Imbruvica–Venetoclax Combo Demonstrates Superior PFS in CLL

Arnon P. Kater, MD, PhD, Professor of Hematology, Department of Hematology, Amsterdam University Medical Centers, Amsterdam, New York, discusses new data from the phase 3 GLOW study of imbruvica plus venetoclax for patients with chronic lymphocytic leukemia (CLL). These data were presented at the EHA2021 Virtual Congress.

Transcript

My name is Arnon Kater. I am a professor of hematology at the Department of Hematology here at the Amsterdam University Medical Centers.

We know that there are two very powerful drugs available in CLL as targeted treatment. It's the group of BTK inhibitors, with ibrutinib the first one, and venetoclax, which is a BCL2 inhibitor. We know that cells are extremely sensitive to BCL2 inhibitors in the peripheral blood, because peripheral blood CL cells very much depend on BCL2 for their survival.

We also know that CL cells don't stay in the blood, but recirculate from their blood to their protective lymphoid tissues. In those tissues, cells get surrounded by other cells. In this microenvironment, not only BCL2 is overexpressed, but also other anti-apoptotic molecules that make the cells sensitive to venetoclax.

What BTK inhibitor, ibrutinib, is doing is it prevents the cells from homing into this microenvironment. Also, it activates egress from those CLL cells from the lymph node to the peripheral blood and, therefore, sensitizing cells again to venetoclax.

The GLOW study is the first study that is a head-to-head comparison in a phase III fashion of the combination of ibrutinib and venetoclax, first at 3 months lead-in over ibrutinib, and then 12 months of combination versus standard chemoimmunotherapy for elderly, unfit patients, which is chlorambucil and obinutuzumab.

What we're seeing is that, for both the primary endpoint and the secondary endpoints all showed a favorable outcome of patients using this one-daily oral, fixed-duration treatment. Progression-free survival was very significantly prolonged, with a hazard ratio of 0.2, which is spectacular, I think.

The progression-free survival advantage was seen in all subgroups that were predefined, including age, comorbidities, but also biological features of the disease, such as mutation status.

In all those subgroups, you saw an advantage in progression-free survival. Complete remissions were higher. Undetectable MRD levels were higher, and maybe more important, the depth of response, and also the sustainability of the response.

If you compared at 3 months post-treatment versus 12 months post-treatment, you see that their depth of response is very durable in the combination of these oral drugs. This all led to an increased time to next treatment.

There were also toxicities in this frail patient group caused by known factors, the side effects of these drugs. The good news is that there were no new side effects by this combination than the ones we already knew from their single-agent use.

The most surprising was this very relevant hazard ratio, because so far, the ibrutinib is a very powerful drug, but it is used, and almost all studies have tested this, until progression. This is, I think, the first phase 3 trial where ibrutinib is actively stopped with this combination. It shows so far extremely good result, and you can indeed stop the drug if you have a good companion drug.

We have a very valuable, novel combination treatment for a fixed duration without chemotherapy. We had already venetoclax and obinutuzumab. Now, we also have venetoclax and ibrutinib.

The exact merits versus disadvantages of this oral regimen versus the venetoclax/obinutuzumab, which is partly IV, is still unknown. We have to look into that.

The good thing is that there is a study currently ongoing in Europe where the 3 targeted treatment regimens for these patient groups are studied. It is 17, which tests venetoclax and ibrutinib, versus venetoclax and obinutuzumab, versus ibrutinib maintenance. This was a late-breaking abstract, so we still need to learn from this specific trial, the toxicities, but mostly, how does MRD kinetics work.

Which patients profits most, and which patients less, and what can we do to maybe improve the sensitivity to this combination?

One of the studies we do here in the Netherlands, is that we give the same regimen, so ibrutinib and venetoclax, and we give patients that have less than a very good response, so less than CR and/or undetectable MRDs of the MRD-positive. We treat patients another 6 months with the combination of ibrutinib and obinutuzumab. Instead of giving all 3 drugs at the same time, you tailor-made the different drugs based on the response.  

There is some very good evidence from the UK group that indeed shows that, after one year of ibrutinib treatments, the patients become sensitized to obinutuzumab treatment.

We hope, with this staggered approach, first combination A, and then wait for response, and then come up with an intensification period, that we really can eradicate the disease for very long times, and in all groups.