8:00 am Check-In & Light Breakfast
8:50 am Chair’s Opening Remarks
Examining Precision Monotherapies Post-Approval: Learnings from Approved Drugs to Charter the Course for Next-Generation RAS-Targeting
9:00 am Learnings from the RAS-Targeted Therapeutics Clinical Trials of Sotorasib
Synopsis
• Showcasing where the approved KRAS inhibitors are today and how they get there
• Reviewing learnings from the sotorasib development journey
• Exploring what the future of monotherapies and combination regimes hold
9:30 am Fulzerasib – A Journey from Second Line to First Line
Synopsis
• From Discovery to IND: Critical criteria to accelerate the pre-clinical development process
• Picking the best partner, at/for the right timing
• Key to survival: Differentiated global clinical development strategy and CMC
10:00 am Session Reserved for Biodesix
10:30 am Morning Networking Break
TRACK A: Drug Discovery & Pre-Clinical Development
Spearheading the Development of RAS-Targeting PROTACs & Molecular Glues with Improved Selectivity to Overcome Acquired Resistance
11:45 am Development of the Pan-RAF-MEK Molecular Glue NST-628 & Opportunities for RAF Paralog Selective Molecular Glues
Synopsis
• A rationale for developing a non-degrading RAF-MEK molecular glue in RAS-MAPK dependent cancers
• Design of NST-628, a pan-RAF-MEK molecular glue with best-in-class potential
• Opportunities for development of RAF paralog-selective induced stabilizers based on novel structural insights into RAF-MEK complexes
12:15 pm Panel : Debating the Therapeutics Utility of PROTACs & Molecular Glues versus Direct Targeting of RAS to Strategies Best-in-Class Therapeutic Interventions
Synopsis
• What are the advantages of degrading versus direct targeting?
• What are the additional complexities associated with degrader development?
• How to monitor RAS turnover and the kinetics of degradation?
• What is the combination potential of PROTACs?
TRACK B: Translation & Clinical Development
Optimizing Therapeutic Dosing & Toxicity Management Across Clinical Phase I-III
11:45 am Divarasib in NSCLC with a KRAS G12C Mutation
Synopsis
• Showcasing pre-clinical divarasib data
• Reviewing the clinical activity of divarasib in patients with NSCLC
• A look to the future: next steps in the development of divarasib in NSCLC
12:15 pm Asking More of Small Molecule KRAS Inhibition: Combination with Immunotherapy & Beyond G12C
Synopsis
• Overall prognosis remains poor for KRAS mutant patients
• Olomorasib is a potent 2nd generation G12C inhibitor with early combination efficacy data suggesting olomorasib may be suited for 1L combinations with standard of care immunotherapy regimens in advanced NSCLC
• Borrowing from the discovery learnings from olomorasib, a highly mutant-selective G12D inhibitor and an isoform selective Pan-KRAS inhibitor are emerging from discovery
12:45 pm Lunch & Networking Break
Employing Chemistry & Biology Insights to Improve the Potency & Safety of RAS-Targeting Candidates
1:45 pm DCC-3116, a First-in-Class Selective ULK1/2 Inhibitor of Autophagy, as a Potential Combination Strategy to Address Mutant KIT & RAS Cancers
Synopsis
• Discussing the rationale behind the development of DCC-3116 and the role of autophagy in cancer cells
• Demonstrating autophagy induction by KIT and KRAS G12C inhibitors in cancer cells
• Demonstrating target engagement and combination efficacy with DCC-3116 and KIT or KRAS G12C inhibitors in xenograft models
2:15 pm Panel : Debating Optimal PK/PD Profiles to Carve Out the Optimal Inhibitor for Targeting RAS
Synopsis
• What are the advantages of covalent versus irreversible binding from a safety and efficacy context?
• How to balance chemical modifications to improve drug-like properties such as solubility, bioavailability, and metabolic stability?
