Overcoming Resistance Mutations Is a Focus for Novel Therapies in R/R CLL


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Nicole Lamanna, MD, discusses the challenges of resistance in patients with CLL, highlights treatment being developed for patients who progress on BTK inhibitor– or venetoclax-based regimens, and emphasizes the need for further enrollment onto clinical trials.

Nicole Lamanna, MD

Nicole Lamanna, MD

Patients with chronic lymphocytic leukemia (CLL) are commonly treated with a covalent BTK inhibitor such as ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa); however, resistance mutations, such as BTK C481, can emerge, and novel treatments are needed for later lines of therapy, according to Nicole Lamanna, MD.

“There are resistance mutations that are developing with some of these [current] therapies. We [are looking] for newer agents to focus on helping these individuals with CLL have alternative strategies once they progress either on covalent BTK inhibitors or venetoclax [Venclexta]-based strategies,” Lamanna explained during an interview with OncLive® during the 41st Annual CFS®.1

In the interview, Lamanna discussed the challenges of resistance in patients with CLL, highlighted treatment being developed for patients who progress on BTK inhibitor– or venetoclax-based regimens, and emphasized the need for further enrollment onto clinical trials. Lamanna is a hematologist/oncologist and an associate clinical professor of medicine in the Hematologic Malignancies Section of the Hematology/Oncology Division at Columbia University’s Herbert Irving Comprehensive Cancer Center.

OncLive: How could novel agents potentially address resistance associated with current treatment options for patients with CLL?

Lamanna: The majority of therapies in CLL have centered upon covalent BTK inhibitors. We have ibrutinib, acalabrutinib, and zanubrutinib. [In] patients have been on these therapies [for an extended time], we are identifying resistance mutations to these therapies. Most of these mutations have been at the BTK C481 binding site domain. However, [we are also seeing] in smaller frequency a numbers of non–BTK C481 mutations, particularly gatekeeper mutations and kinase impaired mutations. These are low in frequency, but they are something that we have to keep an eye on. We will have to see what role [these resistance mutations] will have on the future of sequencing some of the these agents.

What do we do with patients who develop progressive disease or resistance mutations on covalent BTK inhibitors? Normally, we would go to a venetoclax-based regimen, which is a BCL-2 inhibitor that is approved. [Venetoclax is given with] a time-limited approach, unlike covalent BTK inhibitors that are continuous therapy.

However, there are also patients who also progress on venetoclax-based regimens. Here's where we start looking at newer agents. Noncovalent BTK inhibitors are being explored in this space, [including] pirtobrutinib [Jaypirca] and nemtabrutinib [ARQ-53]. Pirtobrutinib is approved for [patients with] mantle cell lymphoma in the relapsed/refractory setting, but is not yet approved in CLL. However, because of the encouraging data from the phase 1/2 BRUIN study [NCT03740520], it is has been added to the National Comprehensive Cancer Network [NCCN] Guidelines. Therefore, for patients [whose disease progresses on] a covalent BTK inhibitor or venetoclax-based therapy, you can certainly look to use pirtobrutinib in that space, as well.

We're also looking at agents with novel mechanisms. Again, these [agents] are all clinical trials and not yet approved for CLL. We have CAR T-cell therapies, BTK degraders, and bispecific monoclonal antibodies. These are all agents that are currently in development on clinical trials for patients who develop resistance mutations to covalent BTK inhibitors or who are refractory to venetoclax-based therapy.

Could you expand on the key findings for pirtobrutinib from the BRUIN trial?

The BRUIN study looked at patients with prior covalent BTK inhibitor exposure. They either were intolerant to a covalent BTK inhibitor, or their disease [progressed on] a covalent BTK inhibitor. Some patients also had prior venetoclax or BCL-2 inhibitor exposure. There were 247 patients on the CLL arm. The BRUIN study also enrolled patients with other lymphoma subtypes.

