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Umbralisib is a dual inhibitor of phosphoinositide 3-kinase-delta (PI3K-δ) and casein kinase-1ε (CK1-ε), and was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with relapsed or refractory (R/R) marginal zone lymphoma (MZL) or follicular lymphoma (FL). Umbralisib is highly selective for the PI3K-δ isoform, which is important as isoforms of PIK3 have different functions, and PIK3-δ is constitutively active in B-cell lymphomas.1 Selectivity for PI3K-δ may be responsible for improved safety and efficacy over other approved PI3K inhibitors, which have been associated with high rates of treatment emergent adverse events (TEAEs) that often lead to treatment discontinuation.
Umbralisib has been investigated in several phase I and II trials which have individually demonstrated low rates of TEAEs and discontinuation of umbralisib, both as a single agent and as combined therapy. An integrated safety analysis of these trials was recently published by Davids et al. in Blood Advances, providing further clarity on the safety of umbralisib in patients with various forms of lymphoma. We summarize the key results below.1
This was a pooled analysis of patients aged ≥18 from four open-label phase I and II trials. Patients in the safety population were treated with ≥1 dose of umbralisib monotherapy (≥800 mg daily), and treatment was administered until disease progression, unacceptable toxicity, or study withdrawal. See Table 1 for a summary of the trials that were included in this pooled analysis.
Table 1. Studies used for the integrated safety analysis*
Trial |
NCT number |
Phase |
Lymphoma type |
Treatment design |
---|---|---|---|---|
TGR-1202-101 |
I |
R/R B-cell NHL, CLL, PTCL, and HL |
3 + 3 design, doses ranging from 50 mg to 1,800 mg daily† |
|
PJP and antiviral therapy at investigator discretion |
||||
UTX-TGR-501 |
II |
B-cell NHL or CLL |
800 mg or 1,200 mg umbralisib daily; concomitant G-CSF support was allowed |
|
PJP and antiviral therapy at investigator discretion |
||||
TGR-1202-202 |
II |
R/R MZL or WM |
800 mg umbralisib daily; concomitant G-CSF was allowed |
|
PJP and antiviral therapy within 7 days prior to Cycle 1 Day 1 |
||||
UNITY-NHL |
IIb |
Previously treated R/R iNHL (FL, SLL, and MZL), MCL, and DLBCL |
800 mg umbralisib daily; concomitant factor-CSF was allowed |
|
PJP and antiviral therapy within 7 days prior to Cycle 1 Day 1 |
||||
CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; G-CSF, granulocyte colony-stimulating factor; HL, Hodgkin lymphoma; iNHL, indolent NHL; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; NHL, non-Hodgkin lymphoma; PJP, Pneumocystis jirovecii pneumonia; PTCL, peripheral T-cell lymphoma; SLL, small lymphocytic leukemia; WM, Waldenström’s macroglobulinemia. |
Key eligibility criteria were similar for all included trials; patients were required to have:
Patients were excluded if they:
A total of 371 patients were available for safety data analysis, and their characteristics are summarized in Table 2.
Table 2. Patient characteristics for the total safety population*
Characteristic |
Total safety population (N = 371) |
---|---|
Age, median (range) |
67 (22–95) |
Female, % |
43.7 |
White, % |
82.7 |
Disease type, % |
|
FL |
39.6 |
MZL |
22.1 |
DLBCL |
19.9 |
CLL/SLL |
11.6 |
Other |
6.7 |
ECOG performance status, % |
|
0 |
47.7 |
1 |
48.2 |
2 |
4.0 |
Time since diagnosis in months, median |
63.8 |
Stage of disease at screening, % |
|
I |
5.9 |
II |
8.1 |
III |
21.6 |
IV |
39.1 |
Unknown |
4.3 |
Number of prior system therapies, median |
2 |
Number of prior lines of therapy, <2, % |
23.5 |
Prior systemic therapy, % |
|
Anti-CD20 monotherapy |
7.0 |
Anti-CD20-based chemoimmunotherapy |
87.6 |
Lenalidomide (monotherapy or in combination) |
11.9 |
Lenalidomide + anti-CD20 antibody |
7.8 |
BTK inhibitor |
14.6 |
Time since most recent progression, months, median |
2.1 |
BTK, Bruton’s tyrosine kinase; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; FL, follicular lymphoma; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; NHL, non-Hodgkin lymphoma; SLL, small lymphocytic leukemia. |
Following a median treatment duration of 5.9 months, the most common, any grade, TEAEs were diarrhea (52.3%), nausea (41.5%), and fatigue (31.8%). The rates of TEAEs did not differ by treatment duration (≤ 3 months to ≥ 2 years), indicating favorable long-term safety. A total of 107 patients received ≥1 year of umbralisib treatment, and the most common TEAEs reported were diarrhea (60.7%), neutropenia (17.8%), aspartate aminotransferase (AST) increase (16.8%), and alanine aminotransferase (ALT) increase (15.0%).
