Abstract
According to results from a phase I/II trial, the investigational WEE1 inhibitor adavosertib combined with gemcitabine and radiation is well tolerated and may benefit patients with locally advanced pancreatic adenocarcinoma by increasing both systemic and local disease control.
Findings from a clinical trial at the University of Michigan in Ann Arbor indicate that patients with locally advanced, inoperable pancreatic adenocarcinoma may benefit from the combination of adavosertib (AZD1775; AstraZeneca)—an investigational agent targeting the cell cycle checkpoint regulator WEE1—with gemcitabine and radiation.
This study builds on the researchers' preclinical work showing that WEE1 inhibition sensitizes pancreatic cancer cells to gemcitabine and radiation, thereby increasing both systemic and local disease control. Chemotherapy and radiation activate WEE1 and the G2 checkpoint in tumors, but adavosertib blocks this DNA-damage response. As such, “enough damage is inflicted that, with the repair pathway closed, it becomes lethal to cancer cells,” explains senior author Theodore Lawrence, MD, PhD.
Thirty-four patients were enrolled in the trial and received four rounds of gemcitabine with adavosertib; radiation was given concurrently during the second and third cycles. Given the trial's dose-escalation design, treatment for most patients “ended up being right around what's maximally tolerated [adavosertib dose],” Lawrence says, “so we got not only solid phase I, but also phase II data out of this study.”
By obtaining sequential skin biopsies and assessing phospho-CDK1 levels—a marker of WEE1 activity—in the hair follicles, the researchers “had evidence that adavosertib was in fact hitting its target,” he adds. Surrogate tissue use is a potential limitation, but “directly biopsying the tumor would have involved doing an endoscopic ultrasound twice, which we couldn't ask of such ill patients.”
The investigators reported a median overall survival (OS) of 21.7 months; the median progression-free survival was 9.4 months. Prior studies evaluating gemcitabine alongside radiation have yielded OS data “in the range of a year, maybe up to 14 months at most,” Lawrence observes, “so to get nearly 2 years with the addition of adavosertib is very exciting.” Nausea and fatigue were the main side effects, but the combination was well tolerated overall.
“There's been some controversy about radiation's role in pancreatic cancer treatment—because the disease has such a propensity to spread, many have questioned the relevance of local control,” Lawrence remarks. “A central theme of our study, however, is that with systemic therapies getting better and reducing the likelihood that patients will die of metastatic disease, locally focused radiation can now actually matter in terms of improving survival.”
John Plastaras, MD, of the University of Pennsylvania in Philadelphia, considers the addition of adavosertib “a clever, mechanism-based sensitizer that appears to have moved the needle for these patients.” Since the Michigan trial was initiated, FOLFIRINOX has become a more common systemic option, so “it would be interesting to know if WEE1 inhibition also impacts 5-fluorouracil-based chemoradiation,” Plastaras says.
Lawrence agrees and is keen to evaluate adavosertib in that context, as well as alongside gemcitabine plus nab-paclitaxel, another newer regimen. A “potential winner to try,” he thinks, would be to start with several cycles of FOLFIRINOX, followed by local control with adavosertib, gemcitabine, and radiation.
“The question then would be what this combination should be compared to” in a larger randomized trial, Lawrence notes. With no established standard for treating locally advanced pancreatic adenocarcinoma, “I'd suggest that participating centers pick the regimen they're most comfortable with as their control arm. You'd call this a practical study, and I do think it would accrue.” –Alissa Poh
