Immuneering Panel & CEO Insights: Atebimetinib Raises the Bar for Survival and Quality of Life in Pancreatic Cancer

In this discussion panel with Pharmacy Times, Meredith Pelster, MD, Ben Zeskind, PhD, and Igor Matushansky, MD, PhD, discuss Immuneering’s investigational MEK inhibitor atebimetinib and its potential to reshape first-line treatment for pancreatic cancer. The panel reviews phase 2 data showing a 64% overall survival rate at 12 months, representing a meaningful improvement over historical benchmarks in a disease with limited therapeutic progress.

The speakers explain how deep cyclic inhibition of the MAP kinase pathway is designed to enhance durability while improving tolerability, allowing patients to remain on therapy longer with fewer high-grade toxicities. They also highlight the importance of a modified every-other-week gemcitabine and nab-paclitaxel regimen, which may further reduce treatment-related adverse events.

Beyond survival, the discussion emphasizes patient-centered outcomes, including improved performance status, weight gain, and quality of life. The panel concludes by outlining plans for a randomized phase 3 trial with overall survival as the primary endpoint and exploring atebimetinib’s broader potential across MAPK-driven cancers.

Pharmacy Times: The Phase 2a trial showed a 64% overall survival rate at 12 months in the first-line setting—nearly double the historical benchmark. From your perspective, how should clinicians interpret this magnitude of benefit in a disease where overall survival has remained largely unchanged for decades?

Meredith Pelster, MD: As you mentioned, overall survival in pancreatic cancer has remained largely unchanged for decades and has been very poor. Nearly 50,000 people will die from pancreatic cancer each year, and 5 year survival rates are grim due to very limited therapeutic innovation in this space. Seeing a 64% overall survival rate at 12 months in the first-line setting does really stand out as a meaningful departure from what we would expect outcomes to be historically. Observing this level of benefit in the first-line setting is particularly important, as this is where we think we can really generate durable benefit for patients and have the greatest downstream impact. I see a lot of patients with pancreatic cancer, and I unfortunately have to discuss with them that, based on historical data, their chances of living a year after a diagnosis of metastatic disease are less than 50% based on our prior data. This would change that conversation in a very meaningful way.

Pharmacy Times: Pancreatic cancer trials often rely on progression-free survival (PFS) as a surrogate endpoint. How does the observed separation in median PFS in this study support the overall survival (OS) signal, and why is that particularly meaningful in pancreatic cancer?

Meredith Pelster, MD: The observed PFS separation really supports the OS signal by showing consistency across endpoints, which I think is the most important thing from a trial perspective. Alignment between PFS, and OS really justifies doing a larger randomized trial where we can assess definitive OS benefit. PFS also provides an early signal, maybe before OS reads out, where we can see signs of a clinically meaningful benefit to patients.

Pharmacy Times: For pharmacists, understanding mechanism-driven differences is critical. How does atebimetinib (Immuneering) differ mechanistically from earlier MEK inhibitors that were often limited by tolerability or resistance?

Ben Zeskind, PhD: You’re absolutely right. MEK has always been considered a really good target because the pathway that it’s in, the MAP kinase pathway, drives about half of all tumors. This is a very common pathway. It goes RAS, RAF, MEK, ERK, and you generally hear the most about RAS because there are a lot of mutations in RAS. However, MEK is a really interesting target because it’s further downstream. Different mutations in RAS and different mutations in RAF can all be blocked by a good MEK inhibitor.

From the standpoint of durability that Dr. Pelster talked about earlier, of really wanting patients to live as long as possible and have great OS, the best way to do that is to make it as hard as possible for the tumor to get around the treatment. Cancer is not actually that smart, but it has a couple of good tricks, and one of its tricks is that it’s really good at adapting. It’s really good at mutating to get around treatment.

If you inhibit the pathway at the level of RAS, you often see resistance mechanisms where the tumor will amplify RAS, get more copies of it, mutate to a different form of RAS, or acquire a RAF mutation. All of those changes, in theory, can be blocked by a MEK inhibitor. So, it’s a good target.

There have been 4 MEK inhibitors approved for a really long time, but they’ve all been very toxic and limited mainly to BRAF-mutant disease and neurofibromas and mainly used in combinations. What we set out to do when we were designing atebimetinib was, number 1- to expand the applicability to RAS-mutant disease as well as BRAF-mutant disease. Number 2- to drastically improve tolerability, so patients would have a much better quality of life on these treatments. Number 3- to extend durability and prevent tumors from being able to get around it as easily.

