Safety analysis of dual PI3Kδ/CK1ε inhibitor Umbralisib in patients with relapsed/refractory lymphoma

The phosphatidylinositol 3-kinase (PI3K) family is at the center of many signaling pathways, including the B cell receptor pathway
.

PI3Kδ signaling is often active in patients with B-cell malignancies, making it a promising therapeutic target in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL)
.

Umbralisib is a novel, oral, selective dual inhibitor of PI3Kδ and casein kinase-1ε (CK1ε)
.

Fowler et al recently reported that with a median follow-up of 27.
7 months, patients with relapsed or refractory (R/R) marginal zone lymphoma (MZL), follicular lymphoma (FL) or small lymphocytic lymphoma (SLL) were After receiving umbralisib monotherapy, the overall response rate (ORR) was 47.
1%, and tumor shrinkage was observed in 86.
4% of patients
.

To better characterize the safety profile of umbralisib, Matthew S.
Davids et al.
performed a comprehensive safety analysis of data obtained from four phase I and phase II single-agent clinical trials with longer follow-up
.

Methods: Data were obtained from a pooled analysis of adult patients (≥18 years) from 4 open-label phase I and II clinical trials
.

The 4 studies include: The TGR-1202-101 study (NCT01767766) is a Phase I dose escalation trial evaluating umbralisib in R/R, histologically confirmed hematological malignancies (B-cell NHL, CLL, peripheral T-cell lymphoid safety and efficacy in patients with cancer and HL)
.

A 3+3 design was used to determine the maximum tolerated dose of oral umbralisib administered once daily (28-day cycles) for all cycles ranging from 50 mg to 1800 mg daily (only patients receiving ≥800 mg were included in the analysis) )
.

Patients who completed the TGR-1202-101 study were allowed to continue umbralisib in the UTX-TGR-501 study (NCT032-07256), an ongoing Phase II, long-term, open-label extension trial, To evaluate the safety and efficacy of umbralisib 800 mg or 1200 mg daily in patients with B-cell NHL or CLL
.

The TGR-1202-202 study (NCT03364231) is an ongoing Phase II clinical trial evaluating the efficacy and safety of umbralisib in patients with R/R MZL or Waldenström macroglobulinemia
.

The UNITY-NHL study (UTX-TGR-205) is an ongoing phase IIb multicohort trial evaluating umbralisib in previously treated R/R indolent NHL (FL, SLL and MZL), mantle cell lymphoma (MCL) ) and diffuse large B-cell lymphoma (DLBCL) patients
.

The primary inclusion criteria for the 4 trials were similar: patients needed to be diagnosed with R/R NHL or CLL, with ≥1 or ≥2 prior treatment regimens, and Eastern Cooperative Oncology Group (ECOG) status score ≤2
.

All patients required ≥1 dose of umbralisib monotherapy (≥800 mg per day) in 28-day cycles until disease progression or unacceptable toxicity or study withdrawal
.

Results As of September 1, 2019, data from 371 patients were available for analysis (FL, n=147; MZL, n=82; DLBCL/MCL, n=74; CLL/SLL, n=43; other tumors type, n=25)
.

The median age was 67 years (range, 22-95 years); 56.
3% were male, 82.
7% were white, and 96.
0% of patients had an ECOG status score of 0 or 1
.

Fifty-four patients (14.
6%) had received prior Bruton's tyrosine kinase (BTK) inhibitor therapy, and 44 patients (11.
9%) had previously received lenalidomide (alone or in combination)
.

Overall, the median number of prior systemic therapy was 2 (range, 1-14), and the median time from most recent therapy to disease progression was 2.
1 months (range, 0.
3-447.
4 months)
.

In addition, 145/371 patients (39.
1%) were resistant to the previous latest treatment regimen
.

Patients received umbralisib for a median of 5.
9 months (range 0.
1-75.
1 months), 92/371 patients (24.
8%) received 12-24 months of treatment, 15/371 of 371 patients (4.
0%) received ≥24 months of treatment (Table 1)
.

Table 1 and Table 2 summarize the incidence of "treatment period" adverse events (TEAEs) for total and different NHL subtypes
.

The most common TEAEs (any grade) were diarrhea (52.
3%), nausea (41.
5%), and fatigue (31.
8%)
.

The incidence of TEAEs was similar in patients with exposure ≤3 months, 3-6 months, 6-12 months, or 1-2 years
.

The most common key TEAEs in patients treated with umbralisib for more than 1 year (n=107) were diarrhea (60.
7%), neutropenia (17.
8%), AST elevation (16.
8%), and ALT elevation (15.
0%)
.

TEAEs with median onset time ≤1 month included constipation (median onset, 1.
0 months; median duration, 1.
1 months) and diarrhea (median onset, 1.
0 months; median duration, 0.
6) months); TEAEs with median onset ≤2 months included infectious colitis (median onset, 1.
4 months; median duration, 0.
4 months) and elevated transaminases (median onset, 1.
9 months) ; median duration, 1.
1 months)
.

Adverse reactions with a median onset of ≥3 months included noninfectious colitis (median onset, 6.
0 months; median duration, 0.
7 months) and pneumonia (median onset, 3.
7 months; median onset, 0.
7 months) duration, 0.
5 months) (Table 3)
.

Figure 1 shows the associated toxicities over time
.

Although the incidence of diarrhea during the first month of umbralisib was high (101/371 cases [≈27%]), the vast majority of events were grade 1 (82/101 cases)
.

Thirty patients (8.
1%) received steroids for AEs (possibly immune-mediated) including diarrhea or colitis (4%), liver dysfunction (2%), rash (2%), and pneumonia (0.
5%).
%)
.

Table 2Table 3Figure 1 TEAEs of any grade occurred in 366 of 371 patients (98.
7%), the most common of which were diarrhea (52.
3%), nausea (41.
5%), and fatigue (31.
8%)
.

Grade ≥3 TEAEs occurred in 189 patients (50.
9%), the most common of which included neutropenia (11.
3%), diarrhea (7.
3%), and elevated transaminases (5.
7%) (Table 4)
.

Serious TEAEs occurred in 95 patients (25.
6%)
.

AEs of particular interest were limited and included pneumonia (29/371 [7.
8%]), noninfectious colitis (9/371 [2.
4%]), and pneumonia (4/371 [1.
1%])
.

Umbralisib was discontinued due to AEs in 51 patients (13.
7%)
.

Four patients (1.
1%) died due to AEs, none of which were thought to be related to umbralisib
.

There were no reports of cumulative toxicity
.

Table 4 Conclusions of the study A comprehensive safety analysis of 371 patients with relapsed or refractory lymphoma found that in patients with B-cell malignancies, continuous treatment with umbralisib was generally well tolerated, with low discontinuation rates and no apparent treatment limitations Sexual toxicity
.

Good long-term tolerability and low immune-mediated toxicity support the potential application of umbralisib, which is expected to benefit the majority of patients with lymphoid malignancies
.

Reference source: Matthew S.
Davids, Owen A.
O'Connor, Wojciech Jurczak et al.
Blood Adv (2021) 5 (23): 5332–5343.
https://doi.
org/10.
1182/bloodadvances.
2021005132.
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