Adavosertib regimen appears safe, shows promise for improving pancreatic cancer survival
The combination of adavosertib, gemcitabine and radiation appeared safe and potentially effective for patients with newly diagnosed, locally advanced pancreatic cancer, according to results of a phase 1 dose-escalation study published in Journal of Clinical Oncology.
Researchers observed significantly higher OS with the regimen compared with previous results of gemcitabine plus radiation, the standard treatment for pancreatic cancer. This warrants further investigation, they noted.
“If we are ever going to cure pancreatic cancer, we’re going to need effective systemic treatment as well as local therapy,” Ted Lawrence, MD, PhD, professor and chair of radiation oncology at University of Michigan, said in a press release. “Our data suggest that [adavosertib] can do both.”
Researchers evaluated adavosertib (AZD1775, AstraZeneca), a Wee1 kinase inhibitor, with gemcitabine alone in a previous phase 1 dose-escalation trial. That trial established 175 mg as adavosertib’s maximum tolerated dose when given twice per week for 3 consecutive weeks in a 4-week cycle.
For the current study, Lawrence and colleagues assigned 34 patients (median age, 64 years; range, 44-78; 56% men) with locally advanced pancreatic cancer to receive four 21-day cycles of gemcitabine (1,000 mg/m2 on days 1 and 8) and adavosertib (once daily on days 1, 2, 8 and 9), with concurrent radiation during cycles 2 and 3. Researchers assessed four dose levels of adavosertib, ranging from 100 mg to 175 mg.
The maximum tolerated dose of adavosertib administered in combination with gemcitabine and radiation served as the study’s primary endpoint. Secondary endpoints included OS, PFS and pharmacodynamic activity of adavosertib in surrogate tissues.
Median follow-up at the time of data analysis was 15 months.
More than half of all patients in the study (53%) experienced grade 3 or grade 4 treatment-related adverse events. Common adverse events included nausea, vomiting, febrile neutropenia, fatigue and fever.
Dose-limiting toxicities occurred among eight patients and included anorexia/nausea (n = 2) and fatigue (n = 2).
Based on a target dose-limiting toxicity rate of 0.3, researchers identified 150 mg as the maximum tolerated dose and the recommended phase 2 dose of adavosertib. They said the difference in the maximum tolerated dose compared with the earlier trial could be a result of the radiotherapy or the long interval (105 days) during which they assessed toxicity.
Median OS among all patients was 21.7 months (90% CI, 16.7-24.8) and median PFS was 9.4 months (90% CI, 8-9.9).
Hair follicle biopsy samples showed evidence of Wee1 inhibition with decreased phosphorylation of cyclin-dependent kinase 1 staining by immunohistochemistry at the 150 mg adavosertib dose level.
The single-arm nature of the study served as its primary limitation.
The dose-response relationship observed in the study suggests adavosertib confers effective primary tumor control, according to researchers.
"If we can disable the DNA damage response in pancreatic cancer cells, it might eliminate treatment resistance and sensitize the cancer to the effects of both radiation and chemotherapy," Kyle C. Cuneo, MD, associate professor of radiation oncology at University of Michigan, said in a press release. “Adding [adavosertib] to radiation and gemcitabine was relatively well tolerated with encouraging survival results. Further studies with this promising combination are needed.” – by John DeRosier
Disclosures: Cuneo reports research funding from BTG International and Varian Medical Systems. Lawrence reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.