Efficacy and Safety of Umbralisib, Ublituximab (U2), and U2 Plus Bendamustine in DLBCL

John Burke, MD, Rocky Mountain Cancer Centers, Aurora, CO, discusses a study analyzing umbralisib alone and in combination with ublituximab (U2), and U2 in combination with bendamustine in patients with relapsed/refractory diffused large B-cell lymphoma (DLBCL).

This study was presented at the 2021 ASH Annual Meeting.

Transcript:  Hello, my name is John Burke. I'm a hematologist/oncologist practicing in Rocky Mountain Cancer Centers in Aurora, Colorado. I'm going to review one of the ASH presentations regarding the Unity DLBCL clinical trial.

This was a trial investigating the novel PI3 kinase inhibitor umbralisib in combination with the novel CD20 antibody called ublituximab and also in combination with the chemotherapy agent bendamustine in patients with relapsed refractory diffused large B-cell lymphoma.

The trial went through several stages, first comparing umbralisib monotherapy with U2, that's umbralisib plus ublituximab. Then, comparing U2 with the triplet of U2 plus bendamustine. Then, finally, expanding the U2/bendamustine cohort.

In all, 30 patients were treated with umbralisib monotherapy. 66 patients were treated with the U2 regimen. Then, 130 patients were treated with U2 plus bendamustine. The results were analyzed by cohort, not by the randomized part of the trial.

The primary endpoint was an overall response rate. The median age was in the 70s for all three cohorts. The median number of prior therapies was two in all of the cohorts. The median follow up was at least 43 months in all the cohorts and was longest for the single agent umbralisib, which had been open the longest.

The results presented are mature. Most patients are now off of therapy. The most common reason for discontinuation of therapy was progression of disease. 7% to 11% of the patients in the different cohorts discontinued therapy due to adverse events.

Common toxicities seen were diarrhea, nausea, fatigue, neutropenia, and vomiting. Grade three or higher diarrhea occurred in 2% to 7% of the patients, depending on the cohort.

Transaminase elevations did occur and increased when ublituximab was added to the umbralisib, but decreased slightly when the bendamustine was added, interestingly. Neutropenia rates increased with the addition of each drug. Other than that, the toxicities were similar across the different cohorts.

The overall response rates were 13% with umbralisib alone, 32% with U2, and 43% with U2 plus benda. The complete remission rates in those same three cohorts were 3%, 11%, and 17%, respectively.

The addition of bendamustine increased the overall response rate in patients with the ABC subtype of DLBCL, but not those with the GCV subtype. We attempted to identify mutations that correlated with response, but there were no clear patterns that we could see.

Interestingly, the median duration of response was longest with U2, a little bit shorter with the triplet. The median progression‑free survival was longest with the triplet due to benda. That was five months, whereas in the other two cohorts it was only two months. Median overall survival was between 8 and 10 months in all three of the cohorts.

In conclusion, the U2 and U2 plus benda triplet were the most active of the regimens. More active than umbralisib alone, although we think it's fair to say that each agent contributed to the efficacy of the overall regimen.

The safety profile was manageable. Further development plans of umbralisib and ublituximab in diffuse large B-cell lymphoma are being considered.