Good evening, everyone, and thank you for joining us this evening to discuss the exciting progress across our robust early-stage pipeline that we presented at AACR 2023 over the last few days. Before we begin, I'd like to remind you that any statements we make on this call that are not historical facts, such as corporate guidance, are forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties, including those set forth in our most recent annual report on Form 10-K, as well as our other SEC filings. On this evening's call, Deciphera's Founder and Chief Scientific Officer, Dan Flynn, will provide an overview of our proprietary switch-control drug discovery platform, the engine that delivered our first commercial drug, QINLOCK, and which continues to feed our pipeline with innovative first- and best-in-class kinase inhibitors at an impressive rate. Stacie Bulfer, Senior Director of Biological Sciences, will present preclinical data on DCC-3084, a potential best-in-class pan-RAF inhibitor that will be our next program to enter clinical development. Madhu Bogdan, Senior Principal Investigator of Biological Sciences, will walk us through new preclinical data for DCC-3116, which support two new combination dose escalation cohorts for the program, including one with ripretinib. Bryan Smith, Vice President of Biological Sciences, will present the data for our most recent development candidate, a new pan-KIT inhibitor, DCC-3009. Finally, Gada Al-ani, Senior Principal Investigator of Biological Sciences, will conclude with the presentation of a newly discovered research program focused on the activation of GCN2 kinase, an exciting target in the integrated stress response pathway. Following these prepared remarks, we'll then open the call to Q&A. We're excited about the progress we've made generating novel product candidates from our research efforts to complement our late-stage and commercial programs. Collectively, this portfolio of products with first or best-in-class potential offer a tremendous opportunity to build shareholder value and benefit thousands of people with cancer around the world. As we continue to entrench QINLOCK as the standard of care in fourth-line gastrointestinal stromal tumor, or GIST, we're excited to also initiate the Phase 3 INSIGHT study of QINLOCK in second-line GIST patients with mutations in KIT exon 11 and 17 or 18 in the second half of this year. Our phase 3 MOTION study for vimseltinib in patients with tenosynovial giant cell tumor, or TGCT, is expected to read out in the fourth quarter. Together, QINLOCK and vimseltinib have a peak worldwide revenue potential of over $1 billion. We believe DCC-3116, our first-in-class autophagy program, presents a broad opportunity across a host of indications. Of course, all of this progress is powered by the proprietary discovery engine we're talking about on tonight's call. We have developed and demonstrated a broad set of capabilities now at every stage of discovery, development, and commercialization, and shown that we can apply that expertise designing product candidates against both validated and novel targets and advance them rapidly from phase 1 through phase 3 and deliver them to patients as approved medicines. As you can see, 2023 is poised to be another catalyst-rich year for the company. In addition to QINLOCK and vimseltinib milestones I've already mentioned, we look forward to initiating one or more expansion cohorts in our phase 1/2 study of DCC-3116 in combination with MEK and KRAS G12C inhibitors, along with new combination studies for DCC-3116 with encorafenib and cetuximab, as well as a new cohort with DCC-3116 and ripretinib, which are both expected to initiate in the second half of the year. We also look forward to submitting an IND for DCC-3084 in the second half of the year and an IND for our next-gen pan-KIT inhibitor, DCC-3009, in the first half of 2024. The data we presented at AACR 2023 is the most comprehensive demonstration of our innovative research in Deciphera's history. As we continue to broaden our reach as a commercial organization, the data and progress discussed on today's call demonstrate the depth and breadth of our research programs, which give us confidence in our ability to create future value. With that, I'll now hand the call over to our Founder and Chief Scientific Officer, Dan Flynn. Dan? Thank you, Steve. Hello. As the Founder and Chief Scientific Officer at Decipher, it is a great pleasure to share the exciting new data from our early stage pipeline that our team presented in 8 poster presentations at this week's AACR conference. To set the stage for the other presentations by my colleagues, I would like to provide a brief overview of our proprietary switch-control inhibitor platform that fuels our research engine and has produced the early stage pipeline that we will review this evening. I will also present and describe our strategy for creating either potential first-in-class or best-in-class therapies for patients in urgent need of new therapies. Here at Decipher, we are leaders in kinase biology, backed by 2 decades of leadership in this space. Our platform has enabled a novel library of switch-control inhibitors that we have leveraged for advancement of our drug candidates from our research laboratories into the clinic, and since 2020 have brought directly to patients with our first approved medicine. We are confident in our ability to continue this track record of success and make a focused investment in our next generation of first or best-in-class medicines for patients. Our team has long understood and appreciated the challenges and the opportunities with targeting kinases as the basis for new medicines to transform the treatment of cancer. Our knowledge of kinase biology has allowed us to develop a switch-control inhibitor platform capable of overcoming the historical and current limitations of other kinase inhibitor approaches. In particular, compared to classical ATP competitive inhibitor approaches, our switch control platform enables high kinome selectivity, the ability to more broadly target kinase mutations, hinder mutational resistance, and develop inhibitors with extended residency time measured in hours compared to minutes, often observed with ATP competitive inhibitors. Also develop inhibitors that retain high cellular potency as cellular ATP levels do not compete with switch control inhibitors. Our switch control inhibitor platform has provided a generalized solution to these limitations. Additionally, we have recently evolved our platform to enable the discovery of kinase activators, which is difficult to achieve using classical approaches. Overcoming these limitations of other approaches contributes to the therapeutic promise of our drug candidates we will be discussing this evening. Our research engine has been incredibly productive, as shown by this side-by-side comparison of our current pipeline of proprietary molecules, which have ranged from a broader kinome profile in the case of QINLOCK, treating 4th-line GIST patients to more spectrum selective inhibitors to more highly selective inhibitors. Each of the candidates produced by our proprietary switch-control kinase inhibitor platform is assigned with unique attributes relevant to their intended indications. Our platform designs molecules to interact with kinase switch regions. This platform has its origin in understanding how kinases are regulated in cells. Kinase signaling networks play an important role in not only regulating many cellular functions, but also in the communication of cells with their environments. Hence, kinase signaling networks must themselves be under tight control in normal cells. Cellular regulation of kinase activity is mostly achieved through flexing between inactive to active shapes. Flexing of kinase shapes between active and inactive shapes is governed by numerous regions of the kinase we call switches. Our approach does not focus on binding into a classical pocket. Rather, we engineer inhibitors that directly bind with switch regions to lock kinase in their inactive shape. This is differentiated from classical ATP competitive inhibitors and has allowed us to create novel chemistry that is potent and selective for the target, and that has favorable pharmaceutical properties to maximize therapeutic benefit. Depending upon the kinase of interest, we have designed our compounds to interact with specific switch regions. Shown in the left figure is a representation of six switch regions we have identified to date. No one kinase makes use of all of these switches shown here. Rather, subsets of kinases make use of a subset of these switches for cellular regulation. This deep knowledge of various switch kinase switch mechanisms has enabled us to continually expand our platform and allow us to design targeted therapies for an increasing number of kinase families. I have indicated which switch regions were used to generate the pipeline molecules we'll be talking about this evening. I'll