Novel Oral Drug Shows Promise

Early nine-month data from a clinical trial suggests a new promising first-line treatment option for patients newly diagnosed with pancreatic cancer.

The novel oral drug atebimetinib (IMM-1-104), combined with standard chemotherapy of modified gemcitabine/nab-paclitaxel (mGnP), helped significantly improve pancreatic cancer survival rates.

Immuneering Corporation shared updated survival and safety data from its ongoing phase IIa trial of 34 first-line pancreatic cancer patients with nine months median follow-up. In patients receiving atebimetinib plus mGnP, the data showed:

• Overall survival observed at six months was 94 percent, and 86 percent at nine months. Compare this to the standard of care benchmark for overall survival, which is approximately 67 percent at six months and 47 percent at nine months.
• Progression-free survival observed at six months was 70 percent, and 53 percent at nine months. In comparison, the standard of care benchmark for progression-free survival is approximately 44 percent at six months and 29 percent at nine months.

The drug regimen demonstrated a favorable tolerability in the trial patients. More than 10 percent of patients developed the adverse effects of neutropenia and anemia, both of which are commonly observed with standard of care treatment. No new adverse events were identified.

“Larger studies are still needed, but these early results are very encouraging,” says Barbara Ma, M.D, M.S., assistant professor in the Department of Medical Oncology at Weill Cornell Medicine in New York. She leads the phase I unit and heads Cellular Therapy for Solid Tumors at NewYork-Presbyterian/Weill Cornell Medicine. Ma is an investigator in the phase I/IIa clinical trial assessing the safety and tolerability of atebimetinib in several solid tumors including pancreatic cancer. “Pancreatic cancer is one of the deadliest cancers with limited durable treatment options that can have tough side effects,” she explains. “We have seen some strong early responses with very few side effects in some patients treated with atebimetinib. Seeing this, especially in pancreatic cancer, is promising.”

What Makes Atebimetinib Different

The conventional wisdom in cancer care is to kill as many malignant cells as possible through chronic and continuous drug exposure. But sometimes, conventional wisdom is turned on its head with striking results, as demonstrated in this trial.

Malignancies like pancreatic cancer as well as melanoma, and others, can be driven by mutations of genes called RAS or RAF. These genes are found in a signaling pathway called MAPK. Signaling pathways play an important role in our bodies, regulating functions like normal cell division and cell death. But in cancer, genetic mutations cause these pathways to no longer functional normally. The result is cancer cells that divide excessively, spread to other organs and resist death. About 90 percent of pancreatic cancers are due to RAS or RAF genetic mutations. MEK is a key control point in the MAPK pathway. Targeting MEK blocks a broader range of MAPK pathway alterations because it is further downstream, creating the potential for more durable benefit.

Atebimetinib is a novel oral MEK inhibitor taken once daily that targets the MAPK pathway using a unique approach called deep cyclic inhibition. This method targets cancer cells—more specifically on and off in cycles. “Traditional MEK inhibitors have helped many cancer patients, but there have been issues of how well they are tolerated, eventual drug resistance, and the sparing of healthy cells,” says Dr. Ma. “Unlike older MEK inhibitors that block the MAPK pathway continuously, atebimetinib inhibits the MAPK signaling pathway in a pulsatile fashion. This allows healthy cells time to recover while keeping pressure on cancer cells. It may lead to fewer side effects and help stop the tumor from developing resistance.”

In a statement from Immuneering, Vincent Chung, M.D., said, “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.” Chung is Professor, Department of Medical Oncology &Therapeutics Research at City of Hope (Duarte, California), and is a principal investigator on this clinical trial; he is also a paid member of the Immuneering scientific advisory board. He explained further that “I have seen firsthand in my own patients the benefits of atebimetinib’s durability and tolerability. The remarkable overall survival, progression-free survival, and tolerability data we are seeing with atebimetinib plus mGnP in first-line pancreatic cancer patients, now out to nine months of median follow-up, represent an important step towards creating urgently needed new options for these patients. We are also planning a confirmatory study.”