MAPKeeper-301 Aims to Confirm the Efficacy of Atebimetinib in Metastatic Pancreatic Cancer

Atebimetinib (IMM-1-104), an investigational oral MEK1/2 inhibitor, may improve the efficacy of standard chemotherapy in the first-line management of metastatic pancreatic ductal adenocarcinoma (PDAC), according to Daniel H. Ahn, DO.

The phase 3 MAPKeeper-301 trial (NCT07562152) is randomly assigning treatment-naive patients with metastatic PDAC to receive modified gemcitabine plus nab-paclitaxel (Abraxane) in combination with either atebimetinib or placebo, building on data from a phase 2a trial (NCT05585320) that were presented at the 2026 ASCO Annual Meeting.^1,2

“MEK inhibitors have been a treatment option available for managing solid tumor malignancies for quite a long time now...but atebimetinib is a next-generation MEK inhibitor, and the way it works, based on its half-life and how it inhibits the MAPK pathway, it inhibits it in almost a pulsatile fashion,” Ahn said in an interview with OncLive®. “Not only does it improve treatment tolerability by minimizing adverse effects, but also, based on the half-life, we think it does a better job of inhibiting the MAPK pathway as well.”

Ahn is a medical oncologist in the Division of Hematology and Oncology at Mayo Clinic Comprehensive Cancer Center in Phoenix, Arizona.

What is the rationale for combining atebimetinib with chemotherapy in pancreatic cancer?

MAPK pathway alterations, largely driven by KRAS mutations, occur in an estimated 90% of pancreatic cancers, but sustained MEK inhibition has historically been limited by toxicity and adaptive resistance in PDAC, according to Ahn. Atebimetinib is designed to address this by cyclically suppressing MEK1/2 rather than continuously blocking it.² Its short half-life allows the MAPK pathway to reset daily, an approach intended to extend durability and improve tolerability relative to earlier MEK inhibitors, and it is resistant to RAF bypass.

Preclinical data showed that atebimetinib inhibited KRAS-mutant cell lines, including in pancreatic cancer, and demonstrated significant synergy with gemcitabine plus nab-paclitaxel, Ahn stated. He noted that atebimetinib was also evaluated in combination with modified FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin), but that gemcitabine/nab-paclitaxel was judged the better-suited chemotherapy backbone for further development.

What did the phase 2a trial show for atebimetinib plus modified gemcitabine plus nab-paclitaxel?

The phase 2a trial enrolled treatment-naive patients with first-line metastatic or locally advanced PDAC who had received no prior systemic therapy for advanced disease.² Patients received a biweekly, modified schedule of gemcitabine at 1000 mg/m² plus nab-paclitaxel at 125 mg/m² on days 1 and 15 of each 28-day cycle, alongside atebimetinib at 320 mg once daily. An initial cohort of 34 patients was expanded by 21 additional patients for a total of 55; all RAS/KRAS mutation subtypes were permitted, and 87% of evaluable patients had KRAS-mutant disease.

Among 50 response-evaluable patients, the objective response rate (ORR) was 36% (95% CI, 23%-51%), and 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); OS data were consistent across the initial and expanded cohorts. Additionally, the median progression-free survival (PFS) was 8.3 months (95% CI, 5.9-9.6).

Ahn placed these results against historical benchmarks for gemcitabine/nab-paclitaxel, saying, “historically, you’re talking about a median [OS of approximately] 10 months and a [median] PFS of about 5 to 6 months...and the [ORR] in the phase 3 study [(NCT00844649) of gemcitabine/nab-paclitaxel in metastatic pancreas adenocarcinoma] was 23% [95% CI, 19%-27%],” he said.³

Regarding safety in the phase 2a trial, only 1 of 55 patients discontinued atebimetinib, and not because of toxicity; this patient continued chemotherapy.² Grade 3 or higher anemia and neutropenia, both being chemotherapy related, occurred in at least 10% of patients each.

“There was no significant toxicity,” Ahn reported. “The addition of atebimetinib to chemotherapy did not lead to any significant toxicities or unknown toxicity that you would see from either chemotherapy alone or from the MEK inhibitor by itself. The treatment was well tolerated with some intriguing clinical outcomes, and that’s leading to the development of the phase 3 trial.”

How is the phase 3 MAPKeeper-301 trial designed?

MAPKeeper-301 is a global, randomized trial enrolling approximately 510 treatment-naive patients with first-line metastatic PDAC and an ECOG performance status of 0 or 1.¹ Patients are being randomly assigned 1:1 to receive atebimetinib plus modified gemcitabine/nab-paclitaxel or standard-schedule gemcitabine/nab-paclitaxel. Patients will be stratified by geography, presence of liver metastasis, and ECOG performance status. The primary end point is OS, with secondary end points of PFS, DCR, ORR, and quality of life.

