In a phase II trial reported in The Lancet, Stephanie Lheureux, MD, of Princess Margaret Cancer Centre, Toronto, and colleagues, found that the addition of the oral Wee1 inhibitor adavosertib to gemcitabine significantly improved progression-free and overall survival in platinum-resistant/refractory recurrent high-grade serous ovarian cancer.¹

Stephanie Lheureux, MD

As stated by the investigators: “Wee1 (WEE1hu) kinase is a crucial regulator of the G2/M checkpoint. The G2/M checkpoint prevents entry of the damaged DNA into mitosis and is altered in several cancers…. TP53 mutations, which are ubiquitous in high-grade serous ovarian cancer, lead to increased dependency on S-phase and G2-phase checkpoints. Wee1 inhibition with adavosertib (AZD1775; MK1775) induces G2 checkpoint escape…. Gemcitabine is an antimetabolite therapy and blocks the progression of cells through the G1/S phase. Combining gemcitabine with Wee1 inhibition can lead to mitotic catastrophe by compromising the G2/M checkpoint.”

Study Details

In the double-blind study, 94 eligible patients with measurable, histologically confirmed, platinum-resistant or platinum-refractory, high-grade, serous ovarian cancer from 11 sites in the United States and Canada 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. The primary endpoint was progression-free survival.

For the combination vs control groups, median patient age was 62 years (range = 54–67 years) vs 62 years (range = 52–65 years). Eastern Cooperative Oncology Group performance status was 0 or 1 (61% vs 79%) in all but three patients (5%) in the combination group and one (3%) in the control group (performance status = 2). Overall, 79% vs 82% were White and 13% vs 6% were Asian. Primary tumor location was epithelial ovary in 92% vs 88%. Among those with a known status, 17% vs 12% had germline or somatic BRCA1/2 mutation. Among 56 vs 32 patients with available data, 93% vs 94% had TP53-mutated tumors on immunohistochemistry and 86% of 56 vs 67% of 33 had TP53 mutation on Sanger sequencing. 

Progression-Free Survival

At the 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.

In post hoc exploratory analyses, the addition of adavosertib to gemcitabine appeared to be associated with progression-free (P = .003) and overall survival (P = .04) among patients with homologous recombination gene mutations in baseline biopsy samples. A similar pattern was observed among patients with BRCA1 or BRCA2 mutations (P = .012 for progression-free and P = .086 for overall survival).

In addition, the combination was associated with a higher response rate among patients with CCNE1-amplified tumors (5 of 8, 62%) than among those with nonamplified tumors (3 of 23, 13%; P = .013). This association corresponded with nonsignificant improvements in progression-free (P = .15) and overall survival (P = .15) among patients in the combination group. No difference in response rates were observed according to amplification (1 of 9, 11%) vs nonamplification (0 of 9, 0%; P = 1.00) in the control group. As noted by the investigators, CCNE1 amplification is a potential predictive marker of cytotoxic chemotherapy resistance.

No correlation between SLFN11 levels and response or progression-free or overall survival was observed in the combination or control groups. As noted by the investigators, evidence from some studies has indicated a correlation between SLFN11 expression and response to DNA-damaging agents.

Adverse Events

The most common grade ≥ 3 adverse events were hematologic, including neutropenia in 62% of patients in the combination group vs 30% of the control group, anemia in 31% vs 21%, thrombocytopenia in 31% vs 6%, and febrile neutropenia in 11% vs 0%. Excluding these side effects, the most common laboratory abnormalities were hypokalemia, increased aspartate aminotransferase, and hypophosphatemia. The most common nonhematologic grade ≥ 3 adverse events in the combination group were fatigue, hypertension, abdominal pain, thromboembolic events, diarrhea, dyspnea, and maculopapular rash. Adverse events led to treatment discontinuation in 21% vs 0% of patients. 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…. This therapeutic approach might be applicable to other tumor types with high replication stress; larger confirmatory studies are required.” 

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. Dr. Lheureux has received honoraria from AstraZeneca; has served as a consultant or advisor to AstraZeneca, GSK, Merck, and Roche/Genentech; and has received institutional research funding from AstraZeneca, Merck, Regeneron, Roche/Genentech, and Tesaro.

REFERENCE

1. Lheureux S, Cristea MC, Bruce JP, et al: Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: A double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 397:281-292, 2021.