be highlighting our switch control platform focused on the Main Switch, the Inhibitory Switch, interior macro switches, and the C-helix Switch. QINLOCK, also known as ripretinib, inhibits KIT kinase and its design provides a great example of how we have used our switch control approach to successfully develop kinase inhibitors in a different way. KIT is a dual switch kinase, possessing a Main Switch shown in green and an Inhibitory Switch shown in salmon. When KIT is in the off state, as shown in the left panel, the inhibitory switch moves in to force the main green switch to the left, blocking both the ATP and the substrate binding pockets with these two amino acids made up from the green switch. This form of KIT is inhibited and cannot signal. For KIT to become activated, the inhibitory switch must be injected, as shown on the right panel. The main switch now moves in to the right, freeing up the ATP and substrate pockets in a catalytically active on state. Reversal of these orchestrated switch movements returns KIT to the off state. In our design of KIT inhibitor ripretinib, a major goal was to engineer an inhibitor that would restore the function of the exon 11 inhibitory switch that is deleted or mutated in the majority of GIST patients. The left-hand panel shows the main switch amino acid shown in green in the off state, while the intact wild type inhibitory switch amino acid, shown in salmon, participates in a larger macro switch called the inhibitory spine. The inhibitory switch amino acid shown in salmon occupies the number 3 position in a vertical spine macro switch comprised of 4 amino acids. By completing this vertical inhibitory spine, the inhibitory switch amino acid 3, shown in salmon, stabilizes KIT in the off state. The center panel illustrates the consequences of GIST patients losing their inhibitory switch by deletion or mutation, the so-called exon 11 primary mutation. The inhibitory switch no longer can regulate KIT to the off state, and the main switch, identified in gray, now moves in to form an activated spine macro switch that maintains KIT in an unregulated oncogenic on state, driving GIST tumors. The right panel shows how ripretinib was engineered to be a surrogate for the lost inhibitory switch by binding into the number 3 slot of the vertical spine, shown in magenta. Ripretinib serves as a proxy for the missing inhibitory switch, restoring the ability of KIT to occupy the off state with a patched and complete inhibitory spine. Ripretinib also compensates for the missing inhibitory switch through its interactions with a second macro switch that exists in KIT, which we call the hydrogen bond macro switch. The left panel shows normal KIT in the off state with a functional inhibitory switch, nucleating a massive network of hydrogen bonds to further stabilize KIT in the off state. A total of 11 hydrogen bonds, shown as dashed lines, form this stabilizing network, again ensuring that the ATP and substrate pockets are blocked with green amino acids as illustrated, and KIT is catalytically off. The right panel illustrates how ripretinib is again a surrogate for the loss of the inhibitory switch. Ripretinib, shown in magenta, nucleates and stabilizes this inhibitory network of hydrogen bonds by adding 4 additional hydrogen bonds, keeping KIT in the off state. All of the amino acids, green or blue, are saccharate, meaning that they are required for kinase switch function and catalytic activity. By participating in a hydrogen bond macro switch with these saccharate amino acids that are resilient to mutational resistance, these ripretinib binding interactions are designed to be durable and to hinder mutational resistance. DCC-3009, our second-generation pan-KIT inhibitor, will be discussed by Dr. Bryan Smith later in this call. It was designed on a similar approach to switch control as I just described for ripretinib, which we have successfully developed as a new therapeutic option for patients in fourth-line GIST. Ripretinib is differentiated from classical ATP inhibitors. Ripretinib is successful in fourth-line GIST patients due to its ability to control a wide range of KIT mutations, as shown in the heat map. Unlike other approved KIT inhibitors, ripretinib preclinically exhibited potent inhibition across a range of primary and secondary mutations, which was particularly important in late-line GIST when the number of secondary mutations and resistance can be driven by multiple mutations across different exons. Other switch control inhibitor attributes that help make ripretinib clinically effective were its resiliency to high cellular levels of ATP and its extended residency time with a T1/2 of nine hours. Our second drug candidate is vimseltinib, a highly selective CSF1R kinase inhibitor that is currently being studied in the pivotal phase 3 MOTION study for the treatment of patients with TGCT not amenable to surgery. The switch control binding mode of vimseltinib is much like that of repretinib in that vimseltinib shown in magenta participates in an inhibitory spine macro switch, again to eject the main switch in green into the off state, blocking both the ATP and substrate pockets in the left panel. Additionally, vimseltinib forms hydrogen bonds to stabilize the hydrogen bond macro switch, illustrated with a network of dashed lines in the middle panel. This stabilized hydrogen bond macro switch further stabilizes the off state of CSF1R. As shown in the right panel, the switch control attributes of vimseltinib include high kinase selectivity, resiliency to high ATP concentrations, and an extended residency time of 3 hours. Vimseltinib was engineered to have high kinase selectivity for CSF1R. The middle panel on this slide shows a close-up of the main switch region in green of CSF1R, highlighting an unusual small glycine amino acid that creates a hole for accommodating the binding of vimseltinib. The magenta mesh surface illustrates the accommodated binding of vimseltinib's methyl substituent into this glycine hole. Most other kinases do not have a glycine in the switch region but instead have much larger amino acids at this location. Highlighted in the lower left table are the larger cysteine amino acids in kinases closely related to CSF1R, including KIT, FLT3, PDGFRα, and PDGFRβ. Binding of vimseltinib to these closely related off targets is hindered due to steric clashes between the larger cysteine amino acids, as illustrated in the right panel. As a result, vimseltinib exhibits high selectivity versus these closely related kinase family members. In addition to deepening our expertise in understanding the switches of receptor tyrosine kinases, we have also broadened the reach of our switch control platform to targeting serine/threonine kinases. DCC-3116 was designed as a potent and selective type 1 ULK inhibitor that binds to saccharate amino acids in the main switch and also binds to a selectivity pocket identified by the arrow. Uniquely available in an unusual ULK MAZ switch region. Similar to ripretinib and vimseltinib, DCC-3116 has many of the same attributes of our switch control inhibitors, including high ULK potency, high kinome selectivity, and an extended residency time of 5 hours. Dr. Madhu Bhagat will later present an update on new combination therapies we intend to evaluate in the phase 1 trial of 3116. One other area where we have significant internal expertise in using our switch-control platform is to design pan-RAF inhibitors. Later on, you will hear about the exciting data on DCC-3084, our next-generation pan-RAF inhibitor that will enter the clinic. First, I would like to begin by highlighting Deciphera's pioneering work in the pan-RAF space, which was published in Cancer Cell recently. This paper disclosed the discovery of LY3009120, a pan-RAF inhibitor that inhibits RAF dimers, which was the product of a research collaboration with Lilly. As shown in the figure on the left, first generation BRAF inhibitors do not inhibit RAF dimers exemplified by the dabrafenib, which binds only to one monomer of the BRAF dimer, leading to paradoxical activation of the pathway signaling through the unbound monomer. Deciphera designed 9120, shown in magenta, to bind to both monomers of the BRAF dimer, leading to pathway inhibition without paradoxical pathway activation. A key to this success was designing an inhibitor that bound in a C-helix in switch state and a main switch DFG out state, as illustrated in the middle figure. The right figure demonstrates dimer occupancy by LY 9120, as determined by X-ray crystallography. We have now built upon our prior discoveries in the creation of DCC 3084, our next generation pan-RAF inhibitor that binds to RAF dimers in the key C-helix in switch state. As illustrated in the graphic on the left, DCC 3084, depicted as diamonds, binds to each RAF monomer, thereby inhibiting RAF dimer pathway signaling. X-ray crystallography, as shown on the right panel, confirms DCC-3084 binding to both monomers of a RAF dimer with a C helix