Adavosertib Plus Gemcitabine and Radiotherapy in Locally Advanced Pancreatic Cancer
In a phase I dose-escalation trial reported in the Journal of Clinical Oncology, Cuneo et al established the phase II dose of the Wee1 kinase inhibitor adavosertib in combination with gemcitabine and radiotherapy in locally advanced pancreatic cancer. Wee1 inhibition impedes DNA damage response and may sensitize tumor cells to gemcitabine and radiation.
A total of 34 evaluable previously untreated patients were enrolled in the dose-escalation trial between March 2014 and April 2018. Patients received four 21-day cycles of gemcitabine (1,000 mg/m2 on days 1 and 8) with adavosertib at 100, 125, 150, or 175 mg/d on days 1, 2, 8, and 9. Cycles 2 and 3 were administered concurrently with radiotherapy (52.5 Gy in 25 fractions delivered 5 times per week); cycles 5 to 8 of gemcitabine plus adavosertib were permitted in patients without evidence of disease progression.
Toxicities and Phase II Dose
Overall, 26 patients (76%) received at least four cycles of gemcitabine with adavosertib and 15 (44%) received the maximum number of eight cycles. A total of 30 patients (88%) completed the full course of radiotherapy.
The recommended phase II dose of adavosertib was 150 mg/d. Dose-limiting toxicities occurred in eight patients (24%), with the most common being anorexia, nausea, and fatigue. Grade 3 or 4 treatment-related adverse events occurred in 18 patients (53%). Serious adverse events occurred in 18 patients (53%), with the most common being febrile neutropenia (12%), fatigue (9%), fever (9%), and anorexia or nausea/vomiting (9%).
Clinical Outcomes
Median follow-up for all patients was 15 months. Median overall survival was 21.7 months, and median progression-free survival was 9.4 months. The 12-month freedom from local failure rate was 68%.
In pharmacodynamics evaluation, hair follicle biopsy samples indicated evidence of Wee1 inhibition (decreased phosphorylation of cyclin-dependent kinase 1 staining on immunohistochemistry) after adavosertib administration at the recommended phase II dose.
The investigators concluded: “Adavosertib in combination with gemcitabine and radiation therapy was well tolerated at a dose that produced target engagement in a surrogate tissue. The overall survival is substantially higher than prior results combining gemcitabine with radiation therapy and warrants additional investigation.”
Theodore S. Lawrence, MD, PhD, of the Department of Radiation Oncology, Michigan Medicine, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by National Cancer Institute grants. AZD1775 (adavosertib) was supplied by AstraZeneca. For full disclosures of the study authors, visit jco.ascopubs.org.
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