Atebimetinib Plus mGnP Shows Efficacy in 1L Metastatic Pancreatic Cancer

Findings from a phase 2a trial (NCT05585320) evaluating atebimetinib in combination with modified gemcitabine/nab-paclitaxel (mGnP) in patients with first-line metastatic pancreatic ductal adenocarcinoma (PDAC) were presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting demonstrated promising efficacy and a manageable safety profile for the novel MEK 1/2 inhibitor combination, supporting advancement to a global randomized phase 3 trial.

Efficacy

Among 50 response-evaluable patients in the expanded cohort (n = 55), the combination of 320 mg once daily atebimetinib plus mGnP produced an objective response rate (ORR) of 36% (95% CI, 23%-51%) per RECIST v1.1 guidelines. The disease control rate (DCR) was 82% (95% CI, 69%-91%).

The median overall survival (OS) was 17.3 months (95% CI, 11.2-not reached [NR]), consistent across both the initial cohort of 34 patients after a median follow-up of 17.0 months, and the expanded cohort of 55 patients after a median follow-up of 11.6 months. The median progression-free survival (PFS) was 8.3 months (95% CI, 5.9–9.6).

Trial Details

The phase 2a trial enrolled patients in 2 sequential cohorts: an initial cohort receiving 320 mg once-daily atebimetinib plus mGnP, and an expanded cohort which received the same regimen. The mGnP regimen consisted of gemcitabine 1000 mg/m² plus nab-paclitaxel 125 mg/m² administered on days 1 and 15 of each 28-day cycle. The trial used a Simon's 2-stage optimal design with 80% power and a 1-sided alpha of 5%.

ORR per RECIST 1.1 was the primary end point of the trial. Secondary end points included DCR, duration of response, PFS, and OS.

Patient Characteristics

The expanded cohort had a median age of 68 years (range, 42–85), with 62% of patients aged 65 or older. The majority had metastatic disease (96%) and were male (55%). The ECOG performance status was 0 in 56% and 1 in 44% of patients. Elevated CA 19-9 at 37 U/mL or greater was present in 89% of evaluable patients.

Liver metastases were present in 51%, peritoneal metastases in 36%, and lung metastases in 27% of patients. De novo metastatic disease was noted in 51%. KRAS mutational status was identified in 87% of patients, with 13% having unknown RAS status at baseline. Of the 44 patients who were off treatment at data cutoff, 21 went on to receive subsequent cancer therapy, and 60% of evaluable patients received second-line treatment.

Safety

The safety profile of atebimetinib plus mGnP was notable for its tolerability. Grade 3 or higher anemia and neutropenia each occurred in at least 10% of patients and were attributed to the chemotherapy components. Only 1 of 55 patients discontinued atebimetinib while continuing chemotherapy, but this was unrelated to toxicity. Eighty-four percent of patients had stable or increased weight at 3 months.

The most common treatment-related adverse effects (TRAEs) of any grade included fatigue (53%), nausea (45%), anemia (42%), rash (36%), diarrhea (36%), vomiting (29%), alopecia (27%), dysgeusia (27%), and peripheral edema (27%). Among MEK inhibitor class effects, grade 3 or higher rash was observed in 5% of patients and resolved with treatment. Ocular, cardiac, and diarrhea events attributed to the MEK inhibitor class were grade 1 to 2 when observed and did not result in treatment discontinuation.

Next Steps

Based on these phase 2a findings, a global randomized phase 3 pivotal trial, MAPKeeper 301 (NCT07562152) is currently recruiting. The trial will enroll patients with first-line metastatic PDAC and ECOG performance status of 0 to 1, with 510 patients undergoing random assignment 1:1 to atebimetinib plus mGnP vs standard-of-care full-schedule gemcitabine plus nab-paclitaxel. The primary end point is OS, with secondary end points including PFS, DCR, ORR, and quality of life. Randomization stratification factors include geography, liver metastasis status, ECOG performancs status, and de novo vs recurrent metastatic disease.

Reference

Chung V, Vu P, Ma VT, et al. Results from a phase 2a study of atebimetinib in combination with mGnP in first-line metastatic pancreatic cancer. J Clin Oncol. 2026;44(suppl 16):4013. doi:10.1200/JCO.2026.4416_suppl.4013