8:00 am Morning Coffee & Networking

Synopsis

Welcome to the 4th RAS Targeted Drug Development Summit! For the first time since 2019, this community will be united once again in Boston. Grab a coffee, reconnect with peers, & settle in for a jam-packed conference ahead of the keynote opening sessions

Keynote Plenary Session: Updates from RAS Global Leaders

9:00 am Keynote Opening Address: A Historic Review to Celebrating 40 Years of Research Against RAS-Mutant Cancers

  • Channing Der Sarah Graham Kenan Distinguished Professor, University of North Carolina - Chapel Hill

Synopsis

  • After forty years since the isolation identification of the first human onco cancer gene, we revisit and review a history of the directions taken to target RAS
  • From multitude thousands of fantastic efforts strategies taken to targeting RAS, we can consider assess a state-of-the-art in RAS therapeutics
  • At the milestone of the first-ever targeted RAS therapeutics, we deliberate future issues and opportunities for this industry

9:30 am Biomarker Insights from KRAS P.G12C-Mutated Subjects Treated with Sotorasib in Codebreak 100

Synopsis

  • Baseline biomarker subgroup associations with response in NSCLC subjects
  • 2-year follow-up assessing biomarker correlates for NSCLC subjects deriving long-term benefit from sotorasib treatment
  • Analysis of acquired mutations NSCLC and CRC to treatment to inform rational combo therapy

10:00 am Targeting Tumors with KRAS G12C Mutations with Adagrasib (MRTX849): Current Status & Future Questions

  • Joshua Mason Director - Medical Affairs Strategy, Mirati Therapeutics

Synopsis

  • History of targeting KRAS in the clinic and recent advancements to directly target KRAS G12C
  • Clinical progress of KRAS G12C inhibitors (eg, adagrasib) in the clinic
  • Future questions and directions for targeting KRAS G12C

10:30 am Development of KRAS Inhibitors – Updated from Boehringer Ingelheim

  • Marco Hofmann Director - Scientific & Group Leader, Boehringer Ingelheim

11:00 am Morning Break & Speed Networking

Track A: Accelerating Discovery & Emerging Strategies

High-Value Modalities Beyond Small Molecule Approaches to Target RAS Driven Cancers

12:30 pm Lymph-Node Targeted Peptide Vaccination Promotes mKRAS-Specific T Cell Immunity & Enhances TCR-T Cell Therapy Against Solid Tumors

  • Peter DeMuth Chief Scientific Officer, Elicio Therapeutics

Synopsis

  • The AMP platform enables enhanced lymph node delivery of peptide immunogens and molecular adjuvants to potently stimulate T cell immunity
  • AMP-vaccination promotes expansion and functional enhancement of endogenous and adoptively transferred mKRAS-specific T cells in vitro and in vivo
  • AMP-vaccine combination with TCR-T cell therapy promotes anti-tumor efficacy in vivo

1:00 pm Session reserved for Promega

1:30 pm Extrahepatic Nucleotide Delivery with Self-Assembling Peptide-Based Nanostructures for RNAi against KRAS

Synopsis

Self-assembling peptide-nucleotide (siRNA, mRNA) polyplexes avoid sequestration in liver, track to myriad pathologies, but do not distribute to tissues/organs with normal vascular barriers

Following cell uptake, the peptide moiety itself facilitates rapid and complete endosomal escape and KRAS siRNA release into cytoplasm to inhibit KRAS production

Peptide-nucleotide polyplexes are safe and stable in circulation, cleared by the kidney, and are not immunogenic after serial dosing

Track B: Optimizing Translation & Pre-Clinical Development

Pre-Clinical Insights into Novel Checkpoint Inhibitors & Combination Approaches

12:30 pm WT RAS Signalling is an Essential Therapeutic Target In RAS-Mutated Cancers

  • Rob Kortum Assistant Professor, Uniformed Services University of the Health Sciences - USUHS

Synopsis

  • RAS isoforms differentially activate RAF/MEK/ERK and PI3K/AKT effector pathways
  • Non-mutated (wild type) RAS family members activate RAS effectors that are activated poorly by mutated RAS
  • Combined inhibition of mutated RAS and WT RAS signalling synergistically kills RAS-mutated cancers

