Patients with locally advanced pancreatic cancer often receive gemcitabine plus radiotherapy. Despite some clinical benefit, virtually all patients have disease progression, indicating a need for more effective therapies. Now, data from a single-arm, dose-escalation phase I trial demonstrate prolonged overall survival (OS) with the addition of the Wee1 kinase inhibitor adavosertib to gemcitabine plus radiotherapy, relative to historical cohorts.

A total of 34 patients received gemcitabine on days 1 and 8 of a 3-week cycle, followed by adavosertib 3–4 and 24 hours after each dose of gemcitabine, for a maximum of 8 cycles with image-guided, intensity-modulated radiation therapy delivered during cycles 2 and 3. The adavosertib dose was determined on the basis of the response of the previous patient using the TITE-CRM algorithm. Determining an optimal target dose and toxicity profile were the primary end points of this study.

Dose-limiting toxicities, including anorexia, nausea, fatigue, abdominal pain, altered mental status, liver enzyme elevation and neutropenic fever or thrombocytopenia were observed in eight patients (24%); 150 mg (dose level 1) was selected as the optimal dose for phase II testing. An analysis of hair follicles in skin biopsy samples revealed phospho-CDK1 suppression, suggesting on-target activity of adavosertib in 16 of 20 consenting patients.

The median OS duration among 20 patients who received any dose of adavosertib was 21.7 months, with a median progression-free survival duration of 9.5 months. As noted by the authors, these data compare favourably to results obtained with gemcitabine plus radiotherapy in previous studies (median OS 11–15 months).

Despite several limitations (among others, use of a single-centre design and a small cohort size), these findings seem promising; data from phase II trials, with larger cohorts of patients, are eagerly awaited.