Ukoniq (Umbralisib) FDA Approved for Adults with Relapsed or Refractory Marginal-Zone Lymphoma or Follicular Lymphoman

December 2021 Twelfth Annual Payers' Guide - FDA Approvals
Loretta Fala
Medical Writer

Marginal-zone lymphoma (MZL) and follicular lymphoma (FL) are chronic, indolent forms of non-Hodgkin lymphoma (NHL) that are categorized as B-cell neoplasms.1 Approximately 81,560 new cases of NHL are diagnosed annually in the United States, with a median age of 67 years at diagnosis. Nearly 21,000 Americans are estimated to die from NHL in 2021.2 MZL accounts for approximately 8% of all cases of NHL, and FL accounts for approximately 17% of all cases of NHL3

MZL arises from B-lymphocytes in the marginal zone of lymph tissue4 The 3 types of MZL include extranodal (or mucosa-associated lymphoid tissue), nodal, and splenic MZL.1

FL originates in B-lymphocytes and affects the lymph nodes, sometimes spreading to the bone marrow or spleen. Some cases of FL progress to an aggressive form of lymphoma, such as diffuse large B-cell lymphoma4

The treatment of patients with MZL or FL may include observation, surgery, radiation therapy, chemotherapy, anti-CD20 monoclonal antibodies, immunomodulating drugs, targeted therapies, anti-CD19 chimeric antigen receptor T-cell therapy, allogeneic hematopoietic cell transplant, methyltransferase inhibitors, and kinase inhibitors5

For patients with relapsed or refractory disease, the treatment options are more limited and generally include chemotherapy, with or without targeted therapies, CD20-directed monoclonal antibodies, and phosphoinositide 3-kinase (PI3K) inhibitors.6 Recently, a novel multiple kinase inhibitor was approved for patients with MZL or FL.7

Ukoniq FDA Approved for Patients with MZL or FL

On February 5, 2021, the US Food and Drug Administration (FDA) approved umbralisib (Ukoniq; TG Therapeutics), a novel multiple kinase inhibitor, for the treatment of adults with relapsed or refractory MZL who have received ≥1 previous anti-CD20–directed regimens, and for the treatment of adults with relapsed or refractory FL who have received ≥3 previous lines of systemic therapy.7

Umbralisib was granted an accelerated approval by the FDA for these indications, as well as an orphan drug designation. Continued approval may be contingent on confirmatory studies demonstrating the clinical benefit of umbralisib.7

“Despite treatment advances, MZL and FL remain incurable diseases with limited treatment options….With the approval of umbralisib we now have a targeted, oral, once-daily option, offering a needed treatment alternative for patients,” said Nathan Fowler, MD, Professor of Medicine, The University of Texas M.D. Anderson Cancer Center, and lead investigator of the phase 2b UNITY-NHL study.8

The approval of umbralisib “offers patients a new treatment option, and new hope in the fight against these diseases,”8 said Meghan Gutierrez, Chief Executive Officer of the Lymphoma Research Foundation.

The National Comprehensive Cancer Network guideline now recommends umbralisib as a second-line or subsequent therapy for patients with MZL and as a third-line or subsequent treatment option for older or infirm patients with FL5

Dosing and Administration

Umbralisib is available as 200-mg tablets. The recommended dose of umbralisib is 800 mg orally once daily, with food; it should be taken at the same time each day. Umbralisib tablets should be swallowed whole, without crushing, breaking, cutting, or chewing. Treatment interruption, dose reduction, or discontinuation of umbralisib may be necessary to manage adverse events.9

Mechanism of Action

Umbralisib is a kinase inhibitor that inhibits multiple kinases, including PI3K-delta and casein kinase-1 (CK1)-epsilon. PI3K-delta is a protein expressed in normal and in malignant B-cells. CK1-epsilon is a protein that plays a role in the pathogenesis of cancer cells, including lymphoid malignancies. In preclinical studies, umbralisib inhibited cell proliferation in lymphoma cell lines.9

