Novel BTK Degrader NX-5948 Yields High Response Rates in Pretreated CLL/SLL

Nirav N. Shah, MD

NX-5948 is one of many BTK degraders that have broken ground in development and following the demonstration of early efficacy in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), the agent is nearing examination in a pivotal clinical trial, according to Nirav N. Shah, MD, MSHP.

“This is exciting and an advancement of science to target BTK in a way we haven’t done previously. We’re seeing efficacy at a high level, even in patients who have been previously treated with a BTK inhibitor,” Shah said in an interview with OncLive^®. “Stay tuned, let the study develop, let us get further follow-up, and let pivotal trials initiate. This class of drugs, not to speak specifically just to this one [agent], has promise. We look forward to being part of the progress here for patients with B-cell malignancies.”

The novel, oral drug NX-5948 induces specific protein degradation of wild-type and mutant forms of BTK by the cereblon E3 ligase. Data presented during the 2024 ASH Annual Meeting and Exposition from the phase 1a/b NX-5948-301 trial (NCT05131022) showed that the agent elicited an objective response rate (ORR) of 75.5% (95% CI, 61.1%-86.7%) at 8 weeks in patients with CLL/SLL (n = 49).¹ Furthermore, at 16 weeks, patients (n = 38) experienced an ORR of 84.2% (95% CI, 68.7%-94.0%).

In the interview, Shah, an associate professor of medicine at the Medical College of Wisconsin at Froedtert Hospital in Milwaukee, detailed how BTK degraders could fill an unmet need for patients with pretreated CLL/SLL and highlighted promising data seen with NX-5948.

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

Shah: They are unique in mechanism of action and the type of drugs we currently have targeting BTK are both inhibitors and how they inhibit is different. The class of covalent inhibitors bind [to] C481 and that includes drugs like ibrutinib [Imbruvica], acalabrutinib [Calquence], and zanubrutinib [Brukinsa], and there’s a new class of noncovalent BTK inhibitors such as pirtobrutinib [Jaypirca]. But this [class] is different in that it’s a degrader and it leads to ubiquitination of the entire BTK enzyme and degradation of the entire enzyme. The preclinical hypothesis is that if you degrade the entire enzyme then even if a patient has mutations in BTK—resistance mutations to covalent or noncovalent inhibitors—this would still potentially be an effective targeted agent in terms of a mechanism.

What is the mechanism of action of NX-5948?

It’s a small molecule that recruits E3 ligase that leads to this ubiquitination of the entire BTK enzyme and then that triggers proteasomal degradation of the entire molecule. Because you’re not necessarily binding at a specific site where a mutation can occur, this degrader may be able to overcome mutations that are present in patients who have [experienced disease progression on] other BTK drugs.

What efficacy data were seen with NX-5948 in the phase 1 trial?

This was a phase 1 dose escalation study and at every single dose level [examined], including the lowest doses, we saw efficacy. The ORR at 8 weeks, which was the primary end point, was 75.5% and that suggests the majority of patients did have meaningful responses, but we [also] saw deepening of response. As an exploratory ORR [analysis], we looked at patients who were on treatment for at least 16 weeks, and there the ORR increased to 84.2%.

It’s exciting to see the evolution of responses and we looked at the mutational profile because these were all patients with relapsed/refractory CLL, so many of them harbored mutations in BTK, had high-risk mutations such as TP53 [and/or] had PLCG2 mutations. Independent of the mutational profile, we saw responses across the board, and when looking at blood samples of patients treated with the degrader, we saw that degradation of BTK occurred in approximately all of the patients independent of the mutations present at the time of enrollment on the trial.

What key safety data were observed with NX-5948?

So far, a very favorable safety profile has been seen. The way I look at safety is thinking about the grade 3 or higher toxicities that occurred in patients. Very low rates of grade 3 or higher toxicities [were observed and] the most common one was neutropenia. Otherwise, they were [typically] singular events that occurred in patients and [regarding] neutropenia, part of that was anticipated because the trial allowed patients to enroll even if they were neutropenic, but it was felt to be due to disease burden.

Consistent with that safety profile, only 1 patient in the CLL cohort discontinued the drug because of a treatment-emergent adverse effect. I believe a better way to measure tolerability is if patients have to stop the drug because of toxicity. Also, the traditional BTK inhibitor-related toxicities were generally low in this clinical trial; there were low rates of hypertension, no new cases of atrial fibrillation, and other than petechiae—which was low grade—we didn’t see significant high grade bleeding complications.

Is there anything else that is important to note about the safety profile of BTK degraders in general?

They look to be safe because they’re highly targeted against BTK. [However], these drugs are taken potentially for months or even years, and one thing we don’t have yet is [data on] the cumulative incidence of toxicities. Are we going to see new things develop over time the longer a patient is on [a BTK degrader]? We’re only going to get that information as we treat more patients and follow them longer.

What are the next steps with NX-5948?

Right now, we’re still finishing the phase 1b arm in CLL. This drug is also being developed in other B-cell malignancies, and a lot of that work is still ongoing. But we hope that these data, and we’re excited by this, are going to lead to the development of pivotal trials to ideally get this drug to patients, at least initially in those patients with relapsed/refractory CLL who have [experienced progression on] other medications. Potentially, we hope that this may be a different modality to offer patients as an earlier line of treatment as well.

How could an efficacious BTK degrader fill an unmet need for patients with CLL?

The way we treat CLL today is patients get small molecules at the time of diagnosis; they’re treated with BTK and BCL2 inhibitors. As more patients get those drugs up front, there’s going to be a growing population of patients who [progress on] those drugs, leaving room for development of new drugs like BTK degraders to fill that gap. We’ve been able to accrue a lot of patients to this trial who have [relapsed or refractory disease following] other lines of treatment and are now tolerating NX-5948 with high efficacy and a favorable safety profile. That’s the unmet need for patients right now and future research is needed to see if this is a better way to treat CLL in an earlier or upfront setting.

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