Ublituximab Plus Ibrutinib Induces Promises Responses in High-Risk Relapsed/Refractory CLL

Jeff P. Sharman, MD

The phase 3 GENUINE clinical trial demonstrated a statistically significant improvement in the objective response rate (ORR) with the addition of ublituximab (TG-1101) to BTK inhibitor ibrutinib (Imbruvica) in patients with high-risk chronic lymphocytic leukemia (CLL).

Progression-free survival (PFS) also favored the combination compared with ibrutinib alone in this study, which was the first randomized trial to demonstrate a PFS benefit with the addition of a CD20-directed antibody to ibrutinib. It is unclear how important the primary end point of ORR was as BTK inhibitors tend to lead to more prolonged responses, but the magnitude of PFS benefit was observed primarily in patients with TP53 mutations or deletion of 17p.

When the study was conducted, deletion of 17p or 11q and TP53 mutations were considered high-risk in the CLL population. However, it has since been noted that 11q deletions are not considered as high of a risk as its counterparts.

Overall, the addition of ublituximab was well-tolerated in this patient population and did not lead to any new or unexpected safety signals when added to ibrutinib.

In an interview with Targeted Oncology, Jeff P. Sharman, MD, director of research at Willamette Valley Cancer Institute and medical director of hematology research for The US Oncology Network, discussed the findings for the combination of ublituximab plus ibrutinib as treatment of patients with high-risk relapsed/refractory CLL.

TARGETED ONCOLOGY: Before we get into the trial results, could you discuss the unmet need of high-risk AML?

Sharman: For most individuals with relapsed CLL, including those with high-risk markers, we know that although ibrutinib and BTK inhibitors, in general, may be some of the most effective therapies in this setting, they have inferior outcomes relative to those patients who lack these markers. In the initial time frame when we were first looking at BTK inhibitors in the relapsed/refractory population, which included patients with 17p deletions, TP53 mutations, or 11q deletions, it now appears subsequent to the conduct and execution of the study that those patients with 11q deletion may not be as high risk as we initially perceived, at least [compared with] patients with 17p deletions and TP53 mutations, who have inferior PFS relative to their counterparts.

TARGETED ONCOLOGY: Could you shed light on ublituximab and its mechanism of action?

Sharman: Ublituximab is a novel anti-CD20 antibody, and it binds to a distinct epitope on the CD20 molecule. It is engineered to enhance antibody-dependent cellular cytokine toxicity nd has a handful of other adaptations. However, it is a second-generation CD20 antibody.

TARGETED ONCOLOGY: How was the trial designed? What were the primary objectives?

Sharman: This was a study in which patients with relapsed/refractory CLL were screened for high-risk markers. Of course, in the relapsed setting, that may be approximately 30% to 40% of patients. They were screened for high-risk markers and essentially verified, and that included 17p deletion, TP53 mutation, or deletion of 17q. They were then randomized 1:1 to receive either ibrutinib with or without ublituximab. Ublituximab was administered as an intravenous infusion, and those patients were followed for ORR, which was the primary end point of the study. The second end point was PFS.

TARGETED ONCOLOGY: What did you ultimately find in these results?

Sharman: The study was initially designed to be a larger study in which there were co-primary end points of ORR and PFS. However, because this was a challenging population to find in the setting in which the trial was conducted, the protocol was amended to have ORR as a primary end point and PFS as the secondary end point.

We did find that there was an improvement in ORR. That improvement was statistically significant. However, a reasonable criticism would be that the ORR may or may not matter when it comes to BTK agents, which are having more prolonged mechanisms of action. Perhaps adding the CD20 antibody only accelerated the response.

What we found in the secondary end point was that PFS also significantly favored those individuals who received ublituximab. Interestingly, as it turns out and as the field has evolved, 11q deletion has been deemed not as high risk as we thought when this study was conceived. The benefit of ublituximab wasn’t seen as much in those patients with 11q. Conversely, in those patients with either TP53 mutations or 17p deletions is where the primary benefit was seen, and that is where the magnitude of PFS was demonstrated.

The reason this is interesting to the field is that the proper role for the addition of CD20 antibodies to BTK inhibitors remains very much uncertain. Two well-conduced clinical trials in which rituximab (Rituxan) was added to ibrutinib demonstrated no meaningful benefit with the addition of rituximab to ibrutinib. In contrast, our group reported earlier at the 2019 ASH that the addition of obinutuzumab (Gazyva) to acalabrutinib (Calquence), so a different CD20 antibody and BTK inhibitor, did have some meaningful improvement in PFS. Now we have this study, in which another second-generation CD20 antibody was added to ibrutinib, which may have efficacy. It simply calls into question where CD20 antibodies fit in the management of patients with CLL treated with a BTK inhibitor.

TARGETED ONCOLOGY: What was the safety profile of this regimen?

Sharman: There weren’t any new safety signals observed in this study. Primary side effects of ublituximab are infusion-related reactions, like neutropenia, but overall, it was a well-tolerated therapy consistent with CD20 antibodies.

TARGETED ONCOLOGY: Minimal residual disease (MRD) negativity was also assessed in this trial, so did you find that was associated with improved outcomes?

Sharman: We saw considerably higher rates of MRD negativity amongst those patients with the addition of the CD20 antibody. We did see deeper responses, higher rates of complete response, and ORRs in the group with MRD negativity with the addition of ublituximab.

TARGETED ONCOLOGY: Would you say we are at a point where we can begin adjusting treatment according to MRD status, or is it fairly investigational at this time?

Sharman: Not yet, which in part is because none of the studies to date have a decision point in which MRD positivity or negativity leads to differential outcomes that demonstrate benefit. We do know that those patients treated with BTK monotherapy rarely obtain MRD negativity, so you have to add additional agents, such as a CD20 antibody or a BCL2 inhibitor, to get to MRD negativity. Amongst those patients treated with BCL2 inhibitors, we know that the failure to achieve MRD negativity probably correlates with a shorter duration of PFS. However, whether you would continue BCL2 antagonist or not remains uncertain.