The UNITY-NHL Pivotal Clinical Trial

The efficacy of umbralisib was evaluated in 2 single-arm cohorts of the UNITY-NHL study (also known as UTX-TGR-205), an open-label, multicohort, multicenter, phase 2b clinical trial. One cohort included patients with MZL, and the other cohort included patients with FL. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of ≤26

The MZL Cohort

The MZL cohort included 69 patients with extranodal, nodal, or splenic MZL (median age, 67 years; range, 34-88 years); 52% were female, and 97% had an ECOG performance status of 0 or 1. Patients who had received a PI3K inhibitor were excluded from the study.

Patients with MZL had to have at least 1 previous therapy; with a median having 2 previous lines of therapy, and 26% had disease refractory to their last anti-CD20–targeted therapy.6,9 Eligible patients with MZL received umbralisib 800 mg once daily until disease progression or unacceptable adverse events. The median follow-up time in this cohort was 20.3 months (range, 15.0-28.7 months). The primary end point was overall response rate (ORR).6

The ORR in patients with MZL was 49%, which included 16% complete responses (Table 1).9 The median duration of response was not reached. The median time to response was 2.8 months (range, 1.8-21.1 months; Table 1). The ORR was 44.7% in patients with extranodal, 60.0% in those with nodal, and 45.5% in patients with splenic MZL6,9

Table

The FL Cohort

The FL cohort included 117 patients with relapsed or refractory disease (median age, 65 years; range, 29-87 years); 38% were female, and 97% had a baseline ECOG performance status of 0 or 1. The patients had to have relapsed or refractory disease after ≥2 lines of systemic therapy, including an anti-CD20 monoclonal antibody and an alkylating agent. Patients were excluded if they had received a PI3K inhibitor, had grade 3b FL, large-cell transformation, previous allogeneic transplant, or a history of central nervous system lymphoma6,9

Patients with FL received a median of 3 previous lines of therapy and 36% had disease refractory to their last therapy. Patients received umbralisib 800 mg once daily until disease progression or unacceptable side effects. The median follow-up time in this cohort was 20.1 months (range, 13.5-29.6 months)..9

The ORR in patients with FL was 43%, including 3.4% complete responses. The median duration of response was 11.1 months, and the median time to response was 4.4 months (range, 2.2-15.5 months; Table 2).9

Table

Adverse Reactions

The most common (≥15%) adverse reactions with umbralisib were increased creatinine (79%); diarrhea-colitis (58%); fatigue (41%); nausea (38%); neutropenia (33%); alanine aminotransferase increases (33%); aspartate aminotransferase increases (32%); musculoskeletal pain (27%); anemia (27%); thrombocytopenia (26%); upper respiratory tract infection (21%); vomiting (21%); abdominal pain (19%); decreased appetite (19%); and rash (18%).9

Serious adverse reactions occurred in 18% of the patients, including diarrhea-colitis (4%), pneumonia (3%), sepsis (2%), and urinary tract infection (2%). In all, 14% of patients permanently discontinued umbralisib because of adverse reactions.9

Umbralisib has no contraindications.9

Warnings and Precautions

Serious infections, some fatal, occurred in patients receiving umbralisib. Patients should be monitored for fever and any new or worsening signs and symptoms of infection.9

Serious neutropenia occurred in patients receiving umbralisib. The patient’s neutrophil counts should be monitored during treatment.9

Patients receiving umbralisib should be monitored for diarrhea or colitis.9

Hepatotoxicity can occur with umbralisib. The patient’s hepatic function should be monitored at baseline and during treatment with umbralisib.9

Severe cutaneous reactions, including a fatal incident of exfoliative dermatitis, occurred in patients receiving umbralisib. Patients should be monitored for cutaneous reactions. Depending on the severity of the cutaneous reaction, it may be necessary to withhold, discontinue, or reduce the dose of umbralisib.9

