Activity of the PI3K-delta,gamma inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma

作者：Horwitz, Steven M.^*; Koch, Raphael; Porcu, Pierluigi; Oki, Yasuhiro; Moskowitz, Alison; Perez, Megan; Myskowski, Patricia; Officer, Adam; Jaffe, Jacob D.; Morrow, Sara N.; Allen, Kerstin; Douglas, Mark; Stern, Howard; Sweeney, Jennifer; Kelly, Patrick; Kelly, Virginia; Aster, Jon C.; Weaver, David; Foss, Francine M.; Weinstock, David M.^*

来源：Blood, 2018, 131(8): 888-898.

DOI：10.1182/blood-2017-08-802470

• B-CELL
• BRENTUXIMAB VEDOTIN
• RESPONSE CRITERIA
• RESISTANCE
• PI3K-GAMMA
• MULTICENTER
• P110-DELTA
• IDELALISIB
• MACROPHAGES
• VORINOSTAT

Duvelisib (IPI-145) is an oral inhibitor of phosphatidylinositol 3-kinase (PI3K)-delta/gamma isoforms currently in clinical development. PI3K-delta/gamma inhibition may directly inhibit malignant T-cell growth, making duvelisib a promising candidate for patients with peripheral (PTCL) or cutaneous (CTCL) T-cell lymphoma. Inhibition of either isoform may also contribute to clinical responses by modulating nonmalignant immune cells. We investigated these dual effects in a TCL cohort from a phase 1, open-label study of duvelisib in patients with relapsed or refractory PTCL (n = 16) and CTCL (n = 19), along with in vitro and in vivo models of TCL. The overall response rates in patients with PTCL and CTCL were 50.0% and 31.6%, respectively (P = .32). There were 3 complete responses, all among patients with PTCL. Activity was seen across a wide spectrum of subtypes. The most frequently observed grade 3 and 4 adverse events were transaminase increases (40% alanine aminotransferase, 17% aspartate aminotransferase), maculopapular rash (17%), and neutropenia (17%). Responders and nonresponders had markedly different changes in serum cytokine profiles induced by duvelisib. In vitro, duvelisib potently killed 3 of 4 TCL lines with constitutive phospho-AKT (pAKT) vs 0 of 7 lines lacking pAKT (P = .024) and exceeded cell killing by the PI3K-delta-specific inhibitor idelalisib. Administration of duvelisib to mice engrafted with a PTCL patient-derived xenograft resulted in a shift among tumor-associated macrophages from the immunosuppressive M2-like phenotype to the inflammatory M1-like phenotype. In summary, duvelisib demonstrated promising clinical activity and an acceptable safety profile in relapsed/refractory TCL, as well as preclinical evidence of both tumor cell-autonomous and immune-mediated effects.

• 出版日期2018-2-22