Integrated safety analysis of umbralisib, a dual PI3Kδ/CK1ε inhibitor, in relapsed/refractory lymphoid malignancies

Davids, Matthew S.; O’Connor, Owen A.; Jurczak, Wojciech; Samaniego, Felipe; Fenske, Timothy S.; Zinzani, Pier Luigi; Patel, Manish R.; Ghosh, Nilanjan; Cheson, Bruce D.; Derenzini, Enrico; Brander, Danielle M.; Reeves, James A.; Knopińska‐Posłuszny, Wanda; Allan, John N.; Phillips, Tycel; Caimi, Paolo; Lech-Maranda, Ewa; Burke, John M.; Agajanian, Richy; Pettengell, Ruth; Leslie, Lori A.; Cheah, Chan Yoon; Fonseca, Gustavo; Essell, James; Chávez, Julio C.; Pagel, John M.; Sharman, Jeff P.; Hsu, Yanzhi; Miskin, Hari P.; Sportelli, Peter; Weiss, Michael; Flinn, Ian W.

doi:10.1182/bloodadvances.2021005132

Cited by 17 publications

(12 citation statements)

References 44 publications

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“…As of July 2020, more than 1,800 patients with B-cell malignancies have been treated with umbralisib, either alone or in combination with 16 other agents. 24 , 27 , 38 , 40 …”

Section: Discussionmentioning

confidence: 99%

Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma

Fowler

Samaniego

Jurczak

et al. 2021

JCO

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119

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PURPOSE Phosphatidylinositol-3-kinase (PI3K) inhibitors have shown activity in relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). PI3K inhibitors have been hampered by poor long-term tolerability and toxicity, which interfere with continuous use. Umbralisib, a dual inhibitor of PI3Kδ/casein kinase-1ε, exhibits improved selectivity for PI3Kδ compared with other PI3K inhibitors. This phase IIb trial was designed to evaluate the efficacy and safety of umbralisib in patients with R/R iNHL. PATIENTS AND METHODS In this multicohort, open-label, phase IIb study, 208 patients with R/R marginal zone, follicular, or small lymphocytic lymphoma (MZL, FL, or SLL) unresponsive to prior treatments (≥ 1 MZL; ≥ 2 FL/SLL), including ≥ 1 anti-CD20–based therapy, were administered umbralisib 800 mg orally once daily until disease progression, unacceptable toxicity, or study withdrawal. Primary end point is overall response rate; secondary end points include time to response, duration of response, progression-free survival, and safety. RESULTS The median follow-up is 27.7 months (efficacy) and 21.4 months (safety). The overall response rate was 47.1%, and tumor reduction occurred in 86.4% of patients. The median time to response was 2.7-4.6 months. The median duration of response was not reached for MZL, 11.1 months for FL, and 18.3 months for SLL. Median progression-free survival was not reached for MZL, 10.6 months for FL, and 20.9 months for SLL. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 53.4% of patients. TEAEs led to umbralisib discontinuation in 32 patients (15.4%). A total of 31 patients (14.9%) discontinued because of a treatment-related adverse event. Grade ≥ 3 TEAEs reported in ≥ 10% of patients: neutropenia (11.5%) and diarrhea (10.1%). Increased ALT/AST (grade ≥ 3) occurred in 6.7%/7.2% of patients. CONCLUSION Umbralisib achieved meaningful clinical activity in heavily pretreated patients with iNHL. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and adverse event–related discontinuations.

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“…As of July 2020, more than 1,800 patients with B-cell malignancies have been treated with umbralisib, either alone or in combination with 16 other agents. 24 , 27 , 38 , 40 …”

Section: Discussionmentioning

confidence: 99%

Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma

Fowler

Samaniego

Jurczak

et al. 2021

JCO

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119

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“…Umbralisib, another next-generation PI3Kδ inhibitor, has been investigated in R/R B cell NHL as a monotherapy and in combination with ibrutinib. The combination of umbralisib and ibrutinib was investigated in a phase I/Ib study that included 21 CLL patients and 21 MCL patients with R/R disease [ 53 , 54 ]. Only 2 MCL patients had prior BTKi therapy.…”

Section: Beyond Btk Inhibitors: Targeted Therapiesmentioning

confidence: 99%

“…The median PFS was 10.5 months, with a 2-year PFS of 49% and an OS of 58%. The most frequent adverse events were diarrhea, infection and transaminitis, with 29% of patients experiencing serious adverse events including atrial fibrillation [ 53 , 54 ]. Longer follow-up studies and additional clinical trials combining these drugs with other agents are ongoing for B cell malignancies, including MCL.…”

