The Bottom Line:
DZD8586 is an experimental noncovalent LYN / BTK dual inhibitor that is being tested in patients with relapsed / refractory B cell cancers.
Who Performed the Research and Where Was it Presented:
Dr. Constantine Tam from Alfred Hospital and Monash University and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting in 2024.
Background:
Covalent Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib revolutionized the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). However, they must be taken continuously, and eventually this can lead to the development of resistance mutations. The most common mutation occurs at the C481 site on BTK, which is where covalent BTK inhibitors bind. Noncovalent BTK inhibitors such as pirtobrutinib do not rely on the C481 site to bind, and pirtobrutinib it is effective in patients who have the C481 mutation. However, patients on pirtobrutinib can develop mutations at other sites that interfere with the drug’s effectiveness. DZD8586 is a noncovalent LYN / BTK dual inhibitor, which binds reversibly to BTK similar to pirtobrutinib, but it is also able to overcome many of the resistance mutations seen with pirtobrutinib.
Methods and Participants:
This analysis pooled data from three phase 1 and phase 2 clinical studies of DZD8586 in patients with relapsed / refractory B cell cancers including CLL / SLL.
Results:
- It is still very early on, and thus far 38 patients have been enrolled and received DZD8586.
- Patients had received a median of 2 prior lines of therapy, including chemoimmunotherapy (87%), BTK inhibitor (40%), and BCL2 inhibor (11%).
- The most common moderate to severe side effects have been low platelet count (13%), low neutrophil count (13%), pneumonia (8%), and low potassium levels (5%).
- All these side effects were reversible after dose interruption and/or with supportive care.
- Preliminary data shows dose-dependent increases in overall response rates (ORR) with an ORR of 44% at the 50 mg dose level and an ORR of 83% at the 100 mg dose level.
Conclusions:
DZD8586 is a new experimental noncovalent LYN/BTK dual inhibitor that continues to be tested in clinical trials and preliminarily looks to be well-tolerated. Blocking the BTK pathway is one of the most important ways of treating CLL / SLL, so scientists keep trying to find new ways to inhibit it when drug resistance develops. Cancers are always changing and developing new mutations, so it is useful to have more tools in our therapy toolbox.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Phase 1/2 Studies of DZD8586, a Non-Covalent BBB Penetrant LYN/BTK Dual Inhibitor, in BTK Inhibitor Resistant Chronic Lymphocytic Leukemia (CLL) and Other B-Cell Non-Hodgkin Lymphoma (B-NHL)
