Chemotherapy with ruxolitinib plus as a pre/post-surgical treatment for ovarian cancer seems feasible
A neoadjuvant, postsurgical regimen involving ruxolitinib and chemotherapy appears to improve progression-free survival in patients with stage III and IV ovarian cancer.
Results from the Phase 1/2 NRG-GY007 (NCT02713386) trial demonstrated the feasibility of twice daily oral ruxolitinib (Jakafi) plus carboplatin and paclitaxel as an initial neoadjuvant and post-surgical treatment for ovarian cancer of the stage III or IV, with the prolongation of progression-free survival (PFS) reported compared to chemotherapy alone at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.
With a median follow-up of 24 months, the median PFS was 14.6 months with ruxolitinib plus chemotherapy versus 11.6 months for chemotherapy alone (HR, 0.70; 90% CI, 0.00-0 .89, log rank P = 0.059). Overall survival analysis showed a hazard ratio of 0.785 in favor of the experimental arm (one-sided 90% CI, 0.44-1.39; log-rank P = 0.70).
“This trial demonstrates the feasibility of early phase randomized studies with novel agents and the collection of biological samples in the first-line neoadjuvant treatment of ovarian cancer family”, Charles ‘Chip’ Landen, Jr, MD, MS, associate professor of obstetrics and gynecology at the University of Virginia at Charlottesville, said during a presentation of the data.
Patients who were candidates for neoadjuvant chemotherapy with a histological diagnosis and an image-guided or laparoscopic core biopsy confirming epithelial cancer of the ovary, fallopian tubes, or primary peritoneum were eligible for treatment in the phase 1 weekly treatment with paclitaxel 80 mg/m2, intravenous carboplatin at area under the curve (AUC) 5 or 6 every 21 days, and oral ruxolitinib 10 mg to 15 mg twice daily, with the first dose being taken at least 1 hour before paclitaxel. Patients were treated with 3 cycles of the regimen, followed by interval tumor-reducing surgery, 3 cycles of additional systemic treatment, and maintenance ruxolitinib. The primary endpoint was the 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 3 further cycles of treatment with a primary endpoint of PFS. There were enough dose-limiting toxicities in Phase 1 for the Phase 2 carboplatin dose to be updated to AUC 6. Overall, 42 patients were treated with carboplatin and paclitaxel alone and 105 were treated with received additional ruxolitinib.
Patient characteristics were well balanced except for a higher rate of BRCA mutations in experimental arms (16.2%) vs controls (7.1%). In both groups, the median age of the patients was 66 years (range: 33-86), with most patients being white (90.5%), non-Hispanic (87.8%), and with chronic disease. histological serous/endometrioid (98.0%). The ECOG performance score was 0 out of 51.0%, 1 out of 43.5% and 2 out of 5.4%.
Higher rates of grade 3/4 anemia were reported with the ruxolitinib combination at 64.2% versus 26.8% with chemotherapy alone, which Laden says is to be expected with a cell-targeting drug strains. Other Grade 3/4 adverse reactions (AEs) of note included decreased neutrophils (52.6% with ruxolitinib versus 29.2% with chemotherapy), infections (19.1% versus 17.1%, respectively), a decrease in platelets (10.5% versus 14.6%) and events (12.7% versus 2.4%). There were 5 grade 5 AEs, with all but 1 febrile neutropenia event considered unrelated to treatment.
“There have been many practical lessons learned from this first trial conducted by NRG in the initial neoadjuvant setting. The most common test deviations relevant to this design include initial pretreatment biopsy indicating adenocarcinoma but not engaging in a serous or clear cell endometrioid phenotype; a difference in histological subtype between the initial biopsy and the sample taken at reduced intervals; the healthcare team being reluctant to perform interval cytoreduction surgery after cycle 3 even in the absence of progressive disease; a delay in the start of cycle 4 of chemotherapy within 4 weeks of surgery; and a desire from the healthcare team to continue chemotherapy, either as a cytotoxic drug or maintenance after 6 cycles,” Landen said. “There was an amendment during the trial to allow the use of PARP inhibitors as maintenance therapy in BRCA-positive patients. Overall, these deviations were still infrequent and likely did not affect the outcome of the study, but can be used to inform future trial designs.
In conclusion, Landen said 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 response biomarkers and confirmation that the STAT3 target is downregulated with treatment are needed and ongoing.”
Landen CN, Buckanovich RJ, Sill M, et al. A phase I/II study of ruxolitinib with first-line neoadjuvant and post-surgical treatment in patients with advanced epithelial cancer of the ovary, fallopian tube or primary peritoneum. J Clin Oncol. 2022;40(supplement 16):5002. doi: 10.1200/JCO.2022.40.16_suppl.5002