A Phase 3 Randomized, Open-Label Study of Atebimetinib in Combination With the Modified Gemcitabine and Nab-Paclitaxel Regimen Versus the Standard Gemcitabine and Nab-Paclitaxel Regimen for the Treatment of Patients With Metastatic Pancreatic Ductal Pancreatic Adenocarcinoma Cancer (MAPKeeper 301)

More details:

Overview

IMM-1-104 (also called atebimetinib) is an oral, small-molecule dual-MEK inhibitor being developed by Immuneering for cancers driven by RAS/MAPK pathway activation. A first-in-human, open-label phase 1/2a study (NCT05585320) started in October 2022 and is ongoing across multiple solid tumors, including dedicated pancreatic ductal adenocarcinoma (PDAC) cohorts. (clinicaltrials.ucsd.edu)

Mechanism of action

IMM-1-104 is a selective, allosteric “dual‑MEK” inhibitor engineered to suppress phosphorylation of MEK and its downstream target ERK, aiming to blunt MAPK signaling and resist CRAF-mediated pathway reactivation. It is designed with a short plasma half‑life to produce once‑daily “deep cyclic inhibition” (DCI): high-level, time‑limited target suppression followed by recovery, with the goal of improving tolerability while limiting adaptive resistance. Preclinical and translational data demonstrate reduced pMEK and pERK across RAS- and RAF‑mutant models and support the DCI pharmacology. (aacrjournals.org)

Efficacy

• Phase 1 (dose escalation; advanced RAS‑mutant solid tumors): As of February 20, 2024, initial activity signals included target lesion regression in 53% of patients treated at 240 or 320 mg QD; best individual lesion regression was −35.7% and best RECIST SLD change was −18.9%. Immune monitoring via ctDNA showed no new acquired RAS alterations among evaluable patients (n=22). The 320 mg QD dose was selected as the candidate RP2D. (ir.immuneering.com)

• Phase 2a (PDAC cohorts):

• First‑line PDAC, atebimetinib + modified gemcitabine/nab‑paclitaxel (mGnP): Company-reported updates include ORR 43% and DCR 86% (Jan 7, 2025 update), and at a later cutoff (n=34) 6‑month OS 94%, 6‑month PFS 72%, ORR 39%, DCR 81%; median OS and PFS not reached at that time. Subsequent coverage reported 9‑month OS 86% and 9‑month PFS 53% with ongoing follow‑up. These results are from an open‑label, nonrandomized study and should be interpreted cautiously pending peer‑reviewed presentation/publication. (ir.immuneering.com)
• Additional PDAC arms (first‑line modified FOLFIRINOX; second‑line monotherapy) have reported early signals of tumor shrinkage, including partial responses, in company communications. (ir.immuneering.com)

Peer‑reviewed clinical efficacy publications are not yet available; early data have been shared via company releases and media summaries. (immuneering.gcs-web.com)

Safety

• Phase 1: IMM-1-104 was generally well tolerated. Among treatment‑related adverse events (TRAEs) ≥10%, most were grade 1–2; no grade 4 TRAEs, one non‑serious grade 3 rash, no serious TRAEs, and no dose‑limiting toxicities were reported at the time of the topline analysis (n=41 as of Feb 20, 2024). Pharmacodynamic data showed ≥90% transient pERK inhibition at 320 mg (≈2.7 hours) and 240 mg (≈1.9 hours), consistent with DCI. (ir.immuneering.com)

• Early phase 2a (PDAC combinations): Company updates describe a “markedly favorable tolerability profile” for atebimetinib + mGnP; detailed AE tables are pending peer‑reviewed presentation. (immuneering.gcs-web.com)

Clinical program and status

• Trial: NCT05585320 (Phase 1/2a, open‑label, dose exploration and expansion; monotherapy and combinations across RAS‑mutant or RAS/MAPK‑activated tumors). Estimated primary completion June 2027. (clinicaltrials.ucsd.edu)
• Dose: Candidate RP2D of 320 mg once daily selected based on phase 1 PK/PD, ctDNA, safety, and initial activity. (ir.immuneering.com)
• Combinations under evaluation/planned include chemotherapy (mGnP, modified FOLFIRINOX) and collaborations with PD‑1 blockade (cemiplimab) and KRAS G12C inhibition (olomorasib). (ir.immuneering.com)

Further reading

• Phase 1/2a trial listing (NCT05585320). (clinicaltrials.ucsd.edu)
• Phase 1 topline results and DCI pharmacodynamics. (ir.immuneering.com)
• Independent coverage of phase 1 topline. (onclive.com)
• PDAC phase 2a updates (company communications and media). (ir.immuneering.com)
• Preclinical/meeting abstracts on mechanism and preclinical activity. (aacrjournals.org)

Notes: Data above reflect interim, nonrandomized early‑phase results reported between March 2024 and September 2025; confirm at future peer‑reviewed meetings/publications as they become available. (globenewswire.com)

Last updated: Oct 2025

Inclusion Criteria:

* Must be ≥18 years of age

* Must have confirmed diagnosis according to AJCC staging as follows:

* Metastatic pancreatic adenocarcinoma at least 12 weeks prior to screening

* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

* Participants must be treatment naive as follows:

* First-line PDAC participants will have received no previous systemic anti-cancer therapy

* Must have evidence of measurable disease (at least one target lesion) per RECIST v1.1 criteria

* Adequate organ function, hepatic function, coagulation studies and protocol determined clinical laboratory values

Exclusion Criteria:

* Inability to swallow oral medications

* Participant has squamous, adenosquamous, neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma

* Participants with only locally advanced disease

* Symptomatic, untreated, or actively progressing known central nervous system (CNS) metastases