Atebimetinib, Immuneering’s lead deep cyclic inhibitor, in combination with chemotherapy shows durable tumor control and improved survival as a first-line pancreatic cancer therapy.
Treating pancreatic cancer remains one of oncology’s greatest challenges. The disease is often diagnosed at an advanced stage, progresses rapidly, and responds poorly to existing treatments. Chemotherapy remains the standard of care, but its benefits are modest and short-lived. Immuneering is challenging this paradigm with a new class of drugs designed not to shrink tumors quickly but to control them over time.
Ben Zeskind, PhD Cofounder and Chief Executive Officer Immuneering
In this Innovation Spotlight, Ben Zeskind, the cofounder and chief executive officer of Immuneering, discusses recent data from the company’s Phase 2a clinical trial of their deep cyclic inhibitor called atebimetinib. In combination with traditional chemotherapy, the treatment showed striking survival results that could signal a turning point in pancreatic cancer care.
Why are pancreatic cancer outcomes so poor?
What matters to cancer patients is living longer and better. Unfortunately, current first-line standard of care treatments for patients with pancreatic cancer do a poor job of keeping them alive. These treatments are all chemotherapy combinations that have very low overall survival due to limited durability and challenging tolerability, meaning that they stop working quickly and cause many harsh side effects.
We set out to change this. With overall survival as the overriding goal from day one, we sought to develop treatments that keep working longer, so patients keep living longer, and at the same time cause fewer harsh side effects. Our recently announced Phase 2a data shows that we are succeeding.
How was your clinical trial designed, and what sets Immuneering’s approach to cancer treatment apart?
Immuneering has figured out how to keep those with pancreatic cancer alive longer. We recently reported Phase 2a data for our clinical trial, which evaluates atebimetinib at a dose of 320 mg daily in combination with chemotherapy (modified gemcitabine/nab-paclitaxel; mGnP) in 34 patients with pancreatic cancer in the first-line setting, meaning they had not previously received treatment for advanced disease. We saw an extraordinary 94 percent overall survival at six months in these people. This far exceeds the benchmark of 67 percent overall survival at six months according to a pivotal study of the most common global standard of care treatment, gemcitabine/nab-paclitaxel chemotherapy alone, as well as the six-month overall survival for the other two standard of care treatments, FOLFIRINOX and NALIRIFOX.1
The dramatic improvement in six-month overall survival that we reported in our Phase 2a study rests on a strong foundation of longer durability and better tolerability. Atebimetinib plus chemotherapy kept working longer: we reported 72 percent progression-free survival at six months, whereas in the pivotal study for the standard of care, gemcitabine/nab-paclitaxel, the six-month progression-free survival was only 44 percent. Atebimetinib plus chemotherapy also showed a low rate of serious side effects, with only two categories of adverse events occurring at the grade 3+ level in at least 10 percent of the patients. In the gemcitabine/nab-paclitaxel study, there were six categories of adverse events occurring at the grade 3+ level in at least 10 percent of the patients.
Additionally, we saw an overall response rate of 39 percent and a disease control rate of 81 percent, including many patients with deepening, durable regressions and multiple examples of individual lesions rendered undetectable.
The bottom line is that the data we reported in June from our Phase 2a study shows that our treatment keeps working longer, with fewer side effects, than what was seen with standard of care treatments, and that ultimately, patients had much longer overall survival than would be expected from gemcitabine/nab-paclitaxel alone.
How does your atebimetinib therapy work, and why do you think this is a better strategy?
To achieve such unprecedented results, we had to tear down the very framework that has governed cancer drug development for the past 50 years: a focus on shrinking tumors as fast as possible. Instead, we rebuilt the entire process around a different set of priorities: durability, tolerability, and combinability, with overall survival as the only goal that matters. This shift from “shrink fast” to “outlast the disease” drove us to make unprecedented yet data-driven, survival-focused decisions at every stage of the drug development process, ultimately creating an entirely new category of cancer medicines called deep cyclic inhibitors.
Atebimetinib is the first in our pipeline of deep cyclic inhibitors, all designed to scramble the resistance process and deliver durable, sustained tumor control so that patients live longer with a quality of life so high that they may even forget they are undergoing treatment. Atebimetinib targets mitogen-activated protein kinase (MAPK) kinase (MEK) in the MAPK pathway, an area of intense focus because it drives the majority of all tumors. Atebimetinib works differently than existing MAPK drugs by deeply suppressing the MAPK pathway for several hours, then releasing it completely by 24 hours. This pulsed approach gives healthy cells time to recover while denying cancer cells the constant signaling they depend on to survive. The result is a therapy that is demonstrating an extraordinary survival benefit with great tolerability.
Atebimetinib uses a pulsed inhibition strategy to first suppress the MAPK pathway, then release it, allowing healthy cells to recover while disrupting cancer growth.
©iStock, SewcreamStudio
Were there any clinical trial results that surprised you?
The extraordinary overall survival that we reported was surprising because it was so dramatically different than the standard of care, but atebimetinib was designed from the beginning to keep cancer patients alive and drive overall survival as the primary objective, with exceptional durability and tolerability as key mechanisms for achieving that result. We also selected this combination based on extensive molecular rationale, and we observed deep, durable tumor regressions in animal models of this combination, which we reported at the 2024 AACR Annual Meeting, so the clinical trial is playing out exactly as the preclinical data suggested. We had seen patients with exceptional durability and tolerability in the Phase 1 trial, and the very first patient in this arm of the study had a complete response, which is an exceedingly rare outcome in pancreatic cancer. It was deeply gratifying, but not surprising, to see this remarkable survival benefit playing out first in pancreatic cancer, one of the most aggressive and deadly types of cancer.
Beyond pancreatic cancer, what other tumor types may be amenable to this treatment strategy?
Atebimetinib targets MEK in the MAPK pathway, which drives the majority of all cancers, so pancreatic cancer is just the beginning. We have announced an agreement with Regeneron to evaluate atebimetinib in combination with their anti-PD-1 Libtayo in lung cancer and with Lilly to evaluate atebimetinib in combination with their second-generation KRAS G12c inhibitor olomorasib also in lung cancer. We are considering additional applications in melanoma, colorectal cancer, acute myeloid leukemia, and other malignancies.
Deep cyclic inhibitors are applicable to many pathways and many different types of cancer, because the mechanisms by which they achieve durability and tolerability are not specific to any one pathway. Our preclinical pipeline includes deep cyclic inhibitors targeted against a variety of key cancer-causing pathways.
Looking ahead, what is next for atebimetinib and Immuneering?
We are excited to share updated overall survival and progression-free survival data from our ongoing Phase 2a trial of atebimetinib in combination with mGnP this quarter, and we are moving full speed ahead towards our Phase 3 pivotal study. We have submitted our end-of-phase 2 meeting request to the US Food and Drug Administration and expect to share regulatory feedback on our trial design in the fourth quarter and begin the pivotal study in 2026. We continue to advance additional studies and our preclinical pipeline of deep cyclic inhibitors.
The extraordinary overall survival results we have shared aren’t just numbers; they are lives extended. Patients stay on treatment longer, and tumors are shrinking slowly but steadily in many cases, just as the drug was designed to do. The result is a long-lasting, combinable treatment that enables patients to have a much better quality of life. In the end, slow and steady may well win the race.