occupying the end orientation. Later on in this presentation, Stacie Bulfer will describe the potential best-in-class profile of DCC-3084 in more detail. While DCC-3084 was designed to bind in a C helix in switch state to inhibit RAF signaling, serine/threonine kinase GCN2 kinase provided the incentive and the opportunity to design an activator of pathway signaling. We saw the GCN2 activator as a rational approach to dedicating cancer cells to an apoptotic signaling pathway. To accomplish this, we engineered a GCN2 agent that bound in a C helix out state, as illustrated in the center panel. In doing so, we accomplished two objectives. One, occupancy of only 1 monomer in a GCN2 tumor in this C helix switch out state. Secondly, transactivation of the unbound monomer to an active C helix in state activating pathway signaling. The binding mode of these DP-9149 also enabled high kinome selectivity, as illustrated on the right panel kinome tree. X-ray crystallography shows the binding of our GCN2 agonist to only 1 monomer of a GCN2 dimer. The bound monomer exhibits a C helix out switch state, hindering the ability of DP-9149 to bind to the other monomer. This binding mode results in transactivation of the unbound monomer, leading to GCN2 activation of the integrated stress response pathway, as measured by increased ATF4 transcription factor signaling. GCN2 activator DP-9149 will be more thoroughly presented by Dr. Gada Al-Ani this evening. Strategically, we have focused our Switch-Control platform to target kinase tumor driver kinases and also cancer adaptive stress response kinases. Tumor drivers, of course, cause oncogenesis, while kinases involved in adaptive stress responses resolve the stressors caused by tumor drivers. Moreover, inhibitors of tumor drivers often ramp up adaptive stress response pathways to cope with even higher levels of stress, causing therapy resistance, resulting in an interplay between tumor drivers and adaptive stress response pathways. Cancers can become addicted to both tumor driver pathway and adaptive stress response pathway signaling. We have demonstrated that inhibition of tumor drivers can further activate one or more of these adaptive stress response pathways, limiting the extent and duration of therapeutic benefit. We believe modulation of adaptive stress response pathways is an important emerging field in oncology targeted therapy. We target tumor drivers in our KIT, CSF1R, and pan-RAF programs, and the adaptive stress response in our ULK, BPS-34, GCN2, PERK, and CSF1R programs. You will now hear from my colleagues as they highlight programs that were presented at this 2023 AACR conference. Together with our existing phase 3 studies of QINLOCK in second-line GIST patients harboring mutations in exons 11 and 17/18, and vimseltinib in TGCT, our earlier-stage programs described today are poised to fuel our pipeline through 2026 and beyond. At this point, I would like to introduce Dr. Stacie Bulfer, who will present our first preclinical disclosures about our pan-RAF inhibitor, DCC-3084. Stacy? Hi, I'm Dr. Stacie Bulfer, Senior Director of Biological Sciences here at Deciphera. I'm gonna spend some time today talking about our pan-RAF inhibitor, DCC-3084, a potential best-in-class BRAF homodimer and BRAF, CRAF heterodimer inhibitor that was engineered using Deciphera's proprietary switch-control platform. DCC-3084 was designed to be a potent inhibitor of both BRAF and CRAF kinases, the preclinical data we presented this week demonstrates its ability to target all the relevant aberrant signaling mechanisms, including inhibition of BRAF monomers, BRAF homodimers, and BRAF, CRAF heterodimers. To facilitate tumor access, DCC-3084 possesses desirable pharmaceutical properties, including high permeability, CNS penetration, and good solubility at gastric pH. In addition, DCC-3084's optimal properties include a long residency time, low efflux, and potent transporter inhibition to enable durable efficacy. Together, the strong preclinical data on DCC-3084 supports single-agent use in tumors driven by RAF and RAS mutations, with even deeper responses observed in combination with MEK inhibitors. Approved BRAF inhibitors today benefit patients with class 1 BRAF mutations, like the BRAF V600E mutant that signals as a BRAF monomer. These inhibitors are not able to benefit patients with mutations in the RAS, RAF, MAPK pathway that signal through RAF homodimers or RAF heterodimers. As a potential best-in-class BRAF, CRAF inhibitor, DCC-3084 was developed to have broad inhibition against both monomer and dimer RAF signaling mechanisms. Some of the key properties that are needed for a best-in-class pan-RAF inhibitor include having a small molecule that is potent and selective for BRAF and CRAF kinases that allows inhibition of aberrant RAF signaling via monomers, homodimers, and heterodimers. The inhibitor should also possess a long on-target residency time with limited inhibition of off-target kinases. Optimized pharmaceutical properties, including high permeability and low efflux, along with inhibition of drug resistance transporters to maximize efficacy are also needed. Improved solubility is likewise required to enhance PK properties and target inhibition. Finally, we want a compound that has excellent tissue distribution to allow for elevated accumulation in tumor cells and CNS penetration to allow targeting of both primary and secondary brain tumors. DCC-3084 possesses all these key properties, which I will describe in more detail in the next few slides. DCC-3084's switch control mechanism allows for binding into both monomers of a RAF dimer to limit paradoxical stimulation that occurs with approved first-generation BRAF inhibitors in RAS mutant cell lines. On the left side is the X-ray crystal structure of DCC-3084 bound to both monomers of a BRAF dimer. DCC-3084 binds to force the main activation DFG switch to adopt an out state and the C helix switch to adopt an in state. The binding mode limits pERK activity due to paradoxical pathway activation that was observed with first-generation BRAF inhibitors like encorafenib and dabrafenib. Compare the gold line in the graph on the right for DCC-3084, where no pathway activation is observed, versus the blue and gray lines for dabrafenib and encorafenib, respectively. DCC-3084 exhibits potential best-in-class inhibition of class 1, 2, and 3 RAF, class 3 BRAF mutations, along with RAF fusion cell lines compared to other pan-RAF candidates, including tovorafenib, naporafenib, belvarafenib, exarafenib, and JZP815. In this table, I'm showing the nanomolar concentration of compound needed to inhibit cellular proliferation by 50% across a panel of BRAF mutant cell lines. First, looking at the class two fusion and class three mutant cell lines, which signal as RAF homo or heterodimers, we found that DCC-3084 achieved the best overall profile with equal or better potency compared to these competitors. At the same time, DCC-3084 was able to maintain superior inhibition of cell lines driven by BRAF class one mutants, unlike these competitors, which appear to be more selective for RAF dimers compared to RAF monomers. DCC-3084 has excellent permeability, low efflux, and is a strong inhibitor of the MDR1 and BCRP drug resistance transporters. These optimized pharmaceutical and distribution properties allow DCC-3084 to readily penetrate tumor cells and accumulate in tumors to durably inhibit aberrant RAF dimer signaling. This contrasts with other pan-RAF inhibitors, which can exhibit decreased diffusion into cells and increased efflux through drug resistance pumps. DCC-3084's optimal pharmaceutical properties for oral administration are quantified here. DCC 3084 has good solubility at gastric pH to allow for oral absorption and higher cellular permeability and low efflux, both which aid in getting compound into the tumor. This compound is an inhibitor of the MDR1 and BCRP drug resistance transporters. Finally, DCC 3084 does not inhibit any of the main cytochrome P450 or CYP isoforms in the liver up to high micromolar concentration. DCC 3084 exhibits strong accumulation in tumors and has good CNS penetration. DCC-3084's excellent permeability and low efflux allow for accumulation in tumor tissue at a ratio between 1.7-1.9-fold. DCC-3084's inhibition of efflux transporters like MDR1 enable higher CNS penetration. This compound's ratio of free unbound drug in the brain versus plasma, or Kp,uu, was measured to be 30%, which is superior to most other pan-RAF candidates. We believe CNS penetration is essential for a pan-RAF inhibitor to enable potential use in primary brain cancers or brain metastases, which are both areas of high unmet medical need. This strong profile in vitro has translated to our initial in vivo data, with DCC-3084 showing single-agent activity across a range of class 1, 2, and 3 BRAF mutants, along with RAF fusions. As a single agent, DCC-3084 produced tumor regressions in RAF mutant cancer xenograft models. Starting on the