John Burke, MD, Rocky Mountain Cancer Centers, Aurora, Colorado, discusses the efficacy and safety of the UNITY-DLBCL clinical trial on umbralisib, ublituximab, and bendamustine for patients with relapsed and refractory (R/R) diffuse large B-cell lymphoma (DLBCL). These data were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

Transcript

Hi, my name is John Burke at Rocky Mountain Cancer Centers in Aurora, Colorado.

The first study is entitled UNITY-NHL. This is a clinical trial in patients with R/R DLBCL, where we tested administration of a PI3-kinase inhibitor drug called umbralisib, given as a single agent and then given in combination with an anti-CD20 antibody that's a novel one called ublituximab. Then finally, we tested a triplet of both of those 2 drugs plus bendamustine. A sequential series of combinations used in patients with relapsed DLBCL.

The other trial that I will not be presenting at ASH, but I was involved with is called POLARIX. This was a randomized trial in patients with previously untreated DLBCL in which patients received either the standard chemotherapy of R-CHOP or the investigational arm of polatuzumab, which is anti-CD79b antibody-drug conjugate in combination with rituximab and CHP, cyclophosphamide, doxorubicin, and prednisone. This was a randomized trial, front-line DLBCL.

Click here to read more on the POLARIX study.

In the UNITY DLBCL trial, we found that single-agent umbralisib led to relatively low response rate of 13 percent, but did have some activity in R/R DLBCL. Then, when we started combining it, we saw responses and outcomes improve. When we gave umbralisib plus ublituximab, we saw an overall response rate (ORR) of 32 percent. Then when we combined the triplet of U2 plus bendamustine, we saw an ORR of 43 percent.

Other significant endpoints of the trial were progression-free survival (PFS), which was relatively short in the umbralisib alone arm at 2 months. Actually, even in the U2 arm, it was only a median of 2 months. Whereas in the triplet arm, it was a median of 5 months.

Interestingly, in both the U2 and the U2 plus bendamustine arms, we did see a handful of patients in the ballpark of 20 percent or so who had meaningful long-term disease-free survival (DFS) extending out for several years. We still have some patients remaining on drug now out several years after initiation of therapy.

The other thing we looked at was safety, which we felt was relatively manageable without too many unexpected toxicities beyond what we already know happened with PI3-kinase inhibitors, and CD20 antibodies, and bendamustine.

We feel that the trial demonstrated that PI3-kinase inhibitors may have some activity in DLBCL — and this is a relatively new finding — but that outcomes were improved when it can be combined with the novel anti-CD20 antibody, and then probably improved even further when combined with bendamustine.

Right now, neither umbralisib or ublituximab is approved for use in DLBCL. It remains to be determined whether such an approval would happen. The further development of this combination is under internal discussion. It is not entirely clear what the next steps are going to be. Whether this will be pursued further or whether the other possible option might be to explore it in combination with other treatments different from bendamustine to see if outcomes could be improved further.

In terms of the real world right now, this is not a regimen that will be used tomorrow by people treating relapsed DLBCL, but it might have applicability in the future. That's what's under discussion right now. Is either whether we're going to take this to another trial, or let's say, a more formal phase 3 trial is a matter of discussion right now internally.