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ASH 2020 | Umbralisib + ublituximab shows superior outcomes to standard of care chemoimmunotherapy in CLL

John Gribben, MD, DSc, FRCP, FRCPath, FMed Sci, Barts Cancer Institute, London, UK, discusses the results of the Phase III UNITY-CLL trial (NCT02612311), which compared umbralisib plus ublituximab (U2) to obinutuzumab plus chlorambucil (O+Chl) in chronic lymphocytic leukemia (CLL). U2 combines a dual PI3Kδ- CK1ε inhibitor with superior delta specificity and a novel anti-CD20 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity capabilities. 421 patients were randomized, of whom 57% were treatment naïve and 43% were relapsed/refractory. The results showed that, across both subgroups, the primary endpoint of median progression-free survival (PFS) was significantly prolonged with U2 use, compared to O+Chl (31.9 months vs 17.9 months). The overall response rate was also improved, supporting approval of the combination in CLL. This interview took place during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, 2020.

Transcript (edited for clarity)

So the U2 study is a study of umbralisib in combination with ublituximab and when you hear those two words, now you know why we call it U2. So umbralisib is a novel oral, once-daily, PI3-kinase delta inhibitor. And we’ve had other PI 3-kinase delta inhibitors in the past, notably idelalisib, of course, which was the first of the targeted therapies approved in CLL. And also, duvelisib.

So, what’s different about umbralisib? Well, it looks as if it’s more specific for delta with less activity against gamma...

So the U2 study is a study of umbralisib in combination with ublituximab and when you hear those two words, now you know why we call it U2. So umbralisib is a novel oral, once-daily, PI3-kinase delta inhibitor. And we’ve had other PI 3-kinase delta inhibitors in the past, notably idelalisib, of course, which was the first of the targeted therapies approved in CLL. And also, duvelisib.

So, what’s different about umbralisib? Well, it looks as if it’s more specific for delta with less activity against gamma. And it looks as if its safety profile looks, on paper at least, to be better than the other PI3-kinase delta inhibitors. So this is a class of drugs that we know to be effective in the treatment of CLL and in low-grade lymphomas. And this study, the U2 combination, was being compared to a Phase III trial to umbralisib plus obinotuzumab.

So, the importance of this study was this is a pivotal study looking for approval of this agent and this combination in CLL. So, the umbralisib plus ublituximab combination is a novel-novel combination. And of course, in the past, you wouldn’t have been able to get approval for two novel drugs together.

But because of that, as the study opened, we had to have an arm looking at umbralisib, ublituximab enrollment alone. And then the DSMB were able to look at the data and close those two arms early. And therefore, what’s being presented at ASH is the direct comparison of the umbralisib plus ublituximab versus obinutuzumab plus chlorambucil.

A novel component of this study is it enrolled both treatment-naïve and relapsed/refractory CLL patients. So in terms of its primary endpoint, it met its primary endpoint in that the U2 had an improved progression-free survival advantage over chlorambucil obinutuzumab – 31.9 months versus 17.9 months. So it met its primary endpoint.

In terms of the treatment-naïve population, the median progression-free survival for the frontline patients was 38.5 months versus 26 months for the chlorambucil, obinutuzumab arm. Again, highly statistically significant improvement. Importantly, a good number of the cases are censored above the median time. So with further follow-up, we are hoping and expecting that that median progression-free survival might be even longer.

Now the treatment-naïve setting population is an important one here because the other PI3-kinase inhibitors that show efficacy all ran into problems in the upfront setting. That is these auto-immune complications that we see were higher in that setting. But we did not see that occurring with this particular combination. There was diarrhea as one of the more common side effects. But colitis, which is the side effect that we fear and pneumonitis were actually very rare in this particular study.

So overall a positive study. And the conclusion is this brings another class of agents to be available for our patients with CLL. And once approval, we should have another PI3-kinase inhibitor out there with a novel anti-CD20 antibody to add to the drugs that we already have that we know to be effective in CLL. And yet another study in CLL demonstrating that novel agents are outperforming chemoimmunotherapy. So basically, another nail in the coffin for chemoimmunotherapy in the treatment of CLL.

 

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