That’s how we developed the deep cyclic inhibition mechanism. Most cancer treatments shut down the pathway continuously by attacking the same target and shutting down the MAP kinase pathway. The challenge with that is that we have these pathways for a reason, other than for cancer to hijack them. If you shut down the pathway 24/7, you hurt a lot of healthy cells that need these pathways too.

What we came to appreciate through our research, and that of others, was that while healthy cells and tumor cells both need the MAP kinase pathway, they need it differently. Tumor cells are always on. They’re constantly growing and dividing. They’re addicted to the pathway and need MAP kinase signaling the way a person needs air. Tumors can’t go for too long without MAP kinase signaling and still be rapidly growing.

Healthy cells use it more transiently, the way a person needs hydration. A few hours without water is fine, 5 or 6 hours you’re getting thirsty, and it’s not until about 24 hours that it becomes a serious medical dehydration situation. The idea of deep cyclic inhibition is to shut down the pathway very completely for several hours a day and then completely release it by the end of the day.

In doing so, we cut tumors off from the sustained high level of MAP kinase signaling they need to rapidly grow and divide, while giving healthy cells back their drink of water, if you will, by the end of the day. This provides enough transient MAP kinase signaling for healthy cells to do well.

In the clinical trial, we only saw 2 categories of adverse events at the grade 3 level in more than 10% of patients, both associated with the chemotherapy we were combining with and neither seen in the monotherapy setting with atebimetinib. This really shows that we were able to achieve a substantial improvement in tolerability.

Pharmacy Times: For oncology pharmacists who regularly manage dose adjustments and supportive care, what counseling considerations or monitoring priorities stand out with this regimen?

Meredith Pelster, MD: That’s a great question, and I certainly agree that effective management of side effects through early intervention, patient education, and symptom control is really essential in keeping patients on therapy longer. Our oncology pharmacists are key partners in helping manage these patients.

As far as what I would want oncology pharmacists to be aware of with this regimen, as Ben mentioned, there is a chemotherapy component, but it is dosed a little bit differently than what oncology pharmacists may initially think of when they hear gemcitabine and nab-paclitaxel. Typically, this treatment is given weekly for 3 weeks with a 1 week break. Here, modified gemcitabine and nab-paclitaxel are used as chemotherapy and are given every other week, and atebimetinib is given as once-daily dosing continuously. That is a key fact for oncology pharmacists to be aware of.

Because of this difference in chemotherapy dosing, which really impacts toxicity compared with standardly administered gemcitabine and nab-paclitaxel, we typically see a lot of cytopenias and neurotoxicity, including peripheral sensory neuropathy. Those are certainly things that still need to be monitored, but the phase 2 data indicate low rates of those side effects with this particular combination regimen. I would want pharmacists to be really aware that this regimen is very different from what we have previously seen.

Ben Zeskind, PhD: That’s a great point, and I would just add that we did that out of a desire to create as patient-friendly a regimen as possible. Not only is it more convenient that patients are only getting the chemotherapy infusions every other week, as opposed to 3 weeks on and 1 week off, as Dr. Pelster said, but the tolerability of having less frequent chemotherapy has been shown to be better.

By combining that improved tolerability on the chemotherapy side with the excellent tolerability we’re seeing with atebimetinib, our goal is really to create great quality of life for these patients. Not only do we want to allow them to have more time through longer OS, but we also want that time to be better quality time and for them to have a great quality of life. That has always been our goal, and that’s part of why we chose the every-other-week regimen for the chemotherapy.

Pharmacy Times: Pharmacists play a key role in managing oral oncology agents.
What should pharmacists know about atebimetinib’s administration, adherence considerations, or potential drug–drug interactions as this therapy advances?

Meredith Pelster, MD: As mentioned, atebimetinib is a once-daily oral pill, which makes compliance significantly easier than a more complex dosing regimen. This is really nice for patients. Many of the other components and guidance on that will be available in the future.

Pharmacy Times: How do you envision pharmacists contributing to toxicity management and patient education as therapies move toward more chronic, tolerable treatment models?

