FDA Approves UKONIQ® for Relapsed or Refractory Marginal Zone and Follicular Lymphomas

SUMMARY: The FDA on February 5, 2021 granted accelerated approval to UKONIQ® (Umbralisib), a kinase inhibitor including PI3K-delta and Casein Kinase CK1-epsilon, for adult patients with Relapsed or Refractory Marginal Zone Lymphoma (MZL) who have received at least one prior anti-CD20-based regimen and adult patients with Relapsed or Refractory Follicular Lymphoma (FL) who have received at least three prior lines of systemic therapy. The American Cancer Society estimates that in 2021, about 81,560 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,720 individuals will die of this disease. Indolent Non Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL). Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas (FL).

Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab). This can result in a median PFS of 6-8 yrs and a median OS of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years and treatment options are limited for patients with relapses, after multiple treatments.

UKONIQ® is an oral, once-daily, dual inhibitor of Phosphatidylinositol-3-Kinase-delta (PI3Kδ) and Casein Kinase 1-epsilon (CK1-epsilon) that exhibits improved selectivity for the delta isoform of PI3K. In contrast with other PI3K inhibitors, there was a low incidence of immune-mediated toxicities with UKONIQ® possibly attributable to enhanced selectivity for the PI3Kδ isoform as well as inhibition of CK1-epsilon.

The present FDA approval was based on the UNITY-NHL trial (NCT02793583), which is global, multicenter, open-label, multicohort, Phase IIb registration study, designed to evaluate the safety and efficacy of UKONIQ® in previously treated NHL patients. This study had a total 208 patients with indolent NHL and included 69 patients with MZL (splenic, nodal, extranodal), 117 patients with FL (grade 1, 2, 3a), and 22 patients with Small Lymphocytic Lymphoma (SLL). MZL patients were Relapsed/Refractory to 1 or more prior lines of treatment, which included an anti-CD20, while FL and SLL patients were Relapsed/Refractory to 2 or more prior lines of therapy, which included an anti-CD20 and an alkylating agent. UKONIQ® was administered at 800 mg orally once daily in 28-day treatment cycles until disease progression or unacceptable tolerability. The median age was 66 years and the median duration of treatment exposure was 8.4 months. Pneumocystis jiroveci Pneumonia (PCP) and anti-viral prophylaxis were mandated for all patients. The Primary endpoint of the study was Overall Response Rate (ORR) as assessed by an Independent Review Committee (IRC) and Secondary endpoints included Duration of Response (DoR), Progression Free Survival (PFS), Time To Response (TTR), and Safety.

With a median follow up of 27.8 months, the ORR for patients with MZL was 49%, with a 16% Complete Response (CR) rate and a Disease Control Rate (CR+PR+SD) of 82.6%. The ORR was consistent amongst MZL subtypes and no patients who achieved CR had experienced disease progression to date. Additionally, the median DoR and median PFS was not reached for this patient population.

Among patients with FL, with a median follow up of 27.5 months, the ORR was 45%, with 5% achieving a CR, and a DCR of 79.5%. The median TTR was 4.6 months and the median DoR was 11.1 months. The median PFS was 10.6 months.

Among SLL patients, with a median follow up of 29.3 months, the ORR was 50%, with 4.5% achieving a CR, and a DCR of 86.4%. The median TTR was 2.7 months and the median DoR was 18.3 months. The median PFS was 20.9 months.

The most common toxicities included increased creatinine, diarrhea/colitis, fatigue, transaminase elevation, musculoskeletal pain, neutropenia, anemia, thrombocytopenia, upper respiratory tract infection, nausea, vomiting, abdominal pain, reduced appetite, and cutaneous reactions.

It was concluded from this study that UKONIQ® has a favorable benefit-risk profile and achieved meaningful clinical activity in a heavily pretreated population of patients with indolent NHL. The authors added that the safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and treatment discontinuations.

Umbralisib, the Once Daily Dual Inhibitor of PI3Kδ and Casein Kinase-1ε Demonstrates Clinical Activity in Patients with Relapsed or Refractory Indolent Non-Hodgkin Lymphoma: Results from the Phase 2 Global Unity-NHL Trial. Zinzani PL, Samaniego F, Jurczak W, et al. Presented at the 62nd ASH Annual Meeting and Exposition, December 5-8, 2020. Abstract # 2934.