Acalabrutinib/Obinutuzumab Shows Improved PFS in Treatment-Naive CLL

Jeff Sharman, MD

Acalabrutinib (Calquence) with or without obinutuzumab (Gazyva) showed promising safety and efficacy findings in patients with treatment-naive chronic lymphocytic leukemia (CLL) at the 6-year follow-up mark of the ELEVATE-TN trial (NCT02475681).¹

The ELEVATE-TN trial enrolled patients with treatment-naive CLL who went to 1 of 3 arms: acalabrutinib alone, acalabrutinib with obinutuzumab, or obinutuzumab with chlorambucil. If patients progressed on the obinutuzumab/chlorambucil arm, they could cross over to receive acalabrutinib monotherapy. A total of 535 patients were randomized in the study, including 179 who were given acalabrutinib monotherapy, 179 who were treated with acalabrutinib and obinutuzumab, and 177 who were given obinutuzumab and chlorambucil.

At a median follow-up of 74.5 months (range, 0.0-89.0) patients treated with acalabrutinib with or without obinutuzumab had similar efficacy and safety results, including those with high-risk genetic features. The progression-free survival (PFS) rate at 6 years was significantly longer among those in the acalabrutinib with obinutuzumab arm vs acalabrutinib alone.

The median PFS was not reached (NR) in the acalabrutinib with obinutuzumab arm and acalabrutinib alone arm vs 27.8 months for obinutuzumab with chlorambucil. At 72 months, the estimated PFS rates were 78%, 62%, and 17% across arms, respectively. Further, for the 79 patients who crossed over from receiving the obinutuzumab with chlorambucil combination to acalabrutinib monotherapy arm, the median time to second disease progression or death (PFS2) was NR with an estimated 72-month PFS2 rate of 54%.

Additionally, while the median overall survival (OS) was not reached in any arm of the study, those given and acalabrutinib with obinutuzumab had significantly longer OS rates vs those given obinutuzumab with chlorambucil (HR, 0.62; P =.0349).

In an interview with Targeted Oncology^TM, Jeff Sharman, MD, medical director of hematology research at US Oncology, further discussed the updated results at 74.5 months of follow-up for the ELEVATE-TN trial.

Microscopic images of red blood cells activated platelets and white blood cells are showcased in the photographs as a result of leukemia: © AkuAku - stock.adobe.com

Targeted Oncology: Can you provide some information on ELEVATE-TN?

Sharman: This was a prospective, randomized, phase 3 study amongst patients with CLL, previously untreated, evaluating 3 different arms. One was sort of a standard chemotherapy, immunotherapy obinutuzumab/chlorambucil, and then there were 2 experimental arms. The first was acalabrutinib monotherapy. The second was acalabrutinib in combination with obinutuzumab.

Can you discuss findings regarding the long-term efficacy?

We have previously had our first look at the data with approximately 2 years follow-up. We have subsequently presented both 4- and 5-year follow-up, this now being the 6-year follow-up. But rather than just sort of rehashing the data, we took a number of steps to pick apart the data in ways that we had not previously. The most important finding in this study surrounds the use of obinutuzumab in addition to acalabrutinib. Within the field, there has been a lot of controversy as to whether or not adding obinutuzumab to the [Bruton tyrosine kinase (BTK)] inhibitor and prior studies with rituximab [Rituxan] and ibrutinib [Imbruvica], and other studies kind of turned people off of the idea. This study, however, showed a pretty clinically meaningful and statistically significant improvement for patients who received acalabrutinib if they also received obinutuzumab. We undertook a number of efforts to try to identify which patients might benefit.

Most interestingly, we found that any patient who got a complete response had a much longer progression-free survival. And with BTK [inhibitors], that may seem obvious. But for patients treated with BTK inhibitors previously, that has not been demonstrated. We subsequently found that those patients who received an obinutuzumab were much more likely to get a complete response. Those patients with complete response had much better progression-free survival. It's 1 thing to say that a complete response helps. The question is well, who should we be treating with this?

The toxicity differences were not too terribly different. There was a little bit more neutropenia with the addition of obinutuzumab.

But we looked at certain molecular risk groups; we looked at IGHV mutation status, both mutated and unmutated. That did not have a bearing on whether or not patients benefited from a acalabrutinib or with the addition of obinutuzumab. Interestingly, though, the patients with deletion 17p, that is the highest risk group in CLL. We found that those patients did not benefit from the addition of obinutuzumab, so I think it provides some guidance for clinicians to pick and identify who they want to treat with the additional anti-CD20 antibody.

Could you discuss a little more about the durability of treatment responses over the 6-year period?

The patients treated with a combination of acalabrutinib and obinutuzumab have a 78% progression-free survival at 6 years. That is some of the best data we have ever seen in CLL. We are nowhere close to a median on that at all, so this is a highly effective regimen for these patients [and it is] very well tolerated as well.

What specific patient subgroups demonstrated favorable responses?

Oftentimes we divide patients into certain risk categories. So, if they are IGHV unmutated, they tend to have less favorable outcomes with therapies. In this study that did not impact patients’ outcome on acalabrutinib. Similarly, those patients with 17p are some of the highest risk patients; those patients did not get additional benefit from obinutuzumab over acalabrutinib alone.

What can you share about long-term safety?

With BTK inhibitors, there have been a lot of questions about either ventricular arrhythmias or atrial fibrillation and so forth. We have a separate presentation that aggregates 5 different prospective CLL studies, 3 randomized studies and 2 single arm studies, and because 3 of them were randomized studies, were actually able to compare rates of atrial fibrillation to patients treated with agents other than BTK inhibitors. We saw numerically fewer ventricular arrhythmias amongst patients who were treated with acalabrutinib relative to their various control arms.

We also observed that rates of atrial fibrillation were quite low and appeared consistent with baseline risk in the population. At least from our understanding right now, we do not see much of a cardiac signal arising from acalabrutinib, which may differentiate it and apart from some of the other BTK inhibitors.

Based on the 6-year follow up data, what are the immediate clinical implications for oncologists?

I think if a patient is going to be treated with a BTK inhibitor, particularly acalabrutinib, I think that the physician needs to have a thoughtful discussion with their patients about whether or not to add the additional anti-CD20 antibody. I do think that a growing number of key opinion leaders have started doing that more frequently. It still remains a little bit controversial, so we will see how this is received by the field. I hope it sparks some conversation.

In light of those 6-year follow up results, what are some potential avenues for future research?

There are a handful of approaches you can take to treat a previously treated [patient with] CLL. That could be BTK monotherapy. It could be obinutuzumab with a BTK inhibitor. It could be obinutuzumab with venetoclax [Venclexta] or a BTK [inhibitor] with a BCL2 [inhibitor]. There are 4 different strategies emerging. We want to know what is going to be the best 1. We are currently conducting a randomized study in which all patients receive venetoclax and half receive obinutuzumab, half receive acalabrutinib, and I am hoping that that gives us some good insight into picking optimal first-line therapy, but there are patients where we are not going to want to choose venetoclax. For those patients, acalabrutinib in combination with obinutuzumab represents a good option.

REFERENCE:

Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab Vs obinutuzumab + chlorambucil in treatment-naive chronic lymphocytic leukemia: 6-year follow-up of Elevate-TN. Blood. 2023; 142(Suppl 1): 636. doi:10.1182/blood-2023-174750