Atebimetinib (IMM-1-104) in combination with chemotherapy could represent a novel frontline treatment option for patients with metastatic pancreatic cancer, due to atebimetinib’s unique mechanism of action targeting MEK via intermittent deep cyclical inhibition, according to Martin F. Dietrich, MD, PhD.

Updated data from an ongoing phase 1/2 trial (NCT05585320)

 demonstrated that evaluable patients with treatment-naive metastatic pancreatic cancer who received atebimetinib in combination with modified gemcitabine and nab-paclitaxel (Abraxane; n = 34) experienced a 9-month overall survival (OS) rate of 86% and a median OS that was not reached.

 Additionally, the 9-month progression-free survival (PFS) rate was 53%. Conversely, prior data from the phase 3 MPACT trial (NCT00844649) had demonstrated that treatment with gemcitabine and nab-paclitaxel alone produced 9-month OS and PFS rates of approximately 47% and 29%, respectively.

“First-line therapy for [patients with] pancreatic adenocarcinoma is heavily dependent on chemotherapy. We’ve [also] come to understand the central role of 

 [mutations] in driving the vast majority of pancreatic adenocarcinoma,” Dietrich, a medical oncologist at The US Oncology Network Cancer Care Centers of Brevard and an assistant professor of internal medicine at the University of Central Florida College of Medicine in Orlando, said in an interview with 

®. “The idea is to see if targeted therapy could augment and potentially synergize with chemotherapy in the first-line setting.”

In the interview, Dietrich discussed the present limitations of frontline chemotherapy for the treatment of patients with advanced/metastatic pancreatic cancer, the early-phase data that have been reported with the agent in this disease setting, and its future in the space.

What are the current first-line chemotherapy regimens for patients with advanced/metastatic pancreatic cancer, and what are their limitations?

: The current first-line standard of care for [patients with] pancreatic adenocarcinoma is dependent on the use of chemotherapy. We have a number of regimens that can be used, and they have to be tailored to the individual patient’s performance status and organ function. One of the standard regimens is gemcitabine [plus] nab-paclitaxel. It’s a doublet of 2 mechanisms that are used together, and it’s generally felt to be a bit milder [in terms of toxicity], but it also has limitations in regard to efficacy. The overall response rate [ORR] was [23%] with a [median] PFS of [5.5] months and a median OS of [8.5 months in the MPACT trial].

We have 2 additional triplet regimens. We started out over 10 years ago with FOLFIRINOX [irinotecan plus oxaliplatin, leucovorin, and 5-fluorouracil (5-FU)], based on phase 2 data in France [NCT00112658]. We saw an ORR of 31.6%, a median PFS of [4.6 months], and a median OS of [11.1 months].

Most recently, we had the readout of the [phase 3] NAPOLI-3 study [NCT04083235] that established NALIRIFOX [irinotecan liposome (Onivyde) with oxaliplatin, 5-FU, and leucovorin] against gemcitabine plus nab-paclitaxel. The ORR was 41.8% [95% CI, 36.8%-46.9%] and the [median] OS was 11.1 months [95% CI, 10.0-12.1].

It’s a heavily chemotherapy-dependent treatment [paradigm]. We don’t have any more targeted therapies [approved] in the first-line setting. The limitations [of chemotherapy] are typically that although [these regimens] may be effective immediately, the concern is durability, not only from a standpoint of efficacy but also from a standpoint of cumulative toxicity. For nab-paclitaxel, we typically worry about cumulative neuropathy, in addition to cytopenias. For FOLFIRINOX and NALIRIFOX, the adverse effects [AEs] of concern are neuropathy from a different angle: the oxaliplatin-induced neurotoxicity. It is very different mechanistically from nab-paclitaxel, but similarly impactful.

There’s a lot of room for improvement [on frontline chemotherapy]. Unfortunately, many patients do not qualify for treatment at all, and there are also a lot of limitations with the durability of these therapies.

What is the mechanism of action of atebimetinib, and would you consider it to be novel, given its specificity for targeting MEK?

Atebimetinib has a unique mechanism of action

 We have had MAP kinase inhibitors for a long time in the clinic, but their concept was very different. They were aiming at chronic suppression of MAP kinase signaling via direct targeting of MEK. We’ve had significant challenges, both in melanoma [as well as] colorectal and lung cancers where they are approved, with concerns for modulation of the immune system, fevers, and liver function test abnormalities. [These agents have also been] implicated in vascular integrity and vascular events.

