Bruton tyrosine kinase (BTK) degraders are emerging as a promising class of agents to address the unmet need for patients with pretreated B-cell malignancies who have developed resistance to traditional BTK inhibitors. Several novel BTK degraders, including AC676, NX-5948, and BGB-16673, are currently under evaluation in early-phase clinical trials, showing encouraging preliminary efficacy and manageable safety profiles. These agents leverage different strategies to overcome resistance mechanisms, offering new hope for patients with relapsed or refractory disease.
Overcoming Resistance with BTK Degraders
Resistance to BTK inhibitors, such as ibrutinib and acalabrutinib, often arises due to mutations in the BTK protein, particularly at the C481S residue. BTK degraders offer a novel approach by inducing the degradation of both wild-type and mutant forms of BTK, thereby circumventing resistance mechanisms. These molecules work by bringing BTK in proximity to E3 ligase, leading to ubiquitination and subsequent degradation of BTK.
Michael T. Tees, MD, MPH, a hematologist/oncologist at Colorado Blood Cancer Institute in Denver, noted that BTK degraders target a similar pathway as BTK inhibitors but in a different context, potentially overcoming resistance mutations. He highlighted the agent AC676, currently in phase 1 development, as a promising option for patients with chronic lymphocytic leukemia, Waldenström macroglobulinemia, marginal zone lymphoma, and mantle cell lymphoma.
Clinical Trial Updates
BGB-16673: This orally available bivalent inhibitor is designed to induce degradation of wild-type and mutant BTK. In the phase 1/2 CaDAnCe-101 trial (NCT05006716), BGB-16673 demonstrated promising results in patients with relapsed/refractory indolent non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and Waldenström macroglobulinemia (WM). Updated results from the trial focused on patients with follicular lymphoma (FL) and marginal zone lymphoma (MZL) showed that the agent was well-tolerated, with no dose-limiting toxicities observed. The overall response rate was 50% (4/8) for FL and 67% (4/6) for MZL. Constantine S. Tam, MBBS, MD, head of the lymphoma service at Alfred Health in Melbourne, Australia, noted the encouraging response rates and suggested further exploration of the agent in earlier lines of therapy and in combination with other agents.
In the CLL/SLL cohort (n = 60), BGB-16673 was safe and well-tolerated in heavily pretreated patients. The overall response rate for the total cohort was 77.6%, with a 93.8% response rate observed in patients receiving the 200-mg dose. Meghan C. Thompson, MD, a leukemia specialist at Memorial Sloan Kettering Cancer Center, highlighted the observed response rates across multiple biologic subsets and prior lines of therapy.
Among 27 patients with WM, the objective response rate was 81%, with a major response rate of 74.1%. Responses were reported in patients previously treated with both covalent and noncovalent BTK inhibitors, as well as in patients with or without BTK mutations.
NX-5948: This BTK degrader recruits the E3 ligase binder, leading to ubiquitination and proteasome degradation of BTK. In the NX-5948-301 trial (NCT05131022), patients with CLL/SLL received varying doses of NX-5948. The objective response rate was 75.5%, with 73.5% of patients exhibiting a partial response. Nirav N. Shah, MD, associate professor of medicine at the Medical College of Wisconsin, emphasized the unmet clinical need for patients who progress after traditional covalent BTK inhibitors and BCL2 inhibitors, highlighting NX-5948 as a potential new therapy for these patients.
AC676: This BTK chimeric degrader utilizes a Protein-Protein Interaction Targeting Chimeras (PPI-TAC) platform from Accutar Biotech. By linking a BTK ligand to the cereblon E3-ligase recruiting ligand, AC676 brings BTK in proximity to cereblon, inducing ubiquitination and degradation of BTK. A phase 1 dose-escalation study (NCT05780034) is currently underway to determine the safety and tolerability of AC676 in patients with B-cell malignancies. Tees noted that the trial may expand inclusion criteria to include patients with central nervous system involvement of disease, given signals suggesting that BTK degraders can cross the blood-brain barrier effectively.
Safety and Tolerability
Early data suggest that BTK degraders have manageable safety profiles, with some similarities to traditional BTK inhibitors. Common adverse events include fatigue, contusion, and neutropenia. While some studies have reported cases of major hemorrhage and atrial fibrillation, these events appear to be infrequent. Continued monitoring and larger patient cohorts are needed to fully characterize the long-term safety of these agents.
Future Directions
The development of BTK degraders represents a significant advancement in the treatment of B-cell malignancies. As these agents continue to advance through clinical trials, they hold the potential to overcome resistance to traditional BTK inhibitors and improve outcomes for patients with relapsed or refractory disease. Future research will focus on exploring BTK degraders in earlier lines of therapy, in combination with other agents, and in other disease entities, such as autoimmune diseases.
