Abstract 4195: Activity of IMM-1-104 alone or in combination with chemotherapy in RAS-altered pancreatic cancer models

Abstract Introduction: Addiction to the MAPK pathway drives a large proportion of cancers, and pancreatic tumors almost universally display RAS mutations. IMM-1-104, a once-daily oral treatment being evaluated in a Phase 1/2a trial for RAS-mutant solid tumors [NCT05585320], offers a novel deep cyclic inhibition (DCI) approach in targeting the MAPK pathway at MEK. Traditionally, MAPK-targeted drugs inhibit the pathway chronically causing serious class-effect toxicities and limited durability due to resistance. In contrast, IMM-1-104’s unique pharmacokinetic (PK) profile was designed to drive pulsatile MEK inhibition, with the goal of improving tolerability and providing more durable activity across a broad range of MAPK-driven tumors. Phase 1 dose escalation of IMM-1-104 revealed no dose-limiting toxicities, high oral bioavailability, plasma half-life of approximately 2-hours, and pharmacodynamic (PD) data supporting DCI of the MAPK pathway. Experimental Procedures: IMM-1-104 responses in humanized 3D tumor growth assays (3D-TGA) were combined with NGS data using machine learning (ML) to refine a pharmacogenomic response model. Evaluation of databases such as AACR Project GENIE enabled prediction of patient alignment of preclinical models based on genomic profile, identification of patient populations displaying MAPK pathway addiction and projected sensitivity to IMM-1-104 mono- or combination therapy. To test combinations with approved chemotherapy agents, IMM-1-104, gemcitabine (GEM) and nab-paclitaxel (PAC) and 5-fluorouracil (5FU) were evaluated in tumor xenograft models with drugs alone or across multiple combinations. Summary of New Data: IMM-1-104 showed promising combination effects when treated with GEM or PAC in 3D-TGA pancreatic cancer models. In a MIA PaCa-2 tumor xenograft model, IMM-1-104 alone showed greater tumor growth inhibition (TGI) than any single or combination chemotherapy tested. Further, combinations of IMM-1-104 plus chemotherapy resulted in near complete responses in a majority of animals. At day 39, antitumor activity (TGI%) was 103% for IMM-1-104 at 125 mg/kg BID PO, 25.2% for GEM at 60 mg/kg IP Q4D, 62.2% for PAC at 10 mg/kg IV Q4D and 36.6% for 5FU at 50 mg/kg IP Q4D. Based on these results and additional 3D-TGA pharmacogenomics data, ML modeling was advanced to query the GENIE database and identify biomarkers of response and resistance with the goal of further informing mono and combination treatment options with IMM-1-104 in pancreatic cancer. Conclusions: The Phase 2a portion of the ongoing IMM-1-104 clinical study includes five arms, three of which focus on patients with pancreatic cancer, where IMM-1-104 will be evaluated as both monotherapy and in select combinations with approved chemotherapeutic agents. The new in vitro, in vivo and ML modeling data presented here further support an advancing translational roadmap for IMM-1-104 in pancreatic cancer. Citation Format: Peter King, Jason Funt, Sarah Kolitz, Praveen Nair, Jan de Jong, Amy Yamamura, Mai Johnson, Jenny Zhang, Kevin Fowler, Anna Travesa, Amy Axel, Chris Walker, Benjamin J. Zeskind, Brett M. Hall. Activity of IMM-1-104 alone or in combination with chemotherapy in RAS-altered pancreatic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4195.