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Activity of the PI3K-δ,γ inhibitor duvelisib in a phase I trial and preclinical models of T-cell lymphoma

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

Key points

  • The oral PI3K-δ,γ inhibitor Duvelisib demonstrated clinical activity and a favorable safety profile in patients with CTCL and PTCL.

  • Duvelisib induced cell-autonomous killing of T-cell lymphoma lines and reprogrammed PTCL-associated macrophages in vivo.

Abstract

Duvelisib (IPI-145) is an oral inhibitor of phosphoinositide-3-kinase (PI3K)-δ/γ isoforms currently in clinical development. PI3K-δ/γ 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=0.32). 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% ALT, 17% AST), maculopapular rash (17%) and neutropenia (17%). Responders and non-responders 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) versus 0 of 7 lines lacking pAKT (p=0.024) and exceeded cell killing by the PI3K-δ-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.

  • Submitted August 22, 2017.
  • Accepted December 1, 2017.