Umbralisib Shows Promise in Relapsed/Refractory CLL

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.

OncLive: What was the rationale for this study?

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.Mato: 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.

What were the safety results?

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.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.

There is a fair proportion of high-risk features. Approximately 68% of patients had at least a 17p deletion, IGHV unmutated, or deletion of 11q. There is also a small proportion of patients who had ibrutinib resistance mutations, including BTK and PLCG2.

Do you have survival results yet?

The toxicity profile of umbralisib in this high-risk population was quite impressive. The drug was well tolerated. There were relatively few grade 3/4 events. Of the 47 patients, only 1 discontinued umbralisib due to the same side effect that led to the discontinuation of the prior kinase inhibitor. In total, only 6 patients discontinued umbralisib due to an AE.The median follow-up was 9.5 months. At this point in time, the median PFS has not been reached, which was quite similar to what we observed in the retrospective analysis where patients were able to switch between kinase inhibitors.

What’s the take-home message from this study?

Based on these findings, what is the next step?

What are the biggest unmet needs in patients with CLL?

In terms of OS, there’s only been 1 death on the study. This was a patient who had been on ibrutinib for 3 months, then umbralisib for 11 months, then progressed and went on venetoclax (Venclexta). Ultimately, several months later, this patient progressed and died of disease progression.Umbralisib was very well tolerated in this high-risk patient population. You could argue that this is the highest-risk patient population for having a toxicity event because they've already experienced 1 on a similar drug. There were few discontinuations due to AEs. [This was] a relatively high-risk patient population, and yet we were able to show durable responses.Umbralisib is being studied in combination with ublituximab, the so-called “U2 regimen,” in frontline and refractory settings as compared with obinutuzumab (Gazyva) and chlorambucil. That’s the registration trial that will look at this drug in combination for frontline and relapsed/refractory CLL. The hope is, in part, that if this drug were to receive approval, that it would be something that clinicians would think about in the setting of having an intolerance event, for example. These data support the activity of this drug and, more importantly, the toxicity profile of this drug.The 3 biggest unmet needs are, first and foremost, patients who have transformation to Richter’s transformation—a very difficult situation with limited survival and no clear strategy for how to manage these patients. The second, in the current landscape, is how to treat patients who progress beyond venetoclax. We have important prospective sequencing data; for example, that ibrutinib could follow chemotherapy and venetoclax could follow ibrutinib, but there's no clear strategy for managing patients who have resistance to venetoclax.

The third [unmet need] is the sequencing question. As we have more and more agents available, which is great for clinicians and more importantly for patients, there are very few comparative clinical trials with relevant control arms that teach us how to use these drugs and in what order.

The big trend in CLL is to combine all these drugs together, but there is very limited information on what resistance looks like beyond these combinations and who needs these combinations. These combinations are generally not compared with other therapies, so we have limited information on how combinations are more important or better than sequential monotherapy.

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. In: Proceedings from the 2018 European Hematology Association Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S808.