In a phase I/II NRG Oncology Group study reported in the Journal of Clinical Oncology, Landen et al found that the addition of ruxolitinib to front-line paclitaxel/carboplatin neoadjuvant chemotherapy and interval debulking surgery improved progression-free survival in patients with stage III to IV ovarian cancer.
As stated by the investigators, “The interleukin-6/Janus kinase (JAK)/signal transducers and activators of transcription 3 axis is a reported driver of chemotherapy resistance. We hypothesized that adding the JAK1/2 inhibitor ruxolitinib to standard chemotherapy would be tolerable and improve progression-free survival in patients with ovarian cancer in the upfront setting.’
Study Details
A total of 147 patients with ovarian/fallopian tube/primary peritoneal carcinoma who were recommended for neoadjuvant chemotherapy were enrolled in the U.S. multicenter trial between January 2017 and January 2020, including 17 into phase I and 130 into phase II. In phase I, treatment was initiated with dose-dense paclitaxel at 70 mg/m2 once daily on days 1, 8, and 15; carboplatin at AUC 5 on day 1; and ruxolitinib at 15 mg twice a day every 21 days (dose level 1). Interval debulking surgery was performed after cycle 3, followed by three additional cycles of ruxolitinib/chemotherapy (and maintenance ruxolitinib).
In phase II, patients were randomly assigned 2:1 to receive paclitaxel/carboplatin with (n = 88) or without (n = 42) ruxolitinib at 15 mg twice a day for three cycles, followed by interval debulking surgery and three further cycles of chemotherapy or ruxolitinib/chemotherapy (with no maintenance ruxolitinib). The primary phase II endpoint was progression-free survival.
Key Findings
In phase I, the maximum tolerated dose and recommended phase II dose were established as dose level 1. The median follow-up in phase II was 24 months. Median progression-free survival was 14.6 months (85% confidence interval [CI] = 11.9–16.9 months) in the ruxolitinib group vs 11.6 months (85% CI = 10.3–14.4 months) in the control group (hazard ratio [HR] = 0.702, 85% one-sided CI = 0–0.89, P = .059), with the outcome meeting the predefined significance level. Median overall survival was not reached in the ruxolitinib group vs 30.9 months in the control group (HR = 0.785, 85% CI = 0.44–1.39, P = .24).
Among the phase I and II cohorts combined, patients receiving ruxolitinib plus chemotherapy had higher rates of grade 3 or 4 anemia (64% vs 27%), neutropenia (53% vs 37%), and thromboembolic events (12.6% vs 2.4%) vs patients receiving chemotherapy without ruxolitinib. Two grade 5 adverse events were observed—febrile neutropenia and infection—among patients receiving ruxolitinib plus chemotherapy.
The investigators concluded: “Ruxolitinib [at] 15 mg [orally] twice a day was well tolerated with acceptable toxicity in combination with paclitaxel/carboplatin chemotherapy. The primary end point of prolongation of progression-free survival was achieved in the experimental ruxolitinib arm, warranting further investigation.”
Charles N. Landen, MD, of the Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by National Cancer Institute grants and Incyte, Inc. For full disclosures of the study authors, visit ascopubs.org.
