Learnings from phosphatidylinositol 3-kinase inhibitors in lymphoma-Moving to a model where less can be more.

The role of Pi3K inhibitors in lymphoma is diminishing due to the adverse results from trials in indolent lymphoma, but is a one-size-fits-all approach to drug development penalising some lymphoma subtypes and the newer generation of Pi3K inhibitors? The report by Soumerai et al. of zandelisib with zanubrutinib in follicular and mantle cell lymphoma is an important addition to the data. Commentary on: Soumerai et al. Safety and efficacy of zandelisib plus zanubrutinib in previously treated follicular and mantle cell lymphomas. Br J Haematol 2024;204:1762-1770.

Safety and efficacy of zandelisib plus zanubrutinib in previously treated follicular and mantle cell lymphomas.

The combination of the phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor zandelisib with the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib was hypothesized to be synergistic and prevent resistance to single-agent therapy. This phase 1 study (NCT02914938) included a dose-finding stage in patients with relapsed/refractory (R/R) B-cell malignancies (n = 20) and disease-specific expansion cohorts in follicular lymphoma (FL; n = 31) or mantle cell lymphoma (MCL; n = 19). The recommended phase 2 dose was zandelisib 60 mg on Days 1-7 plus zanubrutinib 80 mg twice daily continuously in 28-day cycle. In the total population, the most common adverse events (AEs; all grades/grade 3-4) were neutropenia (35%/24%), diarrhoea (33%/2%), thrombocytopenia (32%/8%), anaemia (27%/8%), increased creatinine (25%/0%), contusion (21%/0%), fatigue (21%/2%), nausea (21%/2%) and increased aspartate aminotransferase (24%/6%). Three patients discontinued due to AEs. The overall response rate was 87% (complete response [CR] = 33%) for FL and 74% (CR = 47%) for MCL. The median duration of response and progression-free survival (PFS) were not reached in either group. The estimated 1-year PFS was 72.3% (95% confidence interval [CI], 51.9-85.1) for FL and 56.3% (95% CI, 28.9-76.7) for MCL (median follow-up: 16.5 and 10.9 months respectively). Zandelisib plus zanubrutinib was associated with high response rates and no increased toxicity compared to either agent alone.

Metabolic and toxicological considerations for phosphoinositide 3-kinase delta inhibitors in the treatment of chronic lymphocytic leukemia.

INTRODUCTION: Phosphoinositide 3-kinase delta (PI3Kδ) inhibitors are a class of novel agents that are mainly used to treat B-cell malignancies. They function by inhibiting one or more enzymes which are part of the PI3K/AKT/mTOR pathway. Idelalisib is a first-in-class PI3Kδ inhibitor effective in patients with B-cell lymphoid malignancies. AREAS COVERED: This article reviews the chemical structure, mechanism of action, and metabolic and toxicological properties of PI3Kδ inhibitors and discusses their clinical applications in monotherapy and in combination with other agents for the treatment of chronic lymphocytic leukemia (CLL). A search was conducted of PubMed, Web of Science, and Google Scholar for articles in English. RESULTS/CONCLUSION: PI3Kδ inhibitors hold potential for the treatment of B-cell malignancies, including CLL. However, their use is also associated with severe toxicities, including pneumonia, cytopenias, hepatitis, and rash. Newer drugs are in development to reduce toxicity with novel schedules and/or combinations. EXPERT OPINION: The development of novel PI3Kδ inhibitors might help to reduce toxicity and improve efficacy in patients with CLL and other B-cell lymphoid malignancies.

Zandelisib (ME-401) in Japanese patients with relapsed or refractory indolent non-Hodgkin's lymphoma: an open-label, multicenter, dose-escalation phase 1 study.

The selective phosphatidylinositol 3-kinase δ inhibitor zandelisib demonstrated favorable safety and efficacy [objective response rate (ORR) 79%] in patients with B-cell malignancies in a phase 1b study in the US and Switzerland. In this phase 1 dose-escalation study (NCT03985189), 9 Japanese patients with relapsed/refractory indolent non-Hodgkin's lymphoma (R/R iNHL) received zandelisib on a continuous daily schedule (45 or 60 mg) until progressive disease/unacceptable toxicity. No dose-limiting toxicities were observed. The maximum tolerated dose was not reached. At a median follow-up of 17.5 months, Grade ≥ 3 treatment-emergent adverse events that occurred in 2 or more patients were neutrophil count decreased (55.6%; 5/9) and diarrhea (33.3%; 3/9). Immune-related toxicities, including hepatobiliary disorder, aspartate/alanine aminotransferase increased, diarrhea/colitis, organizing pneumonia, stomatitis, and rash, led to zandelisib discontinuation in 4 patients. The investigator-assessed ORR, based on modified Lugano criteria, was 100%, including 2 complete responses (22.2%; in follicular lymphoma patients receiving 60 mg/day). Median duration of response, progression-free survival, and time to response were 7.9, 11.1, and 1.9 months, respectively. Zandelisib demonstrated a manageable safety profile at 60 mg, the recommended phase 2 dose (RP2D) in Japanese patients. The RP2D resulted in favorable pharmacokinetics and anti-tumor efficacy in Japanese patients with R/R iNHL.Trial registration. NCT03985189 (ClinicalTrials.gov).

PI3K Inhibitors for the Treatment of Chronic Lymphocytic Leukemia: Current Status and Future Perspectives.

Phosphoinositide 3-kinases (PI3Ks) signaling regulates key cellular processes, such as growth, survival and apoptosis. Among the three classes of PI3K, class I is the most important for the development, differentiation and activation of B and T cells. Four isoforms are distinguished within class I (PI3Kα, PI3Kß, PI3Kδ and PI3Kγ). PI3Kδ expression is limited mainly to the B cells and their precursors, and blocking PI3K has been found to promote apoptosis of chronic lymphocytic leukemia (CLL) cells. Idelalisib, a selective PI3Kδ inhibitor, was the first-in-class PI3Ki introduced into CLL treatment. It showed efficacy in patients with del(17p)/TP53 mutation, unmutated IGHV status and refractory/relapsed disease. However, its side effects, such as autoimmune-mediated pneumonitis and colitis, infections and skin changes, limited its widespread use. The dual PI3Kδ/γ inhibitor duvelisib is approved for use in CLL patients but with similar toxicities to idelalisib. Umbralisib, a highly selective inhibitor of PI3Kδ and casein kinase-1ε (CK1ε), was found to be efficient and safe in monotherapy and in combination regimens in phase 3 trials in patients with CLL. Novel PI3Kis are under evaluation in early phase clinical trials. In this paper we present the mechanism of action, efficacy and toxicities of PI3Ki approved in the treatment of CLL and developed in clinical trials.

The Evolving Use of Phosphatidylinositol 3-Kinase Inhibitors for the Treatment of Chronic Lymphocytic Leukemia.

B cells express 4 phosphatidylinositol 3-kinase (PI3K) isoforms and have a dependence on p110δ for survival. The design of isoform-selective inhibitors is possible, and pharmacologic inhibition of p110δ is toxic to neoplastic chronic lymphocytic leukemia (CLL) cells for both cell-intrinsic and cell-extrinsic reasons. Idelalisib is a first-in-class p110δ inhibitor that exhibits efficacy for the treatment of relapsed CLL irrespective of adverse prognostic features. Duvelisib is a p110γ/δ inhibitor with a similar efficacy and safety profile to idelalisib. Recent data indicate that umbralisib, a p110δ/CK-1ε dual inhibitor, is safe and effective when administered to patients with CLL.