The idea [with atebimetinib] is to target a very well-established and important pathway through a novel mechanism. The mechanism here is an intermittent deep inhibition mechanism that is labeled deep cyclical inhibition. This essentially allows for 2 things: We shut off the pathway long enough to allow for a synergistic effect on the efficacy side, but not long enough to induce significant traditional toxicities associated with MAP kinase inhibition.

[It’s a] very interesting concept. We never thought about this. We always thought ‘more is better,’ and the stronger the inhibition of a pathway target, the better. However, this doesn’t necessarily seem to be the case, and at least from the preliminary data that we have, both on a toxicity and efficacy side, the concept seems to be very promising.

How does the administration method of atebimetinib differentiate it from agents such as systemic chemotherapy?

Atebimetinib is an oral [agent]. It’s a different delivery of a therapy. It has a very interesting pharmacokinetic [profile]. We see an on/off activity off the MAP kinase pathway, but it seems to be enough to suppress tumor growth and avoid the escape pathways that we see with other MAP kinase [inhibitors]. It also avoids some of the typical MAP kinase AEs such as pyrexia.

What are the key design elements of the phase 1/2 trial evaluating atebimetinib in first-line pancreatic cancer?

This was a multicohort analysis that looked at atebimetinib in [patients with] pancreatic adenocarcinoma in 2 [groups]: in combination with gemcitabine and nab-paclitaxel and [in combination with] modified FOLFIRINOX [mFOLFIRINOX], as well as in combination with pembrolizumab [Keytruda] for [patients with] melanoma, [in combination with dabrafenib (Tafinlar) for patients with 

-mutated melanoma, and in combination with cemiplimab-rwlc (Libtayo) for patients with unresectable or metastatic, 

 This is a broad investigation. It reflects how important the MAP kinase pathway is, either in the up-front propagation of cancer growth or in the resistance setting, so there’s broad interest [in atebimetinib].

Focusing on the benchmarks here in pancreatic adenocarcinoma, I believe it’s most important to understand the limitation that OS hasn’t exceeded 1 year in any significant way and the durability [of response] remains the main challenge [with chemotherapy alone]. We have early data [with atebimetinib], and they are data that we can contextualize very well historically against the efficacy data both for the doublet and the triplet chemotherapies. For practical purposes, the mFOLFIRINOX [data] are a more internationally accessible standard, [and the regimen] is in many ways similar to NALIRIFOX.

How did the early efficacy data with atebimetinib compare with historical benchmarks?

When we look at data from phase 1, and especially the results from the [phase] 2a part of the study, they set some very competitive benchmarks in the first-line setting for the use of atebimetinib in combination with chemotherapy. We saw that 94% of patients were alive at the 6-month high mark. This is a substantial increase in durability over the historical expectations.

We [also] saw 70% of patients progression-free at 6 months, which signifies that the addition of atebimetinib is adding to the durability of the [chemotherapy] regimen in the first-line setting. This is certainly something that we don’t see with any of the other first-line chemotherapy regimens. There is a significant breakout of the survival curves.

We’ve seen some nice early responses that we would like to follow. The ORR was [approximately] double what we would typically see with first-line pancreatic adenocarcinoma treatment with gemcitabine and nab-paclitaxel, [and] many of these responses [were] deep and durable.

What did the updated data reveal about the combination? 

In extended follow-up, the regimen of atebimetinib combined with gemcitabine and nab-paclitaxel sustained an exemplary 9-month landmark OS rate of 86%, markedly surpassing the historical benchmark of 47% observed with gemcitabine plus nab-paclitaxel alone. This regimen emerges as a promising therapeutic combination, distinguished by its superior efficacy and comparable safety profile. Moreover, these outcomes compare favorably to those of historical triplet chemotherapy regimens, which are encumbered by more formidable toxicities. 

The regimen's robust efficacy is further affirmed by a 53% landmark PFS rate, illuminating atebimetinib's pivotal role in enhancing the durability of chemotherapy for [patients with] pancreatic adenocarcinoma. These results warrant further evaluation in a prospective phase 3 trial to address the profound unmet needs of these patients affected by pancreatic cancer.