left, in the A375 BRAF class 1 model, a 30 mg per kg BID dose of DCC-3084 produced 84% tumor regression. In the BXPC3 BRAF class 2 mutant model, 27% tumor regression was observed at a 50 mg per kg BID dose. In the WM3928 SKAP2 fusion xenograft model, DCC-3084 exhibited dose-dependent tumor regression of 37% at the 25 mg per kg dose and 79% at the 50 mg per kg dose. Finally, in the WM3629 model, which contains a BRAF class 3 mutation plus an NRAS G12D mutation, a dose as low as 25 mg per kg BID achieved 57% tumor regression. Taken together, this in vivo efficacy data validates that single-agent DCC-3084 is a potent inhibitor of BRAF and CRAF kinases that can target BRAF class 1, 2, and 3 mutations as well as BRAF fusions. In addition to targeting BRAF mutations, DCC-3084 produces single-agent tumor regression or tumor growth inhibition in KRAS-mutated xenograft models driven by BRAF and CRAF heterodimers. Starting on the left, a 50 mg/kg BID dose of DCC-3084 achieved 69% tumor regression in the Calu-6 KRAS Q61K lung cancer model. It achieved 80% tumor growth inhibition in the H358 KRAS G12C lung cancer model. Finally, it achieved 55% tumor growth inhibition in the HPAF-2 KRAS G12D pancreatic cancer model. DCC-3084 has even deeper tumor regression in KRAS-mutant cancer models in combination with MEK inhibitors. In the Calu-6 KRAS Q61K-mutant lung model, a combination of DCC-3084 plus a low dose of the MEK inhibitor cobimetinib achieved 78% tumor regression. This combination effect was also observed with the MEK inhibitor binimetinib. In the H358 KRAS G12C lung model, the combination of DCC-3084 plus binimetinib produced 22% tumor regression. Finally, in the higher bar HPAF-2 KRAS G12D pancreatic cancer model, a combination of DCC-3084 plus binimetinib produced 91% tumor growth inhibition. In summary, we believe DCC-3084 is a potential best-in-class pan-RAF inhibitor. DCC-3084 is a potent and selective inhibitor of both BRAF and CRAF kinases and has been shown to target all relevant aberrant signaling mechanisms, including RAF signaling through monomers, heterodimers, and homodimers. DCC-3084 exhibits high permeability, good central nervous system penetrance, and tumor tissue accumulation. In addition, DCC-3084 possesses a long residency time, exhibits low efflux, and is an inhibitor of drug-resistant transporters to enable durable efficacy. Strong preclinical efficacy in cancer models driven by RAF or RAS mutations support exploration of single-agent and combination opportunities. Based on this preclinical profile, we plan to submit an IND to the FDA in the second half of 2023. I'll now turn the call over to my colleague, Dr. Bogdan, to discuss the new DCC-3116 preclinical data. Thanks, Stacy. I'm Dr. Madhu Bogdan, Senior Principal Investigator here at Deciphera. Today, I'll be presenting on two new sets of preclinical data demonstrating combination efficacy with DCC-3116, a first-in-class selective inhibitor of ULK1/2 kinases and autophagy. DCC-3116 is currently in a Phase I/II clinical trial in patients with advanced solid tumors with a documented RAS or RAF mutation. DCC-3116 was designed to be a potent, selective, best-in-class inhibitor of the ULK1/2 kinases, the initiating factor in autophagy, using Deciphera's proprietary switch-control platform. Deciphera has generated strong preclinical data demonstrating combination efficacy with RTK pathway inhibitors in cancers with an RTK pathway driver mutation. These data support the potential for DCC-3116 to be a backbone combination agent across approximately 70% of cancers. Deciphera's ULK inhibitor has single-digit nanomolar potency for both ULK1 and ULK2, while being highly selective across the kinome, with no off-target kinases within 34-fold of ULK1 and only five kinases within 100-fold of ULK1. In addition, DCC-3116 was designed to avoid CNS exposure. Autophagy is a regulated cellular mechanism that removes unnecessary or dysfunctional proteins and recycles other molecules. During this process, ULK initiates the autophagy pathway through the phosphorylation of ATG13 and other proteins, leading to the formation of the isolation membrane. As the pathway progresses, the autophagosome fuses with the lysosome to degrade the proteins or other molecules trapped inside. Lipidated LC3 plays an important role throughout this process and can be used to measure autophagic flux. Cancer cells use autophagy as an adaptive stress response mechanism when there are low nutrients, hypoxia, or chemotherapy treatment, making ULK an attractive target for cancer therapy. In internal and external data demonstrate that RTK, RAS, and RAF mutants cancer cells activate autophagy to survive damage due to therapeutic intervention with RTK pathway inhibitors. Therapeutic intervention can activate autophagy through ULK, which is a serine/threonine kinase responsible for initiating the autophagy pathway through direct phosphorylation of ATG13. To inhibit cancer cell autophagy, Deciphera has developed DCC-3116, a potent and selective inhibitor of ULK1 and 2 that exhibits favorable biopharmaceutical properties to be used in combination with RTK pathway inhibitors, since we do not expect single-agent activity. Deciphera has generated strong preclinical data demonstrating a broad role for autophagy in RTK RAS RAF mutant cancers, which represent approximately 70% of solid tumors. RTK RAS and BRAF mutant cancers are particularly dependent on autophagy as an escape mechanism when treated with pathway inhibitors. DCC-3116 can synergize with these tumor driver inhibitors to reduce tumor burden or lead to regressions, which has been demonstrated in preclinical murine xenograft experiments with ripretinib in GIST, osimertinib and afatinib in EGFR mutated non-small cell lung cancer, sotorasib and adagrasib in KRAS G12C mutated non-small cell lung cancer, encorafenib in BRAF mutant colorectal, and trametinib in pancreatic lung and melanoma, validating the 3116 mechanism of action across indications. Based on our preclinical data, combination strategies with other therapeutic interventions along the pathway, such as with ERK, PI3K, and mTOR inhibitors, may also be beneficial. These preclinical data demonstrate the broad applicability of this mechanism of action and the use of DCC-3116 as a method to improve the efficacy of RTK pathway inhibitors. Cancer cells activate autophagy through ULK1 and 2 kinases as an adaptive stress response mechanism to therapies targeting the RTK pathway, limiting antitumor response. BRAF signals through the MAPK pathway, while EGFR signals upstream through both the MAPK and PI3K pathways, suppressing ULK1/2 kinases and autophagy. Inhibition of mutant BRAF and EGFR reverses this suppression, activating the autophagy adaptive stress response. The BRAF V600E mutation occurs in about 10% of colorectal cancer patients. Approved treatments for these patients include the BRAF V600E inhibitor encorafenib in combination with the EGFR antibody cetuximab. Treatment with encorafenib and cetuximab is initially successful, but drug resistance develops either through RTK or MAPK-resistant mutations or adaptive stress response pathways, including autophagy. In the next few slides, we demonstrate ULK1/2 kinases and autophagy are activated upon treatment with encorafenib and cetuximab, which is inhibited by DCC-3116, leading to strong tumor growth control in preclinical models. Encorafenib and cetuximab treatment led to the activation of ULK1 and 2 around 2 to threefold in BRAF V600E mutated colorectal cell lines, as measured by phosphorylation of the ULK1/2 substrate ATG13. This induction is shown in the blue bars in both the HT-29 and COLO 205 cell lines on the left and right graphs respectively. DCC-3116, which is shown as a titration in the blue line, potently inhibits both encorafenib and cetuximab-induced and basal phospho-ATG13 with IC50 values of 80 and 234 nanomolar in HT-29 and COLO 205 cells respectively, demonstrating similar effects across two colorectal cell lines. Autophagic flux was measured using our mCherry-GFP-LC3 assay as a downstream consequence of autophagy induction or inhibition. Encorafenib and cetuximab induced autophagic flux around 3-fold in both the HT-29 and COLO 205 cells, as shown in the blue bars in the first and third graphs, which was potently inhibited by DCC-3116, as shown as a titration in the blue line with IC50 values of around 66 in HT-29 and 117 nanomolar in COLO 205 cells. In addition, DCC-3116 can sustainably inhibit autophagic flux induced by encorafenib and cetuximab, as seen in the flux over time graphs, as shown in the second and fourth graphs in both the HT-29 and COLO 205 cell lines. Importantly, these in vitro effects translated to in vivo combination efficacy. DCC-3116 was designed with favorable pharmaceutical and ADME properties, which is demonstrated by the PK/PD data in the HT-29 model. Target engagement, as read out by phospho-ATG13 in the tumor, is shown on the left Y-axis, while plasma exposures of DCC-3116 are shown