The Bottom Line:
The hope is that noncovalent BTK inhibitors such as nemtabrutinib and pirtobrutinib will be able to rescue many, but not all, those with double refractory disease.
Who Performed the Research and Where Was it Presented:
Dr. Jennifer Woyach from the Ohio State University and colleagues presented the results at the American Society for Hematology Annual Meeting in 2022.
BTK inhibitors have revolutionized the treatment of CLL/SLL and certain B-cell neoplasms. However, the most common resistance mechanism is due to mutations to BTK at the C481 binding site. Nemtabrutinib (MK-1026, formerly ARQ-531) is a noncovalent, potent inhibitor of wild-type and ibrutinib-resistant C481S-mutated BTK. This means it could potentially help patients who have progressed after being treated with a covalent BTK inhibitor (e.g., ibrutinib, acalabrutinib, zanubrutinib).
Methods and Participants:
This study is an open-label phase 1/2 clinical trial of nemtabrutinib in patients with relapsed or refractory hematologic malignancies, including CLL/SLL. The efficacy analysis included CLL/SLL patients treated with nemtabrutinib 65-mg once-daily dose. The safety analysis included all patients with hematological malignancies treated with the nemtabrutinib 65-mg dose.
- A total of 112 patients were enrolled and treated, including 57 with CLL/SLL, 46 with B-cell non-Hodgkin lymphoma, 6 with Waldenstrom’s macroglobulinemia, and 3 with a diagnosis of “other.”
- This was a heavily pretreated group of CLL/SLL patients. The median number of prior therapies was 4. Ninety-five percent had received prior therapy with a BTK inhibitor, and 42% had been treated previously with both a BTK inhibitor and a BCL2 inhibitor.
- In addition, 63% of patients had C481S-mutated BTK.
- With a median follow-up time of 8 months, the overall response rate was 56%.
- Among the 32 patients who responded to treatment, the median duration of response was 24 months, and the median progression-free survival was 26 months.
- Among all patients with hematological malignancies, the most common treatment-related adverse events were an altered/impaired sense of taste (21%), decreased neutrophils (20%), fatigue (13%), nausea (12%), decreased platelets (12%), diarrhea (10%), and high blood pressure (10%).
- Treatment-related discontinuations occurred in 15 pts (13%).
- No deaths were attributed to treatment.
Nemtabrutinib shows promising antitumor activity and a manageable safety profile in highly relapsed/refractory patients with CLL/SLL. The hope is that noncovalent BTK inhibitors such as nemtabrutinib and pirtobrutinib will be able to rescue many but not all of those with double refractory disease (meaning they failed both a covalent BTK inhibitor and a BCL2 inhibitor). While noncovalent BTK inhibitors are probably not a curative, they may help stabilize disease, improve quality of life, and potentially serve as a bridge to other therapies.
Links and Resources:
You can read the actual ASH abstract here: Efficacy and Safety of Nemtabrutinib, a Wild-Type and C481S-Mutated Bruton Tyrosine Kinase Inhibitor for B-Cell Malignancies: Updated Analysis of the Open-Label Phase 1/2 Dose-Expansion Bellwave-001 Study
Take care of yourself first.
Ann Liu, PhD