What has been observed regarding safety with the addition of atebimetinib to chemotherapy?

There’s always [a point] where we have to balance efficacy and safety. It’s very interesting to see that although we do see a mild increase in toxicity with gemcitabine and nab-paclitaxel being a backbone that is significantly better tolerated than our triplets, we don’t really see substantial increases when we look at the addition of atebimetinib in the first-line setting. This was a very favorable ratio of benefit to risk with this treatment, and certainly a de-escalation of toxicity from mFOLFIRINOX and NALIRIFOX.

It is also important to recognize that when we look at these datasets, the study looked at patients with less favorable [disease factors and characteristics]. They were typically older. We saw a patient population that was generally demonstrating all features of high-risk disease: CA 19-9 elevation, significantly high levels of liver and lung metastases, and a strong subset of peritoneal metastases. This was, if anything, a less favorable patient population in which these data were produced. [These findings] require verification in a prospective study, side-by-side with chemotherapy in a randomized fashion, but the first signal here [is] certainly incredibly strong.

What are the next steps that are needed in order for the combination to move forward?

It’s very clear that we have to do more for patients. There are 2 factors: One is the efficacy of the first-line therapy, and the other is the significant drop-off in the number of patients who are able to receive second-line [therapy]. The second-line options after exhausting first-line therapy, especially if patients start on a triplet in the first-line setting, [are sparse]. I believe that’s where atebimetinib is going to find a wide-open treatment opportunity.

This is a new mechanism, one that historically doesn’t have a side-by-side comparison. We’re using a well-established pathway in pancreatic adenocarcinoma, but with a new way of approaching it through intermittent deep cyclical inhibition that allows for a gain in efficacy, as the data would suggest, without a significant increase in toxicity. Most of the toxicity experience will remain defined here by the underlying chemotherapy backbone.

This presents opportunities, [including potential] combination options independent of the chemotherapy regimen. If you think about [how] we would normally like to offer fit and performance status–eligible patients a triplet in the first-line setting to maximize outcomes, maybe there’s an opportunity here of giving targeted therapy with atebimetinib plus chemotherapy to achieve equal or better outcomes than we see with the triplet therapies [alone]. A global, randomized prospective phase 3 study [expected to launch by the end of 2025] will answer these questions in more clarity.

 This article has been updated with commentary on the 9-month data with atebimetinib in combination with modified gemcitabine and nab-paclitaxel.

Immuneering announces extraordinary 86% overall survival at 9 months in first-line pancreatic cancer patients treated with atebimetinib + mGnP. News release. Immuneering. September 24, 2025. Accessed October 2, 2025. https://ir.immuneering.com/news-releases/news-release-details/immuneering-announces-extraordinary-86-overall-survival-9-months

Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. 

. 2013;369(18):1691-1703. doi:10.1056/NEJMoa1304369

Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. 

. 2011;364(19):1817-1825. doi:10.1056/NEJMoa1011923

Wainberg ZA, Melisi D, Macarulla T, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. 

. 2023;402(10409):1272-1281. doi:10.1016/S0140-6736(23)01366-1

Immuneering announces clinical supply agreement with Regeneron Pharmaceuticals to evaluate IMM-1-104 in combination with Libtayo (cemiplimab). News release. Immuneering. February 6, 2025. Accessed October 2, 2025. https://ir.immuneering.com/news-releases/news-release-details/immuneering-announces-clinical-supply-agreement-regeneron

Articles

Martin F. Dietrich, MD, PhD, discusses the potential role of atebimetinib plus chemotherapy in frontline pancreatic cancer.

Atebimetinib Plus Chemo Makes Case As Potential Frontline Option in Pancreatic Cancer

Dr Dietrich on the Limitations of Chemotherapy in Pancreatic Cancer

“[Although chemotherapy] may be effective immediately, the [main] concern is durability. [This is] not only from an efficacy standpoint, but [in regards to] cumulative toxicity.”

Martin F. Dietrich, MD, PhD, a medical oncologist at The US Oncology Network Cancer Care Centers of Brevard and an assistant professor of internal medicine at the University of Central Florida College of Medicine, discussed the limitations of frontline chemotherapy for the treatment of patients with advanced/metastatic pancreatic cancer.

