Anthony R. Mato, MD
The next generation PI3K-delta inhibitor umbralisib (TGR-1202) showed promising safety results while inducing durable responses in high-risk patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to data from a phase II study.
All patients (N = 50) in the multicenter study had discontinued treatment with a BTK or PI3K inhibitor. These data include 47 patients evaluable for safety and 46 evaluable for the primary endpoint of progression-free survival (PFS).
Seventy-seven percent of patients required treatment within 6 months of discontinuing their prior kinase inhibitor therapy. Sixty-eight percent had high-risk molecular or genetic markers, and 6% had an ibrutinib resistance mutation. Seven (15%) patients had 17p deletion, 8 (17%) had 11q deletion, and 25 (53%) had IGHV unmutated.
Anthony R. Mato, MD, MSCE, director of the Chronic Lymphocytic Leukemia Program at Memorial Sloan Kettering Cancer Center, presented the data at the 2018 EHA Congress. He said that, so far, 6 patients (13%) had discontinued umbralisib and only 1 had discontinued due to the same adverse event (AE) that led to the previous discontinuation.
“You could argue this is the highest-risk patient population for having a toxicity event because they've already experienced 1 on a similar drug,” he said. “There were few discontinuations due to AEs [with umbralisib].”
Investigators recorded 16 grade 3/4 AEs in the trial. The most common grade 3/4 AE was neutropenia (15%) followed thrombocytopenia (9%), diarrhea (6%), anemia (2%), and pyrexia (2%).
Mato added that patients in the study had durable responses to umbralisib despite their high-risk status. As of the data cutoff, 47% of patients had been on umbralisib longer than they had received their prior kinase inhibitor. The median time on prior treatment was 9 months (range, 1-38).
Moreover, median PFS and overall survival were not reached at a median follow-up of 9.5 months.
In an interview with OncLive®
during the 2018 European Hematology Association Congress, Mato discussed the next steps for umbralisib and the biggest challenges still facing patients with CLL.
OncLive: What was the rationale for this study?
: In clinical practice, about half of the discontinuation of drugs like ibrutinib (Imbruvica) or idelalisib (Zydelig) have been due to a toxicity or AE. What we've noticed, at least retrospectively, is that those side effects tend to be different—the ibrutinib-related toxicities are different than the idelalisib-related toxicities. From a retrospective study that we did, we noticed that in practice, when patients are switched from ibrutinib to idelalisib or idelalisib to ibrutinib in the setting of intolerance, you could maintain the response without having to switch to another agent. We felt that this intolerant patient population was a large number of patients and that this was an unmet clinical need.
The trial looks at a new PI3K-delta inhibitor called umbralisib, or TGR-1202. The trial was specifically geared at patients who discontinued a BTK or PI3K inhibitor in the setting of intolerance. To participate in this study, you had to meet our protocol-specified definition of intolerance, which essentially was any patient who had 2 or more toxicities that were grade 2 or higher due to a drug like ibrutinib. For example, [this includes] 1 or more grade 3 or 4 toxicity, nonhematologic; 1 grade 3 event of neutropenia with fever or infection; or a grade 4 hematologic toxicity that was long lasting and that the investigator felt was due to a drug and not progression. That was the definition of intolerance.
Then it had to resolve to grade 1 or less to see if that same toxicity reoccurred. If patients met that criteria and they didn't progress within 14 days of stopping the prior kinase inhibitor, they were eligible and treated with umbralisib at a dose of 800 mg once per day.
This is a multicenter trial. Fourteen centers participated across the United States. The study, as of September of [last] year fully accrued and we have 50 patients who participated in this study. [I presented] safety data on 47 of the 50 patients, and data on the primary endpoint, which is PFS, on 46 of the patients.
What were the safety results?
In the 47 patients, there were 68 total toxicity events that led to discontinuation, and they're the ones that you would expect. From the BTK inhibitors, we had bleeding events; for example, this includes atrial fibrillation. From the PI3K inhibitor part of the cohort, we had patients who had colitis and pneumonitis.
The patient population is a relatively typical relapsed/refractory CLL population, although there are significant high-risk features. The median age was 72, median number of prior therapies was 2, 85% of patients discontinued a prior BTK inhibitor, and 15% [discontinued] a PI3K inhibitor.