Tartrazine (FD<C yellow no. 5), an inactive additive in umbralisib, can cause allergic-type reactions (eg, bronchial asthma) in some patients.9

Pregnant women should be advised of the potential risk to a fetus during treatment with umbralisib. Females of reproductive potential should be tested for pregnancy status before initiating umbralisib therapy. In addition, females of reproductive potential and males with female partners of reproductive potential should be advised to use effective contraception during treatment with umbralisib and for 1 month after the last dose.9

Use in Specific Populations

Data are not available on the use of umbralisib in pregnant women or its effects on milk production or on the breastfed child. Umbralisib can cause fetal harm when administered to pregnant women.9 Given the potential risk for serious adverse effects from umbralisib in the breastfed child, women should be advised not to breastfeed during treatment with umbralisib and for 1 month after the last dose.9

No overall differences in the effectiveness of umbralisib were observed between older (aged ≥65 years) and younger (aged <65 years) patients. Serious adverse reactions were reported in 23% of patients aged ≥65 years versus 12% of patients aged <65 years.9

For patients with mild or moderate renal impairment, dose adjustment of umbralisib is not recommended. Data are not available on patients with severe renal impairment.9

For patients with mild hepatic impairment, dose adjustment of umbralisib is not recommended. Data are not available on patients with severe hepatic impairment.9

Conclusion

The FDA approval of umbralisib for relapsed or refractory MZL or FL offers a new treatment option for patients with one of these diseases whose disease recurred or did not respond to other treatments. Umbralisib is a novel multiple kinase inhibitor that provides a convenient, once-daily oral treatment option for patients with MZL or FL, which may bring new hope to this patient population. In the study that led to its approval, umbralisib had an ORR of 49% in patients with MZL and 43% in patients with FL.

References

  1. American Cancer Society. Types of B-cell lymphoma. Updated January 29, 2019. www.cancer.org/cancer/non-hodgkin-lymphoma/about/b-cell-lymphoma.html. Accessed June 16, 2021.
  2. National Cancer Institute SEER Program. Cancer stat facts: non-Hodgkin lymphoma. https://seer.cancer.gov/statfacts/html/nhl.html. Accessed June 16, 2021.
  3. National Cancer Institute. Adult non-Hodgkin lymphoma treatment (PDQ)–patient version. Updated January 8, 2021. www.cancer.gov/types/lymphoma/patient/adult-nhl-treatment-pdq#_419. Accessed April 16, 2021.
  4. Al-Hamadani M, Habermann TM, Cerhan JR, et al. Non-Hodgkin lymphoma subtype distribution, geodemographic patterns, and survival in the US: a longitudinal analysis of the National Cancer Data Base from 1998 to 2011. Am J Hematol. 2015;90:790-795.
  5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): B-Cell Lymphomas. Version 4.2021. May 5, 2021. www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed June 16, 2021.
  6. Fowler NH, Samaniego F, Jurczak W, et al. Umbralisib, a dual Pl3Kδ/CK1ε inhibitor in patients with relapsed or refractory indolent lymphoma. J Clin Oncol. 2021;39:1609-1618.
  7. US Food and Drug Administration. FDA grants accelerated approval to umbralisib for marginal zone lymphoma and FL. February 5, 2021. www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-umbralisib-marginal-zone-lymphoma-and-follicular-lymphoma. Accessed June 16, 2021.
  8. TG Therapeutics. TG Therapeutics announces FDA accelerated approval of Ukoniq (umbralisib). February 5, 2021. https://ir.tgtherapeutics.com/news-releases/news-release-details/tg-therapeutics-announces-fda-accelerated-approval-ukoniqtm#:~:text=(NASDAQ%3A%20TGTX)%2C%20today,patients%20with%20relapsed%20or%20refractory. Accessed April 12, 2021.
  9. Ukoniq (umbralisib) tablets, for oral use [prescribing information]. TG Therapeutics; February 2021. https://tgtherapeutics.com/prescribing-information/uspi-ukon.pdf. Accessed June 16, 2021.
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