The current first-line standard of care for patients with advanced/metastatic pancreatic cancer remains chemotherapy, Dietrich began. As multiple chemotherapy regimens can be used in this setting, these must be personalized to the individual patient; accordingly, chemotherapy selection should account for factors such as performance status and organ function, he added.

One standard regimen is gemcitabine plus nab-paclitaxel (Abraxane), Dietrich said. Although this regimen is mild in terms of toxicity, it often has limited efficacy, with an overall response rate (ORR) between 20% and 25%, a median progression-free survival (PFS) of approximately 6 months, and a median overall survival (OS) of less than 1 year, he noted. 

Two triplet regimens are also available for this patient population, Dietrich said. mFOLFIRINOX (irinotecan plus oxaliplatin, leucovorin, and 5-fluorouracil [5-FU]) has previously demonstrated efficacy in terms of ORR, PFS, and OS, he added. Recently, data from the phase 3 NAPOLI 3 study (NCT04083235) demonstrated that NALIRIFOX (irinotecan liposome [Onivyde] with oxaliplatin, 5-FU, and leucovorin) produced an ORR of 41.8% (95% CI, 36.8%-46.9%), he noted.

Dietrich emphasized that there are presently no targeted therapies available in the frontline setting and that the chemotherapy approaches, although initially effective, have a limited durability of response. Toxicity concerns can also arise with chemotherapy regimens, including cumulative neuropathy and cytopenias for gemcitabine plus nab-paclitaxel, and neurotoxicity for the triplets, he said. Overall, there is a lot of room for improvement in frontline, advanced/metastatic pancreatic cancer, and many patients do not qualify for treatment at all, he concluded.

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Martin F. Dietrich, MD, PhD, discusses the limitations of frontline chemotherapy in advanced/metastatic pancreatic cancer.

The combination of atebimetinib (IMM-1-104) and modified gemcitabine/nab-paclitaxel (Abraxane; mGnP) elicited relatively high survival rates compared with historical standard-of-care (SOC) data at a median follow-up of 9 months in patients with treatment-naive pancreatic cancer, according to updated findings from the phase 2a portion of an ongoing phase 1/2 trial (NCT05585320).

At a data cutoff date of August 26, 2025, among 34 evaluable patients, the 9-month overall survival (OS) rate with the combination was 86% (95% CI, 66%-94%), and the median OS was not reached; in an illustrative comparison with historical SOC data, this rate with the SOC benchmark regimen of gemcitabine plus nab-paclitaxel was approximately 47% in the pivotal phase 3 MPACT trial (NCT00844649). Additionally, the 9-month progression-free survival (PFS) rate with atebimetinib plus mGnP was 53%; this rate was approximately 29% with SOC in MPACT.

“Pancreatic cancer remains one of the most challenging cancers we face in the clinic with far too few treatment options available to patients and survival rates that have remained unacceptably low for decades,” Vincent Chung, MD, FACP, a professor in the Department of Medical Oncology and Therapeutics Research at City of Hope in Duarte, California, as well as the principal investigator of the phase 2a trial and a paid member of Immuneering’s scientific advisory board, stated in a news release. “I have seen firsthand in my own patients the benefits of atebimetinib’s durability and tolerability. The remarkable OS, PFS, and tolerability data we are seeing with atebimetinib plus mGnP in [patients with] first-line pancreatic cancer, now out to 9 months of median follow-up, represent an important step toward creating urgently needed new options for these patients. We are also planning a confirmatory study.”

Immuneering, the developer of atebimetinib, expects to receive regulatory feedback in the fourth quarter of 2025 regarding its plans for a pivotal trial. Based on that feedback, the company plans to initiate the pivotal trial by the end of 2025 and begin dosing patients by the middle of 2026. Further updated OS and PFS data from the phase 2a trial are also planned to be presented at a scientific meeting in 2026.

“OS is the gold standard in oncology and has been Immuneering’s goal from the beginning,” Ben Zeskind, PhD, cofounder, president, and chief executive officer of Immuneering, added in the news release. “In cancer, nothing matters more than keeping patients alive and helping them thrive. We are beyond thrilled to report that not only was our extraordinary 94% OS [rate] at 6 months sustained with additional follow-up time, but our observed 9-month OS [rate] of 86% shows an even larger gap [compared with] SOC benchmarks. To combine such meaningful OS with such favorable tolerability has the potential to be truly game-changing for [patients with] first-line pancreatic cancer.”