What could atebimetinib mean for the pancreatic cancer treatment paradigm?

Ahn situated MAPKeeper-301 within a pancreatic cancer treatment landscape now crowded with MAPK-pathway–directed agents, including RAS(ON) inhibitors, RAS degraders, other MEK inhibitors, and PRMT5 inhibitors for MTAP-deleted disease.

“Pancreas cancer has gone from an area we often considered to be a disease with limited treatment options to [one] where there’s a lot more excitement going on, fortunately due to the development of a lot of these novel agents specifically targeting the MAPK pathway,” he said. He cautioned that if multiple agents show benefit, sequencing will become a central question.

“There’s a lot of interest with the RAS inhibitors, specifically looked at in the refractory setting,” he explained. “The question that’s going to potentially be pertinent in the future is: How do we use all these novel targeted therapies? How does sequencing come into play, especially as all these studies are going on at the same time?”

That question is growing more relevant by the day. In August 2026, the RAS(ON) inhibitor daraxonrasib (Rasonque) received FDA approval for the treatment of patients with previously treated metastatic PDAC based on data from the phase 3 RASolute 302 trial.⁴ That agent is now being tested in the first-line metastatic PDAC setting in the phase 3 RASolute 303 study (NCT07491445) and in the adjuvant setting after resection in the phase 3 RASolute 304 trial (NCT07252232).^5,6 Separately, the PRMT5 inhibitor vopimetostat [TNG462] combined with daraxonrasib produced a 92% ORR in a small cohort of patients with MTAP-deleted, RAS-mutant PDAC (n = 12).⁷

Ahn raised the open question of how a frontline MEK inhibitor and a RAS(ON) inhibitor used later, or vice versa, might affect each other’s activity.

“If a patient were to [receive a RAS(ON) inhibitor] in the refractory setting, will they still have the same benefit [as] if they were to get it first?” he asked. “Or if there are data to suggest [the benefit of] using a RAS(ON) inhibitor in the frontline setting, would there still potentially be a role for atebimetinib in the refractory setting? You have to look at the question both ways.”

Ahn also noted that positive MAPKeeper-301 trial data would not resolve the question of whether all patients with metastatic PDAC are best served by a MEK inhibitor/chemotherapy doublet or by a more aggressive triplet chemotherapy regimen, particularly in patients selected by performance status or germline or somatic mutations.

“Patients may derive more benefit from platinum-based chemotherapy if they have a germline BRCA1 or BRCA2 mutation, or other mutations associated with homologous recombination repair, such as PALB2 or ATM,” he noted.

If the MAPKeeper-301 data are positive, Ahn said, “this will represent a first-line treatment option for patients who are appropriate candidates to receive [atebimetinib plus chemotherapy].”

References

1. Atebimetinib + GnP as a first line treatment in patients with metastatic pancreatic adenocarcinoma (MAPKeeper 301). ClinicalTrials.gov. Updated August 28, 2026. Accessed August 31, 2026. https://clinicaltrials.gov/study/NCT07562152
2. 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.2026.44.16_suppl.4013
3. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-703. doi:10.1056/NEJMoa1304369
4. FDA approves first in class targeted therapy for metastatic pancreatic cancer. FDA. August 26, 2026. Accessed August 31, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-class-targeted-therapy-metastatic-pancreatic-cancer?utm_medium=email&utm_source=govdelivery
5. Study of daraxonrasib and daraxonrasib + GnP as first-line treatment in patients with metastatic pancreatic adenocarcinoma (RASolute 303). ClinicalTrials.gov. Updated August 27, 2026. Accessed August 31, 2026. https://clinicaltrials.gov/study/NCT07491445
6. Study of daraxonrasib (RMC-6236) in patients with resected pancreatic ductal adenocarcinoma (PDAC) (RASolute 304). ClinicalTrials.gov. Updated August 25, 2026. Accessed August 31, 2026. https://clinicaltrials.gov/study/NCT07252232
7. Tango Therapeutics announces combination of vopimetostat and daraxonrasib demonstrated 92% objective response rate in pancreatic cancer. News release. Tango Therapeutics. June 8, 2026. Accessed August 31, 2026. https://www.globenewswire.com/news-release/2026/06/08/3307926/0/en/tango-therapeutics-announces-combination-of-vopimetostat-and-daraxonrasib-demonstrated-92-objective-response-rate-in-pancreatic-cancer.html