Copanlisib: An Intravenous Phosphatidylinositol 3-Kinase (PI3K) Inhibitor for the Treatment of Relapsed Follicular Lymphoma

Abstract

Objective: To review the mechanism of action, clinical efficacy, safety, dosage, administration, and role of copanlisib in the treatment of relapsed follicular lymphoma (FL). Data Sources: Sources of information were identified through searches of PubMed (August 2014 to January 2019) using the key terms copanlisib, Aliqopa, PI3K inhibitor, and BAY 80-6946. Unpublished abstract information was obtained from the American Society of Clinical Oncology. Study Selection and Data Extraction: Review articles and studies in the English language evaluating the pharmacology, efficacy, and safety of copanlisib were included. Data Synthesis: Copanlisib is the first intravenous phosphatidylinositol 3-kinase (PI3K) inhibitor approved for the treatment of relapsed FL in patients who have received at least 2 prior systemic therapies. The safety and efficacy of copanlisib has been studied in the multicenter, single-arm, phase II CHRONOS-1 study. The results reported for FL patients were an objective response rate of 59%, a complete response of 14%, median duration of response of 22.6 months, and median progression-free survival of 11.2 months. The most common adverse events reported were hyperglycemia and hypertension, which were infusion related and transient. Relevance to Patient Care and Clinical Practice: Copanlisib is unique in that it is a pan–class I PI3K inhibitor with preferential inhibitory activity against the PI3K-α and PI3K-δ isoforms. It has a more favorable safety profile than the other agents in its class with no late-onset toxicities. Conclusions: Copanlisib provides an alternative option for patients with relapsed FL. It is safe and effective and has an acceptable toxicity profile.

Immunological characterization of HM5023507, an orally active PI3Kδ/γ inhibitor

“…The efficacy of PI3K inhibitors in human cancers is consistent with the evidence linking gain of function mutations in PI3Ks (α,β and γ) as drivers of malignancy . Unfortunately, the efficacy often requires complete/sustained inhibition of PI3K signaling resulting in dose‐limiting toxicities (eg, colitis, hepatitis, pneumonitis, hypertension, hyperglycemia, skin rash, and opportunistic infections), likely driven by the disruption of homeostatic innate/adaptive immune PI3K signaling .…”

“…These efforts have focused initially on pan‐PI3K inhibitors, and subsequently on isoform‐selective and dual isoform inhibitors . Nearly 15 compounds of varying PI3K isoform selectivity have been explored in the clinic culminating in the launch of four drugs to treat different forms of cancers: idelalisib [Zylidig®, a PI3Kδ selective inhibitor],] duvelisib [Copiktra®, a dual PI3Kδγ inhibitor], alpelsib [Piqray®, a PI3Kα inhibitor], and copanlisib [Aliqopa®,BAY 80‐6946, a dual PI3Kδα inhibitor] …”

“…8,[10][11][12][13] Nearly 15 compounds of varying PI3K isoform selectivity have been explored in the clinic culminating in the launch of four drugs to treat different forms of cancers: idelalisib [Zylidig®, a PI3Kδ selective inhibitor], 5 ] duvelisib [Copiktra®, a dual PI3Kδγ inhibitor], 14 alpelsib [Piqray®, a PI3Kα inhibitor], 15 and copanlisib [Aliqopa®,BAY 80-6946, a dual PI3Kδα inhibitor]. 16 Dual inhibitors of PI3Kδ and PI3Kγ are considered high-value targets both for inflammation/ autoimmunity and oncology. 8,9 Compelling preclinical biology of PI3Kδ/γ, initially garnered from gene knockout studies and later substantiated through the use of small-molecule inhibitors, 7,[17][18][19][20][21][22][23][24][25][26] led to significant investments by the pharmaceutical industry in the last two decades reflected in approximately ~220 patent publications (~80% on PI3Kδ inhibitors, ~15% on PI3Kγ inhibitors, and ~5% for dual inhibitors).…”

SHC014748M, a novel selective inhi-bitor of PI3Kδ, demonstrates promising preclinical antitumor activity in B cell lymphomas and chronic lymphocytic leukemia

“…But it also has a black box warning regarding the risks of fatal and serious toxicities including severe diarrhea, colitis, pneumonitis, infections and cutaneous reaction [29 , 30] . Copanlisib has predominant inhibition against PI3Kα and PI3Kδ isoforms, which has been proved by FDA for the treatment of patients with relapsed FL after at least 2 prior systemic therapies [31] . Although these treatments approved by FDA showed encouraging efficacy for iNHL, serious adverse drug reactions are difficult to avoid.…”

Hypertension and QT interval prolongation associated with targeted systemic cancer therapies

“…Drug-induced hypertension associated with the intravenous phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitor copanlisib is transient, self-limiting, peaks within the first two hours of infusion, and typically lasts no more than 24 hours. 30,31 One proposed mechanism for the hypertension seen with use of this targeted cancer therapy is post-infusion hyperglycemia. 32 A PI3Kα inhibitor class effect, this hyperglycemia leads to insulin-dependent vasoconstriction which increases systemic vascular resistance and subsequently, elevates blood pressure.…”