Novel Therapies for CLL

William Wierda, MD, PhD: We have just a few more minutes. I think we will wrap things up with the new agents. I’m going to ask Dr Allan in a second about the reversible inhibitors of BTK [Bruton tyrosine kinase]. But John Burke, maybe you can comment on the cellular therapy and CAR T [chimeric antigen receptor T-cell therapy] and whether that represents promise for our patients with CLL [chronic lymphocytic leukemia].

John Burke, MD: At the ASH [American Society of Hematology Annual Meeting], we saw data on the CD19-directed CAR T-cell product liso-cel, and they showed data on 23 patients, most of whom had failed ibrutinib and demonstrated an overall response rate of 81%, a complete response rate of 45%, and then an MRD [minimal residual disease] undetectable rate of 75% to 85%, depending on blood vs bone marrow. The toxicities were not trivial—74% of patients had some degree of cytokine release syndrome, although only 2 were rated as grade 3.

They saw tumor lysis syndrome in 17% of patients, suggesting clear activity. The data remain fairly early. That particular product would certainly appear active in this high-risk population, but it’s also pretty toxic. CAR T is not something I have referred many patients for, and right now I save it for last. We’ve also seen data that CAR T can be added to ibrutinib, but these data weren’t presented at the last ASH.

Patients who had been treated with ibrutinib for 6 months and failed to achieve a certain degree of remission, then had CAR T added. The CAR T helped clear the bone marrow, and patients achieved deeper remissions but at a fairly considerable toxicity cost and financial cost as well. I’m a little uncertain about where the final role of CAR T will be, but right now it remains a research tool.

William Wierda, MD, PhD: In terms of newer agents in development, there’s a lot of work going on with the next generation of BTK inhibitors, the reversible inhibitors. Dr Allan, I know you’ve done some work with the reversible inhibitors. Can you highlight some of the features of those new agents? How do they differ from what we have available with the irreversible inhibitors and what we’re seeing with the activity for those in compounds?

John Allan, MD: Absolutely. It’s important to remember that the 3 big FDA-approved BTK inhibitors are all covalently bound to the protein BTK at the Cys481 amino acid, which is within the kinase pocket, prevents activation and phosphorylation, and inhibits and kills the enzyme irreversibly. Therefore, the only way for the cell to make more BTK is to transcribe it, translate it, and then repopulate the protein, which then is inhibited the next day when you take the new BTK inhibitor.

We know that the resistance mechanism is a mutation developed in BTK at that Cys481 residue, which is then turned from a cysteine to a serine, disrupting the irreversible binding and covalently binding to the protein. Therefore, the molecule gets kicked out. That’s the major mechanism of resistance we recognized in the vast majority of patients who progress that have been reported, a BTK mutation is typically present. These covalently bound molecules have short half-lives.

Therefore, the drug is in and out of the kinase pocket, gets washed out of the system based on its pharmacokinetics [PK], and the enzyme is then able to fire again, allowing the CLL to signal through the B-cell receptor. One way that has been devised to overcome that is to use what’s called a reversible BTK inhibitor, where the drug no longer binds into the pocket irreversibly but instead goes in, interacts with the pocket, inhibits activation, and throughout the day goes in and out of the pocket within that cell.

The PK is a little better on these reversible BTK inhibitors. These molecules have longer PKs. They’re hanging around the body. Therefore, they’re staying in the cell longer. They’re not getting broken down. By having a reversible inhibitor, you can have relatively prolonged inhibition of the protein and have high occupancy rate, even though the drug is not covalently bound. There are 3 reversible BTK inhibitors currently advancing in clinical stage and at least 1 or several others that are coming on board and trying to get into the clinic now.

The current studies are entering phase 2 populations and are emerging from their phase 1 data. Limited data have been demonstrated. These patients that are recommended for these studies are very high risk. They have BTK mutations. Most are 17p deletion, so it’s a really difficult patient population to treat. It’s hard to glean efficacy from this specific population.

We found that these inhibitors do have activity and different selectivity for their kinome. Some are rather specific, much like acalabrutinib and zanubrutinib, and don’t have a lot of other off-target inhibition. Others have similar kinase inhibition, like ibrutinib. Then there are other molecules that have a broader inhibition of other molecules. What we’re starting to tease out is if it all depends on BTK inhibition, or is it some other off-target effect based on these different molecules?

We’re starting to learn and see activity. As we start to expand in these phase 2 populations, that’s where we’re going to glean from our efficacy. We’re going to get less patients who have been pretreated. It remains unclear to me if these drugs will be in a niche in which we’re only going to be using them for patients who progress with BTK inhibitors and patients who have BTK mutations. Or will the reversible BTK inhibitors be able to potentially unseat covalently bound BTK inhibitors?

It is possible that you may be able to prevent the mutation by using reversible BTK inhibitors because that evolutionary pressure is not there, but that remains to be seen. What has been reported is that these drugs do appear safe. They don’t appear to have huge rates of atrial fibrillation. They don’t have huge rates of other toxicities that we sometimes attributed to our covalently bound BTK inhibitors, such as arthralgias and diarrhea. We’re learning here and we’re starting to target our resistant mechanism, and that’s where we are in the current state.

We’ll see at ASH, I think, the big 3 companies that have a molecule in advanced stages showing more results with larger patient populations, and we’ll start to glean if there are differences among the molecules. We don’t quite understand that yet. We don’t know if there’s a winner of the 3 that are currently far ahead, but we’ll start to understand that and the toxicities and to make sure that these patient populations are similar so we can understand why 1 is better. Is it a potency issue?

Is it a patient population issue? What patient factor might predict response? Or is it some other off-target effect that, as the science catches up, we would start to learn? We’re using these drugs. They’re coming down the pike, and I do think there will be some value in them, especially in this special resistance niche of patients. It remains to be seen if reversible BTK inhibitors can cross the threshold to be adopted broader.

Transcript Edited for Clarity