What Is the Mechanism of Action of Atebimetinib?

Atebimetinib is a MEK-targeting deep cyclic inhibitor, part of a class of agents that is designed to pulse quicker than tumor reaction times, shrinking tumors gradually and more durably than agents that employ sustained inhibition and may trigger tumors to adapt and develop treatment resistance. Sustained inhibition is also associated with suppressed transient signaling in healthy cells, which can lead to adverse effects (AEs). In comparison, deep cyclic inhibitors restore full transient signaling abilities to healthy cells and may therefore lead to fewer AEs.

“Deep cyclic inhibitors like atebimetinib represent a fundamental shift in targeted therapy, away from continuous inhibition and toward pulsatile modulation of key oncogenic pathways,” Brett Hall, PhD, chief scientific officer at Immuneering, added in the news release. “This approach has the potential to deliver both durability and tolerability, two patient-centered essentials oncology has long struggled to balance.”

What Is the Design of the Phase 1/2 Trial Investigating Frontline Atebimetinib in Pancreatic Cancer?

The first-line pancreatic cancer combination portion of the trial enrolled patients at least 18 years of age with histologically or cytologically confirmed locally advanced unresectable or metastatic pancreatic ductal adenocarcinoma who had received no prior systemic anticancer therapy.

 Patients also needed to have measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function.

Patients in this arm received atebimetinib at 320 mg once daily plus mGnP.

Overall response rate serves as the primary end point of the phase 2a portion.

 Secondary end points in this portion include pharmacokinetics, disease control rate, PFS, duration of response, 3-month survival outcomes, 6-month survival outcomes, and OS.

What Findings Have Been Previously Reported From the Phase 2 Portion of the Trial of First-Line Atebimetinib Plus mGnP in Pancreatic Cancer?

Notably, at a median follow-up of 6 months, the OS rate was 94% (95% CI, 77%-98%) with atebimetinib plus mGnP; this rate was 67% among patients who received SOC in MPACT.

 The 6-month PFS rates were 70% and approximately 44% in these respective arms.

What Is the Safety Profile of First-Line Atebimetinib Plus mGnP in Pancreatic Cancer?

With extended follow-up, the combination continued to show a favorable safety profile, and no new safety signals were reported, according to the news release. The most frequently observed grade 3 or higher AEs were anemia (24%), neutropenia (18%), fatigue (6%), vomiting (3%), febrile neutropenia (3%), hypokalemia (3%), and nausea (3%). No grade 5 AEs were observed.

Immuneering announces extraordinary 86% overall survival at 9 months in first-line pancreatic cancer patients treated with atebimetinib + mGnP. News release. Immuneering. September 24, 2025. Accessed September 25, 2025. https://ir.immuneering.com/news-releases/news-release-details/immuneering-announces-extraordinary-86-overall-survival-9-months

A phase 1/​2a study of IMM-1-104 in participants with advanced or metastatic solid tumors. ClinicalTrials.gov. Updated September 2, 2025. Accessed September 25, 2025. https://clinicaltrials.gov/study/NCT05585320?a=8

Immuneering reports positive overall survival data for atebimetinib (IMM-1-104) from ongoing phase 2a trial in first-line pancreatic cancer patients. News release. Immuneering. June 17, 2025. Accessed September 25, 2025. https://ir.immuneering.com/news-releases/news-release-details/immuneering-reports-positive-overall-survival-data-atebimetinib

The combination of atebimetinib and modified gemcitabine/nab-paclitaxel demonstrated promising survival outcomes in treatment-naive pancreatic cancer patients, with a 9-month overall survival rate of 86% compared to 47% with standard care. Atebimetinib, a MEK-targeting deep cyclic inhibitor, offers a novel approach by pulsing quicker than tumor reaction times, potentially reducing adverse effects. The ongoing phase 1/2 trial showed favorable safety, with no new safety signals. Immuneering plans to initiate a pivotal trial by the end of 2025, with further data expected in 2026.

Atebimetinib plus modified gemcitabine/nab-paclitaxel continued to elicit high OS rates in patients with treatment-naive pancreatic cancer.

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