BTK Degraders May Be a Promising Approach in CLL/SLL for Patients With Disease Progression

Several Bruton tyrosine kinase (BTK) degraders have emerged in early-phase studies and yielded high response rates in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), and the agents may be poised to fill an unmet need for patients who have experienced disease progression on BTK inhibitors.1,2 With novel BTK degraders such as NX-5948 offering additional treatment modalities, the new class of drugs are looking to not only overcome BTK inhibitor resistance mutations, but also appear to penetrate the blood-brain barrier.1,2

“[NX-5948] is different [from BTK inhibitors] in that it is 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,” Nirav N. Shah, MD, MSHP, said in an interview with OncologyLive. Shah is an associate professor of medicine at the Medical College of Wisconsin at Froedtert Hospital in Milwaukee.

“For many of the B-cell malignancies, we’re running into [situations where patients treated with available] therapies have lost response,” Michael T. Tees, MD, MPH, a hematologist/oncologist at Colorado Blood Cancer Institute in Denver, added in an interview with OncologyLive. “For a while, the available agents weren’t able to keep up with those resistance mutations. BTK degraders target the similar pathway, but in a whole different context....Generally speaking, 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.”

For example, NX-5948 induces specific protein degradation of wild-type and mutant forms of BTK by the cereblon E3 ligase, and the BTK degrader BGB-16673 induces BTK degradation by binding specifically to BTK and the E3 ligase.1,2

As more than half of patients who experience disease progression on BTK inhibitors have covalent and noncovalent BTK inhibitor resistance mutations, and the population of patients who have disease refractory to both BCL2 and BTK inhibitors is increasing, BTK degraders represent a promising class of agents. NX-5948’s mechanism of action allows for the disruption of BTK scaffolding, and the agent can overcome BTK inhibitor treatment-emergent resistance mutations.1

“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,” Shah noted.

Tees explained that “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?” he asked. “I’m unsure if there are investigations that have started or if there are investigator-initiated trials across the country [in these diseases], but I believe that’s the next step.”

Examining Two of the Furthest Along BTK Degraders in Development: NX-5948 and BGB-16673

NX-5948 degraded wild-type and mutated BTK in patients with CLL/SLL, and findings from the phase 1a/b NX-5948-301 trial (NCT05131022) presented by Shah at the 2024 American Society of Hematology (ASH) Annual Meeting and Exposition revealed this patient population (n = 49) experienced an objective response rate (ORR) of 75.5% (95% CI, 61.1%-86.7%) at 8 weeks; a stable disease rate of 20.4% was also observed. The exploratory ORR analysis showed that at 16 weeks, patients (n = 38) experienced an ORR of 84.2% (95% CI, 68.7%-94.0%), and 10.5% experienced stable disease when treated with the oral agent. All responses in the trial were partial.

“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,” Shah said. “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 patients independent of the mutations present at the time of enrollment in the trial.”

Responses achieved were also durable; 13 patients had a response ongoing for at least 6 months, and 5 patients remained on treatment following a year. The phase 1b dose expansion portion of NX-5948-301 is ongoing, and Shah noted that initiation of a pivotal trial is planned in 2025.

As NX-5948-301 also included patients with non-Hodgkin lymphoma, Waldenström macroglobulinemia, marginal zone lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, and primary central nervous system (CNS) lymphoma/secondary CNS lymphoma, data are expected to be read out from those arms in the future.

The bivalent CNS-penetrating small molecule BGB-16673 is also under evaluation, and safety and efficacy data were presented at the 2024 ASH Annual Meeting and Exposition from the phase 1/2 CaDAnCe-101 trial (NCT05006716).2 Data revealed that patients with CLL/SLL (n = 49) experienced an ORR of 77.6% when treated with the agent across all dose levels. A notably high response rate was observed among patients treated at the 200-mg dose level (n = 16), who achieved an ORR of 93.8%. Additionally, high ORRs were seen in all biologic subsets examined, including in patients who previously received a covalent BTK inhibitor and BCL2 inhibitor (86.7%); received a covalent BTK inhibitor, noncovalent BTK inhibitor, and BCL2 inhibitor (58.3%); had a 17p deletion and/or TP53 mutation (74.2%); had a complex karyotype (73.3%); harbored PLCG2 mutations (66.7%); and harbored BTK mutations (62.5%).

Furthermore, the maximum tolerated dose of BGB-16673 was not reached in the population of patients with relapsed/refractory CLL/SLL; 1 dose-limiting toxicity of grade 3 maculopapular rash occurred at the 200-mg dose level, and the patient continued treatment following a 5-day hold.

Safety of BTK Degraders Appears Manageable

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

Patients treated with BGB-16673 did not experience any treatment-related treatment-emergent adverse effects (TEAEs) leading to death; however, TEAEs led to death in 3 of 60 patients who received the agent. Grade 3 or greater (55.0%) and serious (45.0%) TEAEs also occurred, with 11.7% of patients discontinuing BGB-16673 due to TEAEs. The most common any-grade TEAEs included fatigue (30.0%), contusion (28.3%), and neutropenia (25.0%).

“There are some signals that would suggest that the toxicity profile [of BTK degraders] is very similar to [that of] BTK inhibitors,” Tees said. “Perhaps there can be some hepatic insufficiency that we need to be looking out for and some hematologic toxicities like leukopenia or neutropenia.”

Among those with CLL/SLL treated with NX-5948 (n = 60), the TEAEs most frequently experienced were contusion (36.7%), fatigue (26.7%), and petechiae (26.7%).1 Additionally, 1 case of grade 1 atrial fibrillation occurred in a patient who had prior atrial fibrillation, and 2 grade 5 AEs occurred but were deemed unrelated to 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 with NX-5948 and] the most common one was neutropenia, [at 18.3%],” Shah said. “Consistent with that safety profile, only 1 patient in the CLL cohort discontinued the drug because of a TEAE.”

AC676 Is an Additional BTK Degrader to Watch

Another BTK degrader under examination is the novel agent AC676, which links a BTK ligand to the cereblon E3-ligase recruiting ligand.3 By doing so, AC676 brings BTK in proximity to cereblon, which induces subsequent ubiquitination and degradation of BTK. A phase 1 first-in-human study (NCT05780034) is currently enrolling adult patients with B-cell malignancies at 8 sites in the US to receive the agent; patients must have received at least 2 prior systemic therapies or have no other standard-of-care therapy options that provide significant clinical benefit.

According to Tees, “investigators will probably be advising that we open the inclusion [criteria] to look at patients who have CNS 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.”

Like NX-5948 and BGB-16673, AC676 is also an oral drug.1-3 Investigations of the agents are going beyond CLL and SLL, but Tees noted that “the classic patient who derives benefits from BTK inhibitors [is one with] CLL/SLL, and thus it’s appearing that they derive benefits from BTK degraders.”

He added that “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…. Mantle cell lymphoma 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 patients to derive benefit?”

Furthermore, Shah noted that “potentially, we hope that this may be a different modality to offer patients as an earlier line of treatment as well.”

“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.

References

1. 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
2. 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
3. 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