In terms of the CLL-specific arm, the overall response in patients was 73.3%%.2 More importantly, in patients seemed to respond [irrespective of BTK C481 mutation status]. There's no doubt that pirtobrutinib can overcome the BTK C481S mutation. This is a viable option in patients who have resistance mutations on a covalent BTK inhibitor. The median progression-free survival of this study has been reached at 19.6 months. It was a little shorter for patients who had both covalent BTK inhibitor– and venetoclax-based therapies, [where] the median PFS was 16.8 months. Still, this is a durable response in these heavily pretreated patients who have had venetoclax and covalent BTK inhibitors.

These are patients who are in dire need of alternative therapies. Therefore, [pirtobrutinib] is a very viable option, and hence why it made the NCCN Guidelines for patients who have been exposed to covalent BTK inhibitors or venetoclax-based therapy. You have another option of therapy for these patients.

What has been seen thus far in investigations with nemtabrutinib?

Nemtabrutinib is another noncovalent BTK inhibitor; it just does not have as much mature data as pirtobrutinib, because pirtobrutinib came first. There have been some very good responses [in the post–covalent BTK inhibitor setting], including in patients with a BTK C481S mutation. The overall response is 75% in [patients with CLL treated at 65 mg daily].3 These are a bit more immature data, so we'll wait for some longer follow-up in terms of the duration of response. [Nemtabrutinib could] offer another option for patients who have resistance mutations to covalent BTK inhibitors. We're looking forward to more mature data with nemtabrutinib.

Could you expand on some of the novel strategies for in patients whose disease is double exposed or double refractory?

When we talk about double refractory, we are talking about patients who have [progressed] on a covalent BTK inhibitor and progressed on venetoclax. Double-exposed is a little trickier, because there are some patients who may have gotten exposure to a covalent BTK inhibitor and maybe [discontinued treatment due to] an adverse effect [AE] and moved on to a different agent. Perhaps the patient received and finished [fixed-duration] venetoclax and are off that therapy.

When we talk about double exposed and double refractory, some of these patients may be exposed but not refractory. What we're trying to identify is for patients who have been exposed to both agents, what's an appropriate rechallenging [strategy]? We know from the phase 3 MURANO study [NCT02005471] that you can potentially rechallenge patients with venetoclax who relapse after they finish therapy. However, we're also identifying that if patients have a short remission duration after such therapy, do you want to re-expose them if they've [progressed] within a year of finishing that therapy? The likelihood is no, so some of us would say that they might be double refractory.

There are clinical trials looking to figure things out in terms of timing. When is it suitable [to rechallenge]? Is it less than 12 or 24 months where you're truly calling somebody double refractory because they're progressing already after finishing [venetoclax therapy]? There are some clinical trials looking at that. However, for those patients who have seen both agents, noncovalent BTK inhibitors are where you could go to in that space for anybody that you think has a very short remission duration after a venetoclax-based treatment, or [you could look at] a clinical trial.

We [strongly] encourage for our patients to be enrolled on some of these [trials evaluating] novel targets or CAR T-cell therapies if they're applicable and eligible. That also depends on the age and fit of the patient. We have BTK degraders and bispecific monoclonal antibodies, and these are also very encouraging.

There's very encouraging data with some of these novel mechanisms that are in early-phase development. However, for patients who have [had their disease progress] on all current known strategies, hopefully these [novel] agents will have very good efficacy and could bridge them to alternative therapies.


  1. Lamanna N. Addressing resistance: new agents in development. Presented at: 41st Annual CFS®; November 8-10, 2023; New York, NY.
  2. Mato AR, Woyach JA, Brown JR, et al. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. N Engl J Med. 2023;389(1):33-44. doi:10.1056/NEJMoa2300696
  3. First in human study of the reversible BTK inhibitor nemtabrutinib in patients with relapsed/refractory chronic lymphocytic leukemia and b-cell non-Hodgkin lymphoma. Cancer Discov. 2023. doi.10.1158/2159-8290.CD-23-0670
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