Umbralisib, a dual PI3Kδ/CK1ε inhibitor in patients with relapsed or refractory indolent lymphoma

Nathan H. Fowler, Felipe Samaniego, Wojciech Jurczak, Nilanjan Ghosh, Enrico Derenzini, James A. Reeves, Wanda Knopińska-Posłuszny, Chan Y. Cheah, Tycel Phillips, Ewa Lech-Maranda, Bruce D. Cheson, Paolo F. Caimi, Sebastian Grosicki, Lori A. Leslie, Julio C. Chavez, Gustavo Fonseca, Sunil Babu, Daniel J. Hodson, Spencer H. Shao, John M. BurkeJeff P. Sharman, Jennie Y. Law, John M. Pagel, Hari P. Miskin, Peter Sportelli, Owen A. O'Connor, Michael S. Weiss, Pier Luigi Zinzani

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1609-1618
Number of pages10
JournalJournal of Clinical Oncology
Issue number15
Publication statusPublished - May 20 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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