The evidence to date on umbralisib for the treatment of refractory marginal zone lymphoma and follicular lymphoma

ABSTRACT

Introduction

Between 2014 and 2018 The United States Food and Drug Administration granted approvals for three small molecule inhibitors of phosphoinositide 3-kinases (PI3Ks) as monotherapy for follicular lymphoma relapsed after at least 2 prior therapies. Idelalisib, copanlisib, and duvelisib each showed similar overall response rate and progression-free survival efficacy along with significant toxicity in separate phase II single-arm studies. Umbralisib, as the 4^th iteration in this PI3K-inhibitor class for relapsed/refractory indolent B-cell lymphoma (iB-NHL), appears comparably active but may have improved tolerability.

Areas Covered

We review the use and limitations of PI3K-inhibitors for iB-NHL and discuss the development of and clinical results for umbralisib. Efficacy data are contextualized alongside other PI3K-inihibitors within the limitations of published single-arm studies. We compare and contrast available safety data, covering the off-target inhibition by umbralisib of casein kinase 1ε that is thought to contribute to a more favorable immune-mediated toxicity profile.

Expert Opinion

Though a late-comer to the PI3K-inihibitor party in iB-NHL, umbralisib may carve out an important role in treatment algorithms. Umbralisib's apparently superior safety needs to be confirmed in real-world and, ideally, comparative studies but stands to make it an attractive option in patients who are frail and/or seek treatments more compatible with remote management.

KEYWORDS:

• Follicular lymphoma
• marginal zone lymphoma
• phosphoinositide 3-kinase
• umbralisib

Declaration of Interest

SA Graf has received institutional research funding from Acerta Pharma, BeiGene, GlaxoSmithKline, MorphoSys and TG Therapeutics. He has also served as consultant/advisor for MorphoSys. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.