BTK Degraders Look to Fill Unmet Need for Patients With Pretreated B-Cell Malignancies

Michael T. Tees, MD, MPH

A promising direction for BTK degraders appears to be in the treatment of patients with previously treated B-cell malignancies, and several novel agents such as AC676 are under evaluation in clinical trials, according to Michael T. Tees, MD, MPH.¹

A phase 1 first-in-human study (NCT05780034) is enrolling adult patients with B-cell malignancies across 8 sites in the US to receive AC676. Patients must have received at least 2 prior systemic therapies or have no other standard-of-care therapy options that provide significant clinical benefit. Additionally, agents currently being examined that have shown early efficacy in phase 1 trials include NX-5948 and BGB-16673.^2,3

“[The investigations of BTK degraders are] early phase across the country, but given it’s an unmet need, my hope is that the studies begin to accrue more quickly, and that these medications can eventually get to patients outside of clinical trials,” Tees said in an interview with OncLive^®. “[In] chronic lymphocytic leukemia, Waldenström macroglobulinemia, marginal zone lymphoma [MZL], and perhaps non-germinal center type large cell lymphoma, [the agent AC676] could prove beneficial, as well as in mantle cell lymphoma [MCL]. We’re also looking in follicular lymphoma—that’s another exciting prospect.”

In the interview, Tees described how BTK degraders could fill an unmet need for patients with B-cell malignancies and highlighted the agent AC676 that is under evaluation. Tees is a hematologist/oncologist at Colorado Blood Cancer Institute in Denver.

OncLive: What makes BTK degraders a promising class of agents?

Tees: For many of the B-cell malignancies, we’re running into [situations where patients treated with available] therapies have lost response. The drug class that we need to use for many patients with indolent B-cell lymphomas are BTK inhibitors, and unfortunately over time patients’ diseases acquire resistance. For a bit, the available agents couldn’t keep up with those resistance mutations and BTK degraders target the similar pathway, but in a whole different context.

How could an efficacious BTK degrader fill an unmet need for patients with B-cell malignancies?

The approved BTK inhibitors result in resistance to mutations of the BTK residues. The classic ones are C481S and L528W and that renders several of our BTK inhibitors useless. For a disease such as an indolent lymphoma, upon progression we may be limited [with] other therapeutic options, and this fulfills that unmet need if we see those not only positive safety signals but also efficacy signals.

MCL is a disease entity that we need to be investigating responses [to] BTK degraders [in] because we know that the BTK inhibitors have excellent efficacy, but oftentimes [patients] lose responses over time. Follicular lymphoma is a common indolent B-cell lymphoma [and patients] tend not to have the most robust response to BTK inhibitors. The question is, do BTK degraders provide an opportunity for [those] patients to derive benefit?

What is the mechanism of action of AC676?

Most of the BTK degraders that are under investigation are acting in a similar fashion, perhaps with increased activity in one pathway or the other. But essentially, the molecule is bringing together the BTK and cereblon E3 ligase; it brings them together and subsequently induces the degradation of the BTK molecule. The neat thing is that [as] the proteins are degraded, AC676 seems to be recycled and [is] able to be reused again.

What patient population will be enrolled in the phase 1 dose escalation study of the agent?

The current patients who derive benefit from [targeting] BTK are under investigation [in] many of the BTK degrader studies. The classic patient who derives benefit from BTK inhibitors [is one with] chronic lymphocytic leukemia/small lymphocytic lymphoma, and thus it’s appearing that they derive benefits from BTK degraders; Waldenström macroglobulinemia, MZL, and interestingly diffuse large B-cell lymphoma, specifically the non-germinal center subtype, [also represent] a very promising avenue for the molecule.

Classically when BTK inhibitors are used for patients with diffuse large B-cell lymphomas they tend to acquire resistance relatively quickly—sometimes within 6 to 8 weeks patients’ diseases have already [developed] resistance and therefore that molecule is deemed ineffective. There are some signals [showing it] appears that is not the case for the BTK degrader and mechanistically speaking, that seems to make sense. Perhaps it is a potential option for treating [patients with] aggressive lymphomas with [a] pill.

What are the next steps with AC676?

We’re in the dose escalation phase [of the trial] right now; we’re going to be opening cohort D in the very near future, if not already. We’re still looking at the maximum tolerated dosing for all patients. My suspicion is that the investigators will probably be advising that we open the inclusion [criteria] to look at patients who have central nervous system involvement of disease. It’s currently an exclusion [criterion], but there are some signals with other molecules [suggesting] that [BTK degraders can] cross the blood-brain barrier effectively and could be an exciting opportunity to provide an option for patients who may not have any given age or comorbidities.

What should be known about the safety profile of BTK degraders?

We’re still learning—there are some signals that would suggest that the toxicity profile is very similar to [that of] BTK inhibitors. For example, we are seeing a slight increased risk of bleeding events, which is something that we’re already familiar with for the BTK inhibitors. With BTK degraders, there’s likely a similar off-target effect on platelet function.

The other potential risk, although it’s still too early [to tell]—and [with] pretty much every BTK inhibitor study at this point the more patients [enrolled] the better [to] help us understand—is that perhaps there can be some hepatic insufficiency that we need to be looking out for and some hematologic toxicities like leukopenia or neutropenia.

What would you like your colleagues to take away from this research?

The best takeaway is talk to your colleagues who are investigating this [agent and other BTK inhibitors] at expert centers or complex hematology programs because there are several studies across the country with not only AC676, but with other molecules that are within the same drug class. Just because patients are older or have comorbidities does not mean that there aren’t other options that could be beneficial. Do not be afraid to the discuss the case and see if there are strategies that can be considered for certain patients.

Is there anything else you wanted to add on BTK degraders?

This isn’t the only molecule that’s under investigation. There have been several reports on other agents, [and] we are seeing signals of efficacy across several different molecules. The question is, are there certain degraders that work better than others for certain disease subtypes—for certain lymphoma subtypes? The other question is [regarding] the concept of this therapeutic intervention. Can it be [used] in other disease entities such as autoimmune diseases? Can this be an effective agent for those for example with MS or autoimmune encephalitis? I’m unsure if there are investigations that are started or if there are investigator-initiated trials across the country [in these diseases], but I believe that’s the next step.

References

1. Tees MT, Bond DA, Khan N, et al. A phase 1 study of AC676, a novel BTK chimeric degrader, in patients with B-cell malignancies. Blood. 2024;144(suppl 1):4422.1. doi:10.1182/blood-2024-194009
2. Shah NN, Omer Z, Collins GP, et al. Efficacy and safety of the Bruton’s tyrosine kinase (BTK) degrader NX-5948 in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): updated results from an ongoing phase 1a/b study. Blood. 2024;144(suppl 1):884. doi:10.1182/blood-2024-194839
3. Thompson MC, Parrondo RD, Frustaci AM, et al. Preliminary efficacy and safety of the Bruton tyrosine kinase degrader BGB-16673 in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: results from the phase 1 CaDAnCe-101 study. Blood. 2024;144(suppl 1):885. doi:10.1182/blood-2024-199116