A total of 366 (98.7%) patients reported any grade TEAE, and 84.6% were attributed to umbralisib by the investigators. A total of 189 (50.9%) patients experienced Grade ≥ 3 TEAEs, and 33.4% of patients had Grade ≥ 3 TEAEs attributed to umbralisib. These rates were significantly lower than those reported in studies of other PIK3 inhibitors. The rates of such events were similar between each subtype of NHL analyzed. The most common TEAEs are summarized in Table 3.
Table 3. A summary of TEAEs in the total safety population*
TEAE |
Total safety population (N = 371) |
---|---|
Any grade |
98.7 |
Any grade due to umbralisib |
84.6 |
Diarrhea |
44.5 |
Nausea |
32.6 |
Fatigue |
21.0 |
Any grade AEs of special interest |
|
Pneumonia |
7.8 |
Noninfectious colitis |
2.4 |
Pneumonitis |
1.1 |
Grade ≥ 3, % |
50.9 |
Neutropenia |
11.3 |
Diarrhoea |
7.3 |
ALT or AST increase |
5.7 |
Grade≥ 3 TEAE due to umbralisib |
33.4 |
Neutropenia |
8.9 |
Diarrhea |
6.7 |
ALT or AST increase |
5.4 |
Serious TEAEs |
25.6 |
Serious TEAEs due to umbralisib |
11.9 |
Pneumonia |
1.9 |
Diarrhea |
1.9 |
Sepsis |
1.1 |
ALT, alanine aminotransferase; AST, aspartate aminotransferase; TEAE, treatment emergent adverse event. |
A total of 95 (25.6%) patients experienced serious TEAEs, and 11.9% of the serious TEAEs were attributed to umbralisib use.
Overall, a total of 13.7% of patients discontinued treatment due to TEAEs, which was significantly lower than rates observed with idelalisib, copanlisib, and duvelisib (20%, 25%, and 52%, respectively). TEAEs from umbralisib led to withdrawal in 46 (12.4%) patients, a dose reduction in 34 (9.2%) patients, and treatment interruption in 131 (35.3%) patients.
A total of four patients (1.1%) died from TEAEs that were not related to treatment with umbralisib.
Any grade TEAEs were high in patients irrespective of prior therapy, with similar rates of any grade, Grade ≥ 3, and serious TEAEs seen with each prior treatment (Table 4).
Table 4. TEAEs based on prior treatment*
TEAE, % |
Anti-CD20-based chemoimmunotherapy |
Prior lenalidomide |
Prior BTK inhibitor |
---|---|---|---|
Any grade |
98.5 |
100 |
98.1 |
Grade ≥ 3 |
51.7 |
45.5 |
38.9 |
Serious |
25.8 |
18.2 |
16.7 |
BTK, Bruton’s tyrosine kinase; TEAE, treatment emergent adverse event. |
Integrated safety data from four open-label, phase I and II clinical trials of umbralisib demonstrate a favorable safety profile, with low rates of any grade, Grade ≥3, and serious TEAEs observed with its use in patients with lymphoid malignancies, including R/R FL, MZL, diffuse large B-cell lymphoma (DLBCL), CLL, and Waldenström’s macroglobulinemia (WM). Notably, the rates of TEAEs remained consistent irrespective of treatment duration, suggesting favorable long-term safety. While these data provide evidence of lower rates of immune mediated toxicities and treatment discontinuation with umbralisib compared with other PI3K inhibitors, a direct comparison with prospective, randomized clinical data is needed.
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