Dr Pelster on the Rationale for Investigating Atebimetinib in Metastatic Pancreatic Cancer

“The most important thing to note about the [phase 2] trial design is that this was not a randomized study intended to compare [atebimetinib with] any other treatment.”

Meredith Pelster, MD, MSCI, a medical oncologist and associate director of Gastrointestinal Cancer Research at Sarah Cannon Research Institute, discussed the rationale for and design of a phase 2a trial (NCT05585320) investigating atebimetinib, a novel MEK1/2 inhibitor, in combination with modified gemcitabine plus nab-paclitaxel (Abraxane) for patients with first-line metastatic pancreatic cancer.

Atebimetinib is a deep cyclic MEK inhibitor, Pelster explained. Whereas the MEK inhibitors approved in diseases such as melanoma carry substantial ocular, gastrointestinal, and cardiac toxicities from sustained pathway blockade, atebimetinib potently inhibits MEK but has a short half-life, creating a window in which the pathway is not inhibited, she noted. That intermittent, on-and-off inhibition helps modulate its toxicity and makes the agent a favorable partner to combine with chemotherapy, as utilized in this trial, according to Pelster.

The rationale for MEK inhibition in pancreatic cancer is that most of these tumors are driven by overactivity of the MAPK pathway, typically by RAS mutations, and MEK sits along that cascade, making it a meaningful node at which to achieve pathway inhibition, Pelster said. In the single-arm phase 2 study, patients with first-line metastatic or locally advanced pancreatic ductal adenocarcinoma received atebimetinib at 320 mg once daily plus modified gemcitabine plus nab-paclitaxel, with all RAS/KRAS mutation subtypes permitted.

The most important point about the trial design, Pelster emphasized, is that it was not a randomized study intended to compare atebimetinib against another treatment. Therefore, the data are interesting and generate hypotheses, she said, but they should be interpreted in that context. Those hypotheses form the basis for a randomized, controlled phase 3 MAPKeeper 301 study (NCT07562152), which will compare the combination of atebimetinib and modified gemcitabine/nab-paclitaxel against standard gemcitabine/nab-paclitaxel in patients with first-line metastatic pancreatic cancer.