PI3K Inhibitors in Hematology: When One Door Closes…

Abstract

The PI3K signaling pathway regulates key cellular processes and is one of the most aberrantly activated pathways in cancer. The class I PI3K catalytic subunits p110γ and p110δ are highly enriched in leukocytes, providing an additional rationale for targeting these PI3Ks in hematologic malignancies. In 2014, the PI3Kδ inhibitor idelalisib was the first of four PI3K inhibitors (PI3Ki) to receive regulatory approval for relapsed B-cell malignancies. This was followed by approvals of the pan-class I inhibitor copanlisib (2017), the dual PI3Kγ/δ inhibitor duvelisib (2018), and the PI3Kδ and casein kinase 1ε inhibitor umbralisib (2021). Copanlisib and umbralisib received accelerated approvals, whereas idelalisib and duvelisib received initial accelerated approvals followed by full approvals. The accelerated approvals were based on overall response rates; however, follow-up studies showed increased risk of death and serious side effects. Furthermore, the confirmatory trial with copanlisib failed to show an improvement in progression-free survival when compared with chemoimmunotherapy. These developments led to black box warnings for idelalisib and duvelisib and withdrawal of copanlisib and umbralisib from the market by their manufacturers. Given the uncertain future of this drug class, additional manufacturers terminated ongoing phase III trials with novel PI3Kis. In this study, we review the development and current status of PI3Kis in hematology, limitations to their use, and our perspective on whether there is a future for PI3Kis in hematology.

Figure 1.. The approval history of PI3Ki in hematology

Upper panel: Between 2014–2021, the PI3K inhibitors idelalisib, duvelisib, umbralisib, and copanlisib (columns) received approvals for the indicated hematologic malignancies (shown in green). The columns indicate what type of approval was granted. Lower panel: Between 2022–2023, accelerated approvals were withdrawn (shown in red). Idelalisib and duvelisib have received a black box warning with their package insert (warning sign). CLL; chronic lymphocytic leukemia, EMA; European Medicines Agency, FDA; U.S. Food and Drug Administration, FL; follicular lymphoma, SLL; small lymphocytic leukemia.

Figure 2.. Characteristics of PI3Ki that are or have been approved for hematologic malignancies

¹As of April 2024 ²Available from PubChem BID, bis in die (twice a day); CLL, chronic lymphocytic leukemia; FL, follicular lymphoma; N/A, not applicable; SLL, small lymphocytic leukemia