Combination Therapies With BTK Targeted Therapy in CLL

Alan Skarbnik, MD: In continuing to discuss BTK [Bruton tyrosine kinase] inhibitors and the newer trials that have come out—the ALLIANCE trial and the ECOG-E1912 study—do you use this therapy in combination or use it alone? I mean with the monoclonal antibody. It seems to me that the combination of rituximab with ibrutinib doesn’t add much to the mix.

The ECOG-E1912 trial was a single-arm study with ibrutinib/rituximab. It didn’t have a comparator arm. The ALLIANCE trial studied ibrutinib and rituximab versus ibrutinib versus BR [bendamustine/rituximab], and there was no difference between the ibrutinib/rituximab arm and the ibrutinib arm. So what are your thoughts on the combination of monoclonal antibodies with ibrutinib, particularly?

Jennifer R. Brown, MD, PhD: There’s really no justification to giving ibrutinib with rituximab despite the ECOG-E1912 trial. We have 2 randomized trials that show absolutely no benefit. The curves are completely flat. There was absolutely no difference between the ibrutinib and the ibrutinib/rituximab arms. It’s unfortunate that rituximab was given per ECOG. I usually like to use regimens as they’re given in randomized trials, but I just don’t think that it’s really justified. Plus, the rationale. We know that ibrutinib inhibits ITK and this inhibits the ability of antibodies to add anything to the drug. So I just don’t do that.

Now, obinutuzumab is a more potent antibody in vitro. It does somewhat overcome this ITK inhibition by ibrutinib, and you can see some additional effects with obinutuzumab added to ibrutinib in vitro. But unfortunately, we have no head-to-head trial of ibrutinib versus ibrutinib/obinutuzumab. The only trial compared ibrutinib/obinutuzumab to obinutuzumab/chlorambucil. The data can’t really be directly compared to the ALLIANCE data because the patient populations were a little bit different. There were more patients with a 17p deletion in the iLLUMINATE trial.

So, if you’re adding an antibody, which I don’t think is usually indicated, you could consider adding obinutuzumab. I haven’t really done this. Before acalabrutinib was widely available, I would occasionally do it with high-risk patients for whom I thought additional cytoreduction might help them early. But now, given the alternative data with acalabrutinib, I would just use acalabrutinib with obinutuzumab.

Alan Skarbnik, MD: Yeah, I agree. The ELEVATE-TN trial did have 3 arms. There was acalabrutinib and obinutuzumab, versus acalabrutinib alone, versus chlorambucil/obinutuzumab. The investigators did allow a crossover to the monotherapy arm with acalabrutinib for patients who progressed on chlorambucil/obinutuzumab. Unfortunately, the trial wasn’t powered to compare acalabrutinib alone versus acalabrutinib plus obinutuzumab. But if you look at the hazard ratios there, which are compared with chlorambucil/obinutuzumab, it was 0.1 for the combination of acalabrutinib and obinutuzumab and 0.2 for acalabrutinib alone. The response rates were higher in the acalabrutinib/obinutuzumab arm as well, but it didn’t change the PFS [progression-free survival] curve down the road.

The interesting aspect of that trial is that acalabrutinib monotherapy did not provide better outcomes for patients with IGHV-mutated disease when compared to chlorambucil/obinutuzumab, which is what we see in the ALLIANCE trial and the ECOG-E1912 trial as well. And acalabrutinib plus obinutuzumab did provide, at least in the first plot, an improvement for the IGHV-mutated disease when compared to chlorambucil/obinutuzumab.

I believe that because of the lack of target enzymatic inhibition, you’re not hampering the ADCC [antibody-dependent cellular cytotoxicity] driven by obinutuzumab. Additionally, different from rituximab, obinutuzumab can cause direct cell death. So it’s a different process than the antibody-dependent cellular cytotoxicity, which is more potent to start with obinutuzumab than rituximab based on the CLL11 trial.

So certainly, if I’m going to use an antibody in CLL [chronic lymphocytic leukemia], I would favor obinutuzumab. And if I’m going to use a BTK inhibitor in combination with that, I would favor acalabrutinib based on the ELEVATE-TN data. I think we need more data to compare head-to-head with or without the obinutuzumab. We unfortunately don’t have that for ibrutinib or acalabrutinib, either. It would be interesting to have these trials down the road, but I don’t know if they’re going to be done.

In the newer trials that I see with multiple combinations—acalabrutinib plus venetoclax, or plus obinutuzumab, or acalabrutinib/venetoclax alone compared with chemotherapy— there are some that are being powered to compare the difference between the obinutuzumab and non-obinutuzumab arms. There is at least 1 with acalabrutinib. So, I don’t think we’re going to have a true answer to that question any time soon.

Jennifer R. Brown, MD, PhD: It is an important question. I think it’s possible that people are viewing it as closed, despite the fact that it wasn’t even an end point of ELEVATE-TN to compare acalabrutinib versus acalabrutinib/obinutuzumab. That being said, the PFS curves do look fairly convincing. If they hold up over time, I would be willing to consider them meaningful. I have actually added obinutuzumab to acalabrutinib much more frequently in my clinical practice than I would have with ibrutinib.

The mutated IGVH issue is also quite interesting. It gets back to the idea that patients with the IGVH mutation who get into deeper remissions can have very long remissions. Hence, it’s possible to cure with FCR [fludarabine, cyclophosphamide, and rituximab]. It may be the case that they have high rates of undetectable MRD [minimal residual disease] in CLL14 that may translate into longer remissions. We don’t have the follow-up data for the subgroup analysis yet. And then, adding obinutuzumab, you get a deeper remission with your BTK inhibitor. Again, that may add a benefit, especially if patients are discontinuing the BTK inhibitor for adverse events or other reasons, and they may get a more sustained remission.

Transcript edited for clarity.