Umbralisib demonstrates favorable long-term safety for patients with R/R lymphoid malignancies

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

Methods

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*

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. *Adapted from Davids et al.1 †Only patients who received ≥ 800 mg were included in this study analysis.
Trial	NCT number	Phase	Lymphoma type	Treatment design
TGR-1202-101	NCT01767766	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	NCT03207256	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	NCT03364231	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 (UTX-TGR-205)	NCT02793583	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

Eligibility criteria

Key eligibility criteria were similar for all included trials; patients were required to have:

• A diagnosis of R/R non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL)
• Received ≥1 or ≥2 prior lines of therapy
• An Eastern Cooperative Oncology Group (ECOG) status score of ≤2

Patients were excluded if they:

• Had major surgery, chemotherapy, or immunotherapy within the past 21 days
• Had evidence of hepatitis B or C virus or known HIV infection
• Received an autologous hematopoietic stem cell transplant (HSCT) within 3 months (TGR-1202-101 and UTX-TGR-501) or 6 months (TGR-1202-202 and UTX-TGR-205) of study entry
• Received an allogeneic HSCT (allo-HSCT) within 12 months (TGR-1202-101 and UTX-TGR-501) or any allo-HSCT (TGR-1202-202 and UTX-TGR-205)

Results

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*

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. *Adapted from Davids et al.1
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

TEAEs

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*

ALT, alanine aminotransferase; AST, aspartate aminotransferase; TEAE, treatment emergent adverse event. *Adapted from Davids et al.1
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

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*

BTK, Bruton’s tyrosine kinase; TEAE, treatment emergent adverse event. *Adapted from Davids et al.1
TEAE, %	Anti-CD20-based chemoimmunotherapy (n = 325)	Prior lenalidomide (n = 44)	Prior BTK inhibitor (n = 54)
Any grade	98.5	100	98.1
Grade ≥ 3	51.7	45.5	38.9
Serious	25.8	18.2	16.7

Conclusion

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.