Editor's Note: At this conference, Professor Alexey Danilov (Professor of Hematology, Associate Director of the Lymphoma Center, and Director of the Early Therapeutics Program at City of Hope National Medical Center) presented a report titled "Bexobrutideg (NX-5948), a Novel BTK Degrader, Demonstrates Rapid and Durable Clinical Responses in Relapsed/Refractory CLL Patients: Latest Results from an Ongoing Phase Ia Study." This report elaborated on significant breakthroughs in the treatment of chronic lymphocytic leukemia (CLL), offering new hope for multi-line treatment-failed, refractory CLL patients.Mechanism of Action of Novel BTK Degrader Bexobrutideg and Unmet Needs
Professor Alexey Danilov first introduced the mechanism of action of proteolysis-targeting chimeras (PROTACs) as a new class of drugs. PROTACs leverage the cell’s ubiquitin-proteasome system (UPS) to degrade oncogenic proteins, rather than merely inhibiting their function. Bexobrutideg (NX-5948) is a PROTAC targeting Bruton’s tyrosine kinase (BTK). Its unique aspect is that it not only blocks BTK’s kinase function but also eliminates its scaffolding function, which is considered an indispensable key factor for BTK activity. This dual mechanism of action is expected to overcome the resistance challenges faced by traditional BTK inhibitors. The emergence of Bexobrutideg precisely addresses the growing unmet needs in chronic lymphocytic leukemia treatment. Current standard treatment regimens for CLL primarily rely on BTK inhibitors and BCL2 inhibitors (e.g., Venetoclax). However, resistant mutations to covalent and non-covalent BTK inhibitors are found in over half of patients who progress on BTK inhibitor therapy. Furthermore, the “double-refractory” patient population, who have progressed on both BTK inhibitors and BCL2 inhibitors, including those previously treated with the non-covalent BTK inhibitor Pirtobrutinib, is rapidly expanding and urgently needs new treatment options. Bexobrutideg, as a BTK degrader, offers an additional treatment modality that can effectively overcome BTK resistance mutations arising during treatment and re-disrupt BTK’s scaffolding function, providing a new therapeutic opportunity for these refractory patients.
Phase 1a Study Design and Patient Baseline Characteristics
This report primarily focuses on data from CLL patients in the Phase Ia dose-escalation study of Bexobrutideg. This study involves oral administration, once daily, and identical dose exploration is also being conducted in patients with non-Hodgkin lymphoma (NHL) and Waldenstrom macroglobulinemia. Additionally, the study includes a completed Phase Ib CLL dose-expansion study, which, under the “Project Optimus” framework, evaluates the safety and efficacy of Bexobrutideg at 200 mg or 600 mg daily in CLL patients. The study enrolled 48 CLL patients, with a median age of 68 years, mostly male, consistent with the CLL population characteristics. As of the data analysis cut-off, 16 patients discontinued treatment: 7 due to radiographic progression, 3 due to clinical progression, 2 deaths, and only 1 patient discontinued due to an adverse event. Currently, 32 patients remain on treatment. The enrolled patient cohort was heavily pretreated: all but one patient had received prior BTK inhibitor therapy; over 70% had received chemoimmunotherapy; and a few patients had received CAR-T-cell therapy. Importantly, most patients belonged to the “double-refractory” group, meaning they had received both BTK inhibitors and BCL2 inhibitors. Approximately a quarter of patients had also received the non-covalent BTK inhibitor Pirtobrutinib. The median number of prior treatment lines was 4 (range 2-12), and a few patients had central nervous system (CNS) involvement. Genetic mutation characteristics further confirmed this was a difficult-to-treat patient group: approximately 40% of patients had detectable BTK mutations, and about half had P53 gene mutations, consistent with a history of multiple treatment lines.
Pharmacodynamic Data: Rapid and Thorough BTK Degradation
Pharmacodynamic data presented by Professor Alexey Danilov showed that Bexobrutideg administration led to rapid BTK degradation. By day 8 of the study, the target protein was almost completely cleared, and this degradation effect was largely independent of BTK’s mutation status. Although most mutations were at the C481 site, these mutant BTK molecules, as well as other mutant and wild-type BTK such as L528, T474, and V416, were rapidly degraded. This thorough, mutation-independent degradation highlights the potential of BTK degraders to overcome drug resistance. Safety and Tolerability: Low Toxicity and Manageable Adverse Events Bexobrutideg demonstrated good safety and tolerability, with most treatment-emergent adverse events (AEs) reported as low grade. The most common adverse events included purpura, contusion, diarrhea, and fatigue. Diarrhea was generally self-limiting, with only a few Grade 3 cases. The most common hematologic adverse event was neutropenia, but no cases of febrile neutropenia or severe infections were observed in the study. No dose-limiting toxicities (DLTs) were observed in this study. Only one treatment-related Grade 2 hot flash led to treatment interruption, and one Grade 5 pulmonary embolism event occurred, but it was considered unrelated to Bexobrutideg. Notably, although approximately 30% of patients experienced neutropenia, the study allowed CLL patients with neutropenia to be enrolled. Furthermore, Professor Alexey Danilov pointed out that the timing of Bexobrutideg’s adverse events was similar to that of BTK inhibitors, with many AEs occurring early in treatment, possibly related to the drug’s effect on CLL cells and subsequent cytokine release due to cell death, typically resolving spontaneously within a few weeks of treatment.
