Novel Inhibitor Provides First Proof-of-Principle of Targeting the JAK/STAT Pathway in Lymphoma
“Although a variety of JAK2 inhibitors have entered clinical testing for myelofibrosis and autoimmune disorders, our study is the first clinical trial that investigated the safety and efficacy of a JAK2 inhibitor in lymphoma,” noted Anas Younes, MD, of The University of Texas MD Anderson Cancer Center, Houston, TX.
The phase 1 open-label dose-escalation study of SB1518 enrolled 34 patients with relapsed or refractory Hodgkin or non-Hodgkin lymphoma of any type except Burkitt's or CNS lymphoma. Patients received escalating doses of SB1518 beginning at 100mg/day in a standard 3x3 design for 28-day cycles and response was evaluated after 8 weeks.
“The pharmacokinetic and pharmacodynamic data provided ample basis to recommend 400 mg/day as the dosage for phase 2 study,” they wrote. SB1518 was found to inhibit JAK2 signaling at 4 hours postdose at all levels and maximum tolerated dose was not met.
A total of 17 patients received SB1518 for more than 3 months and 6 for more than 6 months. Median time on study drug was 88 days (range, 1–574 days). Among the 22 evaluable patients treated at the 300mg/day to 600mg/day dose levels, response rate was 14%; median progression-free survival (PFS) was 120 days and median survival, 130 days. Three patients treated at doses ≥300mg/day had a partial response, with time to best response ranging from 50 to 60 days and PFS from 120 to 249 days. Of 15 patients with stable disease, most responses lasted longer than 2 months, and 7 of 13 had tumor reductions of 4% to 46%.
The most common treatment-related events, primarily grade 1 and 2, were gastrointestinal toxicities. “Importantly, hematologic toxicities were observed infrequently, suggesting that SB1518 can be combined with conventional chemotherapy agents,” Dr. Younes stated.
“The data warrant further efficacy studies of JAK/STAT pathway inhibitors, either alone or in combination regimens. Future studies should incorporate biomarker analysis that may predict response to JAK/STAT targeted therapy,” they concluded.
An accompanying editorial noted, “With progress toward the complete genetic characterization of lymphomas, the definition of distinct genetic subtypes with unique therapeutic sensitivities, and the development of novel treatments, the era of combinatorial targeted therapy in lymphoma is rapidly approaching.”