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

Background: Umbralisib is an oral, once-daily, dual inhibitor of phosphatidylinositol-3-kinase-delta (PI3Kδ) and casein kinase-1ε (CK1ε) that exhibits improved selectivity for the delta isoform of PI3K. The UNITY-NHL trial (NCT02793583) is a multicenter, open-label, registration directed Phase 2 study designed to evaluate the safety and efficacy of umbralisib in previously treated NHL patients (pts). Previously reported results in pts with relapsed/refractory (R/R) marginal zone lymphoma (MZL) demonstrated that umbralisib was active with a manageable safety profile. In contrast with other PI3K inhibitors, there was a low incidence of immune-mediated toxicities with umbralisib, possibly attributable to enhanced selectivity for the PI3Kδ isoform as well as inhibition of CK1ε. Herein, we present results from the final analysis of the iNHL population treated with single agent umbralisib.

Methods: Eligible pts had histologically confirmed iNHL: MZL (splenic, nodal, extranodal), follicular lymphoma (FL; Gr 1, 2, 3a), or small lymphocytic lymphoma (SLL). MZL pts were R/R to ≥1 prior lines of treatment, which must have included an anti-CD20, while FL and SLL pts were R/R to ≥2 prior lines, which had to include an anti-CD20 and an alkylating agent. Umbralisib was administered orally at 800 mg once-daily in 28-day treatment cycles until disease progression or unacceptable tolerability. The primary endpoint of the study was overall response rate (ORR) as assessed by an independent review committee (IRC), according to the revised IWG criteria (Cheson 2007). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), time to response (TTR), and safety. Pneumocystis jiroveci pneumonia (PCP) and anti-viral prophylaxis were mandated for all pts.

Results: 208 iNHL pts received at least 1 dose of umbralisib, including 69 MZL, 117 FL, and 22 SLL pts. The median duration of exposure was 8.4 mos (range 0.2 - 27.0), median age was 66, and 56.7% were male. Pts had received a median of 2 prior regimens (range 1 - 10) with 46.1% having received ≥ 3 regimens. FL patients had a median of 3 prior regimens.

With a median follow up of 27.8 mos, MZL pts had an ORR of 49.3% (95% CI 37.0% - 61.6%) with 15.9% achieving a complete response (CR), and a Disease Control Rate (DCR: CR+PR+SD) of 82.6%. ORR was consistent amongst MZL subtypes. The median TTR was 2.8 months (95% CI 2.7 - 2.9). The median profession-free survival (PFS) was not reached (95% CI 12.1 mos – not evaluable [NE]) with an estimated 12-month PFS rate of 64.2%. The median DoR was not reached (95% CI 10.3 mos – NE), and no pts who achieved CR have experienced disease progression to date.

With a median follow up of 27.5 mos, FL pts had an ORR of 45.3% (95% CI 36.1% - 54.8%) with 5.1% achieving a CR, and a DCR of 79.5%. The median TTR was 4.6 mos (95% CI 3.0 - 5.6). The median PFS was 10.6 mos (95% CI 7.2 - 13.7) with an estimated 12-month PFS rate of 45.9%. The median DoR was 11.1 mos (95% CI 8.3 - 15.6).

With a median follow up of 29.3 mos, SLL pts had an ORR of 50.0% (95% CI 28.2 - 71.8) with 4.5% achieving a CR, and a DCR of 86.4%. The median TTR was 2.7 mos (95% CI 2.4 - 2.8). The median PFS was 20.9 mos (95% CI 7.4 - 24.1) with an estimated 12-month PFS rate of 62.6%. The median DoR was 18.3 mos (95% CI 2.4 – NE).

Best % change in target lesions form baseline for pts with at least one post-baseline assessment is shown in the figure.

At the data cut-off, 60 pts (26 MZL, 27 FL, 7 SLL) remained on treatment. The most common ≥G3 AEs were neutropenia (11.5%), diarrhea (10.1%) and increased ALT/AST (7.2%). Other AEs of interest included pneumonitis (All G 1.4%; ≥G3 1.0%), and colitis (All G 1.4%; ≥G3 0.5%). Serious AEs were reported in 28.1% of pts, with 24.6% ≥G3. One patient with SLL had a fatal myocardial infarction (unrelated to umbralisib); there were no other G5 AEs. A total of 31 pts (14.9%) discontinued due a treatment-related adverse event (AE). Treatment-related AEs leading to dose reductions occurred in 20 (9.6%) pts.

Conclusions: In the Phase 2 UNITY-NHL study, umbralisib achieved meaningful clinical activity in a heavily pretreated iNHL population. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and AE-related discontinuations. These results suggest umbralisib has a favorable benefit-risk profile in this patient population and further development is ongoing.