Activation of the JAK/STAT pathway with ruxolitinib may be a future option for patients with newly diagnosed, high-grade glioma.
In comparison with historical benchmarks for patients with MGMT methylated and MGMT unmethylated, newly diagnosed, high-grade gliomas, the use of ruxolitinib (Jakafi) in combination with temozolomide and radiation therapy appears to be a safe and feasible option.1
Data for the experimental combination, as explored in the phase 1, non-randomized, prospective CRUX trial (NCT03514069), were presented in June 2023 at the American Society of Clinical Oncology (ASCO) Annual Meeting. Since then, this treatment concept has entered a phase 2 clinical trial (NCT03514069).
This research follows preclinical evidence showing that survival and proliferation of tumor cells may be enhanced when the JAK/STAT pathway in newly diagnosed, high-grade gliomas is targeted.
“The outcomes of patients with high grade gliomas are fairly dismal, despite the advances in surgery, radiation and chemotherapy, hence, novel agents like ruxolitinib, are urgently needed. Ruxolitinib targets the JAK/STAT pathway that has been associated with tumor progression and worse outcomes in patients with glioblastoma,” explained study investigator, Manmeet Ahluwalia, MD. “We combined this agent with radiation alone in the MGMT unmethylated patients, and we combined ruxolitinib along with temozolomide and radiation in the MGMT methylated patients because temozolomide only confers a 21-day benefit in these patients.”
The overall population of patients in phase 1 CRUX study had a 1-year overall survival (OS) rate of 77%. In the MGMT unmethylated group, the 1-year OS rate was 62%, and in the MGMT methylated group, the 1-year OS rate was 93%.
In MGMT unmethylated patients with newly diagnosed, high-grade glioma, the median OS was 18.2 months (95% CI, 10.1 to not assessed). In comparison, the median OS in the MGMT methylated cohort was not reached (P <.0001). Median PFS was also more favorable for patients with MGMT methylated disease compared with the MGMT unmethylated population (P =.00084).
Safety results showed that there were no dose-limiting toxicities. There were several toxicities related to study treatment, including grade 4 seizure, respiratory distress, somnolence, and venous thromboembolism. Fourteen grade 3 events were also observed, which included respiratory distress, seizure, gait disturbance, weakness, thrombocytopenia, cognitive disturbance, urinary retention, and meningitis.
“What we found out was that the agent ruxolitinib was extremely well-tolerated, both in combination with either radiation or with temozolomide and radiation…The outcomes of the patients treated with ruxolitinib led them along with radiation in unmethylated patients and ruxolitinib and temozolomide with radiation appear promising compared to the historical controls with these patients,” said Ahluwalia
CRUX included 60 patients who received escalating doses of ruxolitinib with 60 Gy radiation for 5 weeks. In the MGMT methylated cohort, patients also received temozolomide 75 mg/m2 for 6 weeks. In accordance with the 3+3 design of the study, the starting dose of ruxolitinib was 10 mg twice daily (BID), which was escalated to 15 mg BID, or 20 mg BID and could be deescalated down to 5 mg BID, if necessary. Following dose-escalation, 20 mg twice daily was determined to be the maximum-tolerated dose (MTD) of ruxolitinib.
Patients enrolled were initially assessed for the MTD, which was the primary end point of the study. The secondary end points of the study included safety, median OS, and median progression-free survival. The study also evaluated the relationship between outcomes and genomic signatures as an exploratory end point. Analyses for the exploratory end point are ongoing.
Patients had a median age of 60.5 years (range, 22-78 years). Thirty-eight percent of the study population was female and 62% was male. The MGMT unmethylated cohort included 29 patients (48%), and the MGMT methylated cohort was made up of 31 patients (52%).
“Patients with glioblastoma have dismal outcomes with standard of care treatment. Hence, clinical trials are urgently needed. The initial promising results of ruxolitinib offer a new opportunity for patients with this disease with a novel agent that is extremely well-tolerated, but which is also showing a high degree of preliminary efficacy compared with the historical benchmarks. It has great potential for both the patients and the researchers who are treating this disease.”