ICML 2017: Triplet Combination of Umbralisib, Ublituximab, and Ibrutinib in CLL/SLL/NHL


Key Points

  • An overall response rate of 100% (19 of 19)—including a 32% complete response (CR) rate—was observed in patients with CLL/SLL (4 of 6 CRs pending bone marrow confirmation)
  • The overall reponse rate was 100% (2 of 2), including one CR, in patients with marginal zone lymphoma; 100% (4 of 4), including 50% CR rate, in patients with mantle cell lymphoma; 80% (4 of 5), including 20% CR rate, in patients with follicular lymphoma; and 17% (1 of 6) in patients with diffuse large B-cell lymphoma.

Data from the chemotherapy-free triple combination of umbralisib, an oral, next generation PI3K delta inhibitor; ublituximab, a novel glycoengineered anti-CD20 monoclonal antibody; and ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and non-Hodgkin lymphoma (NHL) were presented at the 14th International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland (Abstract 102), as well at the 2017 ASCO Annual Meeting (Abstract 7511).

Michael S. Weiss, Executive Chairman and Chief Executive Officer of TG Therapeutics, Inc, said, “We had an opportunity to present data on a triple therapy where we layered our proprietary PI3K-delta inhibitor [umbralisib] to the [ublituximab] plus ibrutinib combination, and demonstrated even further enhanced activity, with 100% overall response rate by iwCLL criteria and a high level of complete responses. These data further confirm our approach of building toward multidrug regimens to enhance the outcome for patients, ideally achieving complete responses and avoiding lifelong therapy. We look forward to continuing to explore unique combinations, with ublituximab plus umbralisib, as the backbone.”

Study Details

All patients were relapsed or refractory to prior therapy, except for three patients with CLL who were treatment-naive. Three cohorts for each CLL/SLL and NHL were evaluated with umbralisib dose escalation, starting with doses of 400 mg (cohort 1), followed by 600 mg (cohort 2), and 800 mg (cohort 3), in combination with ublituximab at 900 mg and ibrutinib daily at 420 mg (CLL) and 560 mg (NHL). 

Clinical Activity

Clinical activity was observed at all dose levels, with 36 of 38 patients evaluable for efficacy (19 CLL/SLL patients and 17 NHL patients), with two patients having discontinued prior to first efficacy assessment (one due to pneumonia, and one due to investigator discretion).  

CLL/SLL efficacy highlights include:

  • 100% (19 of 19) overall response rate (ORR), including a 32% complete response (CR) rate observed in patients with CLL/SLL (4 of 6 CRs pending bone marrow confirmation)
  • 50% of patients with CLL had a 17p and/or 11q deletion
  • Three patients with CLL had prior Bruton tyrosine kinase and/or PI3Kδ inhibitor therapy, including one patient refractory to both idelalisib and ibrutinib who attained a complete response (ongoing for 1.5+ years)

Response rates observed in patients with NHL:

  • 100% (2 of 2) ORR, including one CR in patients with marginal zone lymphoma
  • 100% (4 of 4) ORR, including 50% CR rate in patients with mantle cell lymphoma
  • 80% (4 of 5) ORR, including 20% CR rate in patients with follicular lymphoma
  • 17% (1 of 6) ORR in patients with diffuse large B-cell lymphoma (DLBCL)
  • Patients with follicular lymphoma were heavily pretreated, including two with prior autologous stem cell transplant, one refractory to prior ibrutinib, and one with five prior lines of rituximab (Rituxan)-based therapy

Patients with DLBCL had a median of four prior therapies, and four of six were of non–germinal center B-cell subtype.

Safety and Tolerability

Thirty-eight patients were evaluable for safety (20 CLL/SLL patients and 18 NHL patients).

The triple combination appeared to be well-tolerated in all patients, with neutropenia (32% all grades, 18% Grade 3/4) and pneumonia (18% all grades, 11% Grade 3/4), being the only grade 3/4 adverse events in > 10% of patients.  Of the 38 patients treated to date, only two adverse events (sepsis and pneumonia) led to treatment discontinuation. 

Median time on study was 11.1 months (range, 0.4–30+ months), with 81% of patients on study > 6 months.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.