1:00 pm Session Reserved for Applied Biomath

1:30 pm Targeting KRAS: Pre-Clinical Validation & Therapeutic Perspectives to Overcome Drug Resistance

  • Chiara Ambrogio Associate Professor of, Molecular Biology, University of Turin

Synopsis

  • New biomarker needed to predict sensitivity to direct KRAS inhibitors
  • Acquired versus adaptive mechanisms of resistance to G12C inhibitors
  • Novel therapeutic strategies to overcome resistance

Track C: Advancing Clinical Trials & Development

Clinical Insights from RAS Targeted Therapies Leveraging the Immune System

12:30 pm Novel Cell Therapy Method to Generate Antigen Presenting Cells for Multiple KRAS Mutations

  • Scott Loughhead Senior Director of Immuno-Oncology Research, SQZ Biotechnologies

Synopsis

  • SQZ APC mechanism overcomes challenges of previous cancer vaccines with CD8 T-cell activation and can be enhanced with mRNA cargo combinations
  • SQZ APC clinical program overview: Safety and manufacturability of SQZ’s APC candidate in solid tumors
  • Preclinical data for SQZ’s enhanced APC platform in targeting KRAS G12D and G12V mutation

1:00 pm Session Reserved for Tempus

1:30 pm A Novel Arenaviral Immunotherapy for Targeting Multiple Mutated KRAS Epitopes

Synopsis

  • Introduction to HOOKIPAs Platform for induction of tumor specific CD8+ T-cell responses
  • Overview on key clinical data demonstrating induction of unprecedented tumor specific CD8+ responses in humans
  • Overview and preclinical validation of HOOKIPA’s HB700 program targeting most frequent KRas mutations in pancreatic cancer, colorectal cancer and lung adenocarcinoma

2:00 pm Lunch Break & Networking

3:00 pm Roundtable Session – Successes in Modalities Beyond Small Molecules

Synopsis

As this community continues progress targeting RAS mutants harnessing novel modalities, this session will lead the discussion into existing literature, data and ongoing challenges with RAS-mutant drugs leveraging novel degradation strategies, immune therapies and molecular glue approaches

3:00 pm Roundtable with KRASKickers: Bridging the RAS Gap Between Research & Survivors

  • Terri Conneran KRAS Cancer Survivor, Founding Director, KRAS Kickers

Synopsis

Whilst every day, more and more patients with RAS-mutant cancers are being diagnosed, it is critical that we understand the patient journey, and how critical patient perspectives are critical for guiding research. This session will lead discussion into making sense of RAS-mutant cancer biomarkers & the patient diagnostic journey

3:00 pm Roundtable Session – What Have We Learnt from AACR?

  • Channing Der Sarah Graham Kenan Distinguished Professor, University of North Carolina - Chapel Hill
  • Colin Weekes Director, Pancreatic Cancer Research, The Tucker Gosnell Center for Gastrointestinal Cancers, Massachusetts General Hospital, Harvard Medical School  

Synopsis

Following an array of data updates from RAS-mutant therapies at AACR, it is important that we take time to

reflect, digest and consider how this information can be used to guide our next steps. Leading professors will navigate us through what we know, and lead the conversation as we consider the future of RAS targeted therapies

3:00 pm Afternoon Break & Poster Session

Synopsis

Aiming to stimulate discussion in the oncology community about ongoing work and to promote collaboration between peers, we bring to you the RAS Poster Session, back for the third year. As the viability of targeting RAS as an effective therapeutic application against RAS driven cancers is closer than ever to approval, it is more important than ever to collaborate and learn with your peers as we continue to advance RAS targeted therapies through discovery and development. Join our dedicated session to share your latest data and have a first-look at what your peers are working on!

