New kid on the block: ONC201 in NHL

Treatment of relapsed aggressive non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma, Burkitt's lymphoma and mantle cell lymphoma, is challenging. The treatment options for these lymphomas include a combination of stem cell transplantation, radiation, targeted therapies, and intensive chemotherapy regimens. However, many patients relapse due to the development of resistance, and relapsed aggressive NHL remains incurable. Furthermore, resistance increases over multiple treatment courses with various therapies; therefore, there is a clear unmet need for safe and effective agents that overcome resistance by targeting novel pathways.

ONC201 is an orally active novel small molecule anti-cancer agent with an encouraging preclinical safety and efficacy profile that recently entered clinical trials in advanced cancers. In this issue, Talekar et al reports on the therapeutic potential of ONC201 in refractory NHL.¹ The authors expand on a prior report of in vivo efficacy in murine lymphoma² to focus on MCL and Burkitt's lymphoma. The preclinical studies demonstrate that single agent ONC201 induces apoptosis and activates the TRAIL pathway in NHL cells. Further preclinical studies are examining the mechanism of action of ONC201 upstream of TRAIL, which involves a unique activation of a maladaptive ER stress response.³ The study also identifies in vitro synergy with cytarabine in NHL, which adds to the potential for combination therapies that could be deployed in clinical trials.⁴

A first-in-man clinical trial is ongoing in solid tumors (NCT02250781) and additional clinical trials are being initiated in select advanced cancers, including a monoagent phase I/II clinical trial in relapsed/refractory aggressive NHL (NCT02420795). While no pediatric clinical studies have been initiated for ONC201, its lack of genotoxicity⁵ and the preclinical efficacy reported by Talekar et al suggest that Burkitt's lymphoma may warrant clinical investigation following confirmation of its safety profile in adult phase I trials.