1524P - Preliminary phase I safety and activity of IMM-1-104, an orally dosed universal RAS inhibitor that drives deep cyclic inhibition of the MAPK pathway at MEK, in patients with advanced unresectable or metastatic solid tumors

Background

About 33% of tumors have activating RAS mutations making it an attractive target. MEK inhibitors block the downstream signaling of RAS, but earlier inhibitors have been plagued with toxicities. IMM-1-104, a novel MEK inhibitor, blocks both MEK and ERK phosphorylation preventing CRAF bypass and hyperactivation of MEK. A short half-life of 2 hours combined with once daily dosing (QD) drives deep, pulsatile inhibition of the MAPK pathway at MEK in a process called Deep Cyclic Inhibition (DCI). This improves drug safety and tolerability by allowing daily pathway recovery in healthy tissues while limiting adaptive resistance in tumor cells.

Methods

We conducted a first-in-human phase 1 study of IMM-1-104 at 5 U.S. sites. The primary objective was to determine the safety, tolerability and recommended phase 2 dose of IMM-1-104 in advanced, RAS-mutated solid tumors. A rapid dose escalation scheme was used with broad inclusion criteria, and PK, PD, (circulating tumor DNA) ctDNA and initial clinical efficacy were evaluated.

Results

As of May 1, 2024, the phase 1 study completed enrollment of 45 subjects, including 30 PDAC, 5 colorectal, 5 lung, 2 melanoma, 1 cholangiocarcinoma plus 2 others. Evaluation of two candidate optimal doses, 240 and 320 mg QD, supported DCI of the MAPK pathway. Treatment-related adverse events (TRAEs) occurring in ≥10% of patients were transient and limited mainly to grade 1 or 2, when observed. No dose-limiting toxicities or serious TRAEs were noted. Early signs of clinical activity in a heavily pretreated, advanced metastatic patient population were promising and paired CT scans (32) and ctDNA (27) revealed: (1.) 21 (66%) had RECIST SLD < 20%, 8 (25%) had SLD ≤ 0%, (2.) 13 (41%) had ≥ 1 target lesion regression (-4.8% to -50.0%), (3.) reductions in mean ctDNA observed in 9 (33%) patients (-24% to -81%), and (4.) no new variants in RAS ctDNA emerged.

Conclusions

Disrupting MAPK-pathway addicted tumors at MEK with IMM-1-104 using a novel DCI approach was well tolerated and demonstrated lesion and molecular level responses as monotherapy in an advanced, heavily pretreated phase 1 patient population. Phase 2a is underway.

Clinical trial identification

NCT05585320.

Editorial acknowledgement

Legal entity responsible for the study

Immuneering Corporation.

Funding

Immuneering Corporation.

Disclosure

V. Hayreh: Financial Interests, Personal, Full or part-time Employment: Immuneering Corporation; Financial Interests, Personal, Stocks/Shares: Immuneering. J. de Jong, J. Funt, P. Nair, P.J. King, J. Zhang, J. Kim, A. Yamamura: Financial Interests, Personal, Full or part-time Employment: Immuneering Corporation; Financial Interests, Personal, Stocks/Shares: Immuneering Corporation. S. Kolitz: Financial Interests, Personal, Full or part-time Employment: Immuneering Corporation; Financial Interests, Personal, Stocks or ownership: Immuneering Corporation. B. Zeskind, B. Hall: Financial Interests, Personal, Officer: Immuneering Corporation; Financial Interests, Personal, Full or part-time Employment: Immuneering Corporation; Financial Interests, Personal, Stocks/Shares: Immuneering Corporation. All other authors have declared no conflicts of interest.