Section: Beyond Btk Inhibitors: Targeted Therapiesmentioning

confidence: 99%

Relapsed/Refractory Mantle Cell Lymphoma: Beyond BTK Inhibitors

Burkart

Karmali

2022

JPM

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Mantle cell lymphoma (MCL) is a rare mature B-cell non-Hodgkin lymphoma (B-NHL) with historically poor outcomes. Virtually all patients will eventually experience refractory or relapsed (R/R) disease, with a virulent course of resistance and serial relapses, making treatment challenging. The available therapies for R/R MCL are not curative with conventional therapy, their goal being to palliate and prolong survival. A variety of agents approved for R/R MCL, including Bruton’s tyrosine kinase inhibitors (BTKi), changed the treatment landscape of R/R MCL. In the pre-BTKi era, the median progression-free survival (PFS) in R/R disease was 4–9 months. With the introduction of ibrutinib, the median PFS improved to 13–14.6 months. Despite these impressive results, the duration of response is limited, and resistance to BTKi inevitably develops in a subset of patients. Outcomes after progression on BTKi are extremely poor, with a median overall survival (OS) of 6 to 10 months. Certain therapies, such as chimeric antigen receptor (CAR) T cells, have shown promising results after BTKi failure. The preferred combination and sequencing of therapies beyond BTKi remain unestablished and are currently being investigated. In this review, we describe the current evidence for the available treatment of R/R MCL after progression on BTKi.

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“…The introduction of inhibitors of phosphatidylinositol 3-kinase (PI3K) and Bruton tyrosine kinase (BTK) has represented a big step forward in the treatment of patients affected by indolent B cell lymphomas, including marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma (LPL) [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]. Idelalisib was the first-in-class PI3Kδ inhibitor to be approved by the U.S. Food and Drug Administration (FDA), in combination with the anti-CD20 monoclonal antibody rituximab, for the treatment of indolent B cell lymphoma [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…Idelalisib was the first-in-class PI3Kδ inhibitor to be approved by the U.S. Food and Drug Administration (FDA), in combination with the anti-CD20 monoclonal antibody rituximab, for the treatment of indolent B cell lymphoma [ 4 ]. Additional PI3K-inhibitors such as copanlisib, a pan-class I PI3K inhibitor with predominant activity against PI3Kα/PI3Kδ, and umbralisib, the first-in-class dual phosphatidylinositol 3-kinase delta (PI3Kδ) and casein kinase 1 epsilon (CK1ε) inhibitor, also showed clinical activity in patients affected by indolent lymphomas [ 1 , 5 , 6 ]. Bruton’s Tyrosine Kinase (BTK) inhibitors, such as ibrutinib, are also effective in treating MZL and LPL patients [ 2 , 3 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting IRAK4 with Emavusertib in Lymphoma Models with Secondary Resistance to PI3K and BTK Inhibitors

Guidetti

Arribas

Sartori

et al. 2023

JCM

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Inhibitors of phosphatidylinositol 3-kinase (PI3K) and Bruton tyrosine kinase (BTK) represent a recognized option for the treatment of patients affected by indolent B cell lymphomas. However, small molecules as single agents show limited success in their ability in inducing complete responses, with only partial remission achieved in most patients, suggesting the need for combination therapies. IRAK4 is a protein kinase downstream of the Toll-like receptor signaling (TLR), a driver pathway of secondary tumor° resistance in both hematological and solid tumor malignancies. Activation of IRAK4 upon TLRs and IL-1 receptor (IL-1R) stimulation and through the adaptor protein MYD88 initiates a signaling cascade that induces cytokine and survival factor expression mediated by the transcription factor NF-κB. MYD88-L265P encoding mutations occur in diffuse large B-cell lymphomas, in lymphoplasmacytic lymphomas and in few marginal zone lymphomas (MZL). The IRAK4 inhibitor emavusertib (CA-4948) has shown early safety and clinical activity in lymphoma and leukemia patients. In this preclinical study, we assessed emavusertib effectiveness in MZL, both as single agent and in combination with targeted agents, with a particular focus on its capability to overcome resistance to BTK and PI3K inhibitors. We showed that the presence of MYD88 L265P mutation in bona fide MZL cell lines confers sensitivity to the IRAK4 inhibitor emavusertib as single agent. Emavusertib-based combinations improved the sensitivity of MZL cells to BTK and PI3K inhibitors, including cells with a secondary resistance to these agents. Emavusertib exerted its activity via inhibition of NF-κB signaling and induction of apoptosis. Considering the early safety data from clinical trials, our study identifies the IRAK4 inhibitor emavusertib as a novel compound to be explored in trials for patients with MYD88-mutated indolent B cell lymphomas as single agent and as combination partner with BTK or PI3K inhibitors in unselected populations of patients.

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Integrated safety analysis of umbralisib, a dual PI3Kδ/CK1ε inhibitor, in relapsed/refractory lymphoid malignancies

Cited by 17 publications

References 44 publications

Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma

Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma

Relapsed/Refractory Mantle Cell Lymphoma: Beyond BTK Inhibitors

Targeting IRAK4 with Emavusertib in Lymphoma Models with Secondary Resistance to PI3K and BTK Inhibitors

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