According to a report presented at the 23rd Congress of the European Hematology Association, the phosphoinositide 3-kinase (PI3K) and casein kinase-1ε inhibitor umbralisib represents an alternative option for patients with chronic lymphocytic leukemia (CLL) who become intolerant of other kinase inhibitors.
“Many patients treated with first-generation inhibitors [such as ibrutinib, idelalisib, or acalabrutinib] can have excellent results; however, there is a significant portion of patients who discontinue therapy due to the associated side effects,” lead study author and presenter Anthony R. Mato, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, told ASH Clinical News. “Rather than abandon a class of drugs, our data show that [we] can switch from one inhibitor to another with good tolerance.”
The phase II trial enrolled patients with CLL who were intolerant to kinase inhibitors, defined as experiencing at least one grade 3 or at least two grade 2 non-hematologic adverse events (AEs); at least one grade 3 neutropenia with infection or fever; and/or at least one grade 4 hematologic toxicity leading to discontinuation of kinase inhibitors.
All toxicities were required to resolve to no more than grade 1 severity before treatment began with the study drug, and patients were eligible if they had discontinued kinase inhibitor therapy ≥14 days prior to enrollment without CLL progression. However, patients also were eligible if CLL progressed after 14 days of treatment discontinuation.
Participants received umbralisib 800 mg orally, once daily within 12 months of prior kinase inhibitor discontinuation. Umbralisib treatment continued until disease progression, toxicity, or study conclusion.
Primary and secondary endpoints were as follows:
- primary endpoint: progression-free survival (PFS)
- secondary endpoints: duration of response; time to treatment failure; safety
As of February 2018 (data cut-off date), 40 patients were enrolled: 36 were Bruton’s tyrosine kinase (BTK) inhibitor– intolerant and four were PI3K inhibitor–intolerant. The median age was 69 years (range = 52-96 years) and the median number of prior therapies was two (range = 1-7).
Thirty-two patients (80%) began treatment with umbralisib within six months of prior kinase inhibitor discontinuation.
The most common AEs that led to prior kinase inhibitor discontinuation included: arthralgia (n=9; 23%), rash (n=9; 23%), atrial fibrillation (n=6; 15%), diarrhea (n=4; 10%), bleeding (n=3; 7.5%), fatigue (n=3; 7.5%), and weight loss (n=3; 7.5%).
In this phase II study, four patients discontinued umbralisib due to intolerance (e.g., rash, pneumonia, pneumonitis, pancreatitis), while one patient discontinued due to study noncompliance. AEs that occurred with umbralisib treatment appeared similar to those associated with prior kinase inhibitors, but “no patient has discontinued umbralisib as a result of a prior kinase inhibitor– intolerant AE,” the authors reported (TABLE).
Four patients had recurrence of the AE that led to intolerance of their prior therapy, they added, “however, all recurrences were of lesser severity, and none led to discontinuation or dose-modification of umbralisib.” Three patients (7.5%) required dose reductions of umbralisib, due to instances of colitis, headache, and hematologic events, but all reinitiated umbralisib.
At a median of seven months’ follow-up (range = 1-16 months), progression-free survival had not been met, with 90 percent of patients alive and continuing umbralisib. No patients died during follow-up, though the authors noted that longer-term data are needed to better understand the safety profile of umbralisib.
The study’s small population and limited follow-up are limitations of its findings, Dr. Mato explained, but added, “in the future, as we learn about mechanisms of resistance and intolerance, we can use the information regarding discontinuation to guide next therapy.”
Based on these results, the study investigators are collecting and analyzing participants’ peripheral blood samples for a correlative analysis, in the hopes of detecting biomarkers associated with intolerance to kinase inhibitors. In addition, Dr. Mato mentioned that researchers from MSKCC also are investigating the safety and efficacy of umbralisib in combination with other PI3K inhibitors therapies to identify whether safer and more effective combination regimens exist for patients with CLL intolerant to kinase inhibitors.
Dr. Mato reports a financial relationship with TG Therapeutics, the manufacturer of umbralisib.
Mato AR, Schuster SJ, Lamanna N, et al. A phase 2 study to assess the safety and efficacy of umbralisib (TGR-1202) in patients with chronic lymphocytic leukemia (CLL) who are intolerant to prior BTK or PI3K delta inhibitor therapy. Abstract #S808. Presented at the 23rd Congress of the European Hematology Association, June 16, 2018; Stockholm, Sweden.