In a phase II trial reported in The Lancet, Lheureux et al found that the addition of the oral Wee1 inhibitor adavosertib to gemcitabine significantly improved progression-free survival in patients with platinum-resistant/refractory recurrent ovarian cancer.
As related by the investigators, the Wee1 kinase is a critical regulator of the G2/M checkpoint involved in DNA repair. The combination of gemcitabine with Wee1 inhibition can lead to mitotic catastrophe by compromising this checkpoint.
The double-blind study included 94 eligible patients with measurable high-grade serous ovarian cancer from 11 sites in the U.S. and Canada. Patients were randomly assigned 2:1 between September 2014 and May 2018 to receive adavosertib plus gemcitabine (n = 61) or placebo plus gemcitabine (n = 33). An additional 25 women with non–high-grade serous ovarian cancer were enrolled in an exploratory cohort and received the combination. Treatment consisted of gemcitabine at 1,000 mg/m² on days 1, 8, and 15, with either oral adavosertib at 175 mg or placebo once daily on days 1, 2, 8, 9, 15, and 16, in 28-day cycles until disease progression or unacceptable toxicity. Among 56 vs 32 randomly assigned patients with available data, 93% vs 94% had TP53-mutated tumors on immunohistochemistry. The primary endpoint was progression-free survival.
At time of final analysis (March 2019), median progression-free survival was 4.6 months (95% confidence interval [CI] = 3.6–6.4 months) in the adavosertib plus gemcitabine group vs 3.0 months (95% CI = 1.8–3.8 months) in the control group (hazard ratio [HR] = 0.55, 95% CI = 0.35–0.90, P = .015).
Median overall survival at the time of final analysis was 11.4 months (95% CI = 8.2–16.5 months) in the adavosertib plus gemcitabine group vs 7.2 months (95% CI = 5.2–13.2 months) in the control group (HR = 0.56, 95% CI = 0.35–0.91, P = .017).
Objective responses (all partial responses) occurred in 14 patients (23%) in the combination group vs 2 (6%) in the control group (P = .038). Median duration of response was 3.7 months (interquartile rage = 3.5–9.6 months) in the combination group; durations of response in the two control group responders were 5.8 and 12.9 months. Stable disease was observed in an additional 35 patients (57%) in the combination group vs 24 (73%) in the control group. In the exploratory cohort, partial response was observed in four patients (16%), with nine additional patients (36%) having stable disease.
The most common grade ≥ 3 adverse events were hematologic events, including neutropenia in 62% of patients in the combination group vs 30% of the control group, anemia in 31% vs 21%, and thrombocytopenia in 31% vs 6%. The most common nonhematologic grade ≥ 3 adverse events in the combination group were fatigue (16% vs 9%) and hypertension (15% vs 3%). No treatment-related deaths were reported.
The investigators concluded, “The observed clinical efficacy of a Wee1 inhibitor combined with gemcitabine supports ongoing assessment of DNA damage response drugs in high-grade serous ovarian cancer, a TP53-mutated tumor type with high replication stress. This therapeutic approach might be applicable to other tumor types with high replication stress; larger confirmatory studies are required.”
Amit M. Oza, MD, of Princess Margaret Cancer Centre, Toronto, is the corresponding author for The Lancet article.
Disclosure: The study was funded by the U.S. National Cancer Institute Cancer Therapy Evaluation Program, Ontario Institute for Cancer Research, U.S. Department of Defense, Princess Margaret Cancer Foundation, and AstraZeneca. For full disclosures of the study authors, visit thelancet.com.