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Twice-daily oral ruxolitinib plus carboplatin and paclitaxel given as frontline neoadjuvant and post-surgical treatment to patients with stage III or IV ovarian cancer was found to be feasible and to improve progression-free survival compared with chemotherapy alone.
Twice-daily oral ruxolitinib (Jakafi) plus carboplatin and paclitaxel given as frontline neoadjuvant and post-surgical treatment to patients with stage III or IV ovarian cancer was found to be feasible and to improve progression-free survival (PFS) compared with chemotherapy alone, according to data from the phase 1/2 NRG-GY007 trial (NCT02713386) presented during the 2022 ASCO Annual Meeting.1
With a median follow-up of 24 months, the median PFS was 14.6 months with ruxolitinib plus chemotherapy vs 11.6 months for chemotherapy alone (hazard ratio [HR], 0.70; 90% CI, 0.00-0.89; log rank P = .059). Analysis of overall survival showed a HR of 0.785 favoring the experimental arm (1-sided 90% CI, 0.44-1.39; log-rank P = .70).
“This trial demonstrates the feasibility of early-phase randomized studies with novel agents and biospecimen collection in the frontline neoadjuvant treatment of the ovarian family of cancers,” Charles ‘Chip’ Landen, Jr, MD, MS, associate professor of obstetrics and gynecology at the University of Virginia in Charlottesville, said during a presentation on the data.
Patients who were candidates for neoadjuvant chemotherapy with a histologic diagnosis and image-guided core or laparoscopic biopsy confirming epithelial ovarian, fallopian tube, or primary peritoneal cancer were eligible for treatment in the phase 1 portion of weekly intravenous paclitaxel at 80 mg/m2, intravenous carboplatin at area under the curve (AUC) 5 or 6 every 21 days, and oral ruxolitinib at 10 mg to 15 mg twice daily, with the first dose being taken at least 1 hour prior to paclitaxel. Patients were treated with 3 cycles of the regimen, followed by interval tumor reductive surgery, 3 additional systemic treatment cycles, and maintenance ruxolitinib.
The primary end point was safety and tolerability of ruxolitinib plus chemotherapy. In phase 2, patients were treated with either carboplatin and paclitaxel alone or in combination with ruxolitinib for 3 cycles, surgery, and another 3 cycles of therapy with a primary end point of PFS. There were enough dose-limiting toxicities in the phase 1 portion so that the dose of carboplatin in phase 2 was updated to AUC 6. Overall, 42 patients were treated with carboplatin and paclitaxel alone and 105 received additional ruxolitinib.
Patient characteristics were well balanced, except for a higher rate of BRCA mutations in the experimental (16.2%) vs control (7.1%) arms. In both groups, the median patient age was 66 years (range, 33-86) with most patients being White (90.5%), non-Hispanic (87.8%), and with serous/endometrioid histological disease (98.0%). ECOG performance score was 0 in 51.0%, 1 in 43.5%, and 2 in 5.4%.
Higher rates of grade 3/4 anemia were reported with the ruxolitinib combination at 64.2% vs 26.8% with chemotherapy alone, which Laden said is to be expected with a drug targeting stem cells. Other grade 3/4 adverse effects (AEs) of note included decreased neutrophils (52.6% with ruxolitinib vs 29.2% with chemotherapy), infections (19.1% vs 17.1%, respectively), decreased platelets (10.5% vs 14.6%), and thrombotic events (12.7% vs 2.4%). There were 5 grade 5 AEs, with all but 1 event of febrile neutropenia being deemed unrelated to treatment.
“There were many practical lessons learned in this first trial conducted by NRG in the neoadjuvant up-front setting. The most common trial deviations relevant to this design include the initial pretreatment biopsy stating adenocarcinoma but not committing to a serous endometroid or clear cell phenotype; a difference in histologic subtype between the initial biopsy and the specimen taken at interval debulking; the treatment team being reluctant to perform an interval cytoreductive surgery after cycle 3 even in the setting of no progressive disease; a delay in initiating cycle 4 of chemotherapy within 4 weeks of surgery; and a desire of the treating team to continue chemotherapy, either as a cytotoxic drug or as maintenance after 6 cycles,” Landen said. “There was an amendment during the trial to allow the use of PARP inhibitors as maintenance in BRCA-positive patients. Overall, these deviations were still infrequent and did not likely affect the outcome of the study but can be used to inform future trial designs.”
To conclude, Landen stated that further study of this combination should be considered and should include maintenance ruxolitinib added after 6 cycles of treatment to prevent tumor regrowth. “Correlative translational studies for biomarkers of response and confirmation that the STAT3 target is being downregulated with treatment are needed and ongoing.”