationale is hopefully that we don't need trametinib to drive activity. But we wanna explore that because basically the mixed data in our preclinical models, as I mentioned earlier, the interest from investigators who will wanna understand, you know, can that actually boost activity? And we'll have to make a determination on the benefit-risk of what that does to the regimen versus monotherapy alone. But that'll all be data driven. Great. Thanks for taking the questions. This concludes our question and answer session. I would like to turn the conference back over to Andrew Hirsch for any closing remarks. Great. Thank you all for joining the call on a Friday afternoon. Really happy to be able to share this data with you, and we look forward to updating you in Q4 with our cemsidomide data. Have a great weekend, everyone. The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.