Atebimetinib Combination Shows Promising Survival Data in Pancreatic Cancer
New trial data reveals atebimetinib combined with gemcitabine/nab-paclitaxel significantly improves survival rates in pancreatic cancer patients.
3D illustration of pancreas anatomy: ©rasi - stock.adobe.com
New data from an ongoing phase 2a trial (NCT05585320) suggest that atebimetinib (IMM-1-104), an oral, once-daily novel MEK inhibitor, in combination with modified gemcitabine/nab-paclitaxel (mGnP), may offer significant survival benefits in the first line for patients with pancreatic cancer.
With a data cutoff date of May 26, 2025, specifically, at the 320 mg once-daily dose of atebimetinib (n = 34), a 94% overall survival (OS) was observed at 6 months, surpassing the 6-month OS benchmark of 67% for the current standard of care (SOC), full-dose and schedule gemcitabine/nab-paclitaxel (GnP), in this patient population. Median overall survival (OS) had not yet been reached at the time of the data cutoff, further underscoring the promising durability of this combination.
Beyond OS, the data also indicate substantial improvements in disease control. A 72% progression-free survival (PFS) was observed at 6 months in the same patient group receiving atebimetinib at the 320 mg dose level. This compares favorably to the 6-month PFS benchmark of 44% for SOC GnP. Similar to OS, the median PFS had not yet been reached at the data cutoff.
The overall response rate (ORR) was 39%, and the disease control rate (DCR) was 81% in response-evaluable patients at both the 240-mg and 320-mg dose levels of atebimetinib (n = 36). The observed responses included numerous instances of deepening, durable regressions, and even multiple examples of individual lesions becoming undetectable. These ORRs and the high disease control rate indicate a significant antitumor effect, suggesting that the combination actively shrinks tumors or halts their growth. This level of response is particularly encouraging in pancreatic cancer, where achieving substantial tumor regression can be challenging.
Additionally, a favorable tolerability profile was demonstrated by atebimetinib in combination with mGnP. There were no grade 3 or higher adverse events (AEs) observed in a majority of the AE categories commonly associated with SOC chemotherapy in first-line pancreatic cancer. This reduced toxicity profile is a significant advantage, as the often-severe AEs of conventional chemotherapy can impact patient quality of life and adherence to treatment.
About Atebimetinib and the Phase 2a Study
Atebimetinib is an investigational drug with a novel mechanism. The agent targets the MAPK pathway, aiming to effectively inhibit the growth of these cancers. By targeting cancer cells, atebimetinib minimizes impact on healthy cells. This unique approach, utilizing deep cyclic inhibition, potentially overcomes resistance mechanisms seen with other therapies, offering hope for broader efficacy against RAS-mutant tumors.
In February 2024, the FDA granted fast track designation to atebimetinib for the treatment of patients with pancreatic ductal adenocarcinoma (PDAC) who have progressed after 1 line of treatment.
In the open-label, dose-exploration and dose-expansion study, experts sought to examine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of IMM-1-104 alone or in combination with approved agents for the treatment of patients with RAS-mutated or RAS/MAPK activated advanced or metastatic solid tumors.2
All patients must have been at least 18 years of age and have a histologically or cytologically confirmed diagnosis of a solid tumor malignancy. For the monotherapy phase 1, patients needed a locally advanced unresectable or metastatic solid tumor with a RAS activating mutation. In the monotherapy phase 2a, eligible malignancies included locally advanced unresectable or metastatic PDAC, RAS-mutant melanoma, or RAS-mutant non–small cell lung cancer. For the combination therapy arms across both phases, patients with locally advanced unresectable or metastatic PDAC were included, specifically those who had received no previous systemic anti-cancer therapy for their advanced or metastatic disease.
The trial also included specific cohorts for second- and third-line patients with unresectable stage III or IV cutaneous melanoma who had progressed on anti–PD-(L)1 monoclonal antibody therapy, with precise timelines for prior treatment. All patients were required to have evidence of measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function.
The primary end points for phase 1 of the trial were to evaluate AEs, dose-limiting toxicities, and determine the recommended phase 2 candidate optimal dose. ORR served as the primary end point in phase 2a. Secondary end points included PK, DCR, PFS, duration of response, OS, and landmark 3- and 6-month survival.
Next Steps for Atebimetinib
Based on these encouraging phase 2a data, Immuneering, the company developing atebimetinib, has decided to increase the target enrollment in the first-line pancreatic cancer atebimetinib plus mGnP combination arm to approximately 50 patients.1 This expansion aims to gather more comprehensive data to further solidify the observed benefits and prepare for later-stage trials.
Looking ahead, the company has outlined several important milestones. These include seeking regulatory feedback on pivotal study plans in the fourth quarter of 2025 and expecting additional patient data from the ongoing phase 2a trial also in the fourth quarter of 2025. The most significant upcoming step is the planned initiation of a pivotal, randomized trial of atebimetinib in combination with mGnP in first-line pancreatic cancer in 2026. This pivotal trial will be crucial for confirming the efficacy and safety profile of the combination in a larger, randomized setting, which is a prerequisite for potential regulatory approval.
Further, the company plans to initiate additional atebimetinib clinical trial combination arms in 2026, exploring its potential in other indications or in combination with other agents.
