Optimal Sequencing of Therapy in Chronic Lymphocytic Leukemia

Transcript:

Sonali M. Smith, MD: Let’s turn back to the real world. Ryan, you talked earlier about real-world data. Perhaps you could talk about it specifically related to the sequencing of therapies.

Ryan W. Jacobs, MD: This dovetails with the conversation we were having about combinations because 1 thing that trials are going to have a difficult time addressing is whether the combination of these targeted drugs ultimately ends up being better than sequencing 1 after the other. In the timeline of how these agents were approved, most of our patients, for the time being, have seen 1 of these agents independently and not in combination. There’s a lot of interest in how well these agents do following one another: BTK [Bruton tyrosine kinase] and BCL2 or vice versa. Is there a “better approach” for all patients? There isn’t a consensus. Luckily, from early on, because venetoclax approval came after ibrutinib, we had data that reassured us that we could salvage a lot of the ibrutinib patients that had progressed with venetoclax. It took us a longer time to find patients who had seen venetoclax who needed treatment.

Ultimately, some data out there have reassured us that you can use an up-front venetoclax-based approach, like in CLL14, and go to a covalent BTK inhibitor [BTKi] if you need it and get a response. A poster was presented at EHA [European Hematology Association Congress] looking at sequencing data in the real world. Does it seem to match some of the early indications that we had seen, that sequencing these agents 1 after the other is effective. There doesn’t seem to be a clear approach that’s more favorable over the other. What the real-world analysis showed is that you can personalize that first treatment choice to the patient and not worry that 1 particular order seems to be the right way to go. They seem to both work after each other—not 100% of the time, but for the majority of patients.

Sonali M. Smith, MD: John, can you pick up on that thread and talk a little about BTK inhibitors, then BCL2, or vice versa?

John N. Allan, MD: That’s an important question, and we have limited prospective clinical trial data. Obviously, with fixed-duration approaches, where patients are stopping treatment, the question is should you retreat with a venetoclax-based approach, or do you switch to a BTKi? These data are being generated in real-world efforts. There are limited data in terms of patients with a venetoclax-based treatment on a trial who had relapse and then have been re-treated. What’s encouraging is that the patients who have been re-treated, though limited to very small numbers—15 or 20 patients—have been reported essentially in a good rigorous fashion.

The nice thing is that they showed a response initially. Some of them, in fact, got MRD [minimal residual disease] negative. They had remissions because many of these were high-risk patients in this range of a couple of years. What’s nice is that they seem to have sensitivity to venetoclax-based approaches. Sometimes that’s in combination with the BTKi. It’s not necessarily uniform in that respect, but the venetoclax sensitivity seems to be there in patients previously treated with venetoclax. CLL14 is looking at this as well. We’ll continue to see re-treatment strategies shift. In that study, most patients who relapsed, in fact, got BTK inhibitors. We haven’t seen outcome data from there, but they’re being tracked, and we’re identifying them.

Our sequencing comes from real-world data, where we’ve looked at responses of patients who’ve had a BTKi and gone to venetoclax and who’ve gone from venetoclax to BTKi. We all have antidotes that show that the sequence you use doesn’t matter so much. The sensitivity is there. These are very different mechanisms of action for these 2 drugs. There’s no reason to think that there would be cross-resistance from 1 agent and class to the others. Obviously, within a class of BTK inhibitors, there’s cross-resistance, particularly with covalent. Keep that in mind. You can’t necessarily switch within BTK class of truly resistant patients. But within these different classes, the sensitivity is there. Whichever one you decide, patient choice, physician comfort, and biology of that CLL [chronic lymphocytic leukemia] are going to dictate which sequence [you choose] and whether you re-treat or switch a class of drugs, either to BTK or venetoclax.

Nicole Lamanna, MD: We all have our opinions. Does everybody deserve a doublet or a triplet? Susan presented the RESONATE data in the beginning on how well patients have done on ibrutinib monotherapy. We’re trying to do better for patients, but we’re very lucky because we have such great agents to work with.

Transcript edited for clarity.