On February 5, 2021, umbralisib was granted accelerated approval for the following indications: adult patients with relapsed or refractory marginal zone lymphoma who have received at least one prior anti–CD20-based regimen and adult patients with relapsed or refractory follicular lymphoma who have received at least three prior lines of systemic therapy.^1,2

Umbralisib is an inhibitor of multiple kinases, including PI3Kδ, which is expressed in normal and malignant B cells, and casein kinase CK1ε, which has been found to have a role in the pathogenesis of cancer cells, including lymphoid malignancies.

Supporting Efficacy Data

Approval was based on findings in two cohorts of the open-label, multicenter, multicohort UTX-TGR-205 trial (ClinicalTrials.gov identifier NCT02793583).² In the trial, 69 patients with relapsed or refractory marginal zone lymphoma who had received at least one prior therapy, including an anti–CD20-containing regimen, and in 117 patients with relapsed or refractory follicular lymphoma who had received at least two prior systemic therapies, including an anti–CD20 monoclonal antibody and an alkylating agent, were treated with oral umbralisib at 800 mg once daily until disease progression or unacceptable toxicity.

Among the 69 patients in the marginal zone lymphoma cohort, disease was extranodal in 38, nodal in 20, and splenic in 11. Median age was 67 years (range = 34–88 years); 52% were female; 83% were White, 7% were Black, and 3% were Asian; and 97% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The median number of prior lines of therapy was two (range = 1–6), with 26% being refractory to their last therapy.

Among the 117 patients in the follicular lymphoma cohort, median age was 65 years (range = 29–87 years); 38% were female; 80% were White and 4% were Black. Of these patients, 73% had stage III to IV disease, 38% had bulky disease, and 97% had a baseline ECOG performance status of 0 or 1. The median number of prior lines of therapy was three (range = 1–10), with 36% being refractory to their last therapy.

Efficacy in both cohorts was based on overall response rate, as assessed by an independent review committee using criteria adopted from the modified 2007 International Working Group criteria for malignant lymphoma.

In the marginal zone lymphoma cohort, an objective response was observed in 34 patients (49%, 95% confidence interval [CI] = 37.0%–61.6%), with a complete response in 11 (16%). Median duration of response was not reached (95% CI = 9.3 months to not estimable; range = 0.0+ to 21.8+ months).

In the follicular lymphoma cohort, an objective response was observed in 50 patients (43%, 95% CI = 33.6%–52.2%), with a complete response in 4 (3%). Median duration of response was 11.1 months (95% CI = 8.3–16.4 months; range = 0.0+ to 20.9+ months).

How It Works

Umbralisib inhibits multiple kinases. In biochemical and cell-based assays, umbralisib inhibited PI3Kδ and casein kinase CK1ε. PI3Kδ is expressed in normal and malignant B cells; CK1ε has been implicated in the pathogenesis of cancer cells, including lymphoid malignancies. Umbralisib also inhibited a mutated form of ABL1 in biochemical assays. Umbralisib inhibited cell proliferation, CXCL12-mediated cell adhesion, and CCL19-mediated cell migration in lymphoma cell lines in studies conducted in vitro.

How It Is Used

The recommended umbralisib dose in the current indications is 800 mg once daily until disease progression or unacceptable toxicity. Patients should receive prophylaxis for Pneumocystis jirovecii pneumonia during treatment. Prophylactic antivirals during treatment should be considered to prevent cytomegalovirus infection, including cytomegalovirus reactivation.

Recommended dose reductions for umbralisib for managing adverse reactions are sequentially to 600 mg once daily and 400 mg once daily, with treatment being permanently discontinued in patients unable to tolerate 400 mg once daily.

Prescribing information provides instructions on dosage modification, including dose reduction and withholding and discontinuing treatment, for adverse reactions including neutropenia; thrombocytopenia; infection, including opportunistic infection; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation; diarrhea or noninfectious colitis; severe cutaneous reactions; and other severe or life-threatening reactions.

Safety Profile

Safety data come from 221 patients with marginal zone lymphoma (37%) and follicular lymphoma (63%) who received umbralisib at 800 mg once daily in three single-arm, open-label trials, including UTX-TGR-205, and one open-label extension trial. The trials required hepatic transaminases ≤ 2.5 times the upper limit of normal, total bilirubin ≤ 1.5 times the upper limit of normal, and creatinine clearance ≥ 30 mL/min. No patients had prior exposure to a PI3K inhibitor. Among all patients, 60% were exposed to umbralisib for at least 6 months and 34% for more than 1 year.

The most common adverse events of any grade (≥ 15%), including laboratory abnormalities, were increased creatinine (79%), diarrhea/colitis (58%), fatigue (41%), nausea (38%), neutropenia (33%), increased ALT (33%), increased AST (32%), musculoskeletal pain (27%), anemia (27%), thrombocytopenia (26%), upper respiratory tract infection (21%), vomiting (21%), abdominal pain (19%), decreased appetite (19%), and rash (18%). Serious adverse events occurred in 18% of patients and resulted in dose reduction in 11%. 

Umbralisib has warnings/precautions for infections, neutropenia, diarrhea or noninfectious colitis, hepatotoxicity, severe cutaneous reactions, allergic reactions due to the inactive ingredient FD&C Yellow No. 5 (tartrazine), and embryofetal toxicity. Blood cell counts and hepatic function should be monitored during treatment. Patients should be monitored for fever and any new or worsening signs and symptoms of infection and for the development of diarrhea or colitis. Patients should be advised not to breastfeed while receiving umbralisib. 

REFERENCES

1. U.S. Food and Drug Administration: FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-umbralisib-marginal-zone-lymphoma-and-follicular-lymphoma. Accessed February 25, 2021.

2. Ukoniq (umbralisib) tablets prescribing information, February 2021, TG Therapeutics, Inc. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213176s000lbl.pdf. Accessed February 25, 2021.