• How to optimize pharmacokinetic properties and minimize the risk of adverse drug reactions
2:45 pm Intercepting Resistance Gene Amplifications in MAPK Pathway-Activated Cancers
Synopsis
• RNR is a rate-limiting enzyme responsible for cellular de novo synthesis of dNTPs and is essential to the assembly and repair of ecDNA
• BBI-825 is a first-in-class, oral, and selective RNR inhibitor that has been shown to deplete deoxynucleotides (dNTPs) prevent acquired resistance mediated gene amplifications and ecDNA formation leading to anti-tumor efficacy in multiple MAPK driven pre-clinical models
• BBI-825 is currently being evaluated in the Phase 1/2 STARMAP clinical trial for patients with locally advanced or metastatic cancer with resistance gene amplifications (NCT06299761)
Advancing Translational Models to Convey Complex Tumor Microenvironments & Improve Physiological Relevance
1:45 pm In Vivo Modeling of Oncogenic KRAS Signaling Intensity to Elucidate Its Impact on Pancreatic Cancer Tumorigenesis
Synopsis
• The paradoxical impact of Codon-specific KRAS mutations on overall survival of PDAC patients at different stage of disease
• Developing and characterizing the first KRAS (Q61R) mouse model of pancreatic Cancer Generating four novel oncogenic KRAS signaling intensity mouse models to determine the role of KRAS signaling intensity in PDAC tumor development and find new vulnerabilities to different class of RAS inhibitors
2:15 pm The Selective WEE1 Inhibitor Azenosertib Shows
Synopsis
• Combination of Azenosertib, a novel, selective, WEE1 inhibitor, with KRAS G12C inhibitors demonstrates synergistic anticancer activity in vitro and in vivo
• The combination drives regression and extends duration of response in KRAS G12C mutant tumor models of NSCLC, CRC, and PDAC
• The combination overcomes innate and acquired resistance to KRAS G12C inhibition
2:45 pm Reshaping the Tumor Microenvironment of KRAS G12D Pancreatic Ductal Adenocarcinoma with Combined SOS1 & MEK Inhibition for Improved Immunotherapy Response
Synopsis
• How to use scRNAseq data as a blueprint to drive therapy regimens to prolong
• anti-tumor effects of KRAS cancer-targeted therapies
• Mechanistically, SOS1+MEK therapy revealed an increase in inflammatory cancer associated fibroblasts, macrophages, and decreased dendritic cell quality that results in an immunosuppressive microenvironment that can be leveraged therapeutically
• KRAS inhibition affects myeloid cell maturation and highlights the need for combining KRAS cancer-targeted therapy with myeloid activation to enhance anti-tumor effects
3:15 pm Afternoon Networking Break
The Future Outlook on RAS-Targeting: Expanding Beyond NSCLC & G12C to Improve the Standard-of-Care for Patients with Unmet Clinical Need
3:45 pm Inhibiting Phosphocreatine Dependent Energetic Pathway in RAS-Driven Colorectal Cancer by Blocking the SLC6A8 Creatine Transporter by Ompenaclib
Synopsis
• CKB overexpression pathway in RAS mutated mCRC as a therapeutic target
• Ompenaclib – an oral small molecule blocking SLC 6A8 transport of phosphocreatine
• Pre-clinical and clinical data of ompenaclib activity in RAS mutated mCRC
4:15 pm Targeting the RAS-PI3Kα Interaction as an Efficacious & Tolerated Means of Inhibiting the PI3K/AKT Pathway in RAS-Diven Cancers
Synopsis
• Identification and functionalization of C242, unique to p110α, to disrupt RAS-driven activation of PI3Kα
• Pre-clinical models identify disruption of the RAS-PI3Kα interaction as an efficacious and well tolerated means of targeting the PI3K/AKT pathway
• Detailed mechanistic exploration identifies the PI3K/AKT pathway as critical signaling node that drives resistance to direct targeting of KRAS-G12C. In both CDX and PDX models, addition of VVD’s RAS-PI3K disruptors to a KRAS-G12C inhibitor dosing schedule provide more profound and durable responses