Despite advances in targeted therapies for hematologic malignancies, drug resistance and persistent side effects continue to challenge clinicians and limit patient outcomes, underscoring the urgent need for novel therapeutic approaches. At the 2024 Pan Pacific Lymphoma Conference, Marc S. Hoffmann, MD, Director of the Lymphoma Program at the University of Kansas Cancer Center, Kansas City, provided an overview of two emerging classes of therapies that aim to address these challenges: Bruton’s tyrosine kinase (BTK) degraders and cereblon E3 ligase modulators (CELMoDs).1
“Both BTK degraders and CELMoDs represent significant advancements in the treatment of various B-cell malignancies, offering new options for patients with resistant disease or those who cannot tolerate traditional therapies,” said Dr. Hoffmann.
Marc S. Hoffmann, MD
BTK Degraders
Dr. Hoffmann explained the limitations of traditional tyrosine kinase inhibitors, highlighting issues such as resistance due to mutations in kinase binding domains. He then proposed a radical alternative: instead of merely inhibiting these proteins, why not completely eliminate them? This innovative approach led to the development of BTK degraders, which exploit the body’s inherent protein degradation machinery to entirely remove target proteins from cells, potentially overcoming the shortcomings of traditional tyrosine kinase inhibitors.
According to Dr. Hoffmann, the mechanism of these BTK degraders is elegant in its simplicity. They bind to BTK and recruit E3 ligase, triggering polyubiquitination and subsequent degradation of the target protein. Dr. Hoffmann emphasized that this approach not only overcomes mutation-driven resistance, but also can target scaffolding proteins and “kinase-dead” mutations.
Two BTK degraders were highlighted in the presentation: BGB-166732 and NX-5948.3 Both agents demonstrated significant BTK degradation in peripheral blood and tumor tissues, with activity across various dose levels in heavily pretreated patients with chronic lymphocytic leukemia (CLL) and other B-cell malignancies.
“These compounds show good activity in CLL and B-cell non-Hodgkin lymphoma refractory to BTK inhibitors, with a manageable toxicity profile,” said Dr. Hoffmann. “Importantly, both degraders lacked major class-associated toxicities like atrial fibrillation and hypertension, which have been observed with traditional BTK inhibitors.” One particularly noteworthy finding was the central nervous system (CNS) activity of NX-5948 in a patient with relapsed CLL and CNS involvement. “The compound clearly led to elimination of the CLL within the cerebrospinal fluid, and the patient has had a really nice durable remission in a high-risk presentation,” Dr. Hoffmann reported.
Of note, he added, the favorable toxicity profile of BTK degraders opens possibilities for combination strategies. “I’m particularly keen on how these agents might perform with a bispecific in patients who are truly refractory to both BTK inhibitors and BCL2 inhibitors.”
CELMoDs
Dr. Hoffmann introduced CELMoDs as an evolution of immunomodulatory drugs such as lenalidomide. As he explained, CELMoDs have been specifically designed to target lymphoid cells, have significantly more potent inhibition of Ikaros and Aiolos (transcription factors with a well-documented role in lymphocyte development), and have better distribution in lymphoid target organs.
The mechanism of action for CELMoDs involves both immune activation and direct cell lysis, potentially overcoming the cell-of-origin–dependent resistance seen with earlier compounds. Dr. Hoffmann presented data on the CELMoD golcadomide, showcasing its efficacy in various settings.4
In relapsed or refractory follicular lymphoma, golcadomide demonstrated higher response rates at the 0.4-mg dose, with an overall response rate of 100% and a complete response rate of 70%, in combination with rituximab. For relapsed or refractory diffuse large B-cell lymphoma (DLBCL), the 0.4-mg dose again showed superior activity in heavily pretreated patients, with an overall response rate of 55% and complete response rate of 27% in combination with rituximab. Perhaps most notable were results from a front-line DLBCL study combining golcadomide with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) in high-risk patients.5 “We see significant activity, particularly at the 0.4-mg dose,” Dr. Hoffmann reported. “The 12-month progression-free survival rate of 85% was seen across the 0.4-mg dose level regardless of risk stratification.”
The toxicity profile of golcadomide was characterized primarily by neutropenia, which Dr. Hoffmann described as an on-target effect. However, he added, “this side effect is expected and is manageable with growth factor.” He also emphasized that golcadomide lacks some of the “nagging low-grade toxicities” associated with lenalidomide, such as rash and diarrhea, and appears to not be associated with increased risk of venous thrombosis.
KEY POINTS
- BTK degraders leverage the body’s natural protein degradation system to eliminate target proteins, potentially overcoming the limitations of traditional tyrosine kinase inhibitors.
- CELMoDs evolved from earlier immunomodulatory drugs, offering more potent degradation of key proteins and improved distribution in lymphoid tissues.
Future Directions and Implications
Dr. Hoffmann announced an upcoming phase III trial comparing golcadomide plus R-CHOP vs placebo plus R-CHOP in front-line DLBCL. This study will provide crucial data on the long-term efficacy and safety of CELMoDs in combination with standard therapy, and he stressed the importance of ongoing research.
“With longer follow-up, it’s going to be interesting to see response durability and long-term tolerability of these agents in the relapsed population, as well as the safety and efficacy of combinations,” Dr. Hoffmann said. “As the field evolves, determining optimal sequencing and combination strategies will be crucial to maximize patient outcomes while minimizing toxicity. However, their novel mechanisms of action and favorable toxicity profiles make them attractive options for further development.”
DISCLOSURE: Dr. Hoffmann has received consulting fees and honoraria from ADC, Janssen, Pharmacyclics, BeiGene, Novartis, AstraZeneca, AbbVie, Kite, and TG; research funding from Genentech; and reimbursement for travel expenses from BMS.
REFERENCES
2. Wong RL, et al: Mutation in Bruton tyrosine kinase (BTK) A428D confers resistance to BTK-degrader therapy in chronic lymphocytic leukemia. Leukemia 38:1818-1821, 2024.
3. Searle E, et al: Initial findings from a first-in-human phase 1a/b trial of NX-5948, a selective Bruton’s tyrosine kinase degrader, in patients with relapsed/refractory B cell malignancies. Blood 142(suppl 1):4473, 2023.
4. Michot JM, et al: Clinical activity of CC-99282, a cereblon E3 ligase modulator agent, in patients with relapsed/refractory non-Hodgkin lymphoma. 2022 European Hematology Association Congress. Abstract S216. Presented June 12, 2022.
5. Hoffmann M, et al: Golcadomide (GOLCA; CC-99282), a novel CELMoD agent, plus R-CHOP in patients with previously untreated aggressive B-cell lymphoma. 2023 American Society of Hematology Annual Meeting & Exposition. Abstract 4459. Presented December 11, 2023.
