Umbralisib is expected to become a safe and effective treatment for R/R iNHL patients

Professor Nathan H.
Fowler and others conducted a phase IIb clinical study to evaluate the PI3Kδ/CK-1ε dual inhibitor Umbralisib in patients with relapsed or refractory indolent non-Hodgkin’s lymphoma (R/R iNHL) Efficacy and safety.

Research background and purpose Non-Hodgkin's lymphoma (NHL) is a heterogeneous mature lymphocytic tumor, which can be further divided into aggressive and indolent according to the characteristics of the disease.

Common iNHL subtypes include marginal zone lymphoma (MZL), follicular lymphoma (FL), and small lymphocytic lymphoma (SLL).

The standard treatment for newly diagnosed B-cell iNHL (B-iNHL) is usually anti-CD20 monoclonal antibody monotherapy or in combination with other drugs, but for R/R B-iNHL patients, the standard treatment is currently inconclusive.

Phosphatidylinositol-3-kinase (PI3K) inhibitors show good clinical activity in R/R iNHL.

Previous studies have shown that PI3K inhibitors need continuous use (≥6 months) to enable patients to have significant clinical efficacy, but the adverse events (AE) of PI3K inhibitors, especially the high incidence of immune-mediated AEs, make most patients Unable to tolerate it, resulting in limited long-term continuous application.

Umbralisib is different from other simple PI3K inhibitors.
It is a dual inhibitor of PI3Kδ/casein kinase-1ε and has higher selectivity for PI3Kδ.

The results of the phase I dose escalation study showed that Umbralisib has good activity in patients with a variety of relapsed or refractory hematological malignancies, and it is clear that the recommended phase II study dose is 800 mg orally, once a day.

Research Method The study is a multi-cohort, open-label phase IIb clinical study, enrolling a total of 208 R/R B-iNHL (mainly MZL, FL, SLL) patients, including primary refractory and relapse after first-line treatment Of patients.

All patients received Umbralisib 800 mg orally, once a day, until the disease progressed or became intolerable.

The primary study endpoint is the patient's overall response rate (ORR), which is defined as the percentage of patients who achieve complete response (CR) or partial response (PR).

Secondary research endpoints include duration of treatment remission (DOR), progression-free survival (PFS), time to remission (TTR), and safety.

Results of the study: From May 2017 to September 2018, a total of 208 R/R B-iNHL patients were enrolled and treated (MZL[N=69], FL[N=117], SLL[N=22] ).

The deadline for data processing of these intention-to-treat (ITT) populations is July 13, 2020.

Overall, the median age of patients was 66 years (range: 29-88 years); male patients accounted for 56.
7% and white patients accounted for 81.
7%.

In addition, 51.
0% of patients had disease stage IV; the median number of patients who received treatment in the past was 2 (range: 1-10 lines), and 46.
2% of patients had previously received ≥3 lines of treatment.

Among them, 28.
4% of the patients were ineffective in the latest anti-CD20 monoclonal antibody treatment; the vast majority of patients had previously received anti-CD20 monoclonal antibody-based immunochemotherapy, and some patients had previously received Bruton's tyrosine kinase Inhibitor (BTKi) treatment.

When the median follow-up time was 27.
7 months, the ORR in the overall ITT population was 47.
1%; the median time to treatment for the overall patients was 2.
7-4.
6 months. The ORR of patients in the MZL, FL, and SLL subgroups were 49.
3% (95% CI: 37.
0-61.
6), 45.
3% (95% CI: 36.
1-54.
8), and 50.
0% (95% CI: 28.
2-71.
8), respectively; The median DOR of the patients in the group were unreached, 11.
1 months, and 18.
3 months, the median TTR was 2.
8 months, 4.
6 months, and 2.
7 months, respectively, and the median PFS were unreached, 10.
6 months, and 20.
9 months, respectively.
The PFS rates at 2 years were 50.
5%, 18.
1%, and 31.
3% respectively.

The median follow-up time of the safety data collected was 21.
4 months (range: 14.
6-30.
8 months).

53.
4% ​​of patients experienced at least one grade 3 adverse event during treatment (TEAE); the most common TEAEs of grade 3 or higher were neutropenia (11.
5%) and diarrhea (10.
1%).

Among them, the incidence of Umbralisib dose reduction due to TEAE was 11.
5%, and the patients who discontinued Umbralisib due to TEAE accounted for 15.
4%.

The incidence of serious TEAEs related to Umbralisib treatment was 17.
3%; the common ones were diarrhea (3.
4%), acute kidney injury (1.
4%), anemia (1.
4%), dehydration (1.
4%), febrile neutrophils Reduced symptoms (1.
4%), pneumonia (1.
4%), sepsis (1.
4%), and urinary tract infection (1.
4%); Umbralisib-related TEAE resulted in dose reduction in 9.
6% of patients.

Research conclusions Umbralisib has a good effect in R/R B-iNHL patients who have undergone multi-line therapy, and its safety is controllable.
The incidence of immune-mediated AEs and the withdrawal rate due to AEs are comparable to the first-generation PI3K inhibition The agent is relatively low. References: Nathan H Fowler, Felipe Samaniego, Wojciech Jurczak, et al.
Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma.
J Clin Oncol.
2021 Mar 8; JCO2003433.
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