Tumor & Mutant Heterogeneity – Expanding Drugs Targeting Mutations Beyond G12C

4:30 pm NS1 Monobody Targeting the α4-α5 Allosteric Interface of RAS Inhibits Tumorigenesis In Vivo

  • Imran Khan Senior Scientist, Bristol Myers Squibb

Synopsis

  • NS1 Monobody binds to dimer interface of RAS
  • NS1 blocks RAS self-association that in turn impairs BRAF/CRAF heterodimerization
  • The intrinsic cell inhibition of mutant KRAS changes the phenotype of otherwise immunologically cold PDAC tumors by increasing infiltration of T cells

5:00 pm Disruption of the RAS-RAF1 Interaction: A New Synthetic Lethality Strategy for Selectively Blocking RAS-Driven Proliferation of Cancer Cells

Synopsis

  • Using our PPI-disruption identifying platform, ToRPPIDO, we have discovered several new compounds that allosterically disrupt the Ras-Raf1 protein-protein interaction by binding Raf1 in a new pocket distal to its Ras Binding Domain
  • STX200, a cell-permeable member of this set, exhibits a potent anti-proliferative activity against a variety of mutant RAS cancer lines
  • The anti-proliferative activity of STX200 is independent of the kinase activity of Raf1 in canonical MAPK signaling

5:30 pm Chemical Strategies for the Mutant-Specific Targeting of RAS-Driven Cancer

  • Ziyang Zhang Assistant Professor, University of Califorina, San Francisco

Synopsis

  • New covalent chemistry enables mutant specific targeting of Ras mutants beyond G12C
  • The switch II pocket can be access in both GDP- and GTP-bound states
  • Chemo-immunological approach overcomes resistance to small molecule KRAS G12C inhibitors 

Enhancing Tissue Specificity & Understanding PK/PD Relationships in Pre-Clinical Settings

4:30 pm Tumor/Biomarker-Specific Combination Strategies with the RAF/MEK Clamp VS-6766

Synopsis

  • VS-6766 blocks the RAS pathway through a novel RAF/MEK clamp mechanism
  • Rationale for ongoing combination trials with VS-6766 with defactinib or everolimus
  • Novel VS-6766 combinations for tumor/biomarkerspecific patient populations

5:00 pm Development of a Selective, Affinity-Enhanced T-Cell Receptor Bispecific Targeting KRASG12D Neoantigen Driven Cancers

  • Andrew Whale Associate Director, Pipeline Biology, Immunocore Ltd

Synopsis

  • CD3xTCR bispecific proteins (bsp) redirect polyclonal T cells to target intracellular proteins in cancer; TCR bsp offer an attractive opportunity to target KRAS G12D neoantigen peptides presented by cell surface human leukocyte antigen
  • We successfully engineered an off the shelf, soluble CD3xTCR bispecific molecule, IMC-KRAS G12D, that recognises a common shared KRAS G12D neoantigen peptide presented in the context of HLA A*11:01. IMCKRAS G12D incorporates a TCR engineered with strong affinity, increased by over one million fold yet with remarkable ability to distinguish between KRAS G12D and KRAS WT

5:30 pm Approaches To Identify & Test Predictive Biomarkers In RAS Addicted Cancers

  • Josie Hayes Director, Head of Translational Medicine, Revolution Medicines Inc.

Synopsis

  • Predictive biomarkers, what they may be used for and how they are analyzed
  • Nuances of RAS addicted cancer that influence which approaches to use
  • Current biomarkers for RAS addicted cancer and how we can improve

Evaluating Clinical Data for Targeted Combination Therapies Harnessing Upstream & Downstream Molecules

4:30 pm Session Reserved for Resistance Bio

5:00 pm Clinical Development of RAF/MEK clamp VS-6766; Breakthrough Designation & Beyond

Synopsis

  • RAF/MEK clamp VS-6766 and FAK inhibitor defactinib are in clinical development in RAS/MAPK driven cancers
  • Clinical experience and progress in recurrent low-grade serous ovarian cancer (LGSOC) and KRAS mutant NSCLC will be presented
  • Future directions will be discussed – including clinical trials in new indications and combination treatment approaches

5:30 pm Targeting RAS Mutations & MAPK Pathway Aberrations via Vertical Combination

  • Lusong Luo Senior Vice President, External Innovation, BeiGene

Synopsis

  • Vertical combination represents a useful approach to target the MAPK pathway aberrations including RAS mutations
  • The synergistic activity from inhibition of the different nodes of the MAPK pathway leads to more complete and sustained pathway inhibition
  • Inhibition of multiple nodes of the pathway suppresses the feedback activation of upstream signalling and potentially delay the development of drug resistances
  • Preclinical and clinical data of several vertical combinations support using this strategy to target MAPK pathway aberrations including RAS mutations

6:00 pm End of Conference Day One