Next-generation PI3Kδ inhibitor umbralisib warrants further investigation
medwireNews: The phosphatidylinositol 3-kinase isoform p110δ (PI3Kδ) inhibitor umbralisib has shown preliminary activity against relapsed or refractory hematologic malignancies, with fewer autoimmune-like toxicities than other drugs in its class, researchers report.
Owen O’Connor (Columbia University Medical Center, New York, USA) and colleagues explain that umbralisib is structurally distinct from other PI3Kδ inhibitors, such as idelalisib and duvelisib, with improved isoform selectivity, minimal off-target cytochrome P450 inhibition, and a plasma exposure concentration that makes it suitable for once-daily dosing. It also inhibits casein kinase-1ε, a major regulator of protein translation.
The researchers investigated its safety and activity in a phase I dose-escalation trial among 90 patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, B- and T-cell non-Hodgkin lymphoma, or Hodgkin lymphoma, who had received at least one previous treatment regimen.
The drug was initially given once daily as an oral tablet, when the patients were in a fasting state, at a starting dose of 50 mg increasing to 1800 mg until the maximum tolerated dose was reached, or the maximal dose cohort was accrued without a dose-limiting toxicity. The tablet was later switched to a micronised formulation taken in a fed state at an initial dose of 200 mg, increasing to 1800 mg.
The researchers found that umbralisib had a “favourable safety profile” which differed from that of other PI3Kδ inhibitors. Specifically, there were fewer reports of colitis, increased transaminases, and pneumonitis compared with previous data.
During a median treatment duration of 4.7 cycles (133 days), the most common treatment-emergent adverse events were diarrhoea (43%), nausea (42%), and fatigue (31%), most of which were grade 1 or 2 in severity.
Neutropenia (13%), anemia (9%), and thrombocytopenia (7%) were the most commonly reported grade 3 or 4 adverse events, and there were seven serious adverse events at least possibly related to treatment, namely pneumonia (n=3 cases), colitis (n=2), lung infection (n=1), and febrile neutropenia (n=1).
However, O’Connor and team point out that both cases of colitis occurred at above the recommended phase II dose of 800 mg of the micronised formulation. The maximum tolerated dose was 1200 mg of this formulation.
Just over a third (37%) of patients had an objective response to treatment, with the greatest response recorded among 20 patients with chronic lymphocytic leukemia, at 85%.
By comparison, the objective response rate was 31% among the 13 patients with diffuse large B-cell lymphoma, but the researchers note that other PI3Kδ inhibitors have not been reported to be active in this group of patients.
Writing in The Lancet Oncology, O’Connor et al conclude: “The promising safety and activity data for umbralisib suggest that the full potential of PI3Kδ inhibitors for the treatment of haematological malignancies has not yet been realised.”
They add: “Further assessment of umbralisib as a single agent and in combination with other novel targeted agents is warranted, and several clinical studies are ongoing.”
In an accompanying comment, Jacqueline Barrientos, from the Zucker School of Medicine in New York, USA, describes the study findings as “encouraging” but points out that some of the toxicities previously observed with other PI3Kδ inhibitors developed after prolonged treatment.
The relatively short median treatment duration in the current study means that “[i]t will be important to see if a longer follow-up correlates with achievement of deeper remissions without the emergence of complications expected with the administration of other PI3Kδ inhibitors,” she writes.
By Laura Cowen
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