NX-5948 Demonstrates Preliminary Efficacy in High-Risk CLL

NX-5948, a novel BTK degrader, has demonstrated promising early efficacy in patients with chronic lymphocytic leukemia (CLL), positioning it as a potential treatment option for patients with high-risk disease, according to Alvaro Alencar, MD.

“As a single agent [NX-5948] has [demonstrated] clear activity and will certainly have a role in patients who develop resistance to other [drugs],” Alencar said in an interview with OncLive®.

NX-5948 is designed to induce targeted degradation of both wild-type and mutant forms of BTK through the cereblon E3 ligase complex. Findings from the ongoing phase 1 NX-5948-301 trial (NCT05131022), presented at the 2024 ASH Annual Meeting, demonstrated an overall response rate (ORR) of 75.5% (95% CI, 61.1%-86.7%) among 49 evaluable patients with CLL with at least 1 response assessment at 8 weeks. Response rates increased to 84.2% (95% CI, 68.7%-94.0%) in those with at least 2 response assessments at 16 weeks (n = 38) in an exploratory analysis.

In the interview, Alencar, associate professor of clinical medicine, Sylvester Comprehensive Cancer Center, and associate chief medical officer, University of Miami Health System, discussed the potential role of NX-5948 in addressing unmet needs in CLL and other B-cell malignancies, particularly in patients with high-risk genomic features.

OncLive: What is the rationale behind evaluating NX-5948 in patients with CLL?

Alencar: This is a phase 1 study evaluating a new class of drugs called BTK degraders. BTK degraders target a very important part of the B-cell receptor pathway, and we have drugs that target this pathway in CLL and B-cell malignancies in general, but they inhibit the receptor. We have [2 classes of] BTK inhibitors, covalent and non-covalent BTK inhibitors, and we see that as we use these drugs, patients develop resistance in this receptor.

Interestingly, even if the receptor is completely inhibited, we call it a BTK dead, so it supposedly has no activity. In reality, you still see downstream activation, and this happens because even though [the receptor] is dead, [it] serves as scaffolding, so alternative pathways that come through that receptor [can] still activate the cell downstream. The idea of this study [was] to develop a drug that will degrade [and] eliminate this receptor and therefore prohibit the scaffolding mechanism, even when BTK inhibitors no longer work.

This phase 1 study is evaluating this drug across different dose levels in B-cell malignancies that are expected to have response to BTK targeting. This includes CLL, mantle cell lymphoma [MCL], Waldenström macroglobulinemia, and other B-cell malignancies, but the focus of this presentation at ASH 2024 is on [patients with] CLL.

What enrollment criteria did patients have to meet to be enrolled in this trial?

Patients who were [enrolled were] mostly previously exposed to other drugs that were trying to overcome the resistance [mechanism]. Patients who had previous exposure to BTK inhibitors [were enrolled]. More than 90% of [those enrolled] had exposure to a covalent BTK inhibitor. Approximately a quarter of them had exposure to noncovalent BTK inhibitors. The other class of agents that are used in this setting are BCL-2 inhibitors. Most of the patients, over [80%], also had exposure to BCL-2 inhibitors. Patients had also received multiple previous lines of therapy. In fact, the median number of prior lines of treatment was 4, so these were highly pretreated patients.

How does this study seek to address unmet needs within the CLL treatment paradigm?

The challenge is that [BTK targeting agents] are extremely effective, but now we’re starting to see this resistance and lack of options for patients [who develop disease progression]. We know that the majority of patients will do extremely well with this class [of agents] and [are] able to have excellent disease control and tolerability for a long time. [However], we still see more and more patients who, over time, will develop resistance and not have a lot of great options for treatment. Once [patients are] no longer able to use covalent or noncovalent BTK or BCL-2 inhibitors, [there are] other classes, like PI3K inhibitors, but we’re using them less [frequently].

We have CAR T-cell therapy, but there’s very limited access, and there are some peculiarities about [the use of] CAR T-cell therapy in CLL.

How did patients respond to NX-5948 in this phase 1 study?

This is a phase 1 study trying to define the dose and look into toxicity. But, if we want to make sure that this drug is moving forward, it needs to have some efficacy. Of the patients who were enrolled in the overall study, we focused on the CLL [cohort]. A total of [60] patients with CLL were treated, and [49] of these patients had efficacy data available.

We saw a very high response rate, despite this [being a] very highly [pretreated] population. Most patients had a lot of mutations that cause resistance to BTK, with a large proportion of patients having TP53 mutations, which is something that also confers resistance. [However], we saw a 76% response rate in this population, which is very high. Responses are fast and seem to deepen over time, and a lot of patients have been on the drug for 12 months and some patients for 18 months. We see this fast, prolonged, continued and deepening response.

What safety considerations surround the use of NX-5948 in patients with CLL?

This is a very [tolerable] drug, [with a similar safety] profile to other BTK inhibitors, but [with] less [adverse effects (AEs)]. We see some rash, although not a whole lot. We also see some bruising, not much bleeding, some drop in counts, some neutropenia, [and] some anemia. But [these AEs were] also very mild. [There were] not a lot of infectious complications. [There were also] no new toxicities that are different from BTK inhibitors, or the typical toxicities that we’re concerned about [with] BTK inhibitors, like arrhythmias or hypertension. This [is a] very well tolerated drug with very good efficacy.

How will these findings affect the development of NX-5948?

We still have a long way to go in defining the dose. We still have [to perform] more studies focusing on tolerability, but the drug is so active, we know it’s going to move forward. Now, the challenge [is defining] where [this regimen] fits in CLL. We have all these drugs already, but what is the way that we alternate them? Which one do we use first? Should we use it early on? Do we combine it [with another agent]? [All of these questions have yet to be answered].

[There remains a] need for a new class [of drugs], and [I think] we’ll see more of this drug [with] very clear applicability in our clinical practice very soon.

What steps are being taken to further evaluate BTK degraders?

The next steps involve focusing on the disease subtypes in which we’re seeing the activity [of the agent] early in the study. We’re focusing on those [subsets] and trying to better define the dose. We see that the drug has activity even at very low doses, so we’re trying to define what the [optimal dose is]. What is the best dose that has very good activity [while] also minimizing toxicity? These are the next steps of this study.

Reference

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