PI3Kδ Inhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma

By A. Gopal, B. Kahl, S. de Vos, N. Wagner-Johnston, S. Schuster, W. Jurczak, I. Flinn, C. Flowers, P. Martin, A. Viardot and 12 more. New England Journal of Medicine, 2014

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Background Phosphatidylinositol-3-kinase delta (PI3Kδ) mediates B-cell receptor signaling and microenvironmental support signals that promote the growth and survival of malignant B lymphocytes. In a phase 1 study, idelalisib, an orally active selective PI3Kδ inhibitor, showed antitumor activity in patients with previously treated indolent non-Hodgkin's lymphomas. Methods In this single-group, open-label, phase 2 study, 125 patients with indolent non-Hodgkin's lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered idelalisib, 150 mg twice daily, until the disease progressed or the patient withdrew from the study. The primary end point was the overall rate of response; secondary end points included the duration of response, progression-free survival, and safety. Results The median age of the patients was 64 years (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). Subtypes of indolent non-Hodgkin's lymphoma included follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenström's macroglobulinemia (10). The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin's lymphoma, though the numbers were small for some categories. The most common adverse events of grade 3 or higher were neutropenia (in 27% of the patients), elevations in aminotransferase levels (in 13%), diarrhea (in 13%), and pneumonia (in 7%). Conclusions In this single-group study, idelalisib showed antitumor activity with an acceptable safety profile in patients with indolent non-Hodgkin's lymphoma who had received extensive prior treatment. (Funded by Gilead Sciences and others; ClinicalTrials.gov number, NCT01282424.)

Subfields: Genetics, Molecular Biology, Pathology and Forensic Medicine

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Citations in the corpus

The PI3K pathway in human disease (2017, background): “Clinical trials provided important insights into the mechanisms underlying the efficacy of idelalisib, as well as its toxicities (Furman et al., 2014; Gopal et al., 2014).”
Targeting PI3K in cancer: mechanisms and advances in clinical trials (2019, background): “It has been shown that idelalisib has therapeutic effects without inhibiting PI3K signaling essential for normal function of healthy cells [157, 158].”
Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. (2017, neutral): “Emergent* Any event 103 (97) 21 (96) 33 (100) 49 (96) 59 (56) 14 (64) 21 (64) 24 (47) Nausea 51 (48) 9 (41) 15 (45) 27 (53) 0 0 0 0 Diarrhea 48 (45) 7 (32) 14 (42) 27 (53) 3 (3) 0 2 (6) 1 (2) Fatigue 44 (42) 10 (45) 9 (27) 25 (49) 7 (7) 2 (9) 2 (6) 3 (6) Decreased appetite 23 (22) 4 (18) 4 (12) 15 (”