Meredith Pelster, MD: That’s another great question. Education can range from one-time counseling to continuous reinforcement to help patients understand what to expect over the time they are on treatment. Going back to tolerability, we do see that this regimen is quite tolerable and that patients are receiving durable benefits, so they may be on it for a long time. It is very important that we continually offer patients support as they are on this therapy for extended periods of time. That is certainly a place where oncology pharmacists play a role. We want to make sure that just because a patient has been on therapy for a long time, we are not forgetting to check on their compliance. Adding that additional layer of support as part of the oncology care team is really crucial.

I will also take the opportunity, while we’re talking about toxicity and tolerability, to share a bit about what I’ve seen with my own patients who were part of the phase 2 study. I have seen patients do very well on this study. I have 1 patient I was recently talking with in clinic who has been on therapy for over 6 months and has actually had an improvement in her performance status while on therapy, which is really nice to see.

With pancreatic cancer, I think it’s important to talk about how patients are often very symptomatic from their cancer. While we often think about toxicities and symptoms related to treatment, in pancreatic cancer, especially, if you can get control of the cancer, patients can overall feel better, even with treatment toxicities. That is what I have seen with this regimen.

The patient I was referencing initially came in for evaluation with a high degree of symptom burden that limited what she could do day to day. She needed help from her family with transportation to and from clinic. As we have gotten control over her disease, her symptom burden has decreased and she is more independent, which has been really important to her. She shared that she had been part of a walking group in her neighborhood but had to stop. After starting treatment, she has regained strength and is part of her neighborhood walking group again.

Those things are so important to patients on treatment, and I think patients understanding that they can do those things while on treatment is really important.

Igor Matushansky, MD, PhD: I’m just going to add that, more broadly, we have clearly seen that this is a heavy medicine with an anti-cachectic effect. Patients gain weight and patients feel better, and this is somewhat independent of their overall response. Of course, if you’re controlling pancreatic cancer, patients will feel better, but independent of that, these patients are feeling better and gaining weight.

We’ve had patients ask if they can take the medicine more than once a day because they’re feeling so much better on it. Of course, for biological reasons, we say no, but absolutely, patients are just feeling much better on the medicine in general.

Ben Zeskind, PhD: These were design goals from the start, so it’s really gratifying to hear that it’s playing out in the clinic the way we intended. It’s great to hear stories like the one Dr. Pelster told, and we hear those across sites. It’s really wonderful to see patients having such great quality of life.

Pharmacy Times: Immuneering plans to dose the first patient in a global Phase 3 trial in mid-2026. What key endpoints or design elements are most important to confirm the promise seen in Phase 2a?

Igor Matushansky, MD, PhD: The primary endpoint for this trial is OS. That is the gold standard for pancreatic cancer trials, and the FDA has reaffirmed multiple times, including recently, that OS remains the gold standard. Overall survival is our primary and only endpoint.

The trial is going to be fairly straightforward in the sense that it is a one-to-one randomization against the most common global standard of care, which is gemcitabine and nab-paclitaxel given on the standard regimen. Another thing to note is that we are taking a fairly high hazard ratio. In other words, we are attempting to power this trial in such a way that the results will significantly improve upon the standard of care, not only to show superiority over the control arm, but also to show superiority over other potential first-line standards that are out there.

Meredith Pelster, MD: I’ll just add that, as both a clinician treating patients and a clinical investigator, I’m very excited for this trial. I think it is going to be very important for our patients and for our field.

Ben Zeskind, PhD:I want to thank Dr. Pelster and all the oncologists who are treating patients in our trial. It’s really gratifying to see not only the survival—having a 64% overall survival rate at 12 months is so different from the benchmarks that have come before—but also the great tolerability. We’re seeing only 2 categories of grade 3 adverse events in more than 10% of patients, and we’re hearing stories of patients having really meaningful improvements in quality of life, including being able to rejoin a walking group.

This is why we do what we do, and this is why we’re so excited for atebimetinib and what it can do going forward. I would emphasize that pancreatic cancer is just the beginning for atebimetinib. It is such an unmet need, and we’re honored to be able to start here.

We also have a combination trial in lung cancer, where we expect to dose the first patient before the end of the year. As I mentioned earlier, the MAP kinase pathway drives about half of all tumors, so there is a broad range of cancers where we hope to bring the benefits of atebimetinib over time. There is a lot of excitement ahead.