on the right Y-axis in blue. Similar to what's seen in vitro, encorafenib and cetuximab induce phospho-ATG13 in tumors, which is then inhibited by DCC-3116 in a dose-dependent manner. In a comparison xenograft study in the same HT-29 model, the combination of DCC-3116 with encorafenib and cetuximab resulted in greater tumor growth inhibition compared to single agent or the combination of encorafenib and cetuximab, demonstrating a strong PK/PD efficacy relationship. In addition, the combination of DCC-3116 with encorafenib results in 100% regressions in the COLO 205 xenograft model. These preclinical data demonstrate that BRAF inhibitors in combination with EGFR blockades such as encorafenib and cetuximab, activate ALK-mediated autophagy as an adaptive stress response resistance mechanism, which can then be inhibited by our ALK compound, providing the rationale to study the combination of DCC-3116 with encorafenib and cetuximab in BRAF V600E-mutated colorectal patients. As part of our clinical trial collaboration and supply agreement with Pfizer, Deciphera will sponsor the trial, and Pfizer will supply encorafenib at no cost. I'll be shifting over to show you some of our exciting data demonstrating a strong combination effect with DCC-3116 and ripretinib. Most gastrointestinal stromal tumors are driven by mutations in KIT kinase. KIT signals through both the MAPK and PI3K pathways, suppressing ALK1/2 kinases and autophagy. Inhibition of mutant KIT reverses this suppression, activating autophagy and cancer cell survival. Approved therapies for GIST include imatinib, sunitinib, regorafenib, avapritinib, and of course, ripretinib. Treatment with these inhibitors is initially successful, but drug resistance can develop either through KIT secondary mutations or adaptive stress response pathways, including autophagy. In the next few slides, we demonstrate that ULK1 and 2 and autophagy are activated upon treatment with ripretinib in KIT mutant GIST models. A combination of ripretinib with DCC-3116 inhibits autophagy both in vitro and leads to complete tumor regressions in a preclinical model of GIST. Ripretinib treatment led to the activation of ULK1 and 2 by 2-3-fold in mutant KIT GIST cell lines, as shown by phosphorylation of ATG13 in the first graph on the left. Ripretinib also induced phospho-ATG13 around 1.5-2.5-fold in multiple imatinib-resistant cell lines, also shown in the first graph on the left, which was then inhibited by DCC-3116, with IC50 values ranging 9-191 nanomolar, as shown in the second graph. Treatment with GIST-T1 cells with ripretinib increased autophagic flux 3-4-fold, which was then potently inhibited by 3116, with an IC50 value of 38 nanomolar, as shown in the third graph. Lastly, in the graph on the right, DCC-3116 can sustainably inhibit autophagic flux in the GIST-T1 cell line, demonstrated by our flux over time assay. Importantly, these in vitro effects again translated to in vivo target engagement and strong efficacy. In a GIST-T1 PK/PD model, 3116 inhibited ULK1/2-mediated phospho-ATG13, shown in the first graph on the left. Strikingly, the combination of our ULK inhibitor with ripretinib resulted in complete tumor regressions in all 10 mice tested, in comparison to single-agent treatment in the GIST-T1 xenograft model, shown in the middle and right graphs. These data demonstrate preclinically that like other receptor tyrosine kinase inhibitors, such as EGFR inhibitors, osimertinib and afatinib, ripretinib activates ALK1/2-mediated autophagy as an adaptive stress response resistance mechanism, which is then inhibited by our ALK compound, providing the rationale to study the combination of DCC-3116 with ripretinib in GIST patients. In conclusion, DCC-3116 can block both BRAF V600E inhibitor and cetuximab-induced ALK activation and autophagic flux in BRAF V600E-driven colorectal preclinical models and ripretinib-induced ALK activation and autophagic flux in GIST preclinical models, which extends to in vivo combination efficacy, as demonstrated by tumor growth inhibition or strong tumor regressions in xenograft studies. DCC-3116 is currently in a phase 1 combination dose escalation study with trametinib in pancreatic non-small cell lung cancer and colorectal cancer, binimetinib in melanoma, and sotorasib in KRAS G12C mutated non-small cell lung cancer. Based on the compelling preclinical data presented this week, in the second half of 2023, Deciphera expects to launch two new combination dose escalation cohorts, one in combination with encorafenib and cetuximab in colorectal cancer in collaboration with Pfizer, who will provide the encorafenib for the trial, and the other in combination with ripretinib in GIST. I'd like to now introduce my colleague, Dr. Bryan Smith, who will discuss our next-generation pan-KIT inhibitor, DCC-3009. Thanks, Madhu. Hi, I'm Bryan Smith, Vice President of Biological Sciences at Deciphera, and today I'm excited to share preclinical data on our next-generation KIT kinase inhibitor, DCC-3009, which is currently in preclinical development for the treatment of gastrointestinal stromal tumors, or GISTs. DCC-3009 is a potent and selective next-generation KIT inhibitor engineered using Deciphera's switch-control platform. Drug-resistant GIST is a complex cancer that has a diverse spectrum of KIT mutations that arise in response to treatment with tyrosine kinase inhibitors. Many patients harbor multiple different drug-resistant mutations in tumors and/or metastatic tumor sites. There remains an unmet medical need for a pan-KIT inhibitor that can broadly and potently inhibit the spectrum of KIT mutations that drive GIST. To potentially achieve this, we focused on making a drug that can inhibit the spectrum of KIT mutations found in GIST across exons 9, 11, 13, 14, 17, and 18, while maintaining very high selectivity versus the rest of the kinome. With optimized pharmaceutical and ADME properties for oral drug administration and with strong supporting data in preclinical GIST models, we believe DCC-3009 has the potential to be a best-in-class KIT inhibitor for the treatment of GIST. GIST, the most common sarcoma of the GI tract, is driven in over 80% of cases by alterations in the receptor tyrosine kinase KIT. There are 2 main sites of genetic alterations found in KIT in GIST patients at diagnosis: exon 9, which encodes the extracellular dimerization domain, and exon 11, which encodes the inhibitory juxtamembrane domain. Alterations in these exons lead to activation of KIT kinase and uncontrolled cell growth and tumor formation. As Dr. Bogdan mentioned earlier, imatinib, the first FDA-approved KIT kinase inhibitor, is an effective first-line therapy for patients with advanced GIST harboring exon 9 and exon 11 alterations. Most patients eventually develop disease progression due to secondary resistance mutations. 90% of GIST patients with imatinib resistance have acquired secondary KIT mutations, which usually appear in the ATP binding pocket encoded by exons 13 and 14 and/or the activation loop encoded by exons 17 and 18. Complicating matters, GIST patients with drug resistance often harbor multiple heterogeneous secondary KIT mutations in different tumor sites, which makes treatment of drug-resistant GIST a complex problem. An inhibitor that can broadly and potently inhibit the spectrum of KIT mutations across all exons is highly sought. DCC-3009 was designed as a next-generation KIT inhibitor that more broadly and evenly inhibits KIT mutations across exons 9, 11, 13, 14, 17, and 18, and the in vitro and in vivo data we have generated shows the best-in-class profile of DCC-3009. As is shown in these heat maps of IC50 values for inhibition of cell proliferation of various cell lines harboring drug-resistant KIT mutations, imatinib inhibits alterations in KIT exons 9 and 11, albeit with weaker activity versus exon 9 variants. Imatinib, however, lacks activity against drug-resistant KIT mutations in exons 13, 14, 17, and 18, as expected. The FDA-approved second-line therapy for GIST, sunitinib, has potent activity versus alterations in KIT exons 9, 11, 13, and 14 but lacks significant activity versus activation loop mutations in KIT exons 17 and 18. The FDA-approved third-line therapy for GIST, regorafenib, inhibits some mutations found in GIST but lacks efficacy versus key mutations. Ripretinib is broadly active and showed improved median progression-free survival in patients harboring mutations across all exons in GIST in the fourth line plus setting. However, in second-line GIST, in patients in the INTRIGUE study, ripretinib showed a clear preference for inhibition of KIT variants encoded by exons 11, 17, and 18, in contrast to exons 9, 13, and 14. It can be seen in vitro on this heat map that ripretinib has a preference for mutations in KIT exons 11, 17, and 18, which lines up with the clinical results observed in the second-line setting in the INTRIGUE trial. In contrast to these FDA-approved KIT kinase inhibitors, DCC-3009 is designed to more