Resistance Mutations Develop Differently After Noncovalent BTK Therapy in CLL
During a live event, Shuo Ma, MD, PhD, discussed the resistance mutation analysis of patients who had disease progression after receiving pirtobrutinib for BTK inhibitor–pretreated chronic lymphocytic leukemia.
Shuo Ma, MD, PhD
Many patients with chronic lymphocytic leukemia (CLL) continue to face disease progression after the use of Bruton tyrosine kinase (BTK) inhibitor and BCL2 inhibitors. In a recent virtual Case-Based Roundtable meeting, Shuo Ma, MD, PhD, professor of medicine in hematology and oncology at Northwestern University Feinberg School of Medicine in Chicago, discussed the newer approved options for these patients. Ma shared data on the BTK mutations that lead to resistance to covalent BTK inhibitors and distinct mutations that have be observed with noncovalent BTK inhibitor trials. She answered questions on when to use molecular assays and how to interpret results to guide treatment.
This article is part 2 of a 2-part series from a Case-Based Roundtable event.
Targeted OncologyTM: What did investigators in the BRUIN trial (NCT03740529) find regarding resistance mechanisms to pirtobrutinib (Jaypirca)?
Shuo Ma, MD, PhD: Even though the response rate is fairly high and [more than] three-quarters of patients will respond, the median progression-free survival is only [a little over] 19 months, so apparently resistance mechanisms can develop even for pirtobrutinib.1 That is a little bit different compared with the resistance to covalent BTK [Bruton tyrosine kinase] inhibitors. This [agent] is not binding to the C481 site.
There have been studies looking at those patients who become refractory to pirtobrutinib. All patients were analyzed, and 69% of patients [59 of 86] had some kind of mutation when they developed resistance to pirtobrutinib2. The most common ones were the other BTK mutations, like the mutation in the T474x site or mutation in the L528W site. These 2 different amino acid mutations appear to confer resistance to pirtobrutinib and also resistance to covalent BTK, so these are cross-resistant BTK mutations. In contrast, the C481S mutation is only resistant to the covalent BTK inhibitors, but not to pirtobrutinib. So some novel resistance mechanisms are emerging to pirtobrutinib, and there are new clinical trials, and nowadays there are some other products we’re studying—for example, BTK degraders—that might be able to overcome those resistances. So the battle continues. We have to find new ways to fight those resistance mechanisms.
In what scenarios is it necessary to test a patient for BTK mutations before using pirtobrutinib?
If a patient is currently on a BTK inhibitor or previously had a BTK inhibitor, one scenario would be a patient who had a prior BTK inhibitor, came off a treatment because of intolerance, and had been off treatment for a while, and has progression again. Then the question is, are they still going to respond to a covalent BTK inhibitor? If so, you could use an alternative covalent BTK inhibitor. In that case, since the patient has previously been exposed, I would do mutation testing to make sure they don’t have this refractory mutation.
Another scenario I can think of is a patient is currently on BTK inhibitor treatment and is starting to have a little change. They have been very stable for many years, and suddenly you are starting to see their white blood cell count going up. It may or may not be a true progression. Sometimes, a patient can have a recent infection, for example, or they had recent steroid treatment, or they have been holding treatment for some procedures. So when you’re not sure whether a patient is truly [experiencing progression], I think having the mutation testing is very helpful in my experience because sometimes you might find the early sign of resistance developing. I’m sure there are some other scenarios, but especially if you’re thinking about using another covalent BTK inhibitor treatment, then I think the mutational testing would be critical.
How should oncologists perform BTK mutation testing?
There are many different companies that are offering those next-generation sequencing [NGS] panels. And so often in that panel, the BTK molecule is included, and the panel can often give you TP53 status as well, so it’s a very useful thing to do. At Northwestern Medicine, we have our own institutional-developed panel that includes all of those, so that’s very helpful.
One thing I can think of is that often you’re receiving a report, and you might see a mutation present. However, sometimes the mutation might be present in a very low percentage, which means there is a small clone. The resistant clone is just starting to emerge, and the patient might clinically still be responding. You might still be able to hold them on the current treatment for some time. So you don’t necessarily have to switch treatment right away. When I start to see those low-level mutations, I will often watch them closely, and once they truly start to show clinical progression, then I would consider changing treatment. But meanwhile, I would definitely prepare to make sure the next treatment is ready when the patient needs to switch.
Are the results of mutation testing effective for interpreting the mechanism of resistance?
We don’t understand 100% [of the mechanisms of resistance], only those for a certain portion of patients where we can find the mutations. There are also many patients who develop clinical resistance to the BTK inhibitor, but we could not identify the BTK mutation. There is probably more than 1 mechanism of resistance.
It should be relatively easy because so if you send the NGS panel, it will come back and usually it will show the mutations that have clinical significance. If one of them is a BTK mutation, then you should raise the alert. You can see whether it’s a C481S mutation that will be indicating resistance to the covalent BTK inhibitors, and those patients can still respond to pirtobrutinib, whereas if they have other BTK mutations, especially the ones that are known—for example, the T474x or the L528W mutations—those are going to be resistant to all of the known BTK inhibitors. It will give you the variable allele frequency percentage to show you how big that clone is.
DISCLOSURES: Ma previously reported receiving research funding from AbbVie; AstraZeneca; BeiGene, Ltd; Loxo Oncology; and Juno Therapeutics, and is a consultant for Eli Lilly and Company and Janssen.
