As reported in the Journal of Clinical Oncology by Nathan H. Fowler, MD, and colleagues, the phase IIb UNITY-NHL trial has shown that the dual PI3Kδ/casein kinase (CK) 1ε inhibitor umbralisib produced durable responses in patients with relapsed or refractory indolent non-Hodgkin lymphoma.

The study supported the February 2021 accelerated approval for the treatment of:

• Adult patients with relapsed or refractory marginal zone lymphoma who have received at least one prior anti–CD20-based regimen
• Adult patients with relapsed or refractory follicular lymphoma who have received at least three prior lines of systemic therapy.

Study Details

In the multicohort trial, 208 patients with relapsed or refractory marginal zone lymphoma (n = 69), follicular lymphoma (n = 117), or small lymphocytic lymphoma (n = 22) unresponsive to prior treatments (≥ 1 for marginal zone lymphoma, ≥ 2 for follicular lymphoma and small lymphocytic lymphoma), including one or more anti­–CD20-based therapy, were enrolled from sites in nine countries between May 2017 and September 2018. Patients received oral umbralisib at 800 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was overall response rate on independent review committee assessment.  

Nathan H. Fowler, MD

Responses

Median follow-up was 27.7 months for efficacy and 21.4 months for safety. Objective response was observed in 47.1% of patients overall; tumor reduction occurred in 86.4% of patients. Objective response was observed in 34 patients (49.3%) with marginal zone lymphoma (complete response in 11, 15.9%), 53 patients (45.3%) with follicular lymphoma (complete response in 6, 5.1%), and 11 patients (50.0%) with small lymphocytic lymphoma (complete response in 1, 4.5%). An additional 33.3%, 34.2%, and 36.4% of patients had stable disease.

The median time to response was 2.7 to 4.6 months. Median durations of response were not reached (95% confidence interval [CI] = 10.3 months–not estimable) for responders with marginal zone lymphoma, 11.1 months (95% CI = 8.3–15.6 months) for responders with follicular lymphoma, and 18.3 months (95% CI = 2.4 months–not estimable) for responders with small lymphocytic lymphoma.

Median progression-free survival was not reached (95% CI = 12.1 months–not estimable) for patients with marginal zone lymphoma, 10.6 months (95% CI = 7.2–13.7 months) for patients with follicular lymphoma, and 20.9 months (95% CI = 7.4–24.1 months) for patients with small lymphocytic lymphoma. At 2 years, 50.5%, 18.1%, and 31.3% of patients remained progression-free.

Adverse Events

Grade ≥ 3 adverse events occurred in 53.4% of patients, with the most common being neutropenia (11.5%) and diarrhea (10.1%). Grade 3 or 4 elevations in alanine aminotransferase and aspartate aminotransferase occurred in 6.7% and 7.2% of patients. Other grade 3 or 4 adverse events of interest included opportunistic infections (3.4%), rash (1.9%), pneumonitis (1.0%), and noninfectious colitis (0.5%).

Serious adverse events considered related to treatment were observed in 17.3% of patients, with the most common being diarrhea (3.4%), acute kidney injury (1.4%), anemia (1.4%), dehydration (1.4%), febrile neutropenia (1.4%), pneumonia (1.4%), sepsis (1.4%), and urinary tract infection (1.4%). Adverse events led to discontinuation of treatment in 15.4% of patients. An adverse event led to death in one patient in the small lymphocytic lymphoma group (myocardial infarction considered unrelated to treatment).

The investigators concluded, “Umbralisib achieved meaningful clinical activity in heavily pretreated patients with indolent non-Hodgkin lymphoma. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and adverse event–related discontinuations.”

Pier Luigi Zinzani, MD, PhD, of IRCCS Azienda Ospedaliero-Universitaria di Bologna Istituto di Ematologia “Seràgnoli”, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by TG Therapeutics. For full disclosures of the study authors, visit ascopubs.org.