broadly and evenly hit KIT mutations across the spectrum in GIST. DCC-3009 was also designed with superior pharmaceutical and ADME properties to potentially allow for greater total and free drug exposure, enabling deeper suppression of KIT mutants in GIST patients. The drug is stable in microsomes and has a significant unbound or free fraction of drug and plasma. It has high cellular permeability, which aids in getting the drug into tumors, and low to moderate efflux, which aids in keeping the drug out of the brain. This compound does not inhibit any of the main human cytochrome P450 CYP isoforms in the liver up to high micromolar concentrations, nor does it inhibit the hERG potassium channel important for cardiac function. DCC-3009 was negative for genotoxicity in the Ames test. Finally, the drug has high oral bioavailability in rats and dogs and low brain penetration in rats. As GIST does not metastasize to the brain, this allows for potential avoidance of adverse events that may occur in the CNS. DCC-3009 was designed to be more selective than ripretinib and other KIT inhibitors. We tested DCC-3009 versus a large panel of kinases. The results show that the compound inhibits KIT and the KIT kinase family as well as VEGFR-2 but is very selective versus approximately 400 other human kinases. Its selectivity profile is even better than ripretinib, a drug which is known to be generally very well tolerated in patients. We are excited about the potential safety and tolerability profile of DCC-3009. Importantly, the strong in vitro data translated into very promising in vivo results, with DCC-3009 inducing tumor regressions in multiple drug-resistant GIST xenograft models. First, on the left, DCC-3009 treatment leads to regression in a tumor allograft of an engineered cell line dependent on KIT with alterations in both exons 9 and 13. The activity here of DCC-3009 was on par with sunitinib, which we know from our clinical data does very well in these patients. In the center, DCC-3009 treatment leads to significant tumor regression in a GIST patient-derived xenograft that has a KIT exon 11 deletion and an exon 13 V654A mutation, with long-term inhibition of tumor growth observed after cessation of dosing. Finally, on the right, DCC-3009 treatment also leads to nearly complete regression in another GIST patient-derived xenograft model that has a KIT exon 11 deletion plus an exon 17 Y823D mutation, again with long-term regression observed after the end of the dosing period. All of these doses were well-tolerated in mice. In summary, DCC-3009 is a broad and potent inhibitor of KIT mutants found in GIST across the spectrum of exons 9, 11, 13, 14, 17, and 18. Treatment with DCC-3009 exhibited tumor regressions in multiple drug-resistant preclinical GIST models. The drug has optimized pharmaceutical and ADME properties for oral administration and greater kinase selectivity and free drug levels to enable pharmaceutically active exposures needed to suppress the broad spectrum of KIT mutations in GIST. Based on this profile, DCC-3009 has been nominated as a development candidate for the treatment of GIST. We plan to submit an IND to the FDA in the first half of 2024. Thank you. I would now like to introduce Dr. Alani, who will cover preclinical data on another exciting project at Deciphera. Thank you, Bryan. Hello, everyone. I'm Gada Al-Ani, Senior Principal Investigator, Biological Sciences here at Deciphera. It's my pleasure to share with you today data on our novel GCN2 activator, DP-9149, which is currently undergoing further preclinical studies in solid tumors. DP-9149 was designed to be a potent and selective activator of the integrated stress response kinase GCN2 and exhibits strong anti-tumor activity as a single agent and promotes tumor regression when combined with standard of care therapies in vivo. This novel molecule leverages the cytotoxic arm of the integrated stress response pathway and enables the engagement of cancer cell death pathways. The elevated integrated stress response signaling in solid tumors provides a favorable therapeutic window, as evident by its tolerability in preclinical models. Deciphera has generated strong preclinical data demonstrating that the GCN2 kinase activator DP-9149 has broad applicability in several solid tumor indications and mutational backgrounds. DP-9149 is effective in RAS/MAPK-driven cancers as well as other non-RAS-driven solid tumor models such as VHL mutant renal cell carcinoma. DP-9149 combines with other stress-inducing therapies, including anti-angiogenics and tumor driver targeting agents. This is a cartoon describing the role of this adaptive stress response pathway in cancer cells. Cancer cells are under constant need to acquire nutrients to be used as fuel to maintain synthesis of new proteins and to be able to maintain high rates of proliferation and cell growth. This high proliferative nature causes the tumor cells to be under constant nutrient hypoxia and metabolism stress. The exposure of the tumor cells to anti-cancer therapies, such as anti-angiogenics or MAPK pathway inhibitors, exerts an additional layer of extrinsic stress. The integrated stress response pathway, or the ISR for short, is a major adaptive stress response pathway in cancer cells and plays an important role in cell fate determination. Oncogene-driven solid tumors under elevated stress levels are dependent on a well-balanced ISR pathway activity to cope with the high demand for accelerated growth and therapy-induced stress. The ISR pathway has been shown to have a context-dependent nature, where the inhibition or stimulation of this pathway can be pharmacologically leveraged to induce anti-tumor effects. At Deciphera, we have studied the ISR kinases GCN2 and PERK. Deciphera is leveraging its GCN2 kinase activator, DP-9149, as a novel mechanism to upregulate the cytotoxic arm of the ISR and cause anti-tumor effects in solid tumors, both in vitro and in vivo. DP-9149 pharmacologically transactivates the ISR kinase GCN2, leading to an increase in the translation of the downstream transcriptional activator, ATF4. ATF4 translocates to the nucleus, where it upregulates the expression of genes that are part of the cytotoxic arm of the ISR pathway, such as CHOP and other death-promoting genes. This persistent activation of the cytotoxic arm of the ISR in tumor cells that are at an already elevated levels of stress leads to an unresolved damage, causing the cancer cells to commit to cell death. DP-9149-mediated activation of the cytotoxic arm of the ISR, causing the cancer cell to commit to cell death or halt tumor growth, leads to strong single agent activity by DP-9149 in ISR-addicted tumors. Treatment with anti-tumor therapies, for example, anti-angiogenics or MAPK pathway inhibitors, induces cytotoxicity and leads to elevated levels of stress, further sensitizing tumor cells to DP-9149-mediated activation of the ISR pathway, leading to potential synergy and tumor regression when DP-9149 and standard of care therapies are combined. When tested in the VHL mutant renal cell carcinoma cell line, 786-O, DP-9149 was found to upregulate ATF4 up to 7-fold in vitro, as shown in the top left bar graph. DP-9149-mediated ISR activation led to inhibition of in vitro cell growth with a potent IC50 of 1 nanomolar as a single agent, as shown in the middle panel. DP-9149 led to a 6-fold upregulation of ATF4 in the LoVo KRAS mutant colorectal cancer model and promoted cell growth inhibition with an IC50 of 8.2 nanomolar as a single agent, as demonstrated in the bottom panels on the left. These findings, along with other properties, are also summarized in the table on the right. This demonstrates that DP-9149 is a potent and selective activator of the ISR pathway, promoting strong single-agent growth inhibition in cancer cells with different mutational backgrounds in vitro. DP-9149 exhibits strong single-agent activity and promotes tumor regression in combination with therapeutic agents in xenograft models in vivo. Starting on the left, in the HT1080 mutant NRAS fibrosarcoma model, DP-9149 treatment led to an 80% tumor growth inhibition as a single agent. Combining DP-9149 with the MAPK pathway inhibitor, cobimetinib, led to tumor regression where 3 out of 10 mice showed complete response in this fibrosarcoma model. In the center, DP-9149 treatment in the LoVo KRAS-mutant colorectal cancer model led to an 82% tumor growth inhibition as a single agent. Combining DP-9149 with the standard of care anti-angiogenic agent, bevacizumab, promoted a 17% tumor regression in this colorectal cancer model. On the right, you can see that DP-9149 treatment in the 786 renal cell carcinoma model led to a 92% tumor growth inhibition as a single agent. Combining DP-9149 with axitinib, which is a standard of care therapy anti-angiogenic agent, resulted in an impressive 56% tumor regression. All treatments were well-tolerated in mice. Taken together, these in vivo studies demonstrate that ISR activation by DP-9149 potently inhibit tumor growth as a single agent and promotes tumor regression in combination with therapeutic agents in a broad range of tumor models in vivo. In summary, the integrated stress response pathway is a targetable vulnerability in oncogene-driven solid tumors. Deciphera's novel GCN2 activator was designed as a selective and potent activator of GCN2 with an optimized pharmaceutical and selectivity profile. Upregulating the ISR by activation of the ISR family member GCN2 through DP-9149 can be leveraged as a novel mechanism to cause in vitro and in vivo anti-tumor effects, likely through the induction of unresolved stress response. DP-9149 can be developed for the treatment of a broad range of solid tumors, both as a single agent and in combination with approved therapeutic agents. With that, I'll turn the call back over to Steve for closing remarks before we open the call for Q&A. Thank you, Gada. As you've heard this evening, our team in research continues our legacy of generating novel product candidates with first or best-in-class potential by leveraging our proprietary kinase switch-control kinase inhibitor platform. 2023 will be a busy year for Deciphera, with key milestones expected across some of the early-stage programs we discussed today and in our late-stage programs, including the announcement of top-line results from our pivotal phase 3 MOTION study of ensartinib in the fourth quarter. With that, operator, I'd like to open the call for Q&A. We will now begin the Q&A session. If you would like to ask a question, simply click on the right-hand button at the bottom of the screen. Once you have been invited to, please unmute yourself and begin with your question. Thank you. It looks like currently we have no questions from the virtual audience. As a reminder, I just wanted to let you know that if you would like to ask a question, simply click on the Raise Hand button at the bottom of the screen. Once you have been invited to, please unmute yourself and begin with your question. Thank you. Our first question comes from Bijan Mokhtari with Stifel. Please unmute yourself and ask your question. Bijan, you will have to hit star nine to unmute yourself since you are on a telephone. Hopefully you can hear me now. Yeah, Bijan. Good evening, either. This is Bijan with Barclays and Leerink. Congrats on all the posters. On the ALK inhibitor and QINLOCK combo, how are you thinking about the development strategy? Is this a play for eventual combination with the pan-KIT inhibitor, or will it be something that you're gonna layer into the INSIGHT study? What do you need to see in the early data to consider this combination to be exciting and worth continuation? That's a great set of questions, Bijan. It's Steve here. We'll try and take those in turn. First, what I'll do is just ask Dan to cover off on the mechanistic part of the question, which is why combine DCC-3116 with ripretinib and what we're trying to understand with that combination. Matt can comment specifically on the cohort and the design of that cohort and what we hope to learn in the clinic. Dan, do you wanna take the first part? Yes. Mechanistically, what we've known for some time as we have made presentations is that tumor drivers up and down the RTK, MAPK pathway, tend to tonically inhibit ALK, but inhibition of a tumor driver in this pathway, unleashes ALK, sets that off to provide autophagy as a resistance mechanism to cancer cells. What is more particular in this particular case is that ripretinib being an RTK inhibitor, sits at the very top of that axis and actually can activate ALK down two pathways, both the MAPK pathway and the PI3K pathway, leading to substantial induction of autophagy. I think that is the mechanistic basis for the robust combination efficacy we see. Great. Thanks, Dan. Matt, do you wanna talk a little bit about the design of the cohort specifically? Yeah. You know, just to continue. What we've been able to demonstrate today, really excited to show the combination efficacy of DCC-3116 with ripretinib, and we'll take that forward into a new cohort in combination with DCC-3116 in the clinic. As you know, what we focused on in the past has been the 3 combination partners of the two MAPK inhibitors, trametinib and binimetinib, as well as the KRAS G12C inhibitor, sotorasib. Recently, we also talked about the combination with encorafenib and cetuximab, and that was some additional data that we were able to show today. Now the new data that we presented tonight is really the, you know, the great efficacy combination of DCC-3116 plus ripretinib. That will be part of an escalation and expansion cohort in clinical development. Initially, we'll be targeting patients with just with a, you know, with any KIT or pediatric or PDGFRα mutation who have failed first-line therapy. In the expansion cohort, we'll be more specific in looking at KIT exon 11 mutation-only patients in the second line. Okay. Our next question comes from Jess Fye with J.P. Morgan. Jess, please un-mute yourself and ask your question. Hey, guys. Good evening. Thanks for taking my questions. Two for me. First, out of all the ALK combinations you're running, is there anyone in particular that you think has the most logical scientific rationale or in your view, the strongest preclinical evidence? Separately, with the pan-KIT inhibitor, how are you thinking about the development strategy there? Any chance you would try to, you know, go up against imatinib with a product like that? Thank you. Yeah, thanks for the two questions, Jess. It's Steve. I'll ask Dan to comment on, you know, out of all the universe of possibilities that we see with ALK and given all the preclinical data, Dan, do you wanna kinda characterize our thinking or your thinking, around which of those combinations is most promising or how you view them? Well, of course, most of our data we've obtained so far has been in mirroring studies. At least in the mirroring studies, what we've really found is that anytime there is a tumor driver in the pathway from an RTK, like, well, mutant KIT, for instance, through mutant RAS all the way down that cascade, depending upon the robustness of that tumor driver inhibitor, it will set off autophagy. It's a pretty general phenomenon, and I think really I would defer to my clinical colleague, Matt here, to talk about what the priorities might be as we're moving forward into the clinic. Yeah. No, thanks, Dan. You know, hi, Jess. Yeah, so you know, we love all our children, and, you know, we really feel this is, you know, very well thought out, you know, program, you know, based on a very, you know, focused number of combination partners. You know, based on the wealth of preclinical data that we've been able to generate and present over the last several years. As, you know, Dan highlighted, you know, inhibiting the RTK receptor itself, you know, RAS, along the MAP kinase pathway, all those nodes will lead to, you know, dysregulation of autophagy. By adding 3116 in combination, we'll be able to, you know, hopefully show demonstration of, you know, clinical activity. Then, Jess, to take your second question, which was around DCC-3009, the pan-KIT inhibitor, that we disclosed for the first time and where we might take that in the clinic. You know, I think at first I would just, you know, offer that when we look at the profile that we generated preclinically with DCC-3009, we know it to be a very broad spectrum inhibitor. We know it to be exquisitely selective, so even more selective than ripretinib. Ripretinib, of course, is well known and characterized now in the clinic as being a very well-tolerated agent. We see DCC-3009 as even being more selective and therefore potentially better tolerated. It has, really, positive pharmaceutical properties and all of that lends itself as well to whether it's monotherapy, but also combination with other agents. So is there a possibility we could take three-zero-zero-nine into the front line? You know, I would say there is that possibility for certain. We think there are plenty of places in the post-metative setting where a drug like three-zero-zero-nine could play a role because we know that reprenib will continue to play an important role in fourth line. Now, with the new INSIGHT study in a selected patient population in the second line setting, clearly, reprenib has a lot of promise to play a significant role there. Yet there are many patients outside of that group of select patients in the second line that are in need of new treatment options. Three-zero-zero-nine could certainly, potentially play a role in the second line in that group of patients as well. We're excited to build upon our knowledge treating patients with GIST and designing KIT inhibitors in this disease. We're looking forward to getting this program into the clinic next year. Thanks. Just as a reminder, if you would like to ask a question, simply click on the Raise Hand feature at the bottom of your screen. You may have to hover over it to