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

Atebimetinib (IMM-1-104; TEL9243A3N) is an investigational, orally administered MEK1/2 inhibitor being developed for RAS- or RAF-driven solid tumors. Clinical development has focused particularly on pancreatic ductal adenocarcinoma (PDAC). It is not an approved therapy.

Mechanism of action

Atebimetinib is a selective, non-ATP-competitive allosteric inhibitor of MEK1 and MEK2, reducing ERK phosphorylation and signaling through the RAS–RAF–MEK–ERK pathway. It was designed to resist CRAF-mediated pathway reactivation and produce “deep cyclic inhibition”: profound but temporary daily MAPK suppression followed by a low-exposure recovery period intended to reduce toxicity in normal tissues. These proposed advantages are supported primarily by preclinical studies and remain under clinical evaluation. (pubmed.ncbi.nlm.nih.gov)

Efficacy

In a nonrandomized Phase 2a cohort, 55 previously untreated patients with advanced or metastatic PDAC received atebimetinib 320 mg once daily plus modified gemcitabine/nab-paclitaxel. Among 50 response-evaluable patients:

• Objective response rate: 42%—all 21 responses were partial responses
• Disease-control rate: 84%
• Best overall response: 21 partial responses, 21 stable disease, seven progressive disease and one not evaluable
• Median progression-free survival: 8.3 months
• Six- and nine-month overall survival: 88% and 79%, respectively
• Median overall survival: Not reached after 10.4 months’ median follow-up

These interim results were reported in an ASCO 2026 conference abstract. Because the study lacked a randomized control group and used a modified chemotherapy schedule, comparisons with historical standard-of-care outcomes should be interpreted cautiously. (ascopubs.org)

Earlier Phase 1 monotherapy data in 54 heavily pretreated patients found no RECIST responses, although 38% of patients with paired scans had regression of at least one target lesion. (immuneering.com)

Safety

In the Phase 2a PDAC cohort, no grade 5 treatment-related adverse events occurred, and no atebimetinib-related event exceeded grade 3. Grade 3 atebimetinib-related adverse events occurred in 29% of patients; the most frequent were rash, increased ALT and increased AST, each affecting 5%. (ascopubs.org)

In Phase 1 monotherapy, treatment-related events were mostly grade 1–2 and included rash (26%), diarrhea (22%), nausea and fatigue (17% each), vomiting (15%), subretinal fluid (13%) and retinopathy (11%). No dose-limiting toxicities or serious treatment-related events were reported. (immuneering.com)

Further reading

• Phase 2a PDAC results—Journal of Clinical Oncology/ASCO 2026
• Preclinical mechanism study—Cancer Research/PubMed
• Phase 1 ESMO scientific poster
• Clinical trial record: NCT05585320

Last updated: Sep 2026

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