Excellent Clinical Efficacy: High Objective Response Rate and Durable Responses
Bexobrutideg treatment yielded encouraging clinical results, with an overall objective response rate (ORR) of 81%. One patient in the study ultimately achieved a complete response (CR), and with the median follow-up time extending to approximately 9 months, the research team hopes to observe more CR cases in the future. Nearly all patients gained meaningful clinical benefit. The Waterfall Plot clearly demonstrated significant shrinkage of lymphadenopathy, and this shrinkage effect was independent of the presence of BTK mutations, PLCγ mutations, P53 mutations, and other high-risk mutations such as SF3B1, ATM, and NOTCH1, further demonstrating Bexobrutideg’s broad anti-tumor activity. Patient responses showed good durability, with nearly half of patients maintaining responses for one year or longer, and most patients’ responses are ongoing and continue to deepen. Durable responses were observed regardless of whether patients had previously received chemoimmunotherapy or non-covalent BTKi. Clinical improvement occurred rapidly, with clear improvement in lymphadenopathy observed at the first follow-up visit, and even palpable lymph nodes showed shrinkage within the first 7-8 days of treatment. Professor Alexey Danilov shared a specific case: a 71-year-old female CLL patient diagnosed in 2014, with no detectable BTK mutations. She had received Bendamustine Rituximab, Ibrutinib, and Venetoclax combination therapy for three and a half years before stopping treatment and progressing within 12 months. This patient initially received 50 mg Bexobrutideg, with a dose escalation to 100 mg at month 17. She presented with splenomegaly, lymphadenopathy, and a lymphocyte count of 134,000, all of which rapidly resolved within 8 weeks of treatment, achieving a partial response. Although lymphocytosis redistribution occurred, it gradually resolved over 9-12 months. After 26 months of treatment, a bone marrow biopsy finally confirmed a complete response. This case fully demonstrates Bexobrutideg’s potential to achieve deep and durable responses in refractory CLL patients.
Expert Opinion and Future Outlook
During the discussion, Professor Alexey Danilov was asked about the mechanisms in non-responding patients or those with rapid progression. He stated that the research team is actively investigating these mechanisms and mentioned finding an A428D mutation in one patient. However, this patient also had other BTK mutations and genetic mutations, and A428D was initially subcloned and later became clonal, so it is currently unclear whether A428D is fully pathogenic in this case. Currently, no clear predictive biomarkers have been found to distinguish responders from early progressors, but research is actively ongoing. Regarding the differences from other BTK degraders and the possibility of combination with BCL2 inhibitors, Professor Alexey Danilov further elaborated. He pointed out that Bexobrutideg is a BTK degrader lacking IMiD (immunomodulatory drug) activity, while NX2127 developed by Nurix has IMiD activity, making it unique. Meanwhile, BTK degraders from Biogen and ABBV101 also lack IMiD activity. All these degraders bind to Cereblon E3 ligase. Professor Alexey Danilov also emphasized that Bexobrutideg’s ability to penetrate the central nervous system is considered one of its unique advantages. Furthermore, Bexobrutideg is a highly selective compound, with published mass spectrometry data showing excellent selectivity for NX5948, promising differentiated safety and high efficacy. Professor Alexey Danilov’s team will continue to explore optimized biomarker screening strategies, sequential application of novel dual and multi-immunotherapy combinations, and the synergistic integration of cell therapy and immune combinations, aiming to provide CLL patients with more precise and effective treatment regimens.
Conclusion
Professor Alexey Danilov’s report concluded that Bexobrutideg, a novel small molecule BTK degrader, effectively degrades the validated target BTK in CLL by utilizing the ubiquitin-proteasome pathway. In the completed Phase 1a CLL study part, with a median follow-up of 9 months, most patients remain on treatment. The drug was well-tolerated and demonstrated excellent clinical activity in heavily pretreated, advanced CLL patients refractory to both covalent and non-covalent BTK inhibitors, as well as Venetoclax. A high objective response rate of 81% and many durable responses demonstrate Bexobrutideg’s potential as a breakthrough therapy to address the increasingly severe resistance challenges in CLL treatment, offering patients longer progression-free survival and improved quality of life. This research progress not only brings new hope to global CLL patients but also highlights the significant contribution of targeted protein degradation strategies in the field of tumor immunotherapy.
Source/Interview provided by: Oncology Outlook – Oncology News