see it. Our next question comes from Tyler Van Buren with Cowen. Tyler, please unmute yourself and ask your question. Hi, can you hear me? We can. Please go ahead. Okay, great. Hi, guys. Yeah. This is Tara on for Tyler, by the way. To what extent do you envision DCC-3116 adding to QINLOCK's outcomes? Where do you see it being used in a combo, in late line, or can you do earlier line as well? Basically, the reason why I'm asking is, if it's successful, would it change how you view the addressable QINLOCK market across all lines, and how so? Yeah. Thanks, Tara, for the question. I'll take that, and Matt, feel free to chime in if you have anything else that you'd like to add. I mean, we certainly view this combination as being complementary as to, you know, as to QINLOCK generally within GIST. You know, as Dan outlined earlier in his response to an earlier question, one of the reasons we're so excited about the combination of ripretinib is the potential to test this hypothesis that we've seen preclinically with RTK inhibitors. You know, we previously reported data in combination preclinically with osimertinib and with avapritinib, showing profound activity when used in combination with DCC-3116. We've now reported at this meeting on the data in combination with ripretinib, which flatlines tumors preclinically, so very impressive combination activity. We're really testing that hypothesis now with ripretinib, which makes a lot of sense given our expertise with QINLOCK and our insights in treating GIST patients generally. I think this is still, of course, very early, so we're looking forward to generating data with the combination. I would say at a high level, as I mentioned at the outset, we don't view this as cannibalizing our existing QINLOCK business. We view this as being very complementary in our approach to raise the bar for patients with GIST in terms of the quality and efficacy of the treatment options that exist today. This is Matt. Hi, Tara. You know, just to add, you know, we feel very comfortable with the strength of the QINLOCK franchise in the fourth line GIST population. Also, as we highlighted earlier this year, in the second line GIST patients who harbor the exon 11, plus 17 or 18 secondary mutations. You know, an exploratory analysis from the INTRIGUE second line study, you know, showed really compelling data in that subgroup of patients treated with ripretinib. That's the subgroup that we'll be confirming. We'll be conducting a phase 3 study called the INSIGHT study, initiating in the second half of this year. Of course, there's other subgroups that, you know, may benefit from combination of ripretinib with DCC-3116. I think there's you know, opportunity for us to explore it in additional subgroups of patients. Great. Our next question comes from Eun Yang with Jefferies. Eun, please unmute yourself and ask your question. Questions. The DCC-3116, the product avoids CNS exposure. Maybe not in colorectal cancer, but in non-small cell lung cancer, CNS exposure could be helpful. It sounds like you designed the product to avoid the CNS exposure. Can you kind of remind us what the reason behind that? Second question is on DP-9149. Currently further preclinical studies are underway. Can you talk about what additional preclinical studies are needed in order for you to file an IND when the timing might be? Thank you. Yeah. Yeah. Steve, thanks very much for the question. I'll ask Dan, to take the first part of the question, and then I'll come back and pick up on your 9149 question that you had. Yes, you know, thanks for the question about the CNS penetration. We made a purposeful decision with this program to engineer a molecule that would not penetrate the brain, because of literature and KOLs who provided their opinions that neurons, especially neuron axonal health, requires an ongoing autophagy to maintain normal physiology in the brain. We just simply did not want to risk compromising that protection in patients. With respect to your question on DP-9149 unit. We're excited to present the data from this potentially first in class or best in class programs, the GCN2 activator. I think you've seen the data. We're excited about both the single agent as well as combination opportunity moving forward. It's a very selective molecule. We haven't disclosed yet what the timeline would be to get to an IND for that program. All I can say is that it remains a very active program within research, and we'll have updates on that in due course, as we usually do. Thank you. The next question comes from Michael Schmidt with Guggenheim. Michael, please unmute yourself and ask your question. Hey, thanks for taking the question. This is Paul on for Michael Schmidt. I have one on the combo of 3116 with ripretinib. Just wondering, you know, if there are specific KIT mutants that are meaningfully more or less susceptible to the ripretinib-induced autophagy or could be particularly sensitive to that combination. Among the, you know, the less ripretinib-sensitive mutants like exon 9, is there any chance this combo could defeat soon given the synergism that you've seen pre-clinically, and how are you thinking about that setting? My second question is just on the GCN2. You know, just wondering if there are any sort of key biomarkers that might predict sensitivity to a GCN2 modulator and potentially be used in a future clinical trial for patient selection. Thank you. Yeah. Paul, that's a great set of questions. Thanks for the question. Dan, would you like to take the DCC-3116 and ripretinib combination? The question was about which KIT mutants might be sensitive, including exon 9. Mm-hmm. If you'd like to take the GCN2 question as well, that'd be great. Okay. Well, certainly, regarding the ability of DCC-3116 to combine with QINLOCK across KIT mutational space in the clinic, we have demonstrated pre-clinically in Bryan Smith's presentation that all of these mutants set off autophagy by activating ULK. We demonstrated that with increases in phospho ATG13, the ULK substrate, and also, all of them tend to set off autophagic flux. We think that in general, it is reasonable to study DCC-3116 in combination with a variety of patients that have different KIT mutations. The GCN2 question again? The question was about biomarkers that might be informative for further development. Well, I think what we can say now is that, twofold. One is, you know, we have studied which cancer cell lines mostly tend to express GCN2. And there are cell lines that are high expressers of GCN2, which could not only be used for certainly for patient selection, but also ongoing therapy. That's one thing. In those cancers that don't express basal levels of GCN2, you know, what we're figuring out too is that it could be that the standard of care combination that might be used does induce GCN2. There's the possibility of looking into that scenario as well. Okay. Our next question comes from Peter Lawson with Barclays. Peter, please unmute yourself and ask your question. Great. Thank you so much. I guess firstly, just around the exon 11 to 17, 18 data, will you submit that to the NCCN? The second question's around 3116, so the second half data of how many patients we should expect to see with the MEK and the KRAS combination. Thank you so much. Yeah. Hi, Peter. Good evening. It's Steve. Thanks, thanks for joining the call tonight. I'll be happy to take those two questions. First, with respect to the NCCN guidelines, as you may know, the guidelines were updated recently to reflect the use of ripretinib in second line GIST in patients as a preferred option for patients who do not tolerate sunitinib. That listing has now been updated earlier this year. We haven't disclosed any specific plans to make any additional submissions to the NCCN. As you know, the data were, of course, presented at the ASCO Plenary Series at the end of January. There'll be an update that is then presented at ASCO, which is the ordinary course for the ASCO Plenary Series sessions. Of course, we're working to get the data published in the peer-reviewed literature. We'll provide updates, as, you know, as appropriate going forward in terms of future strategies and approaches. Your second question, Peter, was with respect to DCC-3116 and the nature of the update that will be forthcoming later this year. That really is gonna be focused, as we've said, on an update from the monotherapy dose escalation. We haven't disclosed specific patient numbers yet. This would also incorporate an update with initial data from the initial combination doses escalation cohorts that we've previously described. We look forward to providing that update later this year. Great. Thank you so much. Okay. Looks like at this time we have no further questions. Back to you, Steve. Great. Thanks very much. I just wanna thank everyone for joining us this evening for this event as we reviewed the data we presented here at the AACR 2023. Thanks for your continued interest in Deciphera. I wish you all a good evening.