CLL Clinical Trials for Molecularly Defined Patient Subgroups
CLL Clinical Trials for Molecularly Defined Patient Subgroups from Patient Empowerment Network on Vimeo.
What’s the latest in chronic lymphocytic leukemia (CLL) clinical trials for molecularly defined patient subgroups? Experts Dr. Jennifer Brown from Dana-Farber Cancer Institute and Dr. Callie Coombs from the University of California, Irvine discuss research updates for CLL patient subgroups, resistance mutations, and drug intolerance.
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Transcript:
Dr. Nicole Rochester:
So now we’re going to shift to talking about clinical trials and novel targets focused on molecularly defined patient subgroups. We know that by understanding the molecular profile of a patient’s CLL, that oncologists can choose the most effective therapies. So, Dr. Brown, I’m going to start with you for this one. Can you talk about any emerging CLL trials targeting specific molecular subgroups, and also how can CLL experts stay updated on these advancements in clinical trials?
Dr. Jennifer Brown:
So, as you heard from Dr. Coombs, there’s increasing interest in looking at high-risk patients in particular, and I think looking specifically at patients with p53 aberration in dedicated clinical trials, it’s become increasingly clear that the behavior of the disease when it’s higher risk based on p53 mutation, NOTCH mutation, IGHV status is quite different, particularly with time limited therapy compared to lower risk disease. And so having dedicated trials that evaluate outcomes specifically in certain of these subgroups is increasingly important. We do have more trials than we used to focusing specifically on p53 aberration.
My personal belief is that we would be well served to have trials separately in the IGHV groups that Dr. Coombs mentioned, although that has not gained as much traction. And then what we are seeing is now that there are resistance mutations, it actually has turned out that some of the drugs that we use in that setting, venetoclax (Venclexa) and pirtobrutinib (Jaypirca), seem to have pretty similar activity in patients with and without the mutations. But as drugs are being studied in this context, there’s been an increasing tendency to study them in specific subgroups.
So patients who have the mutation and had clinical progression on a covalent inhibitor, patients who don’t have the mutation and had clinical progression, patients who may have come off their covalent inhibitor for adverse events who may not actually be resistant, what is their response to the next line of therapy? And so all of that is just helping us understand in a more nuanced way what the best benefit for patients will be as we look at these different subgroups of patients.
Dr. Nicole Rochester:
Thank you, Dr. Brown. Appreciate that. Dr. Coombs, do you have anything to add?
Dr. Callie Coombs:
Yeah, so I echo all of Dr. Brown’s comments, and I think I’m the person that is bringing all the practical aspects of CLL care because it’s, she’s so thorough. I just always like to contribute a few little pearls. So, pirtobrutinib has been an exciting drug, to see it become available for our double refractory patients. So the current FDA indication is for patients failed by not only a covalent BTKi but also venetoclax. But it’s the first BTK inhibitor that we can effectively use in the setting of a prior BTK inhibitor.
And that’s because of this unique aspect where instead of forming a covalent bond at the C481 residue, it binds reversibly, and we can still see activity. But the practical aspect is that that’s not an effective strategy when you have a patient progressing on, say, ibrutinib (Imbruvica), you can’t switch them to acalabrutinib (Calquence) or zanubrutinib (Brukinsa) because of their shared mechanism of resistance. They’re all covalent inhibitors. They all share the same mechanism of resistance.
And so that’s one thing I’d like to bring up. However, there’s a very different and very common clinical situation that I encounter really a lot in my clinic, which is intolerance. And so that’s where it would be a very effective strategy to switch a patient from one covalent drug to another. And so literally in the past couple weeks of clinic, I’ve had patients with chronic long-standing toxicities to ibrutinib (Imbruvica) that perhaps went underrecognized where I say, “Hey, you’ve had…notice your blood pressure has gone up a lot.
Let’s switch you over to acalabrutinib,” or other patients, “Oh, you’ve had issues with atrial fibrillation, it…let’s try switching you to zanubrutinib.” Because the rates are a lot lower and a lot of patients can have improvement or just complete resolution of the prior side effect. And so I hope that that emphasizes this is something that we think about every day, and switching is appropriate in the setting of intolerance. It’s not appropriate when you’re staying in the covalent class to switch in the setting of progression. But pirtobrutinib being a non-covalent inhibitor is certainly very effective after a covalent. And I think once we see readout of some of the ongoing Phase III trials, we may be able to use it in that setting under an approved FDA label, though that is to be seen in the future.
