Umbralisib Shows Potential For Previously Treated indolent NHL

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Patients with indolent non-Hodgkin lymphoma (iNHL) unresponsive to earlier treatment might benefit from treatment with umbralisib, suggest the phase IIb UNITY-NHL trial findings. 

“Available targeted treatment options for patients with relapsed or refractory disease are limited and associated with treatment-limiting toxicities”, say Pier Luigi Zinzani, from IRCCS Azienda Ospedaliero-Universitaria di Bologna in Italy, and co-investigators. 

“These data demonstrate that umbralisib may provide a novel targeted treatment option for previously treated patients with indolent lymphomas.” 

The oral dual inhibitor of phosphatidylinositol-3-kinase δ-isoform (PI3Kδ) and casein kinase-1ε (CK1ε) was given once daily at a dose of 800 mg until disease progression or unacceptable toxicity to 208 patients with relapsed or refractory marginal zone (MZL), follicular (FL) or small lymphocytic lymphoma (SLL). 

The patients had received up to 10 prior therapies (median 2.0 therapies); the MZL patients all had disease unresponsive to at least one prior treatment, including one or more anti-CD20 agents, while the FL and SLL patients had relapsed or refractory disease after at least two treatments including an anti-CD20 treatment. 

After a median 27.7 months of follow-up for efficacy, 47.1% of patients had responded to treatment according to an independent review committee.  

This included 49.3% of the 69 MZL patients, 45.3% of the 117 patients with FL and 50.0% of the 22 patients with SLL, with complete responses reported for a corresponding 15.9%, 5.1% and 4.5% of the groups.  

And radiographical assessment showed a tumour volume reduction after treatment in 90.6% of the assessed MZL patients, 83.5% of those with FL and 89.5% of those with SLL, the researchers say. 

Median duration of response was unreached for the MZL patients, 11.1 months for the FL patients and 18.3 months for the SLL patients, with median times to response of 2.8, 4.6 and 2.7 months, respectively. 

Median progression-free survival was also unreached for the MZL patients, and a median 10.6 months for the FL and 20.9 months for the SLL patients, with 2-year rates of 50.5%, 18.1% and 31.3%, respectively.  

Safety analysis was performed after a median 21.4 months of follow-up and a median 8.4 months of exposure to umbralisib, with treatment continuing at time of data cutoff in 26 MZL patients, 27 FL patients and seven SLL patients. 

Overall, 53.4% of patients had at least one grade 3 or more severe treatment-emergent adverse event (TEAE), including neutropenia in 11.5% and diarrhoea in 10.1%.  

Of the TEAEs of special interest due to reports of fatal or serious immune-mediated toxicities in first-generation PI3K inhibitors, elevated alanine transaminase (ALT) and aspartate transaminase (AST) were reported at grade 3 or above in 20.2% and 18.8% of patients, respectively. In addition, 3.4% had grade 3–4 opportunistic infection, 1.9% rash, 19.9% noninfectious colitis, and 1.4% pneumonitis. Three patients with grade 3 diarrhoea underwent colonoscopy but none had signs of colitis. 

Diarrhoea and ALT/AST increases at grade 3 or more severe were the most common reasons for treatment discontinuation, affecting 2.9% and 2.4% of patients, respectively, while TEAEs associated with umbralisib led to dose reductions in 9.6%. 

“In UNITY-NHL, umbralisib showed meaningful clinical activity in patients with [relapsed or refractory] iNHL consistent with that demonstrated by prior inhibitors of PI3K”, conclude Pier Luigi Zinzani and co-authors in the Journal of Clinical Oncology. 

“However, the safety profile appears improved compared with first-generation PI3K inhibitors, with manageable toxicities and a relatively low number of AE-related discontinuations.” 

They therefore conclude that their study findings “suggest that umbralisib has a favorable 

benefit-risk profile in this heavily pretreated population.” 

Reference 

Fowler NH, Samaniego F, Jurczak W, et al. Umbralisib, a dual PI3Kδ/CK1ε inhibitor in patients with relapsed or refractory indolent lymphoma. J Clin Oncol; Advance online publication 8 March 2021